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EMERGENCY
DERMATOLOGY
MANY PHYSICIANS and patients do not believe that dermatology involves life-threatening
situations. However, there are many emergencies that the dermatologist needs to address and
many cutaneous diseases in the emergency room that require rapid dermatologic consultation.
The dermatologist is frequently the first physician to examine such patients before a hospital
admission and also the first to identify a critical situation, stabilize the patient, and choose urgent
and appropriate intervention. The first chapters of this book are directed toward those dermatologists who care for hospitalized patients with severe and dangerous skin diseases. Later chapters
are intended for all physicians, including dermatologists, who wish to hone their diagnostic skills,
expand their knowledge and understanding of pathological events, and learn treatment options
available for acute life-threatening skin diseases. This book brings together top dermatologists from around the world to address the complicated and multifaceted field of dermatologic
emergencies for the practicing dermatologist and emergency physician.
Ronni Wolf, MD, is Associate Clinical Professor and Head of the Dermatology Unit at Kaplan
Medical Center, Rechovot, Israel, and the Hebrew University–Hadassah Medical School,
Jerusalem, Israel.
Batya B. Davidovici, MD, is Physician in the Dermatology Unit at Kaplan Medical Center,
Rechovot, Israel.
Jennifer L. Parish, MD, is Assistant Clinical Professor of Dermatology and Cutaneous Biology
at Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, and
Assistant Professor of Dermatology, Tulane University School of Medicine, New Orleans,
Louisiana.
Lawrence Charles Parish, MD, MD(hon), is Clinical Professor of Dermatology and Cutaneous Biology and Director of the Jefferson Center for International Dermatology at Jefferson
Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania. Dr. Parish is also
Visiting Professor of Dermatology at Tulane University School of Medicine, New Orleans,
Louisiana.
EMERGENCY
DERMATOLOGY
Edited by
Ronni Wolf
Kaplan Medical Center
Batya B. Davidovici
Kaplan Medical Center
Jennifer L. Parish
Jefferson Medical College of Thomas Jefferson University
and Tulane University School of Medicine
Lawrence Charles Parish
Jefferson Medical College of Thomas Jefferson University
and Tulane University School of Medicine
CAMBRIDGE UNIVERSITY PRESS
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São Paulo, Delhi, Dubai, Tokyo, Mexico City
Cambridge University Press
32 Avenue of the Americas, New York, NY 10013-2473, USA
www.cambridge.org
Information on this title: www.cambridge.org/9780521717335
C Cambridge University Press 2010
This publication is in copyright. Subject to statutory exception
and to the provisions of relevant collective licensing agreements,
no reproduction of any part may take place without the written
permission of Cambridge University Press.
First published 2010
Printed in China by Everbest
A catalog record for this publication is available from the British Library.
Library of Congress Cataloging in Publication data
Emergency dermatology / edited by Ronni Wolf . . . [et al.].
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-521-71733-5 (hardback)
1. Dermatology. 2. Medical emergencies. I. Wolf, Ronni.
[DNLM: 1. Skin Diseases – therapy. 2. Emergencies. 3. Emergency Treatment. WR 140 E53 2009]
RL72.E443 2009
616.5 025 – dc22
2009007871
ISBN 978-0-521-71733-5 Hardback
Every effort has been made in preparing this book to provide accurate and up-to-date information that is in accord with accepted
standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to
disguise the identities of the individuals involved. Nevertheless, the authors, editors, and publishers can make no warranties that the
information contained herein is totally free from error, not least because clinical standards are constantly changing through
research and regulation. The authors, editors, and publishers therefore disclaim all liabilty for direct or consequential damages
resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information
provided by the manufacturer of any drugs or equipment that they plan to use.
Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party
Internet Web sites referred to in this publication and does not guarantee that any content on such Web sites is, or will remain,
accurate or appropriate.
Contents
C ONTRIBUTORS
P REFACE
Chap. 9. LIFE-THREATENING BACTERIAL
SKIN INFECTIONS 81
Richard B. Cindrich and Donald Rudikoff
vii
xi
Chap. 1. CELL INJURY AND CELL DEATH
Adone Baroni, Eleonora Ruocco, Maria
Antonietta Tufano, and Elisabetta Buommino
1
Chap. 10. BACTEREMIA, SEPSIS, SEPTIC SHOCK,
AND TOXIC SHOCK SYNDROME 98
Geeta Patel, Ryan Hawley, and Noah Scheinfeld
Chap. 2. CLEAN AND ASEPTIC TECHNIQUE
AT THE BEDSIDE 12
Sapna Amin, Aron J. Gewirtzman, and Stephen Tyring
Chap. 11. STAPHYLOCOCCAL SCALDED
SKIN SYNDROME 109
Eleonora Ruocco, Adone Baroni,
Sonia Sangiuliano, Giovanna Donnarumma, and
Vincenzo Ruocco
Chap. 3. NEW ANTIMICROBIALS 18
Maryann Mikhail and Jeffrey M. Weinberg
Chap. 4. IMMUNOMODULATORS AND
THE “BIOLOGICS” IN CUTANEOUS
EMERGENCIES 34
Batya B. Davidovici and Ronni Wolf
Chap. 12. LIFE-THREATENING CUTANEOUS
VIRAL DISEASES 115
Aron J. Gewirtzman, Brandon Christianson,
Anne Marie Tremaine, Brenda L. Pellicane, and
Stephen Tyring
Chap. 5. CRITICAL CARE: STUFF YOU REALLY,
REALLY NEED TO KNOW 50
Haim Shmilovich and Arie Roth
Chap. 13. LIFE-THREATENING CUTANEOUS
FUNGAL AND PARASITIC DISEASES 126
Marcia Ramos-e-Silva, Carlos Gustavo Costanza,
and Sueli Coelho Carneiro
Chap. 6. ACUTE SKIN FAILURE: CONCEPT,
CAUSES, CONSEQUENCES, AND CARE 62
Robert A. Norman and Gwynn Coatney
Chap. 14. LIFE-THREATENING STINGS, BITES,
AND MARINE ENVENOMATIONS 146
Dirk M. Elston
Chap. 7. CUTANEOUS SYMPTOMS AND
NEONATAL EMERGENCIES 66
Daniel Wallach and Pierre-Henri Jarreau
Chap. 15. SEVERE, ACUTE ADVERSE
CUTANEOUS DRUG REACTIONS I:
STEVENS–JOHNSON SYNDROME AND TOXIC
EPIDERMAL NECROLYSIS 154
Ronni Wolf and Batya B. Davidovici
Chap. 8. NECROTIZING SOFT-TISSUE
INFECTIONS, INCLUDING NECROTIZING
FASCIITIS 75
Ronni Wolf, Yalçin Tüzün, and Batya B. Davidovici
v
vi
C ONTENTS
Chap. 16. SEVERE, ACUTE ADVERSE CUTANEOUS
DRUG REACTIONS II: DRESS SYNDROME AND
SERUM SICKNESS-LIKE REACTION 162
Ronni Wolf and Batya B. Davidovici
Chap. 26. SKIN SIGNS OF SYSTEMIC NEOPLASTIC
DISEASES AND PARANEOPLASTIC CUTANEOUS
SYNDROMES 265
Kyrill Pramatarov
Chap. 17. SEVERE, ACUTE COMPLICATIONS OF
DERMATOLOGIC THERAPIES 168
Ronni Wolf, Jasna Lipozenčić, and
Batya B. Davidovici
Chap. 27. BURN INJURY
Samuel H. Allen
Chap. 18. SEVERE, ACUTE ALLERGIC AND
IMMUNOLOGICAL REACTIONS I: URTICARIA,
ANGIOEDEMA, MASTOCYTOSIS, AND
ANAPHYLAXIS 178
Samuel H. Allen
Chap. 19. SEVERE, ACUTE ALLERGIC AND
IMMUNOLOGICAL REACTIONS II: OTHER
HYPERSENSITIVITIES AND IMMUNE DEFECTS,
INCLUDING HIV 184
Samuel H. Allen
Chap. 20. GRAFT VERSUS HOST DISEASE 194
Jasna Lipozenčić and Ronni Wolf
Chap. 21. ERYTHRODERMA/EXFOLIATIVE
DERMATITIS 202
Virendra N. Sehgal and Govind Srivastava
Chap. 22. ACUTE, SEVERE BULLOUS
DERMATOSES 215
Snejina Vassileva
Chap. 23. EMERGENCY MANAGEMENT OF
PURPURA AND VASCULITIS, INCLUDING
PURPURA FULMINANS 233
Lucio Andreassi and Roberta Bilenchi
Chap. 24. EMERGENCY MANAGEMENT OF
CONNECTIVE TISSUE DISORDERS AND
THEIR COMPLICATIONS 245
Kristen Biggers and Noah Scheinfeld
Chap. 25. SKIN SIGNS OF SYSTEMIC
INFECTIONS 256
Jana Kazandjieva, Georgeta Bocheva, and
Nikolai Tsankov
271
Chap. 28. EMERGENCY DERMATOSES OF THE
ANORECTAL REGIONS 278
Yalçin Tüzün and Sadiye Keskin
Chap. 29. EMERGENCY MANAGEMENT OF
SEXUALLY TRANSMITTED DISEASES AND
OTHER GENITOURETHRAL DISORDERS 282
Michael Waugh
Chap. 30. EMERGENCY MANAGEMENT OF
ENVIRONMENTAL SKIN DISORDERS: HEAT,
COLD, ULTRAVIOLET LIGHT INJURIES 293
Larry E. Millikan
Chap. 31. ENDOCRINOLOGIC EMERGENCIES
IN DERMATOLOGY 298
Margaret T. Ryan, Vincent Savarese, and
Serge A. Jabbour
Chap. 32. EMERGENCY MANAGEMENT OF SKIN
TORTURE AND SELF-INFLICTED
DERMATOSES 313
Daniel H. Parish, Hirak B. Routh,
Kazal R. Bhowmik, and Kishore Kumar
Chap. 33. SKIN SIGNS OF POISONING
Batya B. Davidovici and Ronni Wolf
318
Chap. 34. DISASTER PLANNING: MASS CASUALTY
MANAGEMENT 327
Lion Poles
Chap. 35. CATASTROPHES IN COSMETIC
PROCEDURES 331
Marina Landau and Ronni Wolf
Chap. 36. LIFE-THREATENING DERMATOSES
IN TRAVELERS 340
Larry E. Millikan
I NDEX
345
Contributors
Elisabetta Buommino, PhD
Department of Experimental Medicine
Microbiology and Clinical Microbiology
Section
Second University of Naples
Naples, Italy
Samuel H. Allen, FRCP
Department of Infectious Diseases
Ayrshire & Arran
Scotland, United Kingdom
Sapna Amin, MD
Department of Dermatology
Baylor College of Medicine
Houston, Texas
Lucio Andreassi, MD
Department of Dermatology
University of Siena
Siena, Italy
Sueli Coelho Carneiro, MD, PhD
Sector of Dermatology
Federal University of Rio de Janeiro
Hospital Universitario Clementino Fraga Filho
School of Medicine
Rio de Janeiro State University
Rio de Janeiro, Brazil
Adone Baroni, MD, PhD
Department of Dermatology
Second University of Naples
Naples, Italy
Brandon Christianson, MD
Department of Otolaryngology/Head and Neck Surgery
University of Texas Southwestern Medical Center
Dallas, Texas
Kazal R. Bhowmik, MBBS
Paddington Testing Company, Inc.
Philadelphia, Pennsylvania
Richard B. Cindrich, MD
Department of Medicine
Bronx Lebanon Hospital Center
Albert Einstein College of Medicine
Bronx, New York
Kristen Biggers, MD
West Virginia University School of Medicine
Morgantown, West Virginia
Gwynn Coatney, DO
Department of Family Medicine
University of Medicine and Dentistry of New Jersey
Stratford, New Jersey
Roberta Bilenchi, MD
Department of Dermatology
University of Siena
Siena, Italy
Carlos Gustavo Costanza, MD
Sector of Dermatology
Federal University of Rio de Janeiro
Hospital Universitario Clementino Fraga Filho
School of Medicine
Rio de Janeiro, Brazil
Georgeta Bocheva, MD, PhD
Department of Pharmacology
Medical University–Sofia
Sofia, Bulgaria
vii
viii
C ONTRIBUTORS
Batya B. Davidovici, MD
Dermatology Unit
Kaplan Medical Center
Rechovot, Israel
Marina Landau, MD
The Dermatology Unit
Wolfson Medical Center
Holon, Israel
Giovanna Donnarumma, PhD
Department of Experimental Medicine
Microbiology and Clinical Microbiology Section
Second University of Naples
Naples, Italy
Jasna Lipozenčić, MD, PhD
University Hospital Center Zagreb and
University Department of Dermatology and Venereology
School of Medicine
University of Zagreb
Zagreb, Croatia
Dirk M. Elston, MD
Department of Dermatology
Geisinger Medical Center
Danville, Pennsylvania
Aron J. Gewirtzman, MD
Division of Dermatology
Albert Einstein College of Medicine
Bronx, New York
Ryan Hawley, DO
Samaritan Medical Center
Watertown, New York
Serge A. Jabbour, MD
Department of Medicine
Division of Endocrinolgy
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania
Pierre-Henri Jarreau, MD, PhD
Department of Neonatal Medicine
Port-Royal Hospital
Paris, France
Jana Kazandjieva, MD, PhD
Department of Dermatology
Medical University–Sofia
Sofia, Bulgaria
Sadiye Keskin, MD
Department of Dermatology
Cerrahpasa Medical Faculty
Istanbul University
Istanbul, Turkey
Kishore Kumar, MBBS, FCPS
Assistant Registrar
Burn and Plastic Surgery Unit
Dhaka Medical College Hospital
Dhaka, Bangladesh
Maryann Mikhail, MD
Department of Dermatology
St. Luke’s–Roosevelt Hospital Center
Beth Israel Medical Center
New York, New York
Larry E. Millikan, MD
Department of Dermatology
Tulane University School of Medicine
New Orleans, Louisiana
Robert A. Norman, DO, MPH
Department of Dermatology
College of Osteopathic Medicine
Nova Southeastern University
Fort Lauderdale, Florida
Daniel H. Parish, MD, JD
Department of Dermatology and Cutaneous Biology
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania
Formerly, Assistant United States Attorney
Northern District of Illinois
Chicago, Illinois
Jennifer L. Parish, MD
Department of Dermatology and Cutaneous Biology
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania
Department of Dermatology
Tulane University School of Medicine
New Orleans, Louisiana
Lawrence Charles Parish, MD, MD(hon)
Department of Dermatology and Cutaneous Biology
Jefferson Medical College of Thomas Jefferson University
Philadelphia, Pennsylvania
Department of Dermatology
Tulane University School of Medicine
New Orleans, Louisiana
C ONTRIBUTORS
Geeta Patel, DO
Montgomery Regional Hospital
Blacksburg, Virginia
Brenda L. Pellicane, MD
Department of Dermatology
Wayne State University School of Medicine
Dearborn, Michigan
Lion Poles, MD
Deputy Director General
Kaplan Medical Center, Rechovot and the
Ministry of Health, Israel
Kyrill Pramatarov, MD, PhD
Department of Dermatology
Medical University–Sofia
University Hospital Lozenetz
Sofia, Bulgaria
Marcia Ramos-e-Silva, MD, PhD
Sector of Dermatology
Federal University of Rio de Janeiro
Hospital Universitario Clementino Fraga Filho
School of Medicine
Rio de Janeiro, Brazil
Margaret T. Ryan, MD
Department of Medicine
Division of Endocrinology
Riddle Memorial Hospital
Media, Pennsylvania
Sonia Sangiuliano, MD
Department of Dermatology
Second University of Naples
Naples, Italy
Vincent Savarese, MD
Division of Endocrinology
Department of Medicine
Jefferson Medical College of Thomas Jefferson
University
Philadelphia, Pennsylvania
Noah Scheinfeld, MD, JD
Department of Dermatology
Columbia University College of Physicians and Surgeons
New York, New York
Virenda N. Sehgal, MD, FNASc, FAMS, FRAS (Lond.)
Skin Institute and School of Dermatology
Greater Kailash
New Delhi, India
Arie Roth, MD
Division of Cardiology
Tel Aviv Sourasky Medical Center
Sackler Faculty of Medicine
Tel Aviv University
Tel Aviv, Israel
Haim Shmilovich, MD
Division of Cardiology
Tel Aviv Sourasky Medical Center
Sackler Faculty of Medicine
Tel Aviv University
Tel Aviv, Israel
Hirak B. Routh, MBBS
Paddington Testing Company, Inc.
Philadelphia, Pennsylvania
Govind Srivastava, MD, MNAMS
Skin Institute and School of Dermatology
Greater Kailash
New Delhi, India
Donald Rudikoff, MD
Division of Dermatology
Bronx Lebanon Hospital Center
Albert Einstein College of Medicine
Bronx, New York
Eleonora Ruocco, MD, PhD
Department of Dermatology
Second University of Naples
Naples, Italy
Vincenzo Ruocco, MD
Department of Dermatology
Second University of Naples
Naples, Italy
ix
Anne Marie Tremaine, MD
Department of Dermatology
University of California–Irvine School of Medicine
Irvine, California
Nikolai Tsankov, MD, PhD, DrSci
Department of Dermatology
Tokuda Hospital–Sofia
Sofia, Bulgaria
Maria Antoinetta Tufano, MD
Department of Experimental Medicine
Microbiology and Clinical Microbiology
Section
Second University of Naples
Naples, Italy
x
C ONTRIBUTORS
Yalçin Tüzün, MD
Department of Dermatology
Cerrahpasa Medical Faculty
Istanbul University
Istanbul, Turkey
Michael Waugh, MB, FRCP, FRCPI, FAChSHM,
Dip Ven DHMSA
Genito-Urinary Medicine
Nuffield Hospital
Leeds, United Kingdom
Stephen Tyring, MD, PhD
Center for Clinical Studies
Departments of Dermatology, Microbiology and
Molecular Genetics, and Internal Medicine
University of Texas Health Science Center
Houston, Texas
Jeffrey M. Weinberg, MD
Department of Dermatology
Columbia University College of Physicians and Surgeons
Department of Dermatology
St. Luke’s–Roosevelt Hospital Center
Beth Israel Medical Center
New York, New York
Snejina Vassileva, MD, PhD
Department of Dermatology
Medical University–Sofia
Alexandrovska University Hospital
Sofia, Bulgaria
Daniel Wallach, MD
Department of Dermatology
Tarnier Hospital
Paris, France
Ronni Wolf, MD
Head, Dermatology Unit
Kaplan Medical Center
Rechovot, Israel
Hebrew University–Hadassah Medical School
Jerusalem, Israel
Preface
rooms, intensive care units, and burn units in differentiating between skin diagnoses. Treating a severely ill dermatologic patient is always multidisciplinary teamwork.
Although the trained eyes of the dermatologists and their
extensive knowledge about diseases of the skin are indispensable for rapid and correct diagnosis and management
of a dermatological emergency, fundamental knowledge of
internal medicine, including cardiology, nephrology, and
rheumatology, is also essential in this setting. This volume is intended to update and refresh what dermatologists and nondermatologists need to know for dealing with
critically ill dermatologic patients. Emergency Dermatology
should provide the link to the experience, expertise, and
skills of various disciplines with the aim of guiding the medical caretakers of patients who are in true dermatological
crises.
There are plenty of available dermatology textbooks.
Some encompass widespread fields of dermatology (e.g.,
Fitzpatrick’s Dermatology in General Medicine) whereas others are devoted to special issues, such as dermatopathology,
contact dermatitis, dermatologic surgery, photodermatology, and many others. There is currently no publication
that covers all aspects of critically ill dermatologic patients.
In Emergency Dermatology, we have attempted to retrieve
and organize the relevant information and available knowledge on this specific niche of medicine and to fill the gap in
available reference material to guide the medical caretakers
of patients who are in true dermatological crises. Although
we have strived for completeness, we recognize that certain entities have not been addressed as completely as some
readers may wish; however, it is not our intention to provide an encyclopedic textbook, but rather a more usable
volume.
We are indebted to all the distinguished international
specialists who have consented to give of their valuable
time and vast experience to cover this complex and vital
“Dermatology is the best specialty. The patient never
dies – and never gets well.” (anonymous)
Many physicians and patients believe that dermatology
does not involve life-threatening situations and that it is,
like beauty, only skin deep (e.g., it is mainly an aesthetic
specialty). Although the horrors of the syphilitics and the
lepers of medieval times no longer exist, there are contemporary emergencies with which the dermatologist needs to
contend, as well as cutaneous diseases that require rapid
management.
Although the dermatologist is not likely to be the primary care physician responsible for the severely ill patients
in the hospital setting, the skin disease specialist is still frequently the first clinician to examine these patients before
hospital admission. The specialist may be responsible for
making the initial diagnosis; for differentiating mundane
skin ailments from more serious, life-threatening conditions; and also for being the first to identify a critical situation, to stabilize the patient, and to choose urgent and
appropriate interventions.
Dermatologic emergencies and life-threatening skin
diseases should be spared the “atrophy” that threatens
knowledge that is not applied in everyday practice and fails
to be refreshed from time to time. Dermatologists have no
choice but to continue to be on the front line of diagnosing
and treating all skin diseases, especially the more severe and
acute ones.
This book brings together the top “players” in the
lively, complicated, and multifaceted field of dermatologic
emergencies and life-threatening skin diseases with the
purpose of assisting the practicing physician in coping
with dermatologic conditions that require urgent intervention. Although this book is intended primarily for dermatologists, it should also be of help to family practitioners, internists, and all those who practice in emergency
xi
xii
P REFACE
issue in a systematic and practical manner and who have
produced such a comprehensive, state-of-the-art reference source of which we believe we can all be proud.
If this book helps practicing physicians, both dermatologists and nondermatologists alike, to cope with der-
matologic emergencies by knowing what to do whenever they encounter severely ill patients with complicated
skin diseases and reach the correct decisions in urgent
and critical situations, it will all have been worth the
effort.
CHAPTER 1
Cell Injury and Cell Death
Adone Baroni
Eleonora Ruocco
Maria Antonietta Tufano
Elisabetta Buommino
WHEN CELLS are damaged, as often occurs during
trauma and metabolic stress, the organism has to choose
whether to repair the damage by promoting cell survival or
remove irreparably injured cells. Cell injury occurs when
an adverse stimulus reversibly disrupts the normal, complex homeostatic balance of the cellular metabolism. In this
case, after injury the cells attempt to seal breaks in their
membranes, chaperone the removal or refolding of altered
proteins, and repair damaged DNA. On the contrary, when
cell injury is too extensive to permit reparative responses,
the cell reaches a “point of no return” and the irreversible
injury culminates in programmed cell death (PCD). Specific properties or features of cells make them more or less
vulnerable to external stimuli, thus determining the kind
of cellular response. In addition, the characteristic of the
injury (type of injury, exposure time, or severity) will also
affect the extent of the damage.
We present a short overview of the best-known PCD
pathways. We emphasize the apoptotic pathway, considered for years the hallmark of PCD, and the different stimuli that produce cell injury.
CELL INJURY
The survival of multicellular organisms depends on the
function of a diverse set of differentiated cell types. After
development is complete, the viability of the organism
depends on the maintenance and renewal of these diverse
lineages. Within each lineage homeostasis is maintained
through a delicate balance between cell proliferation and
cell death.1 Disorders of either process have pathological consequences and can lead to disturbed embryogenesis,
neurodegenerative diseases, or the development of cancer.2
Therefore, the equilibrium between life and death is tightly
controlled, and faulty elements can effectively be eliminated
by PCD, a term that well defines the planned sequence of
physiological cellular autodestruction, which requires both
energy expenditure and a specific enzymatic network. Cell
death is an essential strategy for the control of the dynamic
balance of the living system, and it is the ultimate result
of most physiological as well as pathological processes.
Skulachev aptly described the concept of cell death using
the metaphor of the “Samurai law of biology” (i.e., it is
better to die than be wrong), showing that the suicide program is a way to purify cells of damaged organelles and
tissues of unwanted cells that use up valuable substrates
and nutrients.3,4 Likewise, cell death also has value for the
species, as it provides a mechanism for eliminating terminally injured individuals who consume necessary society resources or harbor toxic pathogens.3,5 Death, therefore, appears as the unique solution to eliminate what is
unwanted or dangerous to the “community.”
In past decades, PCD was mainly associated with apoptosis, a death process characterized by morphological
changes such as shrinkage of the cell, condensation of
chromatin, and disintegration of the cell into small fragments (so-called “apoptotic bodies”) that are removed by
phagocytosis. On the contrary, necrosis was considered as
an alternative passive cell death occurring in an accidental, violent, or chaotic way.6 Necrosis, however, has been
recently recognized as a specific form of cell death with distinct morphological features.7,8 It is now known that cell
death cannot readily be classified as “apoptosis” or “necrosis,” and alternative types of PCD have been described.9–11
Different PCD pathways exist, either mediated by caspases (a specific family of cysteine proteases, as in apoptosis) or caspase-independent (such as autophagic cell death
[ACD], paraptosis, and programmed necrosis).1 Death patterns may overlap or integrate, reflecting the high flexibility in cell responses to various circumstances and stimuli
(Figure 1.1).
Cell injury occurs as a result of physical, chemical, or
biological insults or as a result of vital substrate deficiency.
The cellular response to injury can be adaptive when it
is designed to restore homeostasis and protect the cell
from further injury. In this context, the gene transcriptional activity is modified in favor of vital genes.5 If the
genetic and metabolic adaptive responses are inadequate
page 1
2
E MERGENCY D ERMATOLOGY
APOPTOSIS
AUTOPHAGY
DEATH
STIMULUS
(physical agents,
UV light, drugs,
calcium influx,
infectious agents,
hypoxia, etc.)
NECROSIS
PARAPTOSIS
PROGRAMMED NECROSIS
c Quill Graphics, www.cellsalive.com).
FIGURE 1.1: Various models of cell death (
for a given injury, or if injury accumulation reaches a critical level, the damaged cells commit suicide.3 Cell injury can,
therefore, be reversible (sublethal) or irreversible (lethal).
Cells may be reversibly injured, but if severely injured, they
may be unable to recover and cell death will occur. The
death stimuli are diverse and include normal physiological signals, such as hormones that trigger deletion of cells
during differentiation or involution of tissues and organs,
maturation of organ systems as, for example, in the immune
system, and removal of cells that have sustained some form
of damage.2 Alternatively, cells already may be primed to
undergo cell death, with the withdrawal of important extracellular components, such as serum or growth factors, providing the signal.12 Other death stimuli also are important from a biomedical perspective. These include physical
agents (ultraviolet [UV] light causing damage to the skin,
hyperthermia, cold, and trauma), cytotoxic drugs, calcium
influx, glucocorticoids, infectious agents (bacteria, virus,
yeast), and hypoxia. The stimuli that initiate the death pathways vary widely with the affected cells.13 In particular, various stimuli (e.g., cytokines, heat, irradiation, pathogens)
can cause both apoptosis and necrosis in the same cell
population (Figure 1.1). Apoptosis can be induced by a
lower concentration or level of almost all the stimuli that
cause necrosis.14 This means that the mechanism of selfdestruction can be activated by a relatively mild stimulus.
Whereas mild hypoxia produced symptoms of apoptosis,
severe hypoxia produced infarction and necrosis;15 similarly, exposure to temperatures between 37◦ C and 43◦ C
induced apoptosis in lymphocytes, and exposure to higher
temperatures induced necrosis.16 Therefore, the character of the injury will determine the pattern of cell death
evoked. This aspect is important to highlight. The three
main features of injury are type of injury, exposure time, and
severity.
Type of Injury
The injury can be, for example, physical, chemical, or toxic,
but the response will be different for different cell types.
In fact, some cells will be more susceptible than others to
agents (heart muscle cells are more susceptible than connective tissue cells to oxygen depletion).
Exposure Time
The length of exposure to a particular stimulus will affect
the chances of cell survival. Relatively resistant cells will be
damaged if the duration of exposure is prolonged.
Severity
The ability of a cell to survive an injury also will depend on
its severity; if the withdrawal of growth factor is partial, the
cell is still able to survive for a long period (depending on
cellular resistance), but if it is complete, cell death occurs
in a very short time with modalities that vary from cell to
cell.
We now describe some models of cellular death, taking into consideration that a clear-cut definition cannot be
given because of the overlapping of the different programs
of cell death.
Apoptosis. Cells have different ways of committing suicide
and may select the fastest and most effective of the options
available. Apoptosis has been considered for years as the
PCD paradigm and is still considered one of the main
pathways activated during stressful conditions, although
alternative pathways were recently identified.1 The term
“apoptosis” derives from the ancient Greek word used to
describe the “falling off ” or “dropping off ” of petals from
flowers or leaves from trees, to emphasize the normal physiological nature of the process.17 In 1972 this kind of cell
death was first described17 and noted that it was truly distinct from necrosis, underscoring the importance of apoptosis in human medicine. As part of the immune response,
apoptosis allows the elimination of virally infected and
cancer cells or the deletion of unnecessary or potentially dangerous lymphocytes.18 Defects of apoptotic cell
death may promote tumor or autoimmune disease development. The apoptotic process has been shown to proceed
Chapter 1
A
B
C
D
●
Cell Injury and Cell Death 3
FIGURE 1.2: Morphological changes occurring in A549 (human carcinoma lung cell line) (panel B) (R. Nicoletti, E. Buommino, A. De
Filippis, M. P. Lopez-Gresa, et al. World J Microbio and Biotechnol. 2008; 24: 189–95) and NCI (human mesothelioma cell line) (panel D)
cells (E. Buommino, I. Paoletti, A. De Filippis, R. Nicoletti, et al. Cell Prolif. forthcoming 2010), treated with proapoptotic metabolites,
with a particular of membrane budding shown in panel B; panel A and C show the morphology of A549 and NCI untreated cells,
respectively. Magnification: 20X.
via a number of discrete steps. Cells undergoing apoptosis are characterized morphologically by cell shrinkage, chromatin condensation, loss of contact with neighboring cells and the extracellular matrix (Figure 1.2), 19
actin cleavage,20 and biochemically by DNA laddering
(Figure 1.3).19 The last is a peculiarity of most apoptotic
pathways. The double-stranded linker deoxyribonucleic
acid (DNA) between nucleosomes is cleaved at regularly
spaced internucleosomal sites, giving rise to DNA fragments representing the length of nucleosomes (180–200
base pairs).13 Molecular characterization of this process
identifies a specific DNase (caspase-activated DNase) that
cleaves chromosomal DNA in a caspase-dependent manner.21 Other features of apoptosis are early depolymerization of cytoskeletal proteins, loss of phospholipid symmetry in plasma membrane with the outer layer exposure of
phosphatidylserine (PS) residues, and the appearance of a
smooth-surfaced protuberance of the plasma membrane
with its preserved integrity. The fragmentation of both
nucleus and whole cell then produces membrane-bound
bodies in which the organelles are intact to form apoptotic bodies (Figure 1.2 [inset]).22 This is also called the
“budding phenomenon” and should not be confused with
blebs, fluid-filled structures typically devoid of organelles.6
The apoptotic bodies are cleared from tissues by professional phagocytes, such as macrophages, but also epithelial
cells and even fibroblasts have been shown to clear apoptotic bodies.23,24 Phagocytosis is initiated by the exposure
of the PS receptor located on the membrane of the phagocytes and vitronectin receptors, resulting in a cell-signaling
response.22 The apoptotic pathway and the engulfment
process are part of a continuum that helps ensure the noninflammatory nature of this death paradigm. Studies in mammals have highlighted the importance of proper disposal
of apoptotic bodies by phagocytic cells.24 The suppression
of proinflammatory factors is necessary during apoptotic
4
E MERGENCY D ERMATOLOGY
FIGURE 1.3: DNA feature of HeLa cells treated or not with
3-O-methylfunicone. DNA fragmentation induced in OMF treated
cells after 48 and 72 h (lane 3 and 4, respectively). Lane 1,
untreated cells; lane 2, cells treated for 24 h; lane 5, negative
control (absolute ethanol). M, 100 bp ladder (Roche Diagnostics)
used as MW-marker. (E. Buommino, R. Nicoletti, G. M. Gaeta,
M. Orlando et al. Cell Proliferation. 2004; 37:413–26)
body clearance. This suppression is accomplished at least
in part by a release of antiinflammatory factors including
transforming growth factor β and IL-10 by macrophages
engaged in corpse engulfment. Furthermore, regulatory
mechanisms help ensure that, when phagocytosing dendritic cells present peptides from apoptotic bodies to T
cells, no immune reaction against self-peptides is initiated.
Defects in the clearance of corpses are predicted to create
a proinflammatory milieu that may predispose to autoimmune disorders.
A cascade of genes is activated as a consequence of the
induction of a defined genetic program in which caspases
have a prominent role. Caspases are cysteine proteases (preexisting as inactive zymogen precursors in the cell) that
cleave substrates at critical aspartic acid residues.18 Activation of caspases is the central event in apoptosis, leading to the cleavage of numerous proteins involved in the
cell structure, cell-cycle control, and DNA synthesis and
repair. The initiator caspases (caspase-2, -8, -9, and -10)
are activated by interaction with caspase adapters, whereas
the effector caspases (caspase-3, -6, and-7) are downstream
of the activator caspases and act to cleave various cellular
targets and substrates and induce cell death.18 The enzyme
poly(adenosine diphosphate [ADP]-ribose) polymerase, or
PARP, was one of the first proteins identified as a substrate
for caspases. PARP is involved in the repair of DNA damage. It functions by catalyzing the synthesis of PARP and by
binding to the DNA strand breaks and modifying nuclear
proteins.25 The ability of PARP to repair DNA damage is
prevented following cleavage of PARP by caspase-3. The
inflammatory caspases are involved in cytokine activation
and are represented by caspases-1, -4, -5, -11, -12, -13,
and -14.
Caspases can be activated through three main pathways: an “extrinsic” death receptor (DR)–mediated process
and two “intrinsic pathways,” a mitochondria-mediated–
and an endoplasmic reticulum (ER)–mediated pathway
(Figure 1.4).1,18
The extrinsic pathway involves the surface DRs, a subfamily of the tumor necrosis factor receptor (TNF-R)
superfamily activated in response to specific extracellular
signals.26 To date, eight DRs have been identified, namely,
Fas (CD95, Apo-1), TNF-related apoptosis-inducing ligand (TRAIL)-receptors 1 (TRAIL-R1) (DR4) and 2 (DR5,
Apo-2), TNF-R1, TRAMP (WSL-1, Apo-3), EDAR, p75
neurotrophin receptor (p75NTR), and DR6.26 Despite
their name, not all of these receptors induce apoptosis, but
they may trigger specific signaling pathways that result in
a variety of cellular outcomes. The DRs comprise three
domains: an extracellular cysteine-rich domain for ligand
binding, a transmembrane domain, and an intracellular
death domain (DD), which is required for apoptotic signal
transduction.26 The DR TNF ligand (TNF-L), Fas ligand
(FasL), and TRAIL induce apoptosis by binding to their cell
membrane receptors. Following ligand binding, a conformational change in the intracellular domains of the receptors reveals the presence of a “death domain,” which allows
the recruitment of various apoptotic proteins to the receptor. This protein complex is known as the death-inducing
signaling complex (DISC). The final step in this process is
the recruitment of one of the caspases, typically caspase-8,
to the DISC. This recruitment results in the activation of
caspase-8 and the initiation of apoptosis.
Interestingly, there are also decoy receptors (DcRs) that
compete to bind ligands to DRs, allowing the cell to escape
death ligand–induced killing. DcR1 and DcR2 compete
with DR4 or DR5 to bind to TRAIL. DcR3 competes with
Fas to bind to the FasL.
The intrinsic cell death pathway involves the mitochondria and ER. The mitochondria-mediated pathway is
induced by lethal intracellular signals such as oncogenic
transformation and DNA damage. Mitochondria contain
many proapoptotic proteins such as apoptosis-inducing factor (AIF), cytochrome c, and Smac/DIABLO.27 The last is
a protein that directly neutralizes inhibitors of apoptotic
proteins (IAPs), such as survivin, originally described as
an inhibitor of apoptosis proteins with a cell-cycle–specific
function.28 AIF, cytochrome c, and Smac/DIABLO are
released from the mitochondria following the formation
of a pore in the mitochondrial membrane called the permeability transition (PT) pore. These pores are thought
to form through the action of the proapoptotic members
of the bcl-2 family of proteins, which in turn are activated by apoptotic signals such as cell stress, free radical damage, or growth factor deprivation.29 In particular, AIF and Smac/DIABLO were also reported to be
involved in the mitochondrial death pathway related not
to apoptosis but to the apoptosis-like death pathway.30
The release of cytochrome c from the mitochondria is a
Chapter 1
Cell Injury and Cell Death 5
●
EXTRINSIC PATHWAY
INTRINSIC PATHWAY
Ligand
UV, radiation, chemo,
hypoxia
ER Stress
(misfolded proteins)
Death
receptor
Plasma
Membrane
Adapter
Procaspase-12
Initiator
Caspase-8
Mitochondria
Initiator
Caspase-12
Bid
Bcl-2/
Bcl-xL
Ca++
IP3R
Cyto c
Effector
Caspases
TRAF2
Ca++
Bcl-2/ Bcl-xL
Apaf-1
Endo G
AIF
Initiator
caspase-9
Endoplasmic
reticulum
Effector
Caspases
Nucleus
APOPTOSIS
APOPTOSIS
APOPTOSIS
Death domain
FIGURE 1.4: The two main pathways for the initiation of apoptosis: the extrinsic pathway and the intrinsic pathway (S. Gupta,
A. Agrawal, S. Agrawal, H. Su et al. Immunity & Ageing 2006; 3:5 doi:10.1186/1742-4933-3-5).
particularly important event in the induction of apoptosis. When cytochrome c has been released into the cytosol
it interacts with a protein called Apaf-1. This interaction
leads to the recruitment of procaspase-9 into a multiprotein complex with cytochrome c and Apaf-1 called the
apoptosome. Specifically, adenosine triphosphate (ATP)
is required for the formation of the apoptosome, necessary for the activation of caspase-9 and the induction
of apoptosis. If damage to the mitochondria is such that
the ATP levels are insufficient to complete the apoptotic process, the mode of death may be directed toward
necrosis.
The bcl-2 proteins are a family of proteins involved in
the response to apoptosis. Some of these proteins (such as
bcl-2 and bcl-XL ) are antiapoptotic, whereas others (such
as Bad, Bax, or Bid) are proapoptotic. The sensitivity of
cells to apoptotic stimuli can depend on the balance of
pro- and antiapoptotic bcl-2 proteins. When there is an
excess of proapoptotic proteins, the cells are more sensitive
to apoptosis, but when there is an excess of antiapoptotic
proteins, the cells will tend to be more resistant. An excess of
proapoptotic bcl-2 proteins at the surface of the mitochondria is thought to be important in the formation of the PT
pore.29 The proapoptotic bcl-2 proteins are often found in
the cytosol, where they act as sensors of cellular damage or
stress. Following cellular stress they relocate to the surface
of the mitochondria, where the antiapoptotic proteins are
located. This interaction between proapoptotic and antiapoptotic proteins disrupts the normal function of the antiapoptotic bcl-2 proteins and can lead to the formation of
pores in the mitochondria and the release of cytochrome
c and other proapoptotic molecules from the intermembrane space. This in turn leads to the formation of the
apoptosome and the activation of the caspase cascade. The
bcl-2 gene has been shown to be transcriptionally repressed
by p53.31 The p53 tumor suppressor gene codes for the
p53 protein and plays an important role in the control of
the cell cycle, apoptosis, senescence, differentiation, and
accelerated DNA repair.32 DNA damage caused by exposure to ionizing radiation, UV light, or some exogenous
or endogenous chemical mutagens, which results in DNA
strand breakage, can trigger an accumulation of p53. This
6
E MERGENCY D ERMATOLOGY
TABLE 1.1: Different Characteristics of the Cell Death Pathways
Types,
characteristics
Apoptosis
Autophagic cell
death
Paraptosis
Programmed
necrosis
Necrosis
Triggers
Death receptors,
trophic factor
withdrawal, DNA
damage, viral
infections, etc.
Serum amino acid
starvation, protein
aggregates
Trophotoxicity
Ischemia,
excitotoxicity
Excessive damage
by physical or
chemical injury, high
intensities of
pathological insult
Plasma
membrane
Membrane-bound
apoptotic bodies,
blebbing
Elongation and
invagination,
blebbing
Shrinkage
Rapid loss of plasma
membrane integrity
Rapid disintegration
Nucleus
Chromatin
condensation,
internucleosomal
DNA cleavage
(ladder)
Pyknosis in some
cases, but neither
prevalent nor
striking, no DNA
laddering
Late disintegration
No chromatin
condensation, in
some cases
chromatin clustering
to loosen speckles
Karyolysis
Cytoplasm
Condensation and
shrinkage,
cytoskeleton
collapse
Vacuolization,
autophagosome
and autolysosome
formation
Vacuolization
Swelling, extensive
vacuolization
Condensation, loss
of structure,
fragmentation,
swelling
Organelles
Preservation
Enwrapped by
membrane sac.
Autodigestion
Swelling
Swelling
Condensation and
final disintegration
gene can activate transcription of growth regulatory genes
such as p21 WAF1/Cip1, GADD-45, and cyclin G, resulting in G1 growth arrest, presumably to allow for repair
of damaged DNA. If irreparable DNA damage exists, the
cell becomes committed to the apoptosis pathway and is
deleted by the system. For this reason, p53 is known as the
“guardian of the genome.” Mutant p53 proteins may allow
an escape from this surveillance mechanism and generation
of a malignant phenotype.
The ER is another important sensor of cellular stress
that can withhold protein synthesis and metabolism to
restore cellular homeostasis. Misfolded proteins are constantly produced; these proteins trigger a protective
stress response, known as the unfolded protein response.
Although this response may put off a cellular catastrophe for
a short time, if the damage to ER is too extensive, the damage can initiate PCD via the unfolded protein response or
via release of calcium into the cytoplasm.33 Thus caspase-12
is activated, which then engages caspase-9 and leads to the
effector cascade recruitment.34 In addition, an intracellular
calcium influx caused by ER stress induces the activation
of a family of cytosolic proteases, the calpains (calciumactivated neutral proteases), which normally reside in the
cytosol as inactive zymogenes.35,36 Calpains, kept in control by their natural inhibitor calpastatin, have been shown
to act downstream of caspase. In fact, it has been demonstrated that vitamin D compounds trigger cell death in
MCF-7 cells via calpains and independent of caspase
activation, thus indicating a role of ER in certain types
of caspase-independent cell death.37 Disorders such as
Alzheimer disease, Parkinson disease, Huntington disease,
amyotrophic lateral sclerosis, and prion protein disease all
share the common features of accumulation and aggregation of misfolded proteins.38
OTHER FORMS OF PCD
Compared to apoptosis, relatively little is known about
autophagic PCD and paraptosis, and even less is known
about other nonapoptotic forms of PCD. Most of what is
known is based on morphological descriptions. The exact
phenotype of a dying cell is certainly dependent on many
different factors that include the cell type, the cellular
context, and the specific death stimulus.30 Characteristic
changes that differ in the various forms also include modifications of the cell shape and architecture, such as alterations
of the cytoskeleton (Table 1.1). Any questions about the
other forms of cell death remain unanswered: How important is the activation of the different PCD for the organism,
and are all the mediators that trigger one type of death or
another known? To these and other questions we will try
to give an answer.
ACD
ACD is a long-known nonapoptotic cell death modality,
also called type II cell death (to distinguish it from apoptosis or type I cell death).39 Phagocytosis and autophagy
Chapter 1
are two well-known processes involved, respectively, in the
removal of extracellular organisms and the destruction of
organisms in the cytosol. Autophagy, for either metabolic
regulation or defense, involves the formation of a double
membrane called the autophagosome, which then fuses
with lysosomes to degrade the contents, a process that
has similarities to phagosome maturation. Autophagy is,
in fact, normally activated during starvation by nutrient
sensors to allow the recycling of substrates and organelles
and to ensure the metabolic precursor.40 Autophagy is also
a means to eliminate dysfunctional organelles and allow
a turnover of long-living proteins, thus preventing their
pathological accumulation in the cells. Consequently, the
cell “cannibalizes itself ” from the inside (autophagy = “selfeating” in Greek). When this self-eating reaches excessive
levels it may progress toward ACD, occurring in response
to prolonged deprivation or stress, during embryogenesis,
in adult tissue remodeling, in human diseases, or during
cytotoxic drug treatment.39 Autophagy is often observed
when massive cell elimination is needed or when phagocytes do not have easy access to the dying cells. ACD is differentiated from apoptosis by certain peculiarities, including autophagosome and/or autolysosome formation, a vast
autodigestion of organelles, a preserved nucleus until late
stages (with the absence of DNA laddering), and cytoskeleton preservation until the final stages. In contrast to apoptosis, ACD occurs in a caspase-independent pathway. Interestingly, autophagy can be a factor in both the promotion
and prevention of cancer, and its role may be altered during
tumor progression.41 The first autophagy gene identified in
humans was Beclin 1. The heterogeneous disruption of this
gene leads to increased tumorigenesis in mice.42 Beclin 1
is inhibited by its interaction with Bcl-2, which thus not
only functions as an apoptotic suppressor, but also as an
antiautophagic factor.43 Another aspect to be considered
is that some malignant cell types respond to anticancer
agents by triggering autophagy, indicating the potential
utility of ACD induction in cancer therapy. Cancer cells
may need autophagy to survive nutrient-limiting and lowoxygen conditions, and autophagy may protect cancer cells
against ionizing radiation by removing damaged elements.
The precise role of this cell death is, therefore, not yet
fully understood, but it is important to underline that
autophagy and apoptosis can be observed simultaneously in
the same tissue, and, in some cases, autophagy may precede
and later trigger apoptosis when the autophagic capacity
is overwhelmed.39 In other settings, autophagy has been
observed to delay or antagonize apoptosis, and there are
also examples in which the two processes can be mutually
exclusive.39
PARAPTOSIS
Recently, a novel nonapoptotic PCD process designated
paraptosis was described by Sperandio and colleagues.10
●
Cell Injury and Cell Death 7
The features of paraptosis differ from those of apoptosis and involve cytoplasmic vacuolation, mitochondrial
swelling, the absence of caspase activation, and typical
nuclear changes including pyknosis and DNA fragmentation.10 There is increasing evidence that this alternative,
nonapoptotic PCD exists in parallel with apoptosis. The
neuropeptide substance P and its receptor, neurokinin-1,
mediate a nonapoptotic form of PCD resembling paraptosis in some cases.44 Activated microglia trigger neuronal
cell death with ultrastructural characteristics of marked vacuolation and slightly condensed chromatin following the
blockage of the caspase cascade.45 In addition, ceramide
induces nonapoptotic PCD with necrosis-like morphology in human glioma cells in the presence of pan-caspase
inhibitors or during overexpression of bcl-XL .46 These
examples support the theory that cells have other intrinsic programs for death that are distinct from apoptosis.
This death program can be mediated by mitogen-activated
protein kinases and can be triggered by the TNF-R
family member TAJ/ TROY, capable of inducing apoptosis independent of DNA fragmentation and caspase activation, and the insulin-like growth factor I receptor.1,47
The idea that PCD might be induced by hyperactivation of a trophic factor receptor (trophotoxicity) is compatible with an earlier observation that some trophic factors may increase neuronal cell death, for example, that
induced by excitotoxicity.48 Such an effect might be protective against neoplasia in that it may eliminate cells
that would otherwise undergo autocrine loop–stimulated
oncogenesis. The resulting program would necessarily be
nonapoptotic because trophic factors inactivate apoptotic
signaling.
NECROSIS AND PROGRAMMED NECROSIS
For a long time necrosis was considered as an alternative to
apoptosis.7,8 Recently, necrosis, once thought of as simply
a passive, unorganized way to die, has emerged as an alternative form of PCD, the activation of which might have
important biological consequences, including the induction of an inflammatory response.49 The term necrosis has,
therefore, been wrongly used for years to define an alternative mode of cell death. It is now evident that we cannot
refer to necrosis to mean a particular program of death
and that this term should be used to describe what happens after a cell is dead. It is, therefore, more correct to use
the term “programmed necrosis” or “necrosis-like PCD”
when we describe certain kinds of cell death governed by
a specific genetic program and quite different from classical apoptosis or not falling within the cell death pathways
described earlier in this chapter.6 There are many examples of programmed necrosis being a normal physiological and regulated (programmed) event. Signaling pathways
(e.g., DRs, kinase cascades, and mitochondria) participate
in both processes, and, by modulating these pathways, it
8
E MERGENCY D ERMATOLOGY
is possible to switch between apoptosis and programmed
necrosis. Moreover, antiapoptotic mechanisms (e.g., bcl-2/
bcl-x proteins, heat shock proteins) are equally effective
in protecting against apoptosis and programmed necrosis.
There are several examples of necrosis during embryogenesis, normal tissue renewal, and the immune response.7
The core events of programmed necrosis are bioenergetic
failure and rapid loss of plasma membrane integrity. These
events can result from specific molecular events that occur
in the dying cell, including increased mitochondrial reactive oxygen species production, channel-mediated calcium
uptake, activation of nonapoptotic proteases, and/or enzymatic destruction of cofactors required for ATP production. Karyolysis of the nucleus occurs as a consequence of
the complete dissolution of the chromatin due to the activity of specific DNase. In addition, these necrotic mediators are often induced in the dying cell simultaneously
and enhance each other’s ability to initiate the demise of
the cell.50 Calpain and lysosomal cathepsin activation have
been shown to contribute to necrotic cell death. Due to the
immunogenic potential of the necrotic cell debris removal,
the target induction of programmed necrosis is gaining
attention among immunologists and oncologists in cancer immunotherapy.51 At this point, it is important to note
that, to complicate the intricate net of terminologies used
to define the area of apoptosis versus necrosis, the term
“oncosis” (from the Greek word for swelling), a form of
cell death activated by ischemia, has also been used through
the years to define all the situations in which marked cellular swelling occurred. Extensive literature on the morphological criteria for oncosis exists, but the biochemical
pathway(s) of oncosis has not yet been described. Oncosis
is thought to be mediated by a failure of plasma membrane
ionic pumps. One potential mediator of oncosis is a calpainfamily protease (possibly a mitochondrial calpain), which
suggests that oncosis may turn out to be related to, or synonymous with, a calcium-activated programmed necrosis
cell death. Majno and Joris proposed this term for designating any programmed cellular suicide characterized by
a marked swelling, whereas the term “necrosis” refers to
the features that appear after the cell has died.6 Necrosis
may be either oncotic or apoptotic in origin. In this context,
oncosis comprises the prelethal changes leading to ischemic
or coagulation necrosis, whereas necrosis describes a morphology but not a process, thus underscoring the final feature of a dead cell.
APOPTOSIS AND HUMAN DISEASES
Nonregulated apoptosis involves different pathophysiological situations such as malignant and premalignant conditions, neurological disorders (e.g., Alzheimer disease,
prion-associated disorders), heart disease (ischemic cardiac damage, chemotherapy-induced myocardial suppression), immune system disorders (e.g., acquired immune
deficiency syndrome [AIDS], type I diabetes, systemic lupus
erythematosus [SLE], Sjögren syndrome), intestinal disorders, and kidney disease.2 In particular, diseases characterized by the accumulation of cells include cancer, autoimmune diseases, and certain viral illnesses. Cell accumulation
can result from either increased proliferation or the failure
of cells to undergo apoptosis in response to appropriate
stimuli.
Cell Death in Cancer
Tumor growth occurs when the cellular birth rate exceeds
the death rate. Control of cell growth is important in the
process of normal development and tissue homeostasis, and
in pathological conditions such as neoplasia. Growth arrest
and cell death are also important in normal and neoplastic
growth.
Inactivation of apoptosis is a hallmark of cancer, an
obligate ritual in the malignant transformation of normal cells. By inactivating apoptosis, cancer cells enhance
their chances of survival and increase their resistance to
chemotherapeutic agents. Because apoptosis is a genecontrolled process, it is susceptible to genetic manipulation
for therapeutic purposes, such as in cancer treatment. The
acquisition of resistance to apoptosis is important in the
transition from normal melanocyte to melanoma. Apoptosis is, in fact, critical for epidermal homeostasis, representing a key protective mechanism removing premalignant cells that have acquired mutations.52
Melanoma is the most aggressive form of skin cancer,
notoriously resistant to current modalities of cancer therapy and known to be a tumor with an elevated metastatic
ability.53 Although today melanoma is more often diagnosed in an early stage of disease and therefore shows a
better overall survival, when tumor cells are detected in
the regional lymph node, the patient has a poorer prognosis. One of the earliest events in melanoma progression
involves the unregulated proliferation of melanocytes. In
this stage of melanoma progression, the cells lose their
ability to maintain the cell-cycle controls that function in
normal unstimulated melanocytes. This loss of cell-cycle
control can lead to sustained proliferation, decreased apoptosis, or both. It also has been reported that melanocytes
displayed a broad expression of apoptotic inhibitors to
maintain their longevity, at the cost of the nonelimination of damaged cells, thus resulting in a high probability of developing melanoma.52 In contrast, keratinocytes
are more prone to undergoing apoptosis to ensure a rapid
turnover and efficiently remove damaged cells and meet
their functional needs in the skin. Melanoma cells are resistant to a wide range of antineoplastic treatments because
of their ability to evade the cytotoxic action of different
insults such as DNA damage, microtubule destabilization,
or topoisomerase inhibition,53 showing, in contrast, strong
resilience. In fact, melanoma cells in vivo demonstrate low
Chapter 1
levels of spontaneous apoptosis compared with other tumor
cell types, and resistance to apoptosis is associated with
increased resistance to chemotherapeutic agents.54 The
knowledge acquired about the altered apoptotic mechanism in melanoma has focused the attention of researchers
on molecules able to compensate for or bypass the cell
death defects and on the development of new chemotherapeutic strategies that facilitate the death of cancer
cells.
Cell Death and Autoimmune Disorders
Physiological regulation of cell death is essential for the
removal of potentially autoreactive lymphocytes during
development and for the removal of excess cells after the
completion of an immune response. Failure to remove
autoimmune cells that arise during development or that
develop as a result of somatic mutation during an immune
response can result in autoimmune disease.55 Upregulated levels of soluble Fas, which might competitively
inhibit FasL–Fas interactions, have been documented in
many autoimmune disorders such as rheumatoid arthritis, SLE, and pemphigus vulgaris (PV).56 PV is a chronic
autoimmune cutaneous disease characterized by circulating autoantibodies that cause blisters and erosions on the
skin and mucous membranes.57 Circulating autoantibodies
bind with the epidermal cell membrane and cause cell–
cell detachment (acantholysis), leading to epidermal tissue
damage. In recent years, the idea that apoptosis might play
a central role in the induction of acantholysis has gained
momentum. In support of this supposition, a study by
Weiske and colleagues demonstrated the proteolytic cleavage of desmoglein 3 (PV antigen) by caspase-3 during apoptosis, thereby causing desmosome disruption only after the
induction of apoptosis.58
In a past study, we showed the ability of pemphigus serum and captopril to induce apoptosis in human
keratinocytes.59 In particular, the authors demonstrated
that a drug (captopril) or antibodies (PV serum) acting,
respectively, by a biochemical or immunological mechanism induced acantholysis through the same genetic program leading to PCD. Of interest is a contribution published by Arredondo and colleagues demonstrating the
therapeutic action of intravenous immunoglobulin (IVIg)
in PV.60 In the plethora of biological effects exerted by IVIg
administration (acceleration of the clearance of autoantibodies, modulation of serum levels of proinflammatory
cytokines, induction of immunocompetent cell death), an
array of antiapoptotic effects should also be mentioned.
IVIg inactivates FasL, protects target cells from apoptosis
by upregulating Bcl-2 expression, interferes with TNF-␣
and interferon-␥ signaling pathways, and increases sensitivity to corticosteroid action, thus strengthening the idea
that apoptosis may play an important role in the onset of
the disease.
●
Cell Injury and Cell Death 9
CONCLUSIONS
Even in diseases in which the affected cells have been shown
to die with “apoptotic morphology,” one cannot exclude the
possibility that a caspase-independent cell death program
occurs in concert with a caspase-dependent program.61 The
knowledge of the genetic program underlying the onset of
the disease might help the researcher to use the appropriate
genetic therapy by inhibiting one pathway or another. In
such cases, it is important to understand whether a program of death is controlled by caspase activation. The
inhibition of the caspase cascade to control apoptosis
induction in some degenerative diseases can delay (but
not prevent) the progression of the disease if some other
caspase-independent program of death is operating. The
occurrence of one or another of the different programs of
cell death is an important aspect to take into account. In
fact, one of the cancer therapy approaches is to kill cancer cells by apoptosis. It is also known that cancer cells
are selected for their acquired resistance to apoptosis. It is,
therefore, important to be able to exploit other genetic programs to complement or integrate apoptosis and perhaps
open new frontiers for tumor therapy.
Despite the numerous models proposed to categorize
PCD, it is difficult to give one single definition, and probably also incorrect, due to the overlap and shared signaling
pathways of the different death programs. It has, therefore, been postulated that the dominant cell death phenotype triggered by cytotoxic agents is determined by the
most readily available death program.62 Besides caspases,
a broad spectrum of proteases can carry out PCD, with
the participation of different cellular organelles, including
mitochondria, lysosomes, or ER, which can act independently or actively collaborate with each other. The multicellular organism can take advantage of the existence of
multiple death pathways because they offer protection, for
example, against the development of malignant diseases.
Many difficulties and obstacles have to be overcome before
a cell becomes a tumor cell, and this in part explains the
rarity of cancer, considering the number of cell divisions
and mutations that occur during human life. The control
of PCD may ultimately offer a new perspective in cancer
immunotherapy, but also in the treatment of autoimmune
diseases and neurodegenerative disorders.
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CHAPTER 2
Clean and Aseptic Technique
at the Bedside
Sapna Amin
Aron J. Gewirtzman
Stephen Tyring
CUTANEOUS SURGICAL INTERVENTIONS are
becoming more and more popular as this area of dermatology continues to rapidly expand. Dermatologists are performing progressively more surgical procedures in their
private offices.1 A survey performed by the American Society of Dermatologic Surgery (ASDS) in 2003 revealed
that 3.9 million procedures were performed that year by
participating ASDS members.2 These outpatient procedures allow the dermatologist to provide more comprehensive care to the patient and present the patient with
a more affordable option, because outpatient procedures
under local anesthesia are less expensive than in the hospital
setting.1,3
With the upsurge in the number of cutaneous surgeries,
an important goal remains to keep patients free of nosocomial and surgical site infections (SSIs). Traditionally, dermatologic procedures and surgeries have benefited from
relatively low infection rates,2,4 despite varying infectioncontrol practices.1 Strict adherence to aseptic technique is
required to maintain this low rate of infectious complications. In addition to the principles of asepsis, the surgeon
must also minimize patient and environmental risk factors,
achieve adequate preoperative preparation, decide if antibiotic prophylaxis is necessary, as well as maintain proper
surgical suite protocol and surgical technique.
SURGICAL SITE INFECTIONS
Postoperative infections after dermatologic procedures are
rare. These surgeries are largely considered either “clean”
or “clean-contaminated,” with infection rates of less than
5%5 and 5%–10%, respectively.2 Studies examining the
rate of infectious complications following dermatologic
procedures have indicated an even lower incidence in this
field. Two studies reported infectious complication rates of
2% following outpatient dermatologic procedures,6,7 and
another study describing the complications following Mohs
Micrographic Surgery showed an infection rate of 1.6%.8
Complication rates have been shown to be higher in
dermatology inpatients. A recent study examining the complication rate of diagnostic skin biopsies performed on inpatients found that 29% of patients developed postoperative complications, with 93% of these complications being
wound infections.9 This increased rate may be attributable
to differences in the patient population. Dermatology inpatients are more likely to be widely colonized with Staphylococcus aureus, to have extensive skin disease, and/or to be
systemically unwell.9,10
Clinically, SSIs are recognized by the extrusion of pus
from a wound that may also exhibit some of the cardinal signs of inflammation in the surrounding skin: redness, heat or warmth, swelling, and pain. Patients may
also display systemic signs of infection, such as fever or
chills. Laboratory confirmation is also necessary to make
the diagnosis. Bacterial cultures taken from the site should
demonstrate a concentration of at least 100,000 colonyforming units per square centimeter. Treatment of infected
wounds requires effectively reducing the bacterial concentration, and debridement is the most important method of
achieving this. Other techniques include the use of topical antibacterials, frequent dressing changes, and biologic
dressings.
The most common cause of wound infections is the
patient’s endogenous skin flora,11,12 with the absolute most
common pathogen being S. aureus.11,13 These microorganisms tend to colonize the uppermost layers of the skin and
hair follicles; approximately 10%–20% of bacteria penetrate deeper into the hair follicles, however, where they
can escape routine disinfection methods. Despite sterilization and disinfection procedures, the skin remains contaminated because these elusive organisms are a viable source
of recolonization after the removal of superficial bacteria.14
page 12
Chapter 2
Researchers have suggested that the rate of SSIs might be
decreased further by decreasing the number of skin flora.11
PATIENT RISK FACTORS
Many factors contribute to the likelihood of a patient contracting a surgical wound infection. Patient-specific characteristics often cannot be eliminated or modified and must
be dealt with on an individual basis. The most common
patient-specific risk factors encountered are specific medical conditions that decrease the immune status of the individual.15–17 Diabetes mellitus, for example, has been shown
to increase the risk of infection and to have a negative
effect on wound healing. Smoking also has been shown
to have similar harmful effects, perhaps from the nicotineinduced vasoconstriction, reducing blood flow to the skin.
In a study examining risk factors for SSIs, diabetes, obesity,
and smoking all were found to be independent risk factors.
Patients should be encouraged to abstain from smoking
in the perioperative period as this will decrease the risk of
SSI and tissue necrosis.13,18,19 Other risk factors include an
immunocompromised state secondary to a variety of causes
(e.g., human immunodeficiency virus/acquired immune
deficiency syndrome [HIV/AIDS], corticosteroids, malignancy, advanced age) and concomitant infections, such as
urinary tract infections, which must be treated before the
surgical procedure is performed. Patients with concurrent
infections have a markedly increased risk for developing
SSIs, even if the infection is distantly located from the
wound.15–17 Location of surgery also contributes to the
risk of SSI development. Due to vascular factors, the lower
extremities pose the highest risk18,20 whereas the wellvascularized face presents the lowest risk of infection.18
ENVIRONMENTAL RISK FACTORS
Factors extrinsic to the patient also contribute to the development of SSIs. These environmental risk factors can often
be modified and/or eliminated to decrease the patient’s risk
of acquiring infection.
DECONTAMINATION OF SURGICAL EQUIPMENT
Surgical procedures involve the use of instruments that
may come into contact with patient skin, mucous membranes, and/or sterile body cavities. Viable microorganisms
and spores must be removed from reusable surgical equipment after each use to decrease the risk of infection and
prevent cross-contamination between patients. Microbial
decontamination may be achieved by cleaning, disinfection, and/or sterilization.21–23
Cleaning
Cleaning removes viable microorganisms and the organic
matter in which they survive from the surfaces of medical
●
Clean and Aseptic Technique at the Bedside
13
equipment. Although cleaning does not kill these bacteria, spores, or viruses, it remains an essential part of the
decontamination process as the removal of these surface
organisms facilitates disinfection and sterilization of equipment. Organic matter may interfere with adequate decontamination by inactivating disinfectants and sterilants and
preventing direct contact with microbial cells. Cleaning is
most effective when performed as soon as possible after
equipment use. Cleaning should only be performed as the
sole method of decontamination on noncritical items – that
is, items that come into contact only with normal and intact
patient skin. In general, automated cleaning methods, such
as washer disinfectors and ultrasonic cleaners, are superior
and preferable to manual methods (paper towels, wet wipes,
etc.) as these methods produce standardized results.21–24
Disinfection
Disinfection refers to the chemical destruction of the
majority of viable microorganisms residing on a given surface. Although some spores may also be targeted, disinfection alone does not reliably kill or inactivate all spores and
viruses. In situations where sterilization by steam under
pressure (autoclaving) is inappropriate or could damage
medical equipment, the disinfection process may be utilized to decontaminate semicritical and critical items that
have been exposed to nonintact patient skin, mucous membranes, or sterile body cavities. Disinfectants may be compromised by some organic matter, highlighting the importance of proper cleaning prior to disinfection. Disinfection
may be achieved by either chemical or physical processes,
with the latter being preferred as they are more amenable
to monitoring and standardization.21–24
Sterilization
Sterilization refers to the complete destruction or elimination of all transmissible organisms from a surface, including
bacteria, spores, viruses, and fungi. Given its thoroughness, this process is appropriate for critical equipment and
instruments. Many different types of sterilization exist;
the most commonly used methods for surgical equipment include autoclaving, dry heat, ethylene oxide, and
irradiation.21,22,24
PREOPERATIVE SKIN ANTISEPSIS
Alcohol
Alcohol is one of the oldest and most effective antiseptics
available. It is abundant, rapid acting, and inexpensive. It is
appropriate for use in minor, clean procedures, and has germicidal properties against most bacteria, fungi, and viruses.
Some bacterial spores may show resistance. Its use is often
limited, however, by its flammability and potential for skin
irritation.16,17
14 E MERGENCY D ERMATOLOGY
Iodinated Preparations
Betadine and other iodophors have broad-spectrum antimicrobial activity. These compounds are rapid acting and
are bactericidal within minutes; however, iodinated compounds are effective only when dry, and they lose their
bactericidal effect when removed from the skin. They also
leave a yellowish discoloration on the skin, are irritating,
and are inactivated by contact with blood and other serum
proteins. Although iodophors are relatively safe, when used
chronically in pregnant women, associated hypothyroidism
has been reported in neonates.16,17,25
Chlorhexidine
Chlorhexidine gluconate (CHG) is active against a wide
range of gram-positive and -negative bacteria, viruses, and
yeast. It is rapid acting, does not stain the skin, and is
not inactivated by contact with blood or other serum proteins. An additional benefit of CHG is that it demonstrates
prolonged antimicrobial activity by binding to the stratum corneum of the skin, allowing for efficacy even after
removal. In comparison with the iodophors, CHG has been
shown to lead to a greater reduction in bacterial counts and
demonstrates a cumulative effect after repeated exposure.
Cases of keratitis and ototoxity have been reported after
prolonged, direct contact with patients’ eyes and tympanic
membranes. The majority of these instances occurred in
patients exposed to CHG while under general anesthesia, who were unable to respond to the antiseptic-induced
irritation.16,17,26–28
Preparation of the Skin
Before prepping the skin with antiseptic, all visible dirt and
organic matter should first be removed. Antiseptic should
then be applied to the area where the skin incision will
be made, extending outward in concentric circles. A large
enough area should be prepped so that the incision can
be extended or new incisions/drain sites can be made if
necessary.16,17
Hair Removal. Hair that may contaminate the operative
site should be removed with scissors or by clipping prior to
the procedure. Shaving of the area should not be performed
within 24 hours of the surgical procedure as open skin,
cuts, and scratches increase the risk of infection. If shaving
is necessary to remove the hair, the skin should first be
scrubbed with an antiseptic and then shaved immediately
prior to the procedure. Adhesive tape can then be used to
remove excess pieces of hair.16,17
Hand Washing. The majority of hospital-acquired infections are thought to be transmitted via the hands of health
care workers. As many as 10,000 colony-forming units
can be transmitted by brief hand contact alone!29 Studies
have found hand washing to be the most effective method
of reducing hospital-acquired infections.30 These results
assume satisfactory hand-washing methods are undertaken;
past studies have shown that adequate washing is hardly
achieved and that approximately 89% of staff do not cleanse
the entire hand surface.15,31 Hands should be washed before
and after each patient contact.32 Three varieties of handwashing agents are currently available.
Plain Soaps
Plain soaps derive their cleaning activity from their detergent bases. Soap and water are most effective in removing dirt, soil, and some organic substances. Although
soaps have no inherent antimicrobial activity and cannot remove resident microorganisms, they can eliminate
transient microorganisms from the hands;21,32,33 however,
hand washing with soap can also cause an increase in the
total number of bacteria on the hands.15,34 This paradoxical
increase has been explained by enhanced release of bacterial particles from the skin after hand washing. Soaps may
also contaminate the hands if the source has become extrinsically contaminated. Several cases of extrinsic contamination of nonmedicated liquid soaps with Serratia marcescens
have been previously documented.35,36
Antiseptic Detergents. Antiseptic detergents, like plain
soap and water, are also effective at removing dirt and soil.
These agents do have antimicrobial activity and are more
effective in removing both transient and resident microorganisms from the hands.15,21,34
Alcohol-Based Hand Rubs. Alcohol-based hand rubs are
the most effective at removing microorganisms from the
hands and reducing hand flora. These solutions have germicidal activity against a broad range of gram-positive
and -negative bacteria, including some multidrug-resistant
pathogens. Alcohols are also active against certain viruses
when tested in vitro. To be most effective, these hand rubs
should contain 60%–95% alcohol.17 Additionally, these
agents are simple and quick to use and require less effort
than traditional soaps, which may lead to increased compliance with hand washing. Alcoholic hand rubs should not be
used on visibly soiled hands as these agents are not effective at removing dirt or other physical contaminants. In
this case, hands should first be washed with soap and water
before applying the alcohol-based hand rub.16,21,34
Scrubbing. “Scrubbing” refers to the process by which
members of the surgical team who will be in contact with
the sterile field or instruments significantly decrease the
bacterial counts on the hands and forearms. Although the
majority of dermatologic surgeries are performed on an
outpatient basis, some procedures require the dermatologist to perform the traditional surgical scrub.
Chapter 2
Three types of antiseptics exist for scrubbing: aqueous
scrubs, alcohol rubs, and alcohol rubs with additional active
ingredients. Aqueous scrubs are water-based preparations
with active ingredients such as CHG and povidone–iodine.
Alcohol rubs, described earlier in this chapter, are also
approved for the purpose of scrubbing. The third class
of antiseptic is a modification of the alcohol rub with the
addition of active ingredients (usually CHG or povidone–
iodine) to impart greater antimicrobial activity.28 CHG
and povidone–iodine are the recommended antiseptics for
scrubbing in the United States.17
The quality and effectiveness of scrubbing is also affected
by factors other than the choice of antiseptic. The condition
of the skin on the hands, the scrubbing technique and duration, and the gowning and gloving technique must all be
considered. Although studies have not yet shown an optimum duration of scrubbing, it has been shown that scrubbing for 2 minutes is as effective as for 10 minutes. The
first scrub of the day should always be the most thorough,
and it is at this time that surgical team members should
thoroughly clean under their fingernails. The hands and
forearms should then be vigorously cleaned with a brush
up to the elbows and rinsed. Hands and arms should be
held up with the elbows flexed, avoiding contamination,
until dried with sterile towels immediately before dressing
in a sterile gown and gloves.17
WOUND CLASSIFICATION
Antibiotic selection to prevent wound infection first
requires a discussion of wound types. Clean wounds (class I)
refer to surgical sites without contamination that do not
involve entry into the gastrointestinal, respiratory, or urinary tracts. No inflammation is present at the wound.
Risk of infection is less than 5%. Most dermatologic surgeries fall into this category. Clean-contaminated wounds
(class II) involve controlled entry into the gastrointestinal,
respiratory, or urinary tracts without spillage or gross contamination. The risk of infection of dermatologic surgery
into a class II wound is approximately 10%. Contaminated wounds (class III) occur by various means: breaks
in sterile technique, spillage of gastrointestinal or urinary
tract contents, or traumatic accidents. This category also
includes wounds with nonpurulent discharge. The infection rate from dermatologic surgery in a class III wound is
20–30%. Finally, dirty wounds (class IV) include wounds
with purulent discharge, fecal contamination, foreign bodies, or necrotic tissue or entry into a perforated viscus. Risk
of infection is 40%.16,37
ANTIMICROBIAL SELECTION
Whether to use antibiotic prophylaxis in dermatological
surgery is a frequent topic of debate. As discussed earlier in this chapter, most dermatological procedures are
performed on class I or class II wounds and carry an
●
Clean and Aseptic Technique at the Bedside
15
inherent risk of postoperative infection of no greater than
10%. Although it is clear that antibiotic prophylaxis can
reduce this already low infection rate, antimicrobials themselves may cause problems. Use of antimicrobials can add
to the number of adverse drug events and allergic reactions, promote drug-resistant organisms, and interact with
concomitant medications, in addition to adding cost.5,16,38
Antimicrobial prophylaxis should not be used routinely for
dermatological procedures, but rather in a select group of
patients at high risk for SSI or other infectious complications.
Class I wounds do not require antimicrobial prophylaxis,
nor do most cases of class II wounds. Antimicrobials may be
beneficial for class II wounds in which oronasal or anogenital mucosae are breached or for large axillary or inguinal
wounds.16 In class III and IV wounds, antimicrobials serve
a therapeutic rather than prophylactic purpose, and should
be used routinely.
Besides reducing SSIs, another reason dermatologists
often use antimicrobial prophylaxis is for the prevention of
infection at a distant site such as a heart valve or prosthetic joint.16,39 Endocarditis or seeding of a prosthetic
joint theoretically can be caused by bacteremia induced
during skin surgery. The incidence of bacteremia during
skin surgery has been found to be only 0.7%,40 which
compares favorably to the 0%–2.1% incidence of bacteremia in random blood cultures of healthy volunteers.41
The routine use of antimicrobial prophylaxis during dermatological procedures in otherwise healthy individuals
for prevention of endocarditis or joint infection seems
unwarranted. In fact, no randomized clinical trial to date
has established that antimicrobial prophylaxis prevents
endocarditis.42
Should the decision to use antimicrobials be made, the
next most important step is to use them optimally. Effective
prophylaxis provides a high blood and tissue level of antimicrobial at the time of anticipated bacteremia.39 Antimicrobials given at the conclusion of a procedure are not as effective in preventing infection, and after the wound is closed
there is generally no longer any risk of contamination.16 A
large loading dose of the appropriate antimicrobial should
be given approximately 1 hour before surgery.
The route of antimicrobial prophylaxis is generally
thought of as either oral or intravenous. Intraincisional
antimicrobial prophylaxis injected along with buffered lidocaine and epinephrine has also shown to reduce wound
infection. Benefits of intraincisional antimicrobial prophylaxis include immediate delivery to the site where it is
needed, ease of use (in the same syringe as anesthetic),
enhanced compliance, and relatively low cost.43 Additionally, because the dose of intraincisional antimicrobials
is low compared with the amount necessary in oral or
intravenous prophylaxis and is applied locally, the risk of
systemic side effects and bacterial resistance is theoretically lower. Intraincisional antimicrobials are not widely
16 E MERGENCY D ERMATOLOGY
used currently, but their potential benefits warrant further
investigation. In the future, they may become more common as an alternative to traditional prophylaxis.
For class III and IV wounds, in which antimicrobial
use is recommended routinely, the choice of antimicrobials should be based on the presumed organism causing
the infection. If a wound culture with sensitivities is available prior to a procedure, this should obviously be taken
into account prior to antimicrobial selection. In absence
of wound culture results, first-generation cephalosporins
are a good choice because of their excellent coverage
of staphylococcal organisms (the most common cause of
wound infection) as well as common gram-negatives such
as Escherichia coli and some Proteus species.5 Penicillins,
especially beta-lactamase–resistant variants are also good
choices. Many patients have penicillin sensitivity, and due
to cross-reactivity with cephalosporins, both of these firstline choices would be inappropriate for these patients. In
these cases, macrolides (e.g., erythromycin) or quinolones
(e.g., ciprofloxacin) can be used. Current American Heart
Association guidelines recommend amoxicillin as the first
choice for standard prophylaxis (or ampicillin for patients
unable to take oral medications), with clindamycin as an
alternative for patients with penicillin allergy.42
CONCLUSIONS
With the number of dermatological procedures being performed increasing each year, ensuring a minimal amount of
nosocomial and SSIs is important, while understanding the
inherent risk factors of a procedure and that using proper
aseptic technique can help prevent such complications. Surgical equipment decontamination, preoperative skin asepsis, and proper hand washing are all techniques that can
keep infections to a minimum. Antimicrobial prophylaxis
is generally unnecessary for dermatological procedures, as
the risk of adverse events due to the antimicrobials often
outweighs the benefit of further reducing an already low
incidence of infection.
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of cutaneous malignant melanoma by dermatologists of the
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5. Babcock MD, Grekin RC. Antibiotic use in dermatologic
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10. Helbling I, Muston HL, Ferguson JE, McKenna M. Audit of
admissions to dermatology beds in Greater Manchester. Clin
Exp Dermatol. 2002;27:519–22.
11. Cantlon CA, Stemper ME, Schwan WR, Hoffman MA,
Qutaishat SS. Significant pathogens isolated from surgical site
infections at a community hospital in the Midwest. Am J Infect
Control. 2006;34:526–9.
12. Finn L, Crook S. Minor surgery in general practice–setting
the standards. J Public Health Med. 1998;20:169–74.
13. Maragh SL, Otley CC, Roenigk RK, Phillips PK. Antibiotic prophylaxis in dermatologic surgery: updated guidelines.
Dermatol Surg. 2005;31:83–91.
14. Davis CP. Normal flora. In: Baron S, editor. Medical microbiology. 4th ed. Galveston,TX: The University of Texas Medical Branch at Galveston; 1996.
15. Aseptic technique. In: Dougherty L, Lister S, editors. The
Royal Marsden Hospital manual of clinical nursing procedures. 6th ed. Oxford: Blackwell. 2004. 50–63.
16. Hurst EA, Grekin RC, Yu SS, Neuhaus IM. Infectious complications and antibiotic use in dermatologic surgery. Semin
Cutan Med Surg. 2007;26:47–53.
17. Mangram AJ, Horan TC, Pearson ML, et al., The Healthcare
Infection Control Practices Advisory Committee. Guidelines
for prevention of surgical site infection, 1999. Atlanta, GA:
Centers for Disease Control and Prevention.
18. Dixon AJ, Dixon MP, Askew DA, Wilkinson D. Prospective study of wound infections in dermatologic surgery in
the absence of prophylactic antimicrobials. Dermatol Surg.
2006;32:819–26; discussion 826–7.
19. Olsen MA, Lock-Buckley P, Hopkins D, et al. The risk factors for deep and superficial chest surgical-site infections after
coronary artery bypass graft surgery are different. J Thorac
Cardiovasc Surg. 2002;124:136–45.
20. Garland R, Frizelle FA, Dobbs BR, Singh H. A retrospective audit of long-term lower limb complications following
leg vein harvesting for coronary artery bypass grafting. Eur J
Cardiothorac Surg. 2003;23:950–5.
21. Hart S. Using an aseptic technique to reduce the risk of infection. Nurs Stand. 2007;21:43–8.
22. NHS Estates. Guide to decontamination of reusable surgical instruments. London: Department of Health; 2003,
39 pp.
23. Rutala WA, Weber DJ. Disinfection and sterilization in
health care facilities: what clinicians need to know. Clin Infect
Dis. 2004;39:702–9.
24. Spencer RC, Perry C. Decontamination of reusable surgical
instruments. Hosp Med. 2001;62:662–3.
Chapter 2
25. Danziger L, Hassan E. Antimicrobial prophylaxis of gastrointestinal surgical procedures and treatment of intraabdominal
infections. Drug Intell Clin Pharm. 1987;21:406–16.
26. Perez R, Freeman S, Sohmer H, Sichel JY. Vestibular and
cochlear ototoxicity of topical antiseptics assessed by evoked
potentials. Laryngoscope. 2000;110:1522–7.
27. Murthy S, Hawksworth NR, Cree I. Progressive ulcerative
keratitis related to the use of topical chlorhexidine gluconate
(0.02%). Cornea. 2002;21:237–9.
28. Tanner J, Swarbrook S, Stuart J. Surgical hand antisepsis to
reduce surgical site infection. Cochrane Database Syst Rev.
2008; CD004288.
29. Gould D, Ream E. Assessing nurses’ hand decontamination
performance. Nurs Times. 1993;89:47–50.
30. Gould DJ, Chudleigh J, Drey NS, Moralejo D. Measuring handwashing performance in health service audits and
research studies. J Hosp Infect. 2007;66:109–15.
31. Taylor LJ. An evaluation of handwashing techniques-1. Nurs
Times. 1978;74:54–5.
32. Boyce JM, Pittet D. Guideline for hand hygiene in healthcare settings. Recommendations of the Healthcare Infection
Control Practices Advisory Committee and the HICPAC/
SHEA/APIC/IDSA Hand Hygiene Task Force. Society for
Healthcare Epidemiology of America (Association for Professionals in Infection Control/Infectious Diseases Society of
America. MMWR Recomm Rep. 2002;51:1–45, quiz CE41–
44.
33. Grinbaum RS, de Mendonca JS, Cardo DM. An outbreak
of handscrubbing-related surgical site infections in vascular surgical procedures. Infect Control Hosp Epidemiol.
1995;16:198–202.
34. Winnefeld M, Richard MA, Drancourt M, Grob JJ. Skin
tolerance and effectiveness of two hand decontamination
35.
36.
37.
38.
39.
40.
41.
42.
43.
●
Clean and Aseptic Technique at the Bedside
17
procedures in everyday hospital use. Br J Dermatol.
2000;143:546–50.
Sartor C, Jacomo V, Duvivier C, et al. Nosocomial Serratia marcescens infections associated with extrinsic contamination of a liquid nonmedicated soap. Infect Control Hosp
Epidemiol. 2000;21:196–9.
Archibald LK, Corl A, Shah B, et al. Serratia marcescens
outbreak associated with extrinsic contamination of 1%
chlorxylenol soap. Infect Control Hosp Epidemiol. 1997;
18:704–9.
Bell RM. Surgical procedures, techniques, and skills. In:
Lawrence PF, Beel, RM. Dayton, MT editors. Essentials of
general surgery. 3rd ed. Philadelphia: Lippincott Williams &
Williams: 1999. 519–62.
Lamberg L. Dermatologists debate sentinel node biopsy,
safety of liposuction, and antibiotic prophylaxis. JAMA.
2000;283:2223–4.
George PM. Dermatologists and antibiotic prophylaxis: a survey. J Am Acad Dermatol. 1995;33:418–21.
Carmichael AJ, Flanagan PG, Holt PJ, Duerden BI. The
occurrence of bacteraemia with skin surgery. Br J Dermatol.
1996;134:120–2.
Wilson RW, Van Scoy RE, Washington JA. Incidence of
bacteremia in adults without infection. J Clin Microbiol.
1975;2:94–5.
Scheinfeld N, Struach S, Ross B. Antibiotic prophylaxis
guideline awareness and antibiotic prophylaxis use among
New York State dermatologic surgeons. Dermatol Surg.
2002;28:841–4.
Huether MJ, Griego RD, Brodland DG, Zitelli JA.
Clindamycin for intraincisional antibiotic prophylaxis in
dermatologic surgery. Arch Dermatol. 2002;138:1145–
8.
CHAPTER 3
New Antimicrobials
Maryann Mikhail
Jeffrey M. Weinberg
WITH THE continuing development of clinical drug
resistance among bacteria and the advent of resistance to
the more recently released agents quinupristin/dalfopristin
and linezolid, the need for new, effective agents to treat
multidrug-resistant gram-positive infections remains important. With treatment options limited, it has become
critical to identify antibiotics with novel mechanisms of
activity. Several new drugs have emerged as possible
therapeutic alternatives. This chapter focuses on agents
newly introduced and those currently in clinical development for the treatment of skin and skin structure
infections. In addition, novel antifungal agents will be
reviewed, as will novel dosing of antiviral agents for herpes
labialis.
dalfopristin, daptomycin, oritavancin and dalbavancin, the
quinolones (moxifloxacin and gatifloxacin), and tigecycline
(Table 3.1).
LINEZOLID
Linezolid (Figure 3.1) is an oxazolidinone antibiotic
shown to be effective for nosocomial and communityacquired pneumonias, vancomycin-resistant Enterococcus
faecium (VREF) infections, and skin infections caused by
certain staphylococcus or streptococcus species.2 The oxazolidinones are a novel class of antibiotics first discovered
in 1987.3
Mode of Action
NOVEL ANTIBACTERIAL AGENTS
There has been an alarming increase in the incidence of gram-positive infections, including resistant bacteria such as methicillin-resistant Staphylococcus aureus
(MRSA) and drug-resistant pneumococci. Although vancomycin has been considered the drug of last defense
against gram-positive multidrug-resistant bacteria, strains
of vancomycin-resistant bacteria, including vancomycinresistant enterococci (VRE), began to emerge by the late
1980s. More recently, strains of vancomycin-intermediateresistant S. aureus (VISA) have been isolated.1
Gram-positive bacteria, such as S. aureus and Streptococcus pyogenes, are often the cause of both uncomplicated
and complicated skin and skin structure infections. Uncomplicated infections are mild, localized to the skin, and
responsive to topical or systemic antibiotics. This category
includes simple abscesses, impetiginized lesions, furuncles,
and cellulitis. Complicated infections are those involving
deeper soft tissues and requiring surgical intervention or
associated with significant systemic disease or comorbidities. Corresponding clinical entities include surgical wound
infections, infected ulcers or burns, severe carbunculosis,
erysipelas, and necrotizing fasciitis.
Several novel agents have emerged as possible therapeutic alternatives. These include linezolid, quinupristin/
Cellular Mechanism. Oxazolidinones, and specifically
linezolid, are theorized to act by inhibiting the initiation
phase of translation and thus interfering with bacterial protein synthesis.4 It is thought that linezolid binds to the 23S
portion of the 50S ribosomal subunit, preventing initiation
complex formation. This early inhibition of protein synthesis is a unique mechanism and limits cross-resistance with
other antimicrobial agents, because there is no preexisting
resistance mechanism in nature.4
Pharmacokinetics. Oral bioavailability of the antibiotic in
a normal host is 100%. The drug can be administered
with or without meals. Food may slightly decrease the
rate of absorption but has no effect on the amount of the
drug absorbed. Linezolid shows a protein binding of only
31% and a half-life of 5–7 hours. At a dosing schedule of
600 mg administered orally every 12 hours, the average
steady-state plasma concentrations exceed the minimum
inhibitory concentration required to inhibit the growth of
90% of organisms (MIC90) for staphylococci, streptococci,
and enterococci. It is primarily metabolized by oxidation of
the morpholine ring, which produces two inactive metabolites. Its metabolism is unaffected by the cytochrome P450
enzyme system. Kinetics are similar in patients with mild
to moderate renal or hepatic compromise. In patients older
page 18
Chapter 3
●
New Antimicrobials
19
TABLE 3.1: Novel Antibacterial Agents for Skin and Skin Structure Infections
Generic
name
Brand
name
Linezolid
R
Zyvox
Quinupristin/
Dalfopristin
R
Synercid
Mechanism of action
Dosage
Skin infection
usage
Binds to 23S portion of the 50S ribosomal
subunit and prevents initiation complex
formation
400–600 mg PO/IV
q12h for 10–14 d
Uncomplicated/
Complicated
Binds to different sites on the 50S subunit
and inhibits protein synthesis
7.5 mg/kg IV q12h
for at least 7 d
Complicated
Disrupts bacteria plasma membrane
function
4 mg/kg IV q24h for
10–14 d
Complicated
Daptomycin
R
Cubicin
Oritavancin
———
Inhibits biosynthesis of cell wall
peptidoglycan
1.5–3.0 mg/kg IV qD
for 3–7 d
Complicated
Dalbavancin
———
Inhibits biosynthesis of cell wall
peptidoglycan
500–1000 mg IV qwk
Complicated
Moxifloxacin
R
Avelox
Inhibits DNA gyrase and topoisomerase IV
400 mg PO/IV qD for
7d
Uncomplicated
Gatifloxacin
R
Tequin
Inhibits DNA gyrase and topoisomerase IV
400 mg PO/IV qD for
7–10 d
Uncomplicated
Tigecycline
R
Tygacil
Inhibits protein synthesis by blocking the
30S ribosomal subunit
Initial: 100 mg, then
50 mg BID IV over
30–60 min for 5–14 d
Complicated
Retapamulin
R
Altabax
Inhibits bacterial protein synthesis by
interacting with the 50S ribosomal subunit
Topical application
BID for 5 d
Uncomplicated
(impetigo)
PO, per os (orally); IV, intravenous; DNA, deoxyribonucleic acid; BID, twice daily.
than 5 years, a dose of 10 mg/kg every 12 hours displays
similar pharmacokinetic properties.2
In Vitro Activity. In vitro studies have shown linezolid to
be effective against many antibiotic-resistant gram-positive
organisms, including MRSA, penicillin-resistant Streptococcus pneumoniae, and VRE.5–9 Linezolid is bacteriostatic
against most susceptible organisms, but has shown bactericidal activity against Clostridium perfringens, Bacteroides fragilis, and some strains of S. pneumoniae.10 In addition to its
coverage of antibiotic-resistant gram-positive organisms,
it has some broad-spectrum activity against gram-positive
cocci, gram-negative anaerobes, and some mycobacteria. It
has also shown moderate in vitro inhibitory activity against
Haemophilus influenzae and Moraxella catarrhalis, although
it was not effective against Enterobacteriaceae and Pseudomonas aeruginosa.
O
N
O
F
N
O
O
C
N
H
FIGURE 3.1: Linezolid.
CH3
Clinical Indications
Currently, linezolid is U.S. Food and Drug Administration
(FDA) approved for the treatment of various gram-positive
infections, including both hospital- and communityacquired pneumonias, complicated and uncomplicated skin
and skin structure infections, and VRE infections. Studies
have been conducted comparing (head to head) linezolid
and standard antibiotic therapies in the treatment of skin
and soft-tissue infections (SSTIs). In terms of efficacy, a
double-blind, randomized study in 332 adult patients with
uncomplicated skin infections (cellulitis, skin abscesses, and
furuncles) secondary to staphylococcus and streptococcus
compared linezolid 400 mg twice daily with clarithromycin
250 mg twice daily for a course of 7–14 days. Following treatment, 91% of the linezolid-treated patients had
a clinical cure, compared with 93% in the clarithromycin
group, demonstrating that linezolid is as effective as clarithromycin.11
Another randomized, double-blind, multicenter trial
compared the efficacy and safety of linezolid, an oxazolidinone, with those of oxacillin–dicloxacillin in patients with
complicated SSTIs (cSSTIs).12 A total of 826 hospitalized
adult patients were randomized to receive linezolid (600 mg
intravenously [IV]) every 12 hours or oxacillin (2 grams IV)
every 6 hours. Following sufficient clinical improvement,
patients were switched to the respective oral agents, linezolid 600 mg orally every 12 hours or dicloxacillin 500 mg
orally every 6 hours. Primary efficacy variables were clinical
20 E MERGENCY D ERMATOLOGY
cure rates in both the intent-to-treat (ITT) population
as well as clinically evaluable (CE) patients and microbiological success rate in microbiologically evaluable (ME)
patients. Safety and tolerability were evaluated in the
ITT population. Demographics and baseline characteristics were similar across treatment groups in the 819 ITT
patients. In the ITT population, the clinical cure rates
were 69.8% and 64.9% in the linezolid and oxacillin–
dicloxacillin groups, respectively (95% confidence interval [CI], –1.58 to 11. 25; p = .141). In 298 CE linezolidtreated patients, the clinical cure rate was 88.6%, compared with a cure rate of 85.8% in 302 CE patients
who received oxacillin–dicloxacillin. In 143 ME linezolidtreated patients, the microbiological success rate was
88.1%, compared with a success rate of 86.1% in 151 ME
patients who received oxacillin–dicloxacillin. Both agents
were well tolerated; most adverse events were of mild-tomoderate intensity. No serious drug-related adverse events
were reported in the linezolid group.12
Linezolid was also found to be as effective as vancomycin in the treatment of skin and soft-tissue MRSA
infections.13,14 In VRE infections, a clinical success rate of
81% was noted, indicating that treatment with linezolid
may be superior to comparator antibiotics in patients with
complicated skin infections who also have comorbid conditions.15 There have been reports of development of resistance to linezolid in some patients with E. faecium.16
Dosage Regimens
The recommended dosage of linezolid depends on the
severity of the skin or soft-tissue infection. Uncomplicated
infections should be treated with 400 mg every 12 hours for
10–14 days. For complicated infections, 600 mg twice daily
either via IV infusion or orally is recommended. No dose
adjustment is needed when switching from IV to oral therapy,4 because the absolute bioavailability after oral dosing
is nearly 100%.
Contraindications/Cautions
Linezolid is generally well tolerated, with the most common adverse effects being diarrhea (8.3%), headache
(6.5%), and nausea (6.2%).10 Because linezolid is a nonselective, reversible inhibitor of monoamine oxidase, it
may interact with serotonergic or adrenergic agents.17 Like
many other antibiotics, it may cause pseudomembranous
colitis, as a result of overgrowth of Clostridium difficile.
Approximately 2% of patients develop thrombocytopenia, which appears to be dependent on duration of therapy. The effect is reversible; however, the manufacturer
recommends monitoring patients with preexisting thrombocytopenia or those whose treatment will exceed 2
weeks. No deaths related to thrombocytopenia have been
reported.2
Conclusions
Linezolid is the first of a novel class of antibiotics called
oxazolidinones and is indicated for use both in uncomplicated and complicated skin and skin structure infections
caused by MRSA or streptococcal species.
QUINUPRISTIN/DALFOPRISTIN
Quinupristin/dalfopristin (Figure 3.2) is a combination of
two semisynthetic pristinamycin derivatives and is the first
parenteral streptogramin antibacterial agent. Both quinupristin and dalfopristin have antibacterial capability individually, but demonstrate synergistic activity when used
in combination. Much of the clinical experience with
this antibiotic is derived from five comparative trials and
an FDA-sanctioned emergency-use program for patients
without alternative therapies.
Mode of Action
Cellular Mechanism. Quinupristin and dalfopristin enter
bacterial cells by diffusion and bind to different sites on the
50S ribosomal subunit, resulting in an irreversible inhibition of bacterial protein synthesis.18 Dalfopristin blocks the
reaction catalyzed by the peptidyl transferase catalytic center of the 50S ribosome via inhibition of substrate attachment to the P-site and the A-site of the ribosome. Quinupristin inhibits peptide chain elongation. The synergistic
effect of the combination appears to result from the fact
that these compounds target early and late steps in protein
synthesis.19
Pharmacokinetics. Quinupristin/dalfopristin is rapidly
cleared from the blood and is widely distributed. It is eliminated through the bile into the feces. Its clearance may
be slightly reduced in patients with severe chronic renal
failure. Its pharmacokinetics are unaffected by age or gender. Quinupristin has a half-life of approximately 1 hour,
and dalfopristin has a half-life of approximately 30 minutes.
The postantibiotic effect of the drug is prolonged to greater
than 7.4 hours against streptococci regardless of penicillin
susceptibility.20 Quinupristin/dalfopristin inhibits the biotransformation rate of cytochrome P450 substrates in
vitro.
In Vitro Activity. Quinupristin/dalfopristin has inhibitory
activity against a broad spectrum of gram-positive bacteria
including MRSA, VREF, and drug-resistant S. pneumoniae.
It is bactericidal against methicillin-resistant staphylococci
and S. pneumoniae and bacteriostatic against most E. faecium
in vitro. Quinupristin/dalfopristin also has demonstrated
synergy with other antibiotics. Rifampin is synergistic with
quinupristin/dalfopristin against MRSA, and doxycycline
is synergistic against VREF in vitro.
Chapter 3
●
New Antimicrobials
21
N
N
H
N
O
NH
O
H
O
H
O
H
N
N
S
O
HN
H
N
O
H
H
H
O
N
O
O
H
OH
A
O
H
OH
N
H
H
O
O
O
N
H
O
N
H
O
H
S
O
O
N
B
FIGURE 3.2: Quinupristin (panel A) and dalfopristin (panel B).
Clinical Indications
FDA indications for quinupristin/dalfopristin are serious
infections associated with VREF bacteremia and complicated skin and skin structure infections caused by
methicillin-sensitive S. aureus or S. pyogenes. VREF infections are difficult to treat, and few therapeutic options
are currently available. These pathogens are resistant to
most -lactam and aminoglycoside antibiotics. Judicious
use of vancomycin is currently being advocated to reduce
the incidence of resistant organisms, but their presence
continues. In 1995, quinupristin was approved for emergency use. During this emergency-use basis in the treatment of VREF infections, in which no other treatments
were available, patients using quinupristin/dalfopristin had
a 71% success rate21 and a significantly lower mortality rate
than did patients using other agents.22 In another study,
patients with complicated skin and skin structure infections who were given quinupristin/dalfopristin had almost
identical clinical success rates (68%) when compared
to those using vancomycin, oxacillin, and/or cefazolin
22 E MERGENCY D ERMATOLOGY
(71%).23 In addition, in the treatment of patients with
gram-positive nosocomial pneumonia, it was found to be
as efficacious as vancomycin.24
increase in hepatic transaminases and bilirubin.27 Use is
contraindicated in patients with known hypersensitivity
to streptogramins, or with any drugs metabolized by the
cytochrome P450 3A4 enzyme system (some anti–human
immunodeficiency virus [HIV] agents, vinca alkaloids, benzodiazepines, immunosuppressives, corticosteroids, and
calcium channel blockers). In addition, particular care
should be taken when using medications that prolong the
QT interval (e.g., astemizole, cisapride, disopyramide, lidocaine, quinidine, and terfenadine).27 Caution is also recommended if using cyclosporin concomitantly.28 Resistance
to quinupristin/dalfopristin has been encountered infrequently among VREF, and resistance among staphylococci
is rare in the United States.29,30
Dosage Regimens
For complicated skin or skin structure infections, the recommended dose is 7.5 mg/kg IV twice daily for at least
7 days. The drug can be administered up to three times
daily for bacteremic patients. Dose adjustment to 5 mg/kg
is recommended for patients with hepatic insufficiency. No
dose adjustment is needed for elderly or renally impaired
patients.
Contraindications/Cautions
Conclusions
Approximately 63% of patients receiving quinupristin/
dalfopristin reported at least one adverse effect. Evaluation of these adverse effects is difficult because they are
often assessed in the context of severe underlying illnesses. Adverse venous events at the IV site of administration of the drug were the most common. Reports
of pain and/or inflammation during its administration
were reported in 34.9%–74.0% of patients.23,25 Atrophy, edema, hemorrhage, hypersensitivity, burning, and
thrombophlebitis were also reported. A statistically significant number of venous events occurred with quinupristin/dalfopristin compared with oxacillin, cefazolin, or
vancomycin (66.2% vs. 28.4%).21 Suggested but unproven
management options to limit these events include administration in a larger volume of fluid or via a central
line. Mild to moderate myalgias and/or arthralgias have
been reported.26 Gastrointestinal events also occurred with
4.6% of patients experiencing nausea, 2.7% experiencing
vomiting and diarrhea, and 2.5% developing a rash.27 The
most common laboratory abnormalities reported were an
O
HO2C
O
H
N
O
O
HN
NH
O
Daptomycin (Figure 3.3) is a novel lipopeptide antibiotic
derived from the fermentation of a strain of Streptomyces
roseosporus. It has demonstrated potent antimicrobial activity against a wide variety of gram-positive bacteria including MRSA and VRE. Initially developed in the early 1980s,
NH2
O
N
H
HN
HO2C
DAPTOMYCIN
CH3
O
HO
O
O
Quinupristin/dalfopristin is the first parenteral streptogramin and offers a unique alternative treatment against
multidrug-resistant gram-positive bacteria. Because of its
potency, bactericidal activity, long postantibiotic effect,
and rare resistance, it has excellent potential for treatment
of serious gram-positive infections. Its efficacy should be
weighed against possible adverse effects, tolerability, and
interactions prior to utilizing this potent antibiotic. In seriously ill patients with unresponsive infections and minimal
other potential treatment options, it should be considered
the treatment of choice.
HO2C
NH H
N
CH3 O
FIGURE 3.3: Daptomycin.
O
N
H
HN
CH3
O
N
H
HO2C
H2NOC
H
N
O
O
N
H
H
N
(CH2)3CH3
O
N
H
O
NH2
Chapter 3
daptomycin was temporarily shelved due to concerns about
skeletal muscle toxicity. At lower doses, this toxicity was
not seen, but clinical trials using daptomycin were again
halted due to treatment failures in patients with S. aureus
endocarditis. Recently, due to the need for new agents with
activity against vancomycin-resistant bacteria, this IV therapy was reevaluated and now has supportive data from phase
III clinical trials.31
Mode of Action
Cellular Mechanism. The precise mechanism of action
of daptomycin is unknown. It kills by disrupting bacteria
plasma membrane function, but does not enter the cytoplasm. Proposed mechanisms include inhibition of lipoteichoic acid synthesis32,33 and dissipation of bacterial membrane potential.34,35
Pharmacokinetics. Following once-daily dosing, it exhibits linear pharmacokinetics and minimal accumulation. It
has a half-life of approximately 8.5 hours.36 It is highly
protein bound (94%), and its in vitro activity is altered
in the presence of serum or abumin.37,38 Daptomycin
is eliminated by the kidney; therefore, dose adjustments
based on creatinine clearance are required. Because hepatic metabolism of daptomycin is limited, interactions with
other drugs metabolized by the liver are minimal.
In Vitro Activity. Daptomycin has rapid, concentrationdependent bactericidal activity against gram-positive
organisms. Using the standard definition of a 3-log reduction in viable organisms, daptomycin (and not vancomycin)
is bactericidal against both S. aureus and Enterococcus faecalis.39 In addition, in vitro studies designed to evaluate the bactericidal activity of daptomycin (compared
with vancomycin, linezolid, and quinupristin/dalfopristin)
against various gram-positive organisms found that the
bactericidal activity of daptomycin is improved when concentrations are ≥4 times the MIC.40 At these levels, daptomycin and vancomycin achieved 99.9% killing of MRSA
at 8 hours, which was greater than the killing seen with
linezolid and quinupristin/dalfopristin. It also had greater
activity against VRE at 8 hours and 24 hours when compared with linezolid and quinupristin/dalfopristin. Spontaneous acquisition of resistance is rare as long as therapeutic serum levels of daptomycin are maintained. Synergistic
interactions were noted most frequently with aminoglycosides and against enterococcal organisms.
Clinical Indications
Daptomycin was recently approved for the treatment of
complicated skin and skin structure infections caused by
gram-positive bacteria, including those caused by MRSA
and MSSA (methicillin-susceptible S. aureus). In early
●
New Antimicrobials
23
phase II trials, the clinical efficacy of daptomycin was compared with that of conventional agents such as -lactams,
semisynthetic penicillins, and vancomycin for the treatment of skin infections and bacteremia.41 In patients with
SSTIs, 2 mg/kg daily resulted in clinical cure or improvement in 29/30 patients, compared to 37/39 patients treated
with conventional therapy. Two multicenter phase III trials
have now been completed, involving a total of 1079 subjects with cSSTIs.31,41 In both studies, patients were randomized for treatment with IV daptomycin (4 mg/kg, once
daily) or standard treatment with a semisynthetic penicillin
or vancomycin. Of all the CE patients, 89% had clinical
success with daptomycin, and 88% were treated successfully with standard treatment.31 These two groups were
statistically equivalent. Of note, the group that received
daptomycin required a significantly shorter course of treatment, with 63% of patients receiving daptomycin requiring only 4–7 days of treatment and 67% of patients being
treated with standard therapy requiring 8 or more days of
treatment.31
Dosage Regimens
The recommended dosage of daptomycin is 4 mg/kg IV
every 24 hours for 7–14 days.42 Because daptomycin is eliminated primarily by the kidney, a dosage modification is
recommended for patients with creatinine clearance <30
mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The recommended dosing regimen is 4 mg/kg once every 24 hours
for patients with creatinine clearance ≥30 mL/min and
4 mg/kg once every 48 hours for patients with creatinine clearance ≥30 mL/min, including those on hemodialysis or CAPD. When possible, daptomycin should be
administered following hemodialysis on hemodialysis
days.43
Contraindications/Cautions
Daptomycin is well tolerated with an incidence and
nature of serious adverse effects comparable to those seen
with conventional therapy. The most frequently reported
adverse events were headache and constipation in approximately 4% of patients. These events were not dose related
and did not persist. Skeletal muscle has been identified
as the primary target organ of daptomycin toxicity.44
Reversible skeletal muscle toxicity occurred only at the
highest dose tested (4 mg/kg every 12 hours). Transient
muscle weakness and myalgia were noted, but resolved 1
week after discontinuing daptomycin. By monitoring creatine phosphokinase (CPK) levels, muscle toxicity can be
prevented, as CPK elevations precede muscle toxicity. No
signs of cardiac or smooth muscle toxicity were noted. In
addition, once-daily dosing has been shown to minimize
associated muscle toxicity.
24 E MERGENCY D ERMATOLOGY
H3C
H 3C
H 3C
N
CH3
H3C
H
H
N
CH3
OH
O
H
N
NH2
N
H
H3C
OH
O
OH
O
OH
O
FIGURE 3.4: Tigecycline.
of tigecycline is bound to plasma proteins. Following IV
administration, tigecycline serum concentrations initially
decline rapidly during distribution into body tissues.49 The
mean half-life of tigecycline after a single 100-mg dose was
27.1 hours; after multiple dosing of 50 mg every 12 hours,
the mean half-life was 42.4 hours.49 Approximately 59% of
the drug is eliminated by biliary and/or fecal excretion, and
33% is excreted in urine. Of the total dose, approximately
22% is excreted as unchanged tigecycline in urine.
Conclusions
Clinical Indications
As resistance to conventional antibiotics increases, daptomycin may be a useful adjunct to our antibiotic armamentarium. It possesses efficacy against resistant bacteria and
provides for a rapid and concentration-dependent kill time,
a broad spectrum of activity, and a low frequency of resistance.45
Tigecycline is indicated for cSSTIs as well as for complicated intraabdominal infections. Its efficacy as monotherapy was demonstrated to be similar to combination therapy
with vancomycin and aztreonam in two double-blind phase
III comparison studies. Patients (total = 1116) with cSSTIs
received tigecycline (100 mg, followed by 50 mg IV twice
daily) or vancomycin (1 g IV twice daily) plus aztreonam (2 g
IV twice daily) for up to 14 days. Clinical responses to tigecycline and vancomycin–aztreonam at test-of-cure were
similar: 79.7% (95% CI, 76.1% to 83.1%) versus 81.9%
(95% CI, 78.3% to 85.1%; p = .4183). Adverse events were
similar, with increased nausea and vomiting in the tigecycline group and increased rash and elevated hepatic aminotransferase levels in the vancomycin–aztreonam group.50
TIGECYCLINE
Tigecycline (Figure 3.4) belongs to a novel class of antibiotics called the glycylglycines. It was approved by the FDA
in June 200546 for the treatment of adults 18 years old
or older with complicated skin or skin structure infections caused by Escherichia coli, E. faecalis (vancomycinsusceptible isolates only), S. aureus (methicillin-susceptible
and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus group, S. pyogenes, and B. fragilis. It is also
approved for the treatment of complicated intraabdominal
infections caused by a variety of species.
Mode of Action
Cellular Mechanisms. Glycylcyclines are semisynthetic
derivatives of tetracycline antibiotics in which a glycylamido moiety is attached at the 9 position of the D-ring
of the base molecule. This modification maintains the
antibacterial effect but provides stability against mechanisms of tetracycline resistance.47,48 Like the tetracyclines,
tigecycline is bacteriostatic and inhibits bacterial protein
translation by binding to the 30S ribosomal subunit and
blocking entry of amino-acyl transfer RNA molecules into
the A site of the ribosome.49
In Vitro Activity. Tigecycline shows broad spectrum in
vitro activity against gram-positive pathogens (including
MRSA, methicillin-resistant Staphylococcus epidermidis, and
VRE), gram-negative organisms (such as acinetobacter),
anaerobes, and rapidly growing mycobacteria.49 It is not
active against Pseudomonas strains.
Pharmacokinetics. In healthy subjects given IV tigecycline, peak concentration is linearly proportional to doses
over the range of 12.5–300 mg. Approximately 71%–89%
Dosage Regimens
The recommended regimen is an initial dose of 100 mg,
followed by 50 mg every 12 hours. IV infusions should be
administered over approximately 30–60 minutes every 12
hours. The recommended duration of treatment for cSSTIs
or for complicated intraabdominal infections is 5–14 days.
No dose adjustment is warranted in patients with mild-tomoderate hepatic impairment. In patients with severe liver
disease, the initial dose of tigecycline should be 100 mg,
followed by 25 mg every 12 hours. No dosage adjustment
is necessary in patients with renal disease or in patients on
hemodialysis. The safety and efficacy of tigecycline has not
been tested in patients younger than 18 years.49
Contraindications/Cautions
In phase III clinical studies with 1415 patients, the most
commonly reported adverse events were nausea (29.5%)
and vomiting (19.7%). Nausea and vomiting generally
occurred within the first 2 days of treatment. Only 1.3% of
patients discontinued therapy due to nausea and 1.0% due
to vomiting.49
Laboratory abnormalities reported during tigecycline
treatment included increased prothrombin time and partial thromboplastin time, without significant bleeding
episodes, increased blood urea nitrogen without concomitant nephrotoxicity or increase in creatinine, and
Chapter 3
hyperbilirubinemia. Although in phase III clinical studies, infection-related serious adverse events were more
frequently reported for subjects treated with tigecycline
(6.7%) versus comparators (4.6%), the relationship of this
outcome to treatment cannot be established due to differences between treatment groups at baseline.
Glycylglycines are structurally similar to tetracyclines
and, therefore, may have similar adverse events such as
photosensitivity, pseudotumor cerebri, and pancreatitis.
Patients with a history of tetracycline hypersensitivity
should be closely monitored if treated with tigecycline.
Tigecycline may cause fetal harm if administered to pregnant women and may cause permanent tooth discoloration
during development. It should not be administered simultaneously with amphotericin B or diltiazem. Coagulation
studies should be monitored in patients on warfarin and
tigecycline.49
Conclusions
Tigecycline monotherapy is as effective as combination
therapy with vancomycin and aztreonam in the treatment
of cSSTIs. This new agent thus holds promise as an alternative to the -lactams and fluoroquinolones for the initial
empiric treatment of serious dermatologic infections.51
RETAPAMULIN
Retapamulin (Figure 3.5) is an antibiotic ointment
approved in April 2007 for the treatment of impetigo due
to MSSA and S. pyogenes. It is a semisynthetic derivative
of the compound pleuromutilin, which is isolated through
fermentation from the fungus, Clitopilus passeckerianus.52
Mode of Action
Cellular Mechanisms. Retapamulin selectively inhibits
bacterial protein synthesis by interacting with the ribosomal 50S subunit L3 protein to inhibit peptidyl transfer,
block P-site interactions, and prevent the normal formation of active 50S ribosomal subunits.53
OH
N
O
H
S
O
O
FIGURE 3.5: Retapamulin.
●
New Antimicrobials
25
In Vitro Activity. Retapamulin is bacteriostatic against S.
aureus and S. pyogenes at the retapamulin in vitro MIC
for these organisms. At concentrations 1000× the in vitro
MIC, retapamulin is bactericidal against these same organisms. Retapamulin demonstrates no in vitro target-specific
cross-resistance with other classes of antibiotics. Two
mechanisms that cause reduced susceptibility to retapamulin identified in vitro are mutations in ribosomal protein
L3 or the presence of an efflux mechanism. Decreased susceptibility of S. aureus to retapamulin (highest retapamulin
MIC was 2 mcg/mL) develops slowly in vitro via multistep mutations in L3 after serial passage in subinhibitory
concentrations.53
Pharmacokinetics. Systemic exposure following topical
application of retapamulin through intact and abraded skin
was low. In a study of healthy adults, applying retapamulin
ointment, 1%, once daily to intact skin (800 cm2 ) and
abraded skin (200 cm2 ) under occlusion for up to 7 days,
provided a median maximum concentration plasma value
at day 7 of 3.5 ng/mL (range, 1.2–7.8 ng/mL) from intact
skin and 9.0 ng/mL (range, 6.7–12.8 ng/mL) from abraded
skin. Retapamulin is 94% bound to human plasma proteins regardless of concentration. Metabolism takes place
mainly in the liver, and the major enzyme responsible for
this is cytochrome P450 3A4. The apparent volume of distribution and retapamulin elimination in humans has not
been investigated due to low systemic exposure after topical
application.54
Clinical Indications
Retapamulin ointment is indicated for use in adults and
pediatric patients 9 months old or older for the topical treatment of impetigo (up to 100 cm2 in total area in adults or
2% total body surface area in pediatric patients 9 months
old or older) due to MSSA or S. pyogenes.52
Retapamulin ointment has been studied in a multicenter,
randomized, double-blind, placebo-controlled parallelgroup study of adult and pediatric (9 months old or older)
patients applying retapamulin ointment twice daily for 5
days for the treatment of impetigo. Of the 210 patients
enrolled, 164 (78%) were younger than 13 years. Clinical success was defined as the absence of treated lesions,
treated lesions that had become dry without crusts or without erythema compared with baseline, or treated lesions
that improved such that no further antimicrobial treatment
was required. At 2 days posttreatment, the ITT clinical
population for retapamulin showed a success rate of 85.6%
(119 of 139 patients) compared with the placebo group,
which had a success rate of 52.1% (37 of 71 patients). A
follow-up examination 9 days after treatment showed a
similar trend: retapamulin with a success rate of 75.5%
(105 of 139 patients) and placebo with 39.4% (28 of
71 patients).55
26 E MERGENCY D ERMATOLOGY
Cl
H
N
OH
OH
O
O
HO
HO
O
O
O
Cl
Cl
OH
O
O
O
HO
H2N
H
O
HN
O
O
H
N
N
H
H
O
N
H
O
N
H
O
O
CO2H
H
N
H
NHCH3
NH2
OH
HO
OH
A
FIGURE 3.6: Oritavancin (panel A) and dalbavancin (panel B).
Dosage
A thin layer of retapamulin should be applied to the affected
area (up to 100 cm2 in total area in adults or 2% total body
surface area in pediatric patients 9 months old or older)
twice daily for 5 days. Retapamulin is dispensed as a 1%
ointment in 5-, 10-, and 15-g tubes. To reduce the development of drug-resistant bacteria and maintain the efficacy
of retapamulin, use should be limited to treatment or prevention of infections that are proven or strongly suspected
to be caused by susceptible bacteria.52
Contraindications/Cautions
Retapamulin ointment is pregnancy category B; therefore,
it should be used in pregnancy only when the potential
benefits outweigh the risks and at the discretion of the prescribing physician.
Long-term studies in animals to evaluate carcinogenic
potential have not been performed with retapamulin. It
has shown no genotoxicity, and no evidence of impaired
fertility has been found in either male or female rat studies.
The safety of retapamulin ointment has been assessed
in a study of 2115 adult and pediatric patients who used at
least one dose from a 5-day, twice-daily regimen. Adverse
events rated by the investigator as drug-related occurred
in 5.5% (116 of 2115) of patients treated with retapamulin
ointment, the most common of which was application site
irritation (1.4%). A safety profile has not been established
for patients younger than 9 months.52
Due to low systemic exposure to retapamulin following topical application in patients, dosage adjustments
for retapamulin are unnecessary when coadministered
with CYP3A4 inhibitors, such as ketoconazole. From
in vitro P450 inhibition studies and the low systemic
Chapter 3
●
New Antimicrobials
27
O
OH
NH
HO
HO
O
O
Cl
O
O
HO
O
H
O
N
O
H
N
N
H
H
O
N
H
O
Cl
H HN
N
HO
O
N
H
NHCH3
N
H
O
O
OH
OH
HO
O
OH
O
OH
OH
OH
B
FIGURE 3.6 (continued)
exposure observed following topical application, retapamulin is unlikely to affect the metabolism of other P450
substrates. The effect of concurrent application of other
topical products to the same area of skin has not been studied.52
ANTIBIOTICS IN DEVELOPMENT
Oritavancin (Figure 3.6A) and dalbavancin (Figure 3.6B)
are two novel semisynthetic glycopeptide antibiotics,
belonging to the same class as vancomycin. The antibac-
terial activity of glycopeptide antibiotics results from the
inhibition of bacterial cell wall formation. More specifically, these antibiotics inhibit the biosynthesis of bacterial
cell wall peptidoglycan. These two agents are currently in
late stages of clinical development.
Oritavancin
Oritavancin is distinguished from vancomycin by its bactericidal activity against enterococci, S. pneumoniae, and
staphylococci, including MRSA.45,56,57 In animal studies
28 E MERGENCY D ERMATOLOGY
O
OH
F
O
H
N
N
HN
O
H
FIGURE 3.7: Moxifloxacin.
using rabbits as models, oritavancin was successful in the
treatment of endocarditis from MRSA.58 It also has a longer
half-life (>10 days) than vancomycin, and thus can potentially offer a shorter duration of treatment.59 In a phase III
study, IV oritavancin (either 1.5 mg/kg or 3.0 mg/kg once
daily) followed by placebo was compared to IV vancomycin
(15 mg/kg once daily) followed by oral cephalexin in 517
patients with cSSTIs (unpublished data).60 Efficacy was statistically equivalent in the two groups, with a 76% clinical
success rate in the group that received oritavancin and 80%
in patients who received vancomycin/cephalexin. Patients
in the oritavancin group required an average of only 5.7
days of treatment (in those receiving the 1.5 mg/kg/d
dosage) and 5.3 days of treatment (in those receiving the
3.0 mg/kg/d dosage), compared to 11.5 days in patients
receiving vancomycin/cephalexin.60
A second phase III, double-blind, randomized trial in
1246 patients with cSSTIs corroborated that oritavancin
200 mg daily for 3–7 days IV followed by oral placebo was
as effective as 10–14 days of vancomycin/cephalexin (vancomycin/cephalexin at 15 mg/kg twice daily for 3–7 days
IV followed by 1000 mg twice-daily oral cephalexin). This
study also demonstrated that significantly fewer patients experienced adverse events ( p < .001) and fewer patients discontinued therapy ( p = .003) in the oritavancin group than
in the vancomycin/cephalexin group.61
Targanta Therapeutics submitted a new drug application to the FDA in February 2008 seeking to commercialize
oritavancin in the treatment of complicated skin and skin
structure infections.62
for 7 days. All single and multiple dosages studied were well
tolerated. Dalbavancin also was found to have a long halflife of approximately 10 days.63 These results suggest that
once-weekly dosing could be sufficient to provide trough
concentrations that are bactericidal for staphylococcus.63
In a phase II trial, 62 patients with SSTIs were treated
with one of two dalbavancin-dosing regimens compared to
a standard-of-care antibiotic.64 Clinical success rates were
94.1% in patients receiving two doses of dalbavancin, given
1 week apart, 76.2% for standard-of-care treatment (dosing was daily for 7–21 days), and 64.3% for the group
that received a single dose of dalbavancin (unpublished
data).64
In a randomized, double-blind, phase III noninferiority
study, two doses of dalbavancin (1000 mg given on day 1
followed by 500 mg given on day 8) were as well tolerated
and as effective as linezolid given twice daily for 14 days for
the treatment of patients with complicated SSTIs, including those infected with MRSA.65
As of December 2007, Pfizer received an approvable letter from the FDA and is in the process of providing the
additional data requested.66
NEW INDICATIONS FOR QUINOLONES
The FDA recently added new indications for two newer
generation fluoroquinolone class antibiotics. In April 2001,
moxifloxacin (Figure 3.7), and in October 2002, gatifloxacin
(Figure 3.8), were FDA approved for use in uncomplicated
skin and skin structure infections. Several studies supported
these new indications. In one multicenter trial involving
410 patients with uncomplicated SSTIs, a once-daily gatifloxacin dose of 400 mg orally had a cure rate of 91%.67 This
compared to the control group, which received a once-daily
oral dose of 500 mg of levofloxacin and had a cure rate of
84%. Another study examined the efficacy of moxifloxacin
versus cephalexin in patients with uncomplicated skin infections.68 The clinical effectiveness was 90% for the group
receiving oral moxifloxacin (400 mg once daily) and 91%
for the group receiving oral cephalexin (500 mg three times
O
O
F
OH
Dalbavancin
Dalbavancin also has been shown to be bactericidal in
in vitro studies with gram-positive pathogens.63 In animal studies, using rats as models, dalbavancin successfully
treated lobar pneumonia from penicillin-resistant pneumococci.30 In a phase I study, healthy volunteers received single IV infusions of dalbavancin in doses ranging from 70 mg
to 360 mg.63 Other subjects received dosages of 70 mg/day
N
HN
FIGURE 3.8: Gatifloxacin.
N
O
Chapter 3
●
New Antimicrobials
29
TABLE 3.2: Novel Antifungal Agents for Invasive Fungal Infections
Generic
name
Brand
name
Voriconazole
R
Vfend
Posaconazole
Anidulafungin
R
Noxafil
R
Eraxis
Mechanism of action
Dosage
Indications
Interferes with fungal cell wall synthesis
by inhibiting 14␣-demethylase synthesis
of ergosterol
200 mg BID PO or 3–6
mg/kg BID IV for 14 d after
resolution of symptoms
Candida, IFIs,
drug of choice
for aspergillus
200–400 mg BID PO
Candida, IFIs
50–100 mg IV q24h for 14
d after symptom resolution
Candidemia/
Candidosis
Interferes with fungal cell wall synthesis
by inhibiting 1,3-β-glucan synthase
synthesis of 1–3-β-glucan
BID, twice daily; PO, per os (orally); IV, intravenous; IFI, invasive fungal infection.
daily). Both groups received the antibiotics for a total of 7
days. Other studies also have supported these findings.69
NEW ANTIFUNGAL AGENTS
The increasing burden of invasive fungal infections (IFIs),
especially among hospitalized patients with immune compromise, has created an urgent need for novel antifungal
therapies (Table 3.2). The two major causes of IFI are
Candida albicans and Aspergillus fumigatus, although other
emerging fungi, such as non-albicans Candida (particularly Candida glabrata), Fusarium, and Zygomycetes, are
contributing to the need to expand our armamentarium of
antifungal agents.70
VORICONAZOLE AND POSACONAZOLE
Voriconazole (Figure 3.9) and posaconazole (Figure 3.10)
are new triazole agents with broad-spectrum activity
against many fungi. As with all azole antifungal agents,
voriconazole and posaconazole work by interfering with
synthesis of the fungal cell wall element, ergosterol,
through inhibition of cytochrome P450 14␣-demthylase.71
Voriconazole was FDA approved in 2002 for primary treatment of acute invasive aspergillosis and salvage therapy for
rare but serious fungal infections caused by the pathogens
Scedosporium apiospermum and Fusarium spp. Posaconazole
was approved in 2006 and is indicated for prophylaxis of
invasive Aspergillus and Candida infections in patients (13
years old or older) with immune compromise as well as for
the treatment of oropharyngeal candidiasis, refractory to
itraconazole and/or fluconazole.72
Voriconazole has become the drug of choice for treatment of invasive aspergillosis. In a study comparing
voriconazole with amphotericin B in 277 patients with
proven or probable aspergillosis, voriconazole led to better responses and improved survival and resulted in fewer
severe side effects than the standard approach of initial therapy with amphotericin B.73 Voriconazole may be administered both orally and IV. In clinical trials, oral (200 mg
twice daily) and IV (3–6 mg/kg every 12 hours) doses have
produced favorable response.74 Side effects include doserelated, transient visual disturbances, skin eruption, and
elevated hepatic enzyme levels.74
Two randomized multicenter trials have accessed the
efficacy of posaconazole (200 mg orally twice daily) in preventing IFIs compared to standard azole therapy (fluconazole or itraconazole) in high-risk patients with neutropenia or graft versus host disease (GVHD). A prospective
nonblinded study in high-risk neutropenic patients with
neutropenia due to either acute myelogenous leukemia
or myelodysplastic syndrome randomized 602 patients
to receive posaconazole (n = 298) or either fluconazole
or itraconazole (n = 304) until neutrophil recovery or
occurrence of an IFI for up to 84 days.75 Proven or
probable infections were diagnosed in 7 patients (2%)
in the posaconazole group versus 25 (8%) in the comparator group. The majority of breakthrough infections
in the fluconazole/itraconazole arm were due to aspergillosis.
N
N
N
OH
CH3
F
N
F
F
FIGURE 3.9: Voriconazole.
N
30 E MERGENCY D ERMATOLOGY
O
F
CH3
F
N
O
N
N
N
OH
N
H3 C
O
N
N
N
FIGURE 3.10: Posaconazole.
A double-blinded study in allogeneic hematopoietic
stem cell transplant patients with GVHD compared fluconazole (n = 299) and posaconazole (n = 301) for up
to 112 days or until the occurrence of an IFI. Proven or
probable infections were diagnosed in 16 patients (5%) in
the posaconazole group and 27 (9%) in the fluconazole
group.76
An open-label, multicenter, case-controlled clinical trial
of posaconazole as salvage therapy in patients with IFIs also
has been completed for a variety of IFIs that failed primary therapy (predominantly amphotericin B regimens).
Among patients with aspergillosis (n = 107), the global
response to posaconazole therapy (800 mg/day divided
doses) was 42% versus 26% response in contemporary control patients who received other licensed antifungal therapy
( p = .006).77
Preliminary data also suggest that posaconazole may
be an effective therapy for zygomycosis unresponsive to
amphotericin B–based regimens.78
Posaconazole is available only as an oral suspension and
requires intake with high-fat meals for absorption, limiting
its utility in the critically ill patient. The major adverse
H
H OH
effects appear to be gastrointestinal (including diarrhea,
nausea, and vomiting) and rashes.75,79
ANIDULAFUNGIN
Anidulafungin (Figure 3.11) is a novel echinocandin
approved in 2006 for the treatment of candidemia as well as
for candidal esophagitis, abdominal abscesses, and peritonitis.80 As with other echinocandins, anidulafungin blocks
the synthesis of a major fungal cell wall component, 1–3-glucan, presumably via inhibition of 1,3--glucan synthase.81
In a multicenter, randomized, blinded trial that compared anidulafungin with fluconazole in the treatment of
invasive candidosis, treatment was successful in 75.6%
of patients treated with anidulafungin, as compared with
60.2% of those treated with fluconazole ( p = .01).82
Another randomized, double-blind, double-dummy
study compared the efficacy and safety of intravenous
anidulafungin to that of oral fluconazole in 601 patients
with esophageal candidiasis and found it to be statistically
noninferior.83
O
OC5H11
HO
HO
H
O
HO
HO
H
H 3C
O
H
H3 C
H
NH
NH
CH3
HN
N
O
O
NH
H
OH
N
H
N
H
O
H
O
OH
H
H
H
OH
FIGURE 3.11: Anidulafungin.
OH
H
H
Chapter 3
TABLE 3.3: Novel Dosing of Antivirals for Herpes
Labialis
Generic
name
Brand
name
Dosing
Famciclovir
Valacyclovir
R
Famvir
Valtrex R
1500-mg single dose
2000 mg BID for 1 d
BID, twice daily.
Anidulafungin is available as an IV infusion. Dosing
for esophageal candidiasis is 100 mg on day 1, then 50
mg/day. Dosing for candidemia is 200 mg on day 1, then
100 mg/day. Similar to other echinocandins, anidulafungin
is well tolerated. In clinical trials, the most common side
effects (<5%) are abnormal liver function tests.83
NEW DOSING OF ANTIVIRALS (Table 3.3)
Famciclovir
A recent study in 701 patients with herpes labialis demonstrated that famciclovir 1500-mg single-dose therapy was
as efficacious as 750 mg twice daily for 1 day and reduced
the time to healing of lesions by 2 days when taken within
2 hours of onset of prodromal symptoms.84
Valacyclovir
Two recent multicenter, randomized, double-blind, and
placebo-controlled studies in 1524 and 1627 patients with
herpes labialis demonstrated that high-dose therapy with
valacyclovir (2000 mg twice daily for 1 day) shortened the
healing time of lesions by 1 day compared with placebo
and that a second day of therapy provided no additional
benefit.85
CONCLUSIONS
SSTIs are commonly encountered in the emergency room
setting. As MRSA infection becomes more prevalent and
other resistant organisms continue to emerge, it is essential for physicians to be aware of newly approved antibiotics and their indications for use, dosing, and side-effect
profiles. To maintain an armamentarium of useful agents,
antimicrobials should be utilized only when necessary and
in the context of local resistance patterns.
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25. Moellering RC, Linden PK, Reinhardt J, et al.. The efficacy
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50. Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The efficacy
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51. Fraise AP. Tigecycline: the answer to beta-lactam and fluoroquinolone resistance? J Infect. 2006;53:293–300.
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Oranje AP, Chosidow O, Sacchidanand S, et al. Topical retapamulin ointment, 1%, versus sodium fusidate ointment, 2%,
for impetigo: a randomized, observer-blinded, noninferiority
study. Dermatology. 2007;215:331–40.
Barrett JF. Oritavancin. Eli Lilly & Co. Curr Opin Investig
Drugs. 2001;2:1039–44.
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(LY333328), against Staphylococcus aureus and Enterococcus
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Kaatz GW, Seo SM, Aeschlimann JR, et al. Efficacy of
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Wasilewski MM, Disch D, McGill J, et al. Equivalence
of shorter course therapy with oritavancin compared to
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infections. Program and abstracts of the 41st Interscience
Conference on Antimicrobial Agents and Chemotherapy;
2001 Dec 16–19; Chicago, IL.
Giamarellou H, O’Riordan W, Haas H, et al. Phase 3 trial
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Conf Antimicrob Agents Chemother. Athens, Greece; 2003.
Targanta Therapeutics. Press release. Targanta submits
oritavancin new drug application. Cambridge, MA. http://en
.newspeg.com/Targanta-submits-orvita-vancin-new-drugapplication-4801102.html. Accessed February 11, 2008.
Steiert M, Schmitz FJ. Dalbavancin (Biosearch Italia/
Versicor). Curr Opin Investig Drugs. 2002;3:229–33.
Vesicor Inc. Press release. Vesicor announces positive phase
2 study results with dalbavancin for skin and soft tissue infections. Fremont, CA September 5, 2002.
Jauregui LE, Babazadeh S, Seltzer E, et al. Randomized,
double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis.
2005;41:1407–15.
Pfizer Mediaroom. Pfizer receives approvable letter
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newsLang/en. Accessed February 2, 2008.
Tarshis GA, Miskin BM, Jones TM, et al. Once-daily oral
gatifloxacin versus oral levofloxacin in treatment of uncomplicated skin and soft tissue infections: double-blind, multicenter, randomized study. Antimicrob Agents Chemother.
2001;45:2358–62.
●
New Antimicrobials
33
68. Parish LC, Routh HB, Miskin B, et al. Moxifloxacin versus
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69. Muijsers RB, Jarvis B. Moxifloxacin in uncomplicated skin and
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77. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive
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2004;39:770–5.
84. Spruance SL, Bodsworth N, Resnick H, et al. Single-dose,
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85. Spruance SL, Hill J. Clinical significance of antiviral therapy
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Chemother. 2004;53:703–7.
CHAPTER 4
Immunomodulators and the “Biologics”
in Cutaneous Emergencies
Batya B. Davidovici
Ronni Wolf
BIOLOGIC AGENTS are proteins or antibodies engineered to target specific molecules. They are derived from
the products of living organisms. In recent years, numerous drugs of this type have been added to the therapeutic armamentarium in various disciplines of medicine. In
dermatology, psoriasis is so far the only entity for which
various drugs of this type are approved. Two main groups
of biologic agents are used in psoriasis: The first is tumor
necrosis factor (TNF) blockers, and the second group consists of inhibitors of T lymphocytes or antigen-presenting
cells. Drugs from the anti-TNF group, as well as additional biological agents from other specialties, have been
used off-label in numerous skin diseases – some of them are
dermatologic emergencies. No doubt, the increasing development and use of these drugs will also extend the number of possible indications in numerous skin diseases. This
chapter reviews the current reports on these agents and
their use in various dermatologic emergencies (Table 4.1).
INFLIXIMAB
Infliximab (Remicade; Centocor, Inc., Horsham, PA) is
a chimeric immunoglobulin G1 (IgG1) monoclonal antibody containing human constant regions and murine
variable regions. It binds and inhibits both soluble and
transmembrane TNF-α and activates lysis of cells that
express transmembrane TNF-α. via antibody-dependent
and complement-dependent cytotoxic mechanisms.1,2
Side Effects
Most of the side effects that have been described correspond
to infusion reactions, which occur in approximately 10% of
patients and tend not to be serious.4,5
Part of the infliximab molecule is murine in origin;
hence, the development of neutralizing antibodies has been
described in between 15% and 50% of cases, depending
on the study.6–9 The presence of neutralizing antibodies is associated with an increased risk of adverse effects,
and a higher dose is required to control the disease.9 The
dose of infliximab is not associated with the development
of antibodies, although an association has been described
between low plasma levels of infliximab and the presence
of antibodies.9,10 The concomitant use of immunosuppressant drugs such as cyclosporine or methotrexate has
been shown to reduce the rate of formation of neutralizing
antibodies.10,11
Postmarketing data from infliximab-treated patients
with RA, Crohn disease, or other indications for which
infliximab is approved suggest a potential increased risk for
events such as opportunistic infections, for example, tuberculosis, which can also present as disseminated or atypical
disease,12 lymphoma, demyelinating disease,13–16 or congestive heart failure.17–19 There is no evidence that TNF
inhibitors increase the risk of new-onset cardiac failure in
patients with RA.20,21
INFLIXIMAB IN DERMATOLOGIC EMERGENCIES
Indications
Indications for treating are rheumatoid arthritis (RA),
psoriatic arthritis, ankylosing spondylitis, Crohn disease,
ulcerative colitis, and moderate to severe plaque type psoriasis.
Dosage
Infliximab is administered as an intravenous (IV) 3–5 mg/kg
(in most diseases) infusion, at initiation, week 2, and week
6 and subsequently every 8 weeks.3
Blistering Diseases: Pemphigus Vulgaris
Pemphigus vulgaris (PV) is an autoimmune blistering disorder of the skin and mucous membranes that is characterized by autoantibodies directed against desmoglein
(dsg) 1 and dsg 3. To date, two cases have been described of recalcitrant PV that was refractory to multiple immunosuppressant treatments and that responded
rapidly to treatment with infliximab.22,23 In both cases,
the patients showed a lasting response (4 months and 104
weeks).
page 34
Chapter 4
●
Immunomodulators and the “Biologics” in Cutaneous Emergencies
35
TABLE 4.1: Clinical Use of Immunimodulators and Biologics in Dermatologic Emergencies
Infliximab
Pemphigus vulgaris (PV)
Pemphigus foliaceus
Paraneoplastic pemphigus
Bullous pemphigoid
Cicatrical pemphigoid
Graft versus host disease
SJS-TEN
Angioedema with hypereosinophilia
Etanercept
+
+
+ + +b
++
+
+
++
Rituximab
++a
+
+
++
Intravenous
immunoglobulin
(IVIG)
+++
++
++
+++
+ + +c
+
+ Weak evidence; ++ few supporting reports; +++ many supporting reports.
SJS–TEN, Stevens–Johnson syndrome and toxic epidermal necrolysis.
a
Close surveillance for infectious complications in PV patients undergoing rituximab treatment is warranted.
b
For patients with skin and gastrointestinal tract manifestations who have not responded to standard treatment.
c
Because randomized, controlled, multicenter studies are lacking, treatment with IVIG cannot be considered the
standard of care in these cases. Special caution is indicated in elderly patients with preexisting renal
dysfunction.
Cicatricial Pemphigoid
Cicatricial pemphigoid (CP), also referred to as mucous
membrane pemphigoid, is a heterogenous group of autoimmune subepithelial blistering disorders that primarily affect
mucosal surfaces and, occasionally, the skin. CP was previously called benign mucousal pemphigoid; the outcome
might not always be benign. Due to its scarring nature,
blindness, deafness, or strictures of the pharynx, esophagus,
larynx, and/or anogenital mucosa may result. Autoantibodies to β 4-integrin, α 6-integrin, bullous pemphigoid (BP)
antigen (Ag) 1, BP Ag 2, and laminin 5 have been detected.
Patients with ocular CP have elevated levels of serum TNFα compared with normal controls.24 Only one case, however, has been described of BP of the mucous membranes.25
The process was highly aggressive and refractory to multiple immunosuppressant treatments, in which treatment
with infliximab at standard dose and regimen led to remission of the disease in the oral and pharyngeal mucosa and
stabilized the ocular involvement, which had led to the loss
of an eye.
Acute Graft Versus Host Disease
Acute graft versus host disease (GVHD) has three different phases. TNF-α is implicated both in the first phase, in
which it is released from tissues damaged by the conditioning, and the third phase, in which it is released by effector T lymphocytes from the donor, previously activated by
antigen-presenting cells from the recipient and that lead
to cell death via a mechanism of cytotoxicity involving
TNF-α.26
GVHD is a serious condition in which the first-line
treatment involves high doses of systemic corticosteroids
followed by maintenance treatment with tacrolimus or
cyclosporine. Failure to control the disease with these
drugs represents a difficult therapeutic challenge.27 Biologic agents acting against TNF-α. have proven to be effective in some cases and represent a first-line option for the
treatment of refractory cases. Some authors have observed
greater efficacy with infliximab in cases of gastrointestinal (GI) GVHD,28,29 suggesting that TNF-α. is the main
cytokine involved in the GI disease, whereas in cutaneous
and hepatic GVHD, other cytokines also play an important
role.28,30
Some case series have been published on the treatment
of acute GVHD with infliximab. Most involve patients in
whom severe acute disease that was refractory to traditional
treatments (immunosuppressant drugs and corticosteroids)
developed following bone-marrow transplant. In these case
series the treatment consisted of four infusions of 10 mg/kg
infliximab per week.
The most extensive series28 included 37 patients with
acute GVHD treated with infliximab, of whom 28% had
corticosteroid-resistant disease. After treatment with a
median of 4 weekly infusions of infliximab, 10 mg/kg, the
complete response rate was 75% for skin, 81% for upper
GI tract involvement, 91% for lower GI tract, and 35%
for liver involvement. Twenty-two patients died during
the study; in 13 of these patients, death was attributed
to GVHD progression. No other adverse events were
reported.
It has been reported31 that a series of 11 patients with
steroid-refractory acute GVHD, 10 of whom had grade III
or IV disease were treated with infliximab. Only 2 patients
had a complete response; although 5 of 9 remaining patients
had a partial resolution of symptoms, all 9 eventually died.
Six of these deaths were attributed to progressive GVHD
and infection.
36 E MERGENCY D ERMATOLOGY
Two retrospective studies have been published in which
promising results were obtained with this disease in patients
refractory to corticosteroid therapy. The first was a series
of 21 patients (14% grade I, 67% grade II, and 19% grade
III/IV) treated with infliximab as monotherapy.27 An overall response of 70% was obtained for cutaneous disease
(67% complete response), 75% for intestinal involvement
(65% complete response), and 25% for hepatic disease
(25% complete response). The overall survival was 38%,
but all of the patients went on to develop chronic GVHD.
The second study reported similar results in a series of 32
patients diagnosed with grade II/IV GVHD.30 An adequate
response to infliximab was obtained in 59% of the patients
(19% complete responses and 40% partial responses), and
all the 13 unresponsive patients died. Other series published on acute or refractory GVHD treated with infliximab
encompass a total of 12 patients, of whom 10 died during follow-up, despite 8 having shown improvement with
treatment.32–34 Only two cases have been reported in which
treatment of acute GVHD with infliximab (in both cases
associated with adalizumab) led to a good response.35
A phase III study has been published comparing the
efficacy of infliximab with that of standard treatment in
previously untreated patients.36 Fifty-eight patients were
randomized to receive either infliximab plus methylprednisolone or methylprednisolone alone. Overall response
rates were not significantly different between the two treatment arms (63% response to methylprednisolone alone
compared with 66% response to a combination of methylprednisolone and infliximab). There were no differences in
response by organ. This study suggests that early treatment
with infliximab does not provide added benefit in patients
who have not developed steroid-resistant disease.
Chronic GVHD
An initial study28 also described 22 patients with chronic
GVHD treated with a median of 4 weekly 10 mg/kg
infusions of infliximab in addition to prednisone and
other immunosuppressive therapy. Researchers observed a
response rate of 57% for skin disease and 92% for GI tract
disease in these patients. Eleven patients died, with GVHD
identified as the cause of death in 7 patients. Another
study, which describes 10 patients with steroid-dependent
chronic GVHD treated with etanercept, reported more
than 50% alleviation of symptoms in 5 of 8 patients who
were able to be evaluated and a steroid dose reduction in 6
patients.37 Finally, Reidi and colleagues38 reported a series
of 13 patients, including 8 patients with chronic GVHD,
who received infliximab salvage therapy. Patients received a
median of 4 weekly 10 mg/kg infusions, and responses were
observed in 7 of 8 patients with skin disease who could be
evaluated, 6 of 7 patients with GI tract disease, and 0 of 4
patients with liver disease.
Infliximab was well tolerated in most cases. It is not easy
to reach a conclusion regarding whether it increases the
risk of infection, because patients with refractory GVHD
are immunocompromised and it is difficult to determine
the extent to which infliximab is involved. A retrospective
cohort study concluded that infliximab was associated with
an increased risk of invasive fungal infections; this result
suggests that the possibility of increased infections with
infliximab should be further evaluated.39 Anti-TNF therapy seems to show promise for some patients with acute
and chronic GVHD, although mortality rates for steroidresistant disease remain high. On the basis of the reports
presented herein, infliximab appears to be most effective
for skin and GI tract manifestations and less effective for
liver involvement and high-grade acute disease for those
patients who have not responded to previous treatments.
It does not appear to offer improvements over standard
treatments in previously untreated patients.
There are no human studies available to resolve the
important issue of whether infliximab may be associated
with reduced transplant efficacy as confirmed in animals
following inhibition of transmembrane TNF-α.
Stevens–Johnson Syndrome and Toxic
Epidermal Necrolysis
Stevens–Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) are rare, acute, life-threatening mucocutaneous diseases characterized by widespread sloughing
of the epidermis and of the mucous membranes. Mortality is high and increases with more extensive skin detachment. Although its exact role is not completely clear, TNFα. appears to be important in the pathogenesis of TEN.
Various studies have found that blister fluid from patients
with TEN has an elevated concentration of TNF-α. compared with fluid from patients with thermal burns.40–42 It
has been proposed that TNF-α may contribute to epidermal necrosis both indirectly, through recruitment of
T cells and macrophages, and directly, through facilitation of keratinocyte apoptosis.43,44 Others suggest, however, that the TNF-α found in blister fluid is produced by
keratinocytes as a defensive response to T-cell invasion.45
Interestingly, thalidomide, which is thought to act, at least
in part, through inhibition of TNF-α in other disorders,
was shown to be detrimental in the treatment of TEN in a
randomized, controlled trial.46 Patients in the thalidomidetreated group had higher levels of blister fluid and serum
TNF-α than did control patients, possibly indicating
that thalidomide caused a paradoxical increase of TNF-α
in these patients. Others have suggested that thalidomide’s
stimulatory effect on T cells may have led to the deterioration observed in the treated patients.47
The first case of TEN treated satisfactorily with a single
dose of infliximab (5 mg/kg) was published in 2002.48 Since
Chapter 4
●
then, 5 more cases have been reported,49–51 all with a satisfactory response. The most recent publication reported 3
cases with characteristics compatible with exanthematous
pustulosis and TEN that had not responded to corticosteroids or suspension of the drug responsible for the symptoms. However, in these cases a single dose of infliximab
led to a rapid and significant improvement.51
Further research is clearly needed to elucidate the role
of TNF-α in therapy for TEN and to determine whether
TNF antagonists will have efficacy beyond these case
reports.
ETANERCEPT
Etanercept (Enbrel, Amgen and Wyeth, Thousand Oaks,
CA) is a recombinant fusion protein comprising domains
of the 75-kDa human TNF receptor and human IgG,
which inhibits the activity of TNF-α. It binds primarily
to soluble TNF-α as well as to TNF-β (lymphotoxin).
Binding of etanercept prevents TNF from binding to its
receptor, thereby effectively blocking its physiologic functions.52 Unlike infliximab, it does not fix complement,
cause antibody-dependent cytotoxicity, or trigger T-cell
apoptosis.53
Indications
Etanercept is approved for use in moderate-to-severe RA,
polyarticular-course juvenile RA, ankylosing spondylitis,
psoriatic arthritis, and chronic moderate-to-severe plaque
psoriasis.
Immunomodulators and the “Biologics” in Cutaneous Emergencies
37
ETANERACEPT IN DERMATOLOGIC EMERGENCIES
Autoimmune Blistering Diseases: CP
One report has been published of the successful use of etanercept for the treatment of CP. The case involved a patient
with CP affecting the oral cavity, with disease resistant to
multiple previous treatments.57 Etanercept, 25 mg twice
weekly, was added to the existing regimen of prednisone
60 mg daily. The patient received 6 doses of etanercept. No
new blister formation was observed after the third dose, and
clinical remission persisted through 8 months of follow-up.
During this time, the prednisone dosage was tapered to 1
mg daily.
Bullous Pemphigoid
BP is a subepidermal autoimmune blistering disorder characterized by autoantibodies against BP Ag 1 and 2. BP is
usually considered a benign bullous disease, particularly
compared with PV, yet it can be lethal, especially in elderly
patients or in those with higher daily steroid dosage at discarge. In BP, TNF levels are elevated in both serum and
blister fluid and correlate with the severity of disease.58–62
TNF is thought to mediate the recruitment of neutrophils
and eosinophils seen in the inflammatory infiltrate of BP
lesions and stimulate the production of other inflammatory
cytokines and chemokines.59 Yet, there has only been one
case report of a patient with concurrent BP and psoriasis
who was successfully maintained on a regimen of etanercept after initial treatment with prednisone.63 Etanercept
allowed for the successful tapering of prednisone without
a rebound of the patient’s psoriasis or a flare of the BP.
Dosage
Acute GVHD
Recommended dosage for RA, ankylosing spondylitis, and
psoriatic arthritis is 25 mg administered subcutaneously
twice weekly for the entire year. For plaque-type psoriasis patients; the dosing is 50 mg twice weekly for the first
12 weeks followed by a “step-down” to 25 mg twice weekly
for another 12 weeks or 25 mg twice weekly for 24 weeks.
Etanercept has also shown promise in the treatment of
acute GVHD. One case report has been published of an 11year-old girl who achieved complete remission of steroidrefractory acute GVHD with etanercept treatment.64 In
a phase II study of etanercept in combination with the
interleukin-2 receptor antibody daclizumab for the treatment of steroid-refractory acute GVHD in 21 patients, the
overall response rate was 67% (38% complete response,
29% partial response).65 Similarly, in a pilot study on
the use of etanercept in combination with tacrolimus and
methylprednisolone as initial therapy for 20 patients with
stage II or III acute GVHD, 75% of patients had a complete
response within 4 weeks of initiating treatment.66
Side Effects
Injection site reactions occurring in up to 40% of patients
were the most commonly reported adverse events in initial
psoriasis clinical trials. The rate of development of antietanercept antibodies has been less than 10% and has not
been observed to lead to decreased efficacy.54–56
Long-term data from clinical trials in many patients
receiving etanercept for other indications, such as RA,
found infrequent cases of tuberculosis, a possible increased
risk of certain neurological disorders in patients taking
etanercept, rare cases of pancytopenia, and congestive heart
failure.14
Chronic GVHD
A study that describes 10 patients with steroid-dependent
chronic GVHD treated with etanercept reported more
than 50% alleviation of symptoms in 5 of 8 patients who
were able to be evaluated and steroid dose reduction in
38 E MERGENCY D ERMATOLOGY
6 patients.37 Etanercept was administered at 25 mg twice
weekly for 4 weeks and then once weekly for the subsequent
4 weeks; all patients were receiving concurrent steroids,
and 4 patients were started on a regimen of mycophenolate
mofetil with etanercept.
Two patients died before completion of the study (1 of
relapsed malignancy, 1 of thrombotic thrombocytopenic
purpura), and 1 patient died of infection after relapse of
chronic GVHD that occurred after study completion.
treatment of RA, infections occurred in 35% of patients
in the rituximab group compared with 28% of the placebo
group. Serious infections occurred in 2% of the rituximab
group compared with 1% of the placebo group.77 Human
antichimeric antibodies (HACAs) developed in less than
1% of patients treated for lymphoma.78 The incidence may
be higher, however, in patients treated for autoimmune disease. In a study of rituximab for SLE, 6 of 18 patients developed detectable HACAs; no patients had adverse events
related to this development.79
RITUXIMAB
Rituximab (Rituxan; Genentech, South San Francisco,
CA) is a chimeric murine–human monoclonal antibody
to CD20, which induces depletion of B cells in vivo.67
In 1997, rituximab became the first monoclonal antibody approved for treatment of malignancy. Rituximab’s
cytotoxicity is mediated by several mechanisms, including
antibody-dependent cytotoxicity, complement-mediated
lysis, and direct disruption of signaling pathways and triggering of apoptosis. The contribution of each mechanism
remains unclear, and different mechanisms may predominate in the treatment of different diseases.68,69 Rituximab results in depletion of normal as well as malignant
B cells, leading to investigation of its use in autoimmune
disorders, including systemic lupus erythematosus (SLE),
RA, autoimmune thrombocytopenia and hemolytic anemia, antineutrophil cytoplasmic antibody-positive vasculitis, and autoimmune neuropathies.70,71
Indications
Rituximab is indicated for use in non-Hodgkin lymphoma
(NHL) and active RA not responsive to one or more TNF
antagonist therapies. It is also currently approved for the
treatment of relapsed or refractory, low-grade or follicular,
CD20+ B-cell lymphoma.72
Dosage
The initial approved dosing regiment was four weekly infusions of 375 mg/m2 .
Side Effects
CD20 is a B-cell specific antigen expressed on the surface
of B lymphocytes throughout differentiation from the preB cell to the mature B-cell stage, but not on plasma cells
or stem cells.67,73 Because plasma cells and hematopoietic precursors are spared, immunoglobulin levels do not
fall dramatically and B cells typically begin to return to
the circulation within 6 months of therapy.74,75 Hence the
incidence of serious adverse effects with rituximab is relatively low. Infusion reactions are the most common adverse
effects. In most cases, these are mild and occur only with
the first infusion.74,76 In a recent study of rituximab for the
RITUXIMAB IN DERMATOLOGIC EMERGENCIES PV
Rituximab treatment for PV was first attempted based on its
success in other autoimmune disorders and the hypothesis
that depletion of B cells would result in a decrease in production of the disease-causing autoantibodies.80 The correlation of decreases in PV autoantibody levels with clinical
improvement in most of the patients in whom these levels
were reported would seem to support this theory.80–83 This
theory also seems to suggest that most PV autoantibodies
are produced by CD20+ B-cell clones susceptible to rituximab. Alternatively, it has been suggested that, although
both plasma cells and memory B cells may produce PV
autoantibodies, plasma cells, which are CD20 negative and
thus resistant to the effects of rituximab, may predominantly produce the less pathogenic IgG1 dsg 3 antibodies
whereas the memory B cells produce the IgG4 antibodies
responsible for disease.
This alternative theory might explain the clinical
improvement in the face of persistently elevated PV antibody titers observed in one patient and the improvement
preceding decreased titers in a second patient.84,85 Furthermore, in SLE patients, for whom clinical improvement
after rituximab is regularly correlated with B-cell depletion but not to any decrease in other serologic markers
or autoantibody levels, it is postulated that disruption of
antibody-independent activities of B cells, including presentation of autoantigens, costimulation of T cells, and regulation of leukocytes and dendritic cells, are central to rituximab’s effect on the disease.79 Thus the critical effects of
rituximab in PV may expand beyond decreasing autoantibody production to inhibiting B-cell–dependent activation
of T cells. The successful use of rituximab in more than
20 individual cases of treatment-resistant PV including a
case of refractory childhood PV and also two cases of pemphigus foliaceus has been reported.80–94 In all cases, the
standard course of 375 mg/m2 given IV for 4 weekly doses
was administered initially. B-cell depletion after treatment
was seen in all cases in which it was measured. In most
cases, the response to rituximab was rapid, with improvement noted within the first 2–4 weeks. There is one report
of a delayed response, where improvement was not noted
for 3 months and clinical remission was not achieved until
11 months after the first infusion.
Chapter 4
●
Rituximab was well tolerated in most of the cases
reported, consistent with the observations made in lymphoma and other autoimmune disorders; however, four
cases of serious infections were reported, including pneumonia, a relapse of septic arthritis of the hip,85 sepsis,84 and
fatal Pneumocystis carinii (now renamed Pneumocystis jiroveci)
pneumonia.91 These events may indicate that close surveillance of PV patients undergoing rituximab treatment is
warranted until the incidence of infectious complications
in this patient population is better understood.
Paraneoplastic Pemphigus
Paraneoplastic pemphigus (PNP) usually presents with
painful mucosal ulcerations and polymorphous skin lesions,
which usually progress to blistering eruptions on the trunk
and extremities. A wide variety of both benign and malignant tumors are found in these patients. Most reported
patients die from their underlying tumors, whereas others may die from bronchiolitis obliterans. Before 2005,
there were 5 reported cases of PNP treated with rituximab.
Three case reports describe significant improvement in oral
and cutaneous lesions after rituximab95–97 and two reports
describe less successful treatment, especially with regard
to mucosal lesions.98,99 Rituximab in a patient with PNP
with underlying NHL was treated with rituximab and, not
surprisingly, the patient improved, given the indication for
treatment of NHL with rituximab.100
The mechanism of action in PNP is likely similar to
that in PV. In addition, most of the treated patients experienced at least partial remission of the underlying neoplasm,
and this remission may have contributed to the observed
improvement.
Chronic GVHD
The use of rituximab in the treatment of chronic GVHD
has been reported in 4 series of patients. The largest
series is a phase I/II trial featuring 21 patients with
steroid-refractory disease.101 Cutaneous findings included
both sclerodermatous and lichenoid changes. Patients were
treated with one, two, or three cycles of 4 weekly infusions of rituximab at a dose of 375 mg/m2 . Patients were
allowed to continue stable doses of other immunosuppressive medications throughout the trial. The overall clinical
response rate was 70%, including 2 complete responses.
Cutaneous and musculoskeletal manifestations of GVHD
were more amenable to treatment with rituximab than were
mucous membrane and hepatic manifestations. The other
3 series showed similar findings.102–104 Experimental evidence has indicated that T cells and natural killer cells play
a central role in the pathogenesis of chronic GVHD.105
Evidence for the involvement of B cells has also been
accumulating. In one mouse model of chronic GVHD, an
expansion of host B cells directed by CD41 T cells is a
Immunomodulators and the “Biologics” in Cutaneous Emergencies
39
critical step in the development of disease.104,106,107 It
has been shown that fibrosis in the tight-skin mouse, a
model for systemic sclerosis, is mediated by hyperactive B
cells that overexpress CD19 and overproduce interleukin-6
(IL-6).108 This process may also be active in the sclerodermatous change seen in chronic GVHD.102 Patients with
chronic GVHD develop autoantibodies similar to those
seen in patients with autoimmune disease.102,105,109 Antibodies to Y chromosome–encoded minor histocompatibility antigens are generated after sex-mismatched transplantation, and the presence of these antibodies has been
correlated to the occurrence of GVHD.110,111 In the trial
discussed previously, there were four male recipients of
female grafts.101 All four of these patients had autoantibodies before treatment that became undetectable after
rituximab. The autoantibodies disappearance correlated
with a clinical response. The success of rituximab in these
4 series provides further evidence for the role of B cells in
chronic GVHD. These studies have also raised the question
of whether rituximab may be useful in localized or systemic
scleroderma, and trials are currently under way in these
diseases.
IV IMMUNOGLOBULIN
IV immunoglobulin (IVIG) comes in several formulations, including Carimune (ZLB Behring LLC, King
of Prussia, PA), Flebogamma (Instituto Grifols, SA,
Barcelona, Spain), Gammagard (Baxter, Deerfield, IL),
Gammar (Aventis Behring, King of Prussia, PA), Gamunex
(Talecris Biotherapeutics, Research Triangle Park, NC),
Octagam (Octapharma, Lachen, Switzerland), Panglobulin (ZLB Behring LLC), Polygam (Baxter), Gamimune
(Talecris Biotherapeutics), Iveegam (Oesterreichisches
Institut fuer Hemoderivate GmbH. OIH), Sandoglobulin
(Novartis, Basel, Switzerland), and Venoglobulin (Alpha
Therapeutic Corporation, Grifols USA, Los Angeles, CA).
The mechanism of action of IVIG is not fully understood
and likely differs depending on the disease. The following
mechanisms have been proposed: lowering the levels of
deleterious autoantibodies through idiotypic antibodies
contained in IVIG;112,113 accelerating the catabolism
of pathogenic IgG by saturating neonatal Fc receptors (FcRns) with exogenous IgG;114,115 inhibiting the
pathogenic activation of T lymphocytes by antibodies
to CD4 and other T-cell receptors;116,117 inhibiting
complement-mediated damage;118 interfering with
the production, release, and function of inflammatory
cytokines including interleukins-2, -3, -4, -5, -6, and -10,
TNF-α, and granulocyte–macrophage colony-stimulating
factor;119–123 inhibiting the differentiation and maturation
of dendritic cells, thereby reducing the activation of harmful T cells;124 increasing sensitivity to corticosteroids;125
and inhibition of thromboxane A2 and endothelin, and
increased prostacyclin secretion.126
40 E MERGENCY D ERMATOLOGY
Indications
Indications are primary and secondary immunodeficiencies (i.e., common variable immunodeficiency),
X-linked agammaglobulinemia, severe combined immunodeficiency, Wiskott–Aldrich syndrome, acute and chronic
immune thombocytopenic purpura, human immunodeficiency virus (HIV) in children, chronic lymphocytic
leukemia, Kawasaki disease, Guillain–Barré syndrome, and
GVHD prophylaxis in patients receiving allogeneic bonemarrow transplantation.
Dosage
IVIG is composed of human plasma derived from pools
of 1000–15,000 donors.126 The purified immunoglobulin
is stabilized with glucose, maltose, sucrose, mannitol, sorbitol, glycine, or albumin. IVIG is made up of more than
90% IgG and small amounts of IgM and IgA. Generally,
IVIG is given at a dose of 2 g/kg over 3–5 days, but can be
given over 2 days in younger patients with normal renal and
cardiovascular function. The total amount of immunoglobulins that are infused with a 2 g/kg dose is enormous; serum
IgG will increase approximately fivefold.127
patients receiving IVIG, particularly patients with a history of migraines.134 It usually presents with headache,
meningismus, and photophobia. Severe anaphylactic reactions may occur in patients with IgA deficiency. Acute
tubular necrosis, which is usually reversible, may occur in
individuals with preexisting renal disease and/or diabetes
mellitus and in the elderly population.135 Acute tubular
necrosis has been associated with IVIG products containing
high concentrations of sucrose.134
As with all blood products, there is a risk of transmission
of viruses and prions. IVIG is screened for hepatitis B and
C, HIV, and syphilis, and donors are carefully selected.
Additional methods to remove viruses include physical
inactivation with heat and chemical inactivation with solvents, low pH detergents, and caprylate. Caprylate and
nanofiltration may also remove prions.136 Transmission of
hepatitis B virus and HIV has not been reported.134 Transmission of hepatitis C virus has been reported and was likely
a result of inadequate viral inactivation steps. The introduction of improved viral inactivation techniques, such
as incubation at pH 4 and solvent–detergent treatment,
should minimize this risk.137 In addition, there remains
the risk of transmission of currently unidentified infectious
agents.
Side Effects
Infusion-related side effects occur in less than 10% of
patients and are generally mild and self-limiting.127
These side effects include headache, myalgias, flushing, fever, chills, fatigue, nausea or vomiting, low backache, chest discomfort, hypotension and hypertension,
tachycardia, and skin eruptions such as eczematous reactions, urticaria, lichenoid reactions, pruritus of the palms,
and petechiae.127,128 Premedication with acetominophen,
nonsteroidal antiinflammatory agents, antihistamines, or
low-dose IV corticosteroids may help avoid other infusionrelated adverse events. Myalgias, chills, and chest discomfort may occur during the first hour and respond to halting the infusion for 30 minutes and then resuming it at
a slower rate. Postinfusion fatigue, fever, or nausea may
occur and last for 24 hours. More serious, but rare, adverse
events include thromboembolic events; therefore, caution
should be used in patients with risk factors for thromboembolism, immobilized patients, and patients with hyperviscosity syndromes. The U.S. Food and Drug Administration
has identified high infusion rates and high doses as potential risk factors for thromboembolism in patients at risk.129
Hemolytic anemia may result from blood group antibodies. Neutropenia is common, transient (lasting 2–14 days),
and usually benign.130–132 Some clinicians 132 hypothesize
that this may be a result of antineutrophil antibodies contained in IVIG or from induction of neutrophil apoptosis. Transfusion-related acute lung injury is characterized
by severe respiratory distress occurring 1–6 hours after
the infusion. Aseptic meningitis,129,133 occurs in 11% of
IVIG IN DERMATOLOGIC EMERGENCIES
PV
IVIG has been shown to be effective in the treatment of
PV in numerous studies. IVIG lowers antibody titers to
dsg 1 and dsg 3, often making them undetectable.138–143
In the two largest studies, which are from one institution, 42 patients were treated with IVIG (2 g/kg every
4 weeks) until control was achieved, as defined by healing of old lesions and no new lesions.139,141 The interval
between IVIG treatments was then gradually increased to
every 16 weeks. Prednisone and immunosuppressive agent
(ISA) were tapered off during this time in all patients; IVIG
was then used as monotherapy. Treatment with IVIG led to
a clinical remission in all patients. In another study,141 control was achieved after a mean of 4.5 months, prednisone
was tapered off after a mean of 4.8 months, and ISAs were
tapered off after a mean of 2.9 months. Both studies were
prospective, but uncontrolled.
There have been an additional two case series and six
case reports of the successful treatment of 23 patients with
PV with IVIG.142,144–150 A juvenile case of PV had excellent
response to IVIG.151
In France, 12 patients with PV were treated with IVIG,
and 8 were in complete remission at the end of treatment.152
In Mexico, a patient with refractory PV was treated with
IVIG and healing of her mucosal and cutaneous lesions
was seen in 3 weeks;153 however, IVIG was not always successful; nine case reports of treatment failures from other
Chapter 4
●
institutions have been reported.154–157 In one case, the
patient received only one cycle of IVIG.156
Pemphigus Foliaceus
Pemphigus foliaceus (PF) is an autoimmune blistering
disorder characterized by autoantibodies to dsg 1. Sami and
colleagues158 conducted a prospective study of 8 patients
with severe (body surface area >30%) steroid-resistant PF.
Patients were treated with IVIG (2 g/kg every 4 weeks)
until they were completely healed. The interval between
IVIG treatments was then gradually lengthened to every
16 weeks. All patients attained clinical control after a mean
of 4 months. Prednisone was tapered off in a mean of
2.9 months; IVIG was used as monotherapy thereafter.
Eleven patients with PF were treated with IVIG
(2 g/kg every 4 weeks) until they were completely healed. 159
The interval between IVIG treatments was then gradually
lengthened to every 16 weeks. All patients cleared after an
average of 5.3 months of therapy. Prednisone was tapered
off in a mean of 4.5 months and other ISAs after a mean of
2.6 months; IVIG was used as monotherapy thereafter. All
11 patients maintained remission after discontinuation of
IVIG for a mean follow-up time of 18.6 months. A case of
eyelid PF was also responsive to IVIG.
Overall, there are three published case series158–160 and
two case reports161,162 of the successful use of IVIG in the
treatment of PF. IVIG lowers antibody titers to dsg 1, often
making them undetectable.158 In all, at least 26 patients
were treated successfully with IVIG for PF.158–160,163
Bullous Pemphigoid
There are two published case series141,162,164 and three case
reports (n = 5)144,148,157 reporting the successful use of
IVIG in the treatment of BP. There have been two reported
treatment failures.157 IVIG lowers autoantibody titers to
both BP Ag 1 and Ag 2.164
In the only prospective study141 15 patients were treated
with BP with IVIG (2 g/kg every 4 weeks). The interval
between IVIG treatments was then gradually lengthened to
every 16 weeks after patients cleared. All 15 patients cleared
after a mean of 2.9 months and were able to discontinue
prednisone after a mean of 3.3 months. IVIG was used as
monotherapy thereafter. All 15 patients achieved sustained
remission with a mean duration of follow-up off IVIG of
22.9 months.
Cicatricial Pemphigoid
CP was treated with IVIG, leading to improvement in the
disease in more than 78 patients.158,165–174 One patient had
no response.157 IVIG has been shown to lower titers of
β4-integrin and α6-integrin in patients with CP.165,166
Immunomodulators and the “Biologics” in Cutaneous Emergencies
41
IVIG was effective in the treatment of CP
in several prospective studies from one institution.158,165,166,171,173,175,176 These patients were initially
treated with corticosteroids and other ISAs, which were
tapered off in all cases. Remission was generally attained
in 4–5 months, and treatment with IVIG led to prolonged
remissions that persisted after treatment with IVIG was
discontinued. There have been two additional case reports
of treatment successes and one treatment failure from
other institutions.157,169,172
One study of 16 patients with stage 2 ocular CP compared IVIG with standard treatment with corticosteroids
and ISAs.176 Randomization was based on whether insurance would pay for IVIG. Eight patients (group A) were
treated with IVIG (2 g/kg every 2–4 weeks) until control was achieved. The interval between IVIG treatments
was then gradually lengthened to every 16 weeks, and corticosteroids and other ISAs were tapered off. The other
8 patients (group B) were treated with corticosteroids and
other ISAs. The median times to remission for groups A
and B were 4 and 8.5 months, respectively. There were
no recurrences for group A, whereas 5 of 8 patients in
group B experienced a recurrence. No patients in group A
experienced progression, whereas 4 of 8 patients in group
B progressed to stage 3.
In summary, large, multicenter, randomized, controlled
studies of IVIG for the treatment of autoimmune bullous diseases have not been performed; nevertheless, the
results of the studies presented here suggest that IVIG
can be considered as a viable treatment option for patients
with PV, PF, BP, and CP who are resistant to conventional
therapy, have experienced complications as a result of
conventional therapy, or for whom conventional therapy
is contraindicated. In most cases, patients were treated
in conjunction with corticosteroids or other ISAs, which
could often be tapered or discontinued. Maintenance
infusions are generally required to maintain remission, although the interval between treatments can be
lengthened to 16 weeks. Some patients have maintained
prolonged remissions after treatment with IVIG, and
indeed a consensus statement on the use of IVIG in
the treatment of autoimmune mucocutaneous blistering
diseases has been published.129 The authors recommend
a starting dose of 2 g/kg every 3–4 weeks until control can be achieved. Thereafter, the interval between
treatments can be lengthened in 2-week intervals to 16
weeks. For patients with aggressive ocular CP it appears
that more frequent IVIG treatments every 2 weeks are
required to gain control. Because the vast majority of
the literature on the use of IVIG for autoimmune bullous diseases was generated at a single institution, additional reports of large case series by other authors are
encouraged, as a retrospective series published by the
Mayo Clinic failed to obtain such strikingly positive
results.157
42 E MERGENCY D ERMATOLOGY
Stevens–Johnson Syndrome and Toxic Epidermal
Necrolysis
Patients with SJS–TEN may have a high mortality rate.
The average reported mortality of patients with TEN in
large series ranges between 25% and 35%.177–181 The
mortality of patients with SJS is lower.178 Current treatment options are limited to supportive care in intensive
care and burn units. Treatment with corticosteroids and
other immunosuppressives is controversial and may result
in higher incidences of complications secondary to sepsis.
The mechanism of action of IVIG in the treatment of
TEN is not fully understood, but may partially be explained
by the observation of Viard and colleagues182 that antibodies present in IVIG block Fas-mediated keratinocyte apoptosis in vitro. Because of the low prevalence of TEN, randomized controlled studies have not been performed. The
evidence for and against IVIG in the treatment of SJS and
TEN consists of two open-label, prospective studies and a
number of retrospective case series and case reports.182–209
In addition, there has been one report of the successful use
of IVIG (2.4 g/kg given over 3 days) as prophylaxis for a
patient with recurrent episodes of SJS from IV contrast.210
Particularly in regard to case reports, one should not forget
the possibility of a selection bias toward reporting favorable
results.
IVIG has been reportedly used in at least 162 cases
of TEN,183–186,209,211–214 with improved survival in the
majority of patients. IVIG and plasmapheresis used in 5
patients with severe TEN had a mortality of 20%, compared with the 66% mortality as predicted by a severity-ofillness score for TEN (SCORTEN).211 In an Asian series,
8 patients with TEN and 4 with overlap TEN–SJS demonstrated a 91.6% survival after treatment with IVIG.212
In a German study of 9 patients, 5 were treated with
IVIG. The rate of mortality was 20% in the IVIG group
compared with 50% in the non-IVIG group.215 In 38
Korean patients, 14 received IVIG, and a trend of lower
actual rate of mortality compared with predicted rate was
discovered.190
A pediatric case of a 2-year-old-girl with TEN–SJS
overlap was treated successfully with IVIG.209 Another
pediatric series from India of 10 patients had a rate of mortality of 0% when using low-dose IVIG to treat TEN.216 A
review of published case series found 156 patients treated
with IVIG for TEN or SJS. The data reviewed, however, did not significantly demonstrate efficacy for IVIG.217
Conversely, a 2006 review notes that 6 of 8 studies demonstrate benefit of IVIG at doses greater than 2 g/kg for
TEN.218
Although caution should be used because comparison
across studies is difficult as a result of differences in severity of disease, patient characteristics, efficacy variables, and
outcome measures. Of the 11 studies, 8 concluded that
IVIG was beneficial in the treatment of TEN, although
in only one of the studies using a comparator group was
a statistically significant result achieved.185 Shortt and colleagues186 concluded that IVIG was not beneficial in their
retrospective series; although patients receiving IVIG experienced a lower mortality compared with historic control subjects, the difference was not statistically significant.
There was also a trend toward less progression of skin
sloughing in the IVIG-treated group compared with historic control subjects. A prospective, open-label study 184
and a retrospective study 192 also did not find IVIG to be
beneficial in the treatment of TEN. The study by Bachot
and colleagues184 included patients with SJS. The study by
Brown and colleagues192 was confounded by the fact that
67% of the patients treated with IVIG also received concomitant corticosteroids. Brown and colleagues also used
lower doses of IVIG than did most other studies (mean dose
1.6 g/kg). This finding is important, because Prins and colleagues183 found a higher mortality with lower doses (mean
2.7 g/kg in survivors vs. 2 g/kg in those who died) in their
retrospective review. Moreover, the number of days from
onset of symptoms to treatment was 9.2 in the IVIG group
versus 5.6 in the historic control group, although this difference was not statistically significant. Again, Prins and
colleagues183 found a higher mortality when treatment was
delayed (6.8 days in survivors vs. 10.2 days in those who
died). Because several studies did not include a comparator
group, a compilation of mortality benefit from IVIG across
studies is not possible.
Because of the lack of controlled, prospective, multicenter trials, strong conclusions regarding the effectiveness of
IVIG in the treatment of TEN cannot be reached. Moreover, because IVIG is a biologic substance, there is variation in the final product between manufacturers and batch
to batch that could affect results.219 For example, if interruption of Fas-mediated cell death by antibodies in IVIG
is the mechanism of its action in TEN, then batches that
are lacking these antibodies will not be successful. Thus,
the variability of different batches can account for the difference in results attained by Prins and colleagues183 and
Trent and colleagues,185 who used multiple brands of IVIG
and attained positive results, with Bachot and colleagues184
and Shortt and colleagues,186 who used one brand (Tegeline and Gamimune N, respectively) and did not attain
positive results. The brand used in the study by Brown
and colleagues192 was not stated. Furthermore, Tegeline
contains sucrose, which may be nephrotoxic. Bachot and
colleagues184 noted that mortality in their patients treated
with IVIG mostly occurred in elderly patients with preexisting renal dysfunction.
Although the results from the majority of case series support the use of IVIG in the treatment of TEN and TEN–
SJS overlap. Because randomized, controlled, multicenter
studies are lacking, treatment with IVIG cannot be considered the standard of care in these cases.
Chapter 4
●
Angioedema with Hypereosinophilia
220
Orson treated a 54-year-old man with angioedema and
hypereosinophilia with prednisone (40 mg/d) and IVIG
(400 mg/kg every 3 weeks). The patient had a marked
decrease in symptoms and eosinophil count after 6 weeks,
and prednisone was tapered off in 6 months. Interestingly,
when the brand of IVIG was changed from Panglobulin to
Gamimune N, the patient’s illness recurred. Retreatment
with Panglobulin led to remission again. This case report
emphasizes the biologic variability that may exist between
brands of IVIG.
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Wever S, Zillikenz D, Broker EB. Successful treatment of
pemphigus vulgaris by pulsed intravenous immunoglobulin
therapy. Br J Dermatol. 1996;135:862–3.
Beckers RC, Brand A, Vermeer BJ, Boom BW. Adjuvant high-dose intravenous gammaglobulin in the treatment
of pemphigus and bullous pemphigoid: experience in six
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Bewley AP, Keefe M. Successful treatment of pemphigus
vulgaris by pulsed intravenous immunoglobulin therapy. Br
J Dermatol. 1996;135:128–9.
Szep Z, Danilla T, Buchvald D. Treatment of juvenile pemphigus vulgaris with intravenous immunoglobulins. Cas Lek
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Levy A, Doutre MS, Lesage FX, et al. Treatment of pemphigus with intravenous immunoglobulin. Ann Dermatol
Venereol. 2004;131:957–61.
Nieves Renteria A, Ochoa Fierro JG, Martinez Ordaz VA,
Fernández del Castillo MA. Treatment with high doses of
intravenous immunoglobulin in a case of complicated pemphigus vulgaris. Rev Alerg Mex. 2005;52:39–41.
Jolles S, Hughes J, Rustin M. Therapeutic failure of highdose intravenous immunoglobulin in pemphigus vulgaris. J
Am Acad Dermatol. 1999;40:499–500.
Messer G, Sizmann N, Feucht H, Meurer M. High-dose
intravenous immunoglobulins for immediate control of
severe pemphigus vulgaris. Br J Dermatol. 1995;133:1014–
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Tappeiner G, Steiner A. High-dosage intravenous gamma
globulin: therapeutic failure in pemphigus and pemphigoid.
J Am Acad Dermatol. 1989;20:684–5.
Wetter DA, Davis MD, Yiannias JA, et al. Effectiveness
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Sami N, Bhol KC, Ahmed AR. Influence of IVIg therapy on
auto antibody titers to desmoglein 1 in patients with pemphigus foliaceus. Clin Immunol. 2002;105:192–8.
Ahmed AR, Sami N. Intravenous immunoglobulin therapy
for patients with pemphigus foliaceus unresponsive to conventional therapy. J Am Acad Dermatol. 2002;46:42–9.
Sami N, Qureshi A, Ahmed AR. Steroid sparing effect of
intravenous immunoglobulin therapy in patients with pemphigus foliaceus. Eur J Dermatol. 2002;12:174–8.
Toth GG, Jonkman MF. Successful treatment of recalcitrant penicillamine-induced pemphigus foliaceus by
low-dose intravenous immunoglobulins. Br J Dermatol.
1999;141:583–5.
48 E MERGENCY D ERMATOLOGY
162. Godard W, Roujeau JC, Guillot B, et al. Bullous pemphigoid and intravenous gammaglobulin. Ann Intern Med.
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163. Daoud YJ, Foster CS, Ahmed R. Eyelid skin involvement in
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164. Sami N, Ali S, Bhol KC, Ahmed AR. Influence of intravenous
immunoglobulin therapy on autoantibody titres to BP Ag1
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165. Yeh SW, Usman AQ, Ahmed AR. Profile of autoantibody to
basement membrane zone proteins in patients with mucous
membrane pemphigoid: long-term follow up and influence
of therapy. Clin Immunol. 2004;112:268–72.
166. Sami N, Bhol KC, Ahmed AR. Treatment of oral pemphigoid with intravenous immunoglobulin as monotherapy. Long-term follow-up: influence of treatment on antibody titers to human alpha6 integrin. Clin Exp Immunol.
2002;129:533–40.
167. Foster CS, Ahmed AR. Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid: a preliminary study.
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168. Jolles S. High-dose intravenous immunoglobulin (hdIVIg)
in the treatment of autoimmune blistering disorders. Clin
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169. Urcelay ML, McQueen A, Douglas WS. Cicatricial pemphigoid treated with intravenous immunoglobulin. Br J Dermatol. 1997;137:477–8.
170. Letko E, Bhol K, Foster SC, Ahmed RA. Influence of intravenous immunoglobulin therapy on serum levels of antibeta 4 antibodies in ocular cicatricial pemphigoid: a correlation with disease activity: a preliminary study. Curr Eye Res.
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171. Ahmed AR, Colon JE. Comparison between intravenous
immunoglobulin and conventional immunosuppressive
therapy regimens in patients with severe oral pemphigoid:
effects on disease progression in patients nonresponsive to
dapsone therapy. Arch Dermatol. 2001;137:1181–9.
172. Leverkus M, Gerogi M, Nie Z, et al. Cicatricial pemphigoid
with circulating IgA and IgG autoantibodies to the central
portion of the BP180 ectodomain: beneficial effect of adjuvant therapy with high-dose intravenous immunoglobulin. J
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173. Sami N, Letko E, Androudi S, et al. Intravenous
immunoglobulin therapy in patients with ocular-cicatricial
pemphigoid: a long-term follow-up. Ophthalmology.
2004;111:1380–2.
174. Daoud Y, Amin KG, Mohan K, Ahmed AR. Cost of
intravenous immunoglobulin therapy versus conventional
immunosuppressive therapy in patients with mucous membrane pemphigoid: a preliminary study. Ann Pharmacother.
2005;39:2003–8.
175. Kumari S, Bhol KC, Rehman F, et al. Interleukin 1
components in cicatricial pemphigoid: role in intravenous
immunoglobulin therapy. Cytokine. 2001;14:218–24.
176. Letko E, Miserocchi E, Daoud YJ, et al. A nonrandomized
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177. Revuz J, Penso D, Roujeau JC, et al. Toxic epidermal necrolysis: clinical findings and prognosis factors in 87 patients.
Arch Dermatol. 1987;123:1160–5.
178. Roujeau JC, Guillaume JC, Fabre JP, et al. Toxic epidermal
necrolysis (Lyell syndrome): incidence and drug etiology in
France, 1981–1985. Arch Dermatol. 1990;126:37–42.
179. Schopf E, Stuhmer A, Rzany B, et al. Toxic epidermal
necrolysis and Stevens-Johnson syndrome: an epidemiologic
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180. Bastuji-Garin S, Zahedi M, Guillaume JC, Roujeau JC.
Toxic epidermal necrolysis (Lyell syndrome) in 77 elderly
patients. Age Ageing. 1993;22:450–6.
181. Mockenhaupt M, Norgauer J. Cutaneous adverse drug
reactions. Stevens-Johnson syndrome and toxic epidermal
necrolysis. ACI International. 2002;14:143–50.
182. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous
immunoglobulin. Science. 1998;282:490–3.
183. Prins C, Kerdel FA, Padilla RS, et al. TEN-IVIG Study
Group, et al. Treatment of toxic epidermal necrolysis with
high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol.
2003;139:26–32.
184. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic
epidermal necrolysis: a prospective noncomparative study
showing no benefit on mortality or progression. Arch Dermatol. 2003;139:33–6.
185. Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Analysis
of intravenous immunoglobulin for the treatment of toxic
epidermal necrolysis using SCORTEN: the University of
Miami experience. Arch Dermatol. 2003;139:39–43.
186. Shortt R, Gomez M, Mittman N, Cartotto R. Intravenous immunoglobulin does not improve outcome in toxic
epidermal necrolysis. J Burn Care Rehabil. 2004;25:246–
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187. Stella M, Cassano P, Bollero D, et al. Toxic epidermal
necrolysis treated with intravenous high-dose immunoglobulins: our experience. Dermatology. 2001;203:45–9.
188. Campione E, Marulli GC, Carrozzo AM, et al. High-dose
intravenous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis. Acta Derm Venereol.
2003;83:430–2.
189. Tristani-Firouzi P, Petersen MF, Saffle JR, et al. Treatment
of toxic epidermal necrolysis with intravenous immunoglobulin in children. J Am Acad Dermatol. 2002;47:548–52.
190. Kim KJ, Lee DP, Suh HS, et al. Toxic epidermal necrolysis:
analysis of clinical course and SCORTEN-based comparison of mortality rate and treatment modalities in Korean
patients. Acta Derm Venereol. 2005;85:497–502.
191. Al-Mutairi N, Arun J, Osama NE, et al. Prospective, noncomparative open study from Kuwait of the role of intravenous immunoglobulin in the treatment of toxic epidermal
necrolysis. Int J Dermatol. 2004;43:847–51.
192. Brown KM, Siliver GM, Halerz M, et al. Toxic epidermal
necrolysis: does immunoglobulin make a difference? J Burn
Care Rehabil. 2004;25:81–8.
193. Morici MV, Galen WK, Shetty AK, et al. Intravenous
immunoglobulin therapy for children with Stevens-Johnson
syndrome. J Rheumatol. 2000;27:2494–7.
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194. Metry DW, Jung P, Levy ML. Use of intravenous
immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis: seven cases and review
of the literature. Pediatrics. 2003;112:1430–6.
195. Yip LW, Thong BY, Tan AW, et al. High-dose intravenous immunoglobulin in the treatment of toxic epidermal necrolysis: a study of ocular benefits. Eye. 2005;19:846–
53.
196. Amato GM, Travia A, Ziino O. The use of intravenous highdose immunoglobulins (IVIG) in a case of Stevens-Johnson
syndrome. Pediatr Med Chir. 1992;14:555–6.
197. Moudgil A, Porat S, Brunnel P, Jordan SC. Treatment of
Stevens-Johnson syndrome with pooled human intravenous
immuneglobulin. Clin Pediatr. 1995;34:48–51.
198. Sanwo M, Nwadiuko R, Beall G. Use of intravenous
immunoglobulin in the treatment of severe cutaneous drug
reactions in patients with AIDS. J Allergy Clin Immunol.
1996;98:1112–5.
199. Phan TG, Wong RC, Crotty K, Adelstein S. Toxic epidermal necrolysis in acquired immunodeficiency syndrome
treated with intravenous gammaglobulin. Australas J Dermatol. 1999;40:153–7.
200. Magina S, Lisboa C, Goncalves E, et al. A case of toxic epidermal necrolysis treated with intravenous immunoglobin.
Br J Dermatol. 2000;142:191–2.
201. Straussberg R, Harel L, Ben-Amitai D, et al.
Carbamazepine-induced
Stevens-Johnson
syndrome
treated with IV steroids and IVIG. Pediatr Neurol. 2000;22:
231–3.
202. Brett AS, Philips D, Lynn AW. Intravenous immunoglobulin therapy for Stevens-Johnson syndrome. South Med J.
2001;94:342–3.
203. Samimi SS, Siegfried E. Stevens-Johnson syndrome developing in a girl with systemic lupus erythematosus on highdose corticosteroid therapy. Pediatr Dermatol. 2002;19:52–
5.
204. Simeone F, Rubio ER. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin. J La State Med Soc.
2003;155:266–9.
205. Sidwell RU, Swift S, Yan CL, et al. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin. Int J
Clin Pract. 2003;57:643–5.
206. Tan A, Tan HH, Lee CC, Ng SK. Treatment of toxic epidermal necrolysis in AIDS with intravenous immunoglobulins.
Clin Exp Dermatol. 2003;28:269–71.
207. Mayorga C, Torres MJ, Corzo JL, et al. Improvement of
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Immunomodulators and the “Biologics” in Cutaneous Emergencies
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a single high dose of intravenous immunoglobulin. Ann
Allergy Asthma Immunol. 2003;91:86–91.
Kalyoncu M, Cimsit G, Cakir M, Okten A. Toxic epidermal necrolysis treated with intravenous immunoglobulin
and granulocyte colony-stimulating factor. Indian Pediatr.
2004;41:392–5.
Arca E, Kose O, Erbil AH, et al. A 2-year-old girl
with Stevens-Johnson syndrome toxic epidermal necrolysis
treated with intravenous immunoglobulin. Pediatr Dermatol. 2005;22:317–20.
Hebert AA, Bogle MA. Intravenous immunoglobulin prophylaxis for recurrent Stevens-Johnson syndrome. J Am
Acad Dermatol. 2004;50:286–8.
Lissia M, Figus A, Rubino C. Intravenous immunoglobulins and plasmapheresis combined treatment in patients with
severe toxic epidermal necrolysis: preliminary report. Br J
Plast Surg. 2005;58:504–10.
Tan AW, Thong BY, Yip LW, et al. High-dose intravenous
immunoglobulins in the treatment of toxic epidermal necrolysis: an Asian series. J Dermatol. 2005;32:1–6.
Nasser M, Bitterman-Deutsch O, Nassar F. Intravenous
immunoglobulin for treatment of toxic epidermal necrolysis. Am J Med Sci. 2005;329:95–8.
Neff P, Meuli-Simmen C, Kempf W, et al. Lyell syndrome
revisited: analysis of 18 cases of severe bullous skin disease
in a burns unit. Br J Plast Surg. 2005;58:73–80.
Spornraft-Ragaller P, Theilen H, Gottschlich GS, Ragaller
M. Treatment of toxic epidermal necrolysis experience with
9 patients with consideration of intravenous immunoglobulin. Hautarzt. 2006;57:185–94.
Mangla K, Rastogi S, Goyal P, et al. Efficacy of low dose
intravenous immunoglobulins in children with toxic epidermal necrolysis: open uncontrolled study. Indian J Dermatol
Venereol Leprol. 2005;71:398–400.
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with high dose intravenous immunoglobulins (IVIg): clinical experience to date. Drugs. 2005;65:2085–90.
French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and
Stevens-Johnson syndrome: our current understanding. Int
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Wolff K, Tappeiner G. Treatment of toxic epidermal necrolysis: the uncertainty persists but the fog is dispersing. Arch
Dermatol. 2003;139:85–6.
Orson FM. Intravenous immunoglobulin therapy suppresses
manifestations of the angioedema with hypereosinophilia
syndrome. Am J Med Sci. 2003;326:94–7.
CHAPTER 5
Critical Care: Stuff You Really,
Really Need to Know
Haim Shmilovich
Arie Roth
ALL PHYSICIANS should be experienced in the practices
and procedures of Basic Life Support (BLS) and Advanced
Cardiopulmonary Life Support (ACLS). Outside the hallowed hospital walls, “Is there a doctor in the house?” means
you! Within the hospital, the fundamental equipment and
staff are on hand, but it is the responsibility of the nearest
available physician to get it right and at maximum speed.
The dermatology ward is no stranger to life-threatening
events: This chapter is intended as a brief refresher course
for the situations that cannot wait.
The ultimate goal of resuscitation is to maintain cerebral perfusion until and after cardiopulmonary functions
are restored. Most adult cardiac arrests are due to ventricular arrhythmias for which early defibrillation is critical.
The emphasis is on stabilizing the patient on site so that he
or she can survive to get to an intensive care unit (ICU).
The critically ill patients already on the ward are still not
out of trouble, because they are usually being treated with
many medications, leaving them vulnerable to adverse drug
reactions, toxicity, and side effects, which themselves occur
more frequently in these patients due to altered hemodynamics and metabolism. The high rate and rapid initiation of complications necessitate careful monitoring of
vital signs and frequent physical examinations and laboratory tests. A high index of suspicion and close attention
to changing symptoms and parameters are mandatory for
preventing and/or treating any newly emerging medical
problem. Routine care of a critically ill patient involves
continuous assessment of symptoms, physical examination, hemodynamics, monitoring the need for changing
the dose and/or route of administration of drugs, and constant vigilance in terms of the supportive care that is being
administered.
Sedatives and analgesics are commonly administered to
the critically ill patient. The clinician must recognize the
diverse and often unpredictable effects of critical illness on
the pharmacokinetics and pharmacodynamics of sedatives
and analgesics. Failure to do so may lead to inadequate
or excessive sedation. Bear in mind that sedatives and analgesics may cause prolonged alterations in mental status and
may mask the development of coincident complications of
critical illness.
The provision of resuscitation is based on medical guidelines, written by expert panels from many disciplines. They
provide clear-cut instructions on the measures to be taken
for treating life-threatening situations while allowing alterations in individual cases. First and foremost, the physician must rapidly and correctly recognize the nature of
the emergent situation. To standardize treatment during
resuscitation, a number of algorithms have been developed that were based on large studies and on laboratory
and clinical evidence. These have been compiled into the
BLS and ACLS guidelines published and updated regularly.1,2 The most significant recent changes were made to
simplify cardiopulmonary resuscitation (CPR) instructions
and increase the number of chest compressions delivered
per minute while reducing the number of interruptions in
chest compressions during CPR. After delivering two rescue breaths, the rescuer begins chest compressions immediately. A universal recommendation is to provide a single
compression-to-ventilation ratio of 30:2. An important recommendation is that all rescue efforts – including insertion
of an advanced airway, administration of medications, and
reassessment of the patient – be performed in a way that
minimizes interruption of chest compressions. The most
important determinant of survival from sudden cardiac
arrest (SCA) is the presence of a trained rescuer who is
ready, willing, able, and equipped to act.
Unlike other medical interventions, CPR can be initiated without a physician’s order, based on implied consent
for emergency treatment. A physician’s order, however,
is necessary to withhold CPR. The decision to terminate
resuscitative efforts rests with the treating physician in the
hospital and is based on consideration of many factors,
including time to CPR, time to defibrillation, comorbid disease, prearrest state, and initial arrest rhythm. Witnessed
collapse, bystander CPR, and a short interval from collapse to the arrival of professionals improve the chances
of a successful resuscitation. Local ethical and cultural
norms must be considered when beginning and ending a
page 50
Chapter 5
resuscitation attempt: It behooves the physician to know
what they are. Patients or families may ask physicians
to provide care that is inappropriate. Physicians are not
obliged to provide such care when there is scientific and
social consensus against such treatment. One example is
the administration of CPR for patients with the clear-cut
signs of irreversible death. Whereas health care providers
are not obliged to provide CPR if no benefit from CPR
and ACLS can be expected, few criteria can accurately
predict the futility of CPR. In light of this uncertainty,
all patients in cardiac arrest should receive resuscitation,
unless the patient has a valid Do Not Attempt Resuscitation
(DNR) order, if the patient has the standard signs of irreversible death, or if no physiological benefit can be expected
because vital functions have deteriorated despite maximal
therapy.
BASIC LIFE SUPPORT
BLS includes recognition of life-threatening situations
(such as SCA, heart attack, pulmonary embolism [PE],
stroke, anaphylaxis, and foreign body airway obstruction
[FBAO]) and the provision of rapid and effective CPR and
defibrillation. SCA is a leading cause of death. Four critical points are important for the purpose of resuscitation:
early recognition of the emergency situation, early CPR,
early delivery of a shock, and early ACLS followed by
postresuscitation care. The algorithm of BLS consists of
the mnemonic ABC: A for airway, B for breathing, and C
for circulation/compression. When a person lies unresponsive and without movement, check the airway and open it by
the head tilt–chin lift maneuver. If the patient isn’t breathing, give two breaths. If there is a pulse, give breaths at a rate
of 10–12 per minute and recheck the pulse every 2 minutes.
If there is no central pulse, give a ratio of chest compressions to breaths of 30:2. The chest compressions should
be on the lower half of the sternum at a rate of 100 per
minute. It is important not to interrupt the chest compressions until the return of spontaneous rhythm/circulation
(ROSC) or the arrival of a defibrillator: Chest compressions are preferable to ventilation when there is a single
rescuer.
Supplementary oxygen should be used when available.
When the victim has an advanced airway in place during CPR, two rescuers should no longer deliver cycles of
CPR (compressions interrupted by pauses for ventilation).
Instead, the compressing rescuer should administer continuous chest compressions at a rate of 100 per minute without
pausing for ventilation. The rescuer delivering ventilation
should provide 8 breaths per minute. If the rhythm can
be altered by shock (e.g., a rapid heart rhythm), administer one shock with the highest energy and continue CPR
immediately for five more cycles of 30:2. Recheck pulse and
continue with shocks and CPR. If there is no pulse or the
rhythm had not been suitable for applying shock, continue
●
Critical Care: Stuff You Really, Really Need to Know
51
CPR and begin ACLS consisting of definitive breathing
with intubation and the use of medications.
All BLS providers should be trained to provide defibrillation because ventricular fibrillation (VF) is the most
common rhythm found in adults with witnessed, nontraumatic SCA. For these victims, survival rates are highest
when immediate bystander CPR is provided and defibrillation occurs within 3–5 minutes. The rescuer should intervene if the choking victim has signs of severe FBAO. These
include signs of poor air exchange and increased breathing difficulty, such as a silent cough, cyanosis, or inability to speak or breathe. Do not interfere with the patient’s
spontaneous coughing and breathing efforts. Chest thrusts,
back slaps, and abdominal thrusts are permissible and effective for relieving severe FBAO in conscious adults. If the
adult victim with FBAO becomes unresponsive, the rescuer
should carefully support the patient to the ground, and then
begin CPR.3,4
CARDIAC ARREST
Cardiac arrest, defined as the sudden complete loss of cardiac output and therefore blood pressure, is the leading
cause of death in the developed world. The mechanism of
cardiac arrest in victims of trauma, drug overdose, drowning, and in many children is asphyxia. CPR with both compressions and rescue breaths is critical for resuscitation of
these victims. In the majority of cases, the underlying etiology of arrest is myocardial ischemia in the setting of coronary artery disease. Conversely, cardiac arrest is the initial
presentation of myocardial ischemia in approximately 20%
of patients. A wide variety of other processes can lead to
cardiac arrest, including septic shock, electrolyte abnormalities, hypothermia, PE, and massive trauma.
Survival from cardiac arrest remains low, even after the
introduction of electrical defibrillation and CPR more than
50 years ago. In the best cases (witnessed VF arrest with
rapid defibrillation), survival to hospital discharge is about
35%, although overall out-of-hospital arrest survival is usually much lower, about 15%. Several studies have documented the effects of time to defibrillation and the effects
of bystander CPR on survival from SCA. For every minute
that passes between collapse and defibrillation, survival
rates from witnessed VF-SCA decrease by 10% if no CPR
is provided. If bystanders provide immediate CPR, many
adults in VF can survive with intact neurological function, especially if defibrillation is performed within about
5 minutes after SCA. CPR prolongs VF (the window of time
during which defibrillation can occur) and provides a small
amount of blood flow that may maintain some oxygen to
the heart and brain. Basic CPR alone, however, is unlikely
to eliminate VF and restore a perfusing rhythm. Even after
successful resuscitation from cardiac arrest, most patients
die within 48 hours despite aggressive intensive care treatment.
52 E MERGENCY D ERMATOLOGY
CPR is important both before and after shock delivery. When performed immediately after collapse from VFSCA, CPR can double or triple the victim’s chance of
survival. CPR should be provided uninterruptedly until a
defibrillator is available. After about 5 minutes of VF with
no treatment, outcome may be better if defibrillation is preceded by a period of CPR with effective chest compressions
that deliver some blood to the coronary arteries and brain.
CPR is also important immediately after shock delivery:
Most victims demonstrate asystole or pulseless electrical
activity (PEA) for several minutes after defibrillation, and
CPR can convert these rhythms to a perfusing rhythm.
Most victims of SCA demonstrate VF, which is characterized by chaotic rapid complexes that cause the heart to
tremble so that it is unable to pump blood effectively. Bear
in mind that many SCA victims can survive if bystanders act
immediately while VF is still present, but successful resuscitation is unlikely when the rhythm deteriorates to asystole.
During cardiac arrest, basic CPR and early defibrillation are of primary importance, and drug administration is
of secondary importance. After beginning CPR and defibrillation, rescuers can insert an advanced airway, establish
intravenous (IV) access, and consider drug therapy. If spontaneous circulation does not return after defibrillation and
peripheral venous drug administration, the provider may
consider placement of a central line through the subclavian vein. When dealing with a pulseless arrest rhythm,
begin BLS and CPR and call for help immediately. Attach
defibrillator leads. VF or ventricular tachycardia (VT) are
shockable rhythms. Give one shock (maximum energy)
and continue five cycles of CPR with ACLS. Check again
for rhythm and, if appropriate, give shock medications
until return of a pulse. These medications are epinephrine
(adrenaline) 1 mg IV every 3–5 minutes for 3 doses, or a
single dose of vasopressin 40 U IV. After a second cycle of
shocks–medications without response, consider the administration of amiodarone 300 mg IV, lidocaine IV at 1–1.5
mg/kg, and/or magnesium 1–2 g IV. If asystole is diagnosed, continue CPR while giving epinephrine or vasopressin as already mentioned, and consider atropine 1 mg
IV every 3–5 minutes up to 3 doses. Check routinely for
pulse or shockable rhythms and proceed accordingly, all the
while bearing in mind that chest compressions must not be
interrupted until ROSC. In adults with a prolonged arrest,
shock delivery may be more successful after a period of
effective chest compressions. There is insufficient evidence
to recommend routine administration of fluids to treat cardiac arrest, but fluids should be infused if hypovolemia is
suspected.5–9
Finally, it is important to search for and treat possible reversible etiologies which are summarized as “6h’s
and 5t’s”: hypovolemia, hypoxia, hydrogen ion (acidosis),
hypo/hyperkalemia, hypoglycemia, hypothermia, toxins,
tamponade, tension pneumothorax, thrombosis (coronary
or pulmonary), and trauma.
ASYSTOLE AND PULSELESS ELECTRICAL
ACTIVITY
PEA encompasses a heterogeneous group of pulseless
rhythms. Pulseless patients with electrical activity have
associated mechanical contractions, but these contractions
are too weak to produce a blood pressure detectable by
palpation or noninvasive blood pressure monitoring. PEA
is often caused by reversible conditions (the 6h’s and 5t’s)
and can be treated if those conditions are identified and corrected. Patients who have either asystole or PEA will not
benefit from defibrillation attempts. The focus of resuscitation is to perform high-quality CPR with minimal interruptions and to identify reversible causes or complicating
factors. Providers should insert an advanced airway. Rescuers should minimize interruptions in chest compressions
while inserting the airway and should not interrupt CPR
while establishing IV access. If the rhythm check confirms
asystole or PEA, resume CPR immediately. A vasopressor (epinephrine or vasopressin) may be administered at
this time. Epinephrine can be administered approximately
every 3–5 minutes during cardiac arrest; one dose of vasopressin may be substituted for either the first or second
epinephrine dose. For a patient in asystole or slow PEA,
consider atropine. Do not interrupt CPR to deliver any
medication. Give the drug as soon as possible after the
rhythm check. After drug delivery and approximately five
cycles (or about 2 minutes) of CPR, recheck the rhythm. If
a shockable rhythm is present, deliver a shock. If no rhythm
is present or if there is no change in the appearance of the
electrocardiogram (ECG), immediately resume CPR. If an
organized rhythm is present, try to palpate a pulse. If no
pulse is present, continue CPR. If a pulse is present, the
provider should identify the rhythm and treat accordingly.
If the patient appears to have an organized rhythm with a
good pulse, begin postresuscitative care.
SYMPTOMATIC BRADYARRHYTHMIA OR
TACHYARRHYTHMIA
Cardiac arrhythmias are a common cause of sudden death.
ECG monitoring should be established as soon as possible
for all patients who collapse suddenly or have symptoms
of coronary ischemia or infarction. In general, if bradycardia produces signs and symptoms (acute alteration of mental status, ongoing severe ischemic chest pain, congestive
heart failure, and hypotension) that persist despite adequate
airway and breathing, prepare to provide pacing. For symptomatic high-degree atrioventricular (AV) block (seconddegree AV block Mobitz type II and third-degree AV block)
provide transcutaneous pacing without delay. If the tachycardic patient is unstable with severe signs and symptoms
related to tachycardia, prepare for immediate cardioversion. If the patient with tachycardia is stable, determine if he
or she has a narrow-complex or wide-complex tachycardia
Chapter 5
and then tailor therapy accordingly. In a patient with a heart
rate lower than 60 beats per minute, which is inadequate for
the clinical situation, check for airway and breathing and
provide supplementary oxygen. Check vital signs, establish
an IV access, and try to diagnose the bradyarrhythmia. If
there are signs of adequate perfusion, observe and monitor the patient for the possibility of reversible causes with
either later improvement or continuing deterioration. If
there are signs of poor perfusion, call a cardiologist and
begin to prepare for transcutaneous pacing, while considering atropine 0.5 mg IV for a total dose of 3 mg, and
if the atropine is ineffective, begin to pace. Also consider
epinephrine or dopamine by continuous drip while waiting
for pacing. Use a temporarily external pacemaker if one is
available. In conjunction with all of the above, identify and
treat contributing factors (the 6h’s and 5t’s).
Atropine remains the first-line drug for acute symptomatic bradycardia. An initial dose of 0.5 mg, repeated
as needed to a total of 3 mg, is effective in the treatment of symptomatic bradycardia. Transcutaneous pacing is usually indicated if the patient fails to respond to
atropine, although second-line drug therapy with medications such as dopamine or epinephrine may be successful. Atropine will not suffice for infranodal blocks; they
require a pacemaker. Other medications to consider are
epinephrine (adrenaline), dopamine, or glucagon in the
case of beta blocker or calcium channel blocker toxicity.
Transcutaneous pacing is a class I intervention for any
symptomatic bradycardia. It should be started immediately
for patients who are unstable, particularly those with highdegree AV block.
After defibrillation and stabilization of the patient, the
next step is to treat the factors that may have precipitated
the tachycardia, if possible, such as fever, pulmonary emboli, hyperthyroidism, or acute myocardial infarction (MI).
Supraventricular tachycardias (SVTs) with the pathophysiology of reentry will respond to carotid massage and/or
adenosine 6-mg IV administration with abrupt cessation of
the tachycardia. Other SVTs will necessitate slowing of the
ventricular response by slowing the AV node conduction
with IV medications such as beta blockers and/or calcium
channel blockers and by trying to convert the rhythm to
sinus rhythm if the tachyarrhythmia is not of long duration
and there is a minimal risk of thromboembolism. Widecomplex tachycardias are often hemodynamically unstable
and necessitate defibrillation. If the patient is stable (systolic
blood pressure greater than 90 mm Hg, no angina pectoris,
no altered mentation or signs of hypoperfusion), one can
try IV medications. If there is the possibility of VT (note:
any regular wide-complex tachycardia in an elderly person
with a history of prior MI has a more than 80% chance
of being VT), a trial of amiodarone or lidocaine is recommended. Amiodarone is given as a loading dose of 150
mg over 15 minutes and then in a 1200-mg maintenance
drip over 24 hours. Lidocaine is given as a loading dose of
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Critical Care: Stuff You Really, Really Need to Know
53
1–1.5 mg/kg slow push and then a maintenance drip of
2 g/day. If the diagnosis of VT is not possible, a trial of
procainamide 20 mg every 1 minute should be considered
until the tachycardia responds.
Although synchronized cardioversion is preferred for
treatment of an organized ventricular rhythm, it is not possible for some arrhythmias. The many QRS configurations
and irregular rates that comprise polymorphic VT make
it difficult or impossible to reliably synchronize to a QRS
complex. In addition, the patient with persistent polymorphic VT will probably not maintain perfusion/pulses for
very long, so any attempt to distinguish between polymorphic VT with or without pulses quickly becomes doubtful.
A good rule of thumb is that if your eye cannot synchronize
to each QRS complex, neither can the defibrillator. If there
is any doubt whether monomorphic or polymorphic VT is
present in the unstable patient, do not delay shock delivery
to perform detailed rhythm analysis – provide high-energy
unsynchronized shocks. After shock delivery, be prepared
to provide immediate CPR and follow the ACLS Pulseless
Arrest Algorithm if pulseless arrest develops.
MEDICATION IN ACLS AND OTHER CARDIAC
EMERGENT CASES
Epinephrine
Epinephrine produces beneficial effects in patients during
cardiac arrest, primarily because of its adrenergic receptorstimulating (vasoconstrictor) properties, which increase
coronary and cerebral perfusion pressure during CPR. The
value and safety of the β-adrenergic effects of epinephrine
are controversial because they may increase myocardial
work and reduce subendocardial perfusion. It is appropriate to administer a 1-mg dose of epinephrine IV every 3–5
minutes during adult cardiac arrest. If IV access is delayed
or cannot be established, epinephrine may be given by the
endotracheal route at a dose of 2–2.5 mg.
Vasopressin
Vasopressin is a nonadrenergic peripheral vasoconstrictor that also causes coronary and renal vasoconstriction.
There are no significant differences between vasopressin
and epinephrine for ROSC, 24-hour survival, or survival
to hospital discharge. Because vasopressin effects have not
been shown to differ from those of epinephrine in cardiac
arrest, one dose of vasopressin 40 U IV may replace either
the first or second dose of epinephrine in the treatment of
pulseless arrest.
Atropine
Atropine reverses cholinergic-mediated decreases in heart
rate, systemic vascular resistance, and blood pressure. It
54 E MERGENCY D ERMATOLOGY
can be considered for asystole or PEA. The recommended
dose of atropine for cardiac arrest is 1 mg IV, which can be
repeated every 3–5 minutes (maximum total of 3 doses or
3 mg) if asystole persists.
Amiodarone
IV amiodarone affects sodium, potassium, and calcium
channels as well as ␣- and -adrenergic blocking properties.
It can be considered for the treatment of VF or pulseless
VT unresponsive to shock delivery, CPR, and a vasopressor. It improves survival rates and defibrillation response
when given for VF or hemodynamically unstable VT.
Lidocaine
Lidocaine is an alternative antiarrhythmic of long-standing
familiarity with fewer immediate side effects than may be
encountered with other antiarrhythmics. Lidocaine, however, has no proven short-term or long-term efficacy in
cardiac arrest. It should be considered an alternative treatment to amiodarone. The initial dose is 1–1.5 mg/kg IV.
If VF/pulseless VT persists, additional doses of 0.5–0.75
mg/kg IV push may be administered at 5- to 10-minute
intervals, to a maximum dose of 3 mg/kg.
refractoriness in the AV node. These actions may terminate
reentrant arrhythmias and control ventricular response rate
in patients with a variety of atrial tachycardias. These medications are indicated for stable, narrow-complex, reentry
mechanism tachycardias (reentry SVT) if rhythm remains
uncontrolled or unconverted by adenosine or vagal maneuvers, for stable, narrow-complex, automaticity mechanism
tachycardias if the rhythm is not controlled or converted by
adenosine or vagal maneuvers, and for controlling the rate
of ventricular response in patients with atrial fibrillation or
atrial flutter. IV verapamil 2.5–5 mg is effective for terminating narrow-complex reentry SVT, and it may also be
used for rate control in atrial fibrillation. Verapamil should
be given only to patients with narrow-complex reentry SVT
or arrhythmias known with certainty to be of supraventricular origin. It should not be given to patients with impaired
ventricular function or heart failure.
Diltiazem seems to be equivalent in efficacy to verapamil. It is administered at a dose of 20 mg IV over 2 minutes, and repeated after 15 minutes at a dose of 25 mg.
Verapamil and, to a lesser extent, diltiazem may decrease
myocardial contractility and critically reduce cardiac output in patients with severe left ventricular dysfunction.
-Adrenergic Blockers
Adenosine is an endogenous purine nucleoside that briefly
depresses AV node and sinus node activity. It is recommended for defined, stable, narrow-complex AV nodal or
sinus nodal reentry tachycardias. Adenosine will not terminate arrhythmias, such as atrial flutter, atrial fibrillation,
or atrial or ventricular tachycardias, because these arrhythmias are not caused by reentry involving the AV or sinus
node. Adenosine has a short half-life. Its acute dose is 6
mg IV while monitoring the ECG. If there is no response
within 3–5 minutes, a repeat dose of 12 mg IV should be
tried, and then a third one by the same rules. Each dose of
adenosine should be flushed with 20 cc of saline.
Beta blocking agents (atenolol, metoprolol, labetalol, propranolol, esmolol) reduce the effects of circulating catecholamines and decrease heart rate and blood pressure.
They also have various cardioprotective effects for patients
with ACS. For acute tachyarrhythmias, these agents are
indicated for rate control for narrow-complex tachycardias
that originate from either a reentry mechanism (reentry
SVT) or an automatic focus uncontrolled by vagal maneuvers and adenosine in the patient with preserved ventricular function, and to control the rate in atrial fibrillation and
atrial flutter in the patient with preserved ventricular function. Commonly used drugs in the acute situation are propranolol 1 mg IV and metoprolol 5 mg IV. They can later be
converted to oral propranolol 10 mg three times per day or
oral metoprolol 25 mg twice a day, respectively. Side effects
related to β-blockade include bradycardias, AV conduction
delays, and hypotension. Cardiovascular decompensation
and cardiogenic shock after β-adrenergic blocker therapy
are infrequent complications. Contraindications to the use
of β-adrenergic blocking agents include second- or thirddegree heart block, hypotension, severe congestive heart
failure, and lung disease associated with bronchospasm.
These agents may be harmful for patients with atrial fibrillation or atrial flutter associated with known preexcitation
(Wolff–Parkinson–White [WPW]) syndrome.
Calcium Channel Blockers: Verapamil and Diltiazem
Procainamide
Verapamil and diltiazem are nondihydropyridine calcium
channel blocking agents that slow conduction and increase
Procainamide suppresses both atrial and ventricular
arrhythmias by slowing conduction in myocardial tissue.
Magnesium
Magnesium can effectively terminate torsades de pointes
(irregular/polymorphic VT associated with prolonged QT
interval). It is not likely to be effective in terminating irregular/polymorphic VT in patients with a normal QT interval. The acute treatment is 1- to 2-g IV loading dose and a
maintenance dose of 3–5 g/day. Care must be taken in renal
failure and congestive heart failure, where those dosages
should be halved, and serum magnesium level should be
monitored.
Adenosine
Chapter 5
Procainamide is superior to lidocaine in terminating spontaneously occurring VT when given in doses of 100 mg IV
every 5–10 minutes as tolerated, not to exceed 1000 mg.
Procainamide may be considered in stable monomorphic
VT in patients with preserved ventricular function, control
of heart rate in atrial fibrillation or atrial flutter in patients
with preserved ventricular function, acute control of heart
rhythm in atrial fibrillation or atrial flutter in patients with
known preexcitation (WPW) syndrome and preserved ventricular function, and for AV reentrant, narrow-complex
tachycardias, such as reentry SVT if rhythm is uncontrolled
by adenosine and vagal maneuvers in patients with preserved ventricular function.
OTHER EMERGENCIES
Foreign Body Airway Obstruction
Death from FBAO is an uncommon but preventable cause
of death. Most reported cases of FBAO in adults are
caused by impacted food and occur while the victim is
eating. Because recognition of airway obstruction is the
key to successful outcome, it is important to distinguish
this emergency from fainting, heart attack, seizure, or
other conditions that may cause sudden respiratory distress, cyanosis, or loss of consciousness. When FBAO produces signs of severe airway obstruction, rescuers must
act quickly to relieve the obstruction. If mild obstruction is present and the victim is coughing forcefully, do
not interfere with his or her spontaneous coughing and
breathing efforts. Attempt to relieve the obstruction only
if signs of severe obstruction develop: The cough becomes
silent, respiratory difficulty increases and is accompanied by
stridor, or the victim becomes unresponsive. For responsive adults and children at least 1 year old with severe
FBAO, case reports show the feasibility and effectiveness
of back blows or “slaps,” abdominal thrusts, and chest
thrusts. Although these maneuvers are feasible and effective for relieving severe FBAO in conscious adults and
children at least 1 year of age, for simplicity in training, we recommend that the abdominal thrust be applied
in rapid sequence until the obstruction is relieved. If
abdominal thrusts are not effective, the rescuer may consider chest thrusts. It is important to note that abdominal thrusts are not recommended for infants younger
than 1 year because the thrusts themselves may cause
injuries. Chest thrusts should be used for obese patients
if the rescuer is unable to encircle the victim’s abdomen.
If the choking victim is in the late stages of pregnancy,
the rescuer should use chest thrusts instead of abdominal
thrusts. If the adult victim with FBAO becomes unresponsive, the rescuer should carefully support the patient to
the ground and then begin CPR. A health care provider
should use a finger sweep only when the provider can see
solid material obstructing the airway of an unresponsive
patient.
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Critical Care: Stuff You Really, Really Need to Know
55
Pulmonary Embolism
PE is a life-threatening condition. The embolus usually
derives from the deep veins of the leg or pelvis. Critically ill and bedridden patients are at high risk. Other
common risk factors include thrombophilia and cancer.
The main clues of an existing PE are dyspnea, tachypnea, tachycardia, low saturation, and sometimes pleuritic
chest pain, in the above settings. The gold standard for
diagnosis is computed tomographic (CT) angiography.
The patient should be treated with oxygen and anticoagulation (e.g., subcutaneous [SC] enoxaparin 1 mg/kg
twice a day, reduced to once daily if renal function is
impaired). In severe life-threatening cases assessed clinically and/or echocardiographically, the treatment should
be fibrinolysis (IV streptokinase 250,000 U bolus maintained at 100,000 U/h for up to 48–72 hours). To prevent PE, critically ill patients should be treated with anticoagulation prophylaxis while bedridden (SC enoxaparin
1 mg/kg once daily or SC heparin 5000–7500 U twice or
thrice daily). Recurrent PE or contraindications to anticoagulation will necessitate the usage of an inferior vena caval
filter.
Pulmonary Edema
Pulmonary edema is a life-threatening condition caused
by both cardiogenic and noncardiogenic etiologies, such
as acute MI, acute heart failure, hypertensive crisis, pulmonary emboli, or infections. The etiology must be sought
and treated, in parallel with the administration of diuretics, vasodilators, and morphine, as needed. Recommended
doses are IV furosemide 40 mg (or 60 mg in renal failure), IV nitroglycerin 1 mg/h and uptitrated as blood pressure permits (contraindicated if systolic blood pressure is
<90 mm Hg), and IV morphine 3 mg, repeated as needed.
A continuous positive airway pressure (CPAP) device and
sometimes intubation will be needed until the patient is
stabilized.
Myocardial Infarction
MI is primarily the consequence of atherothrombotic disease of the coronary arteries. Atherosclerosis of the coronary arteries is a common phenomenon in the vast majority of the population, and its occurrence coincides with
“atherosclerotic risk factors,” for example, smoking, diabetes mellitus, hypertension, hyperlipidemia, and family history of premature coronary disease. Atherosclerotic
plaques can disrupt blood flow caused by mechanical or
inflammatory factors, and they can erode and rupture
so that a thrombus evolves rapidly on top of them,
thus atherothrombosis. Other etiologies of MI include
embolization or spasm of the coronary artery. Many
patients suffering an acute MI die instantly because of
acute complications, such as malignant ventricular arrhythmia or mechanical failure of the heart. Others who reach
56 E MERGENCY D ERMATOLOGY
the hospital need to be treated immediately to open the
occluded coronary artery, either medically with thrombolytics or mechanically with percutaneous coronary intervention (PCI). Afterward, the patient must take medications for secondary prevention (aspirin, beta blockers, angiotensin-converting enzyme [ACE] inhibitors) and
aggressively treat any modifiable risk factor.
A patient with risk factors and/or a prior coronary event
who presents with typical chest pain must immediately be
given chewable aspirin 300 mg, IV heparin 80 U/kg, and
sublingual nitrate if his or her blood pressure is normal. An
ECG must be immediately performed and interpreted: If
it shows classical signs of ST elevation MI, the patient has
to be prepared for immediate PCI. If the ECG is normal,
the patient needs to be monitored, undergo repeat ECG,
and have blood drawn for measuring troponin levels at 4–6
hours from the beginning of pain: A high troponin level
means a non-ST elevation MI, and a normal value means
acute coronary syndrome (ACS) or unstable angina pectoris
(UAP). Either way, based on clinical and hemodynamic
parameters and on noninvasive tests, a diagnostic coronary
angiography will need to be performed to evaluate the need
for revascularization.
Stroke
Stroke is the number 3 killer and a leading cause of
severe, long-term disability. Fibrinolytic therapy administered within the first hours of the onset of symptoms contains neurological injury and improves outcome in selected
patients with acute ischemic stroke. The window of opportunity is, however, extremely limited. Effective therapy
requires early detection of the signs of stroke, appropriate evaluation and testing, and rapid delivery of fibrinolytic
agents to eligible patients. The goal of stroke care is to minimize brain injury and maximize patient recovery. When
there is suspicion of stroke, the goal of care is to perform the
initial assessment within 10 minutes, performing and interpreting a CT scan within 25 minutes, and administering
fibrinolytics to selected patients within 3 hours of the onset
of symptoms. If the stroke patient is not eligible for fibrinolytic therapy and there is no suspicion of a hemorrhagic
stroke (either by CT or clinically/anamnestically, such as no
head trauma, no anticoagulation therapy, no uncontrolled
hypertension or arteriovenous malformations), then the
immediate treatment is high-dose aspirin. A rapid assessment of consciousness and neurological status is performed
using the Glasgow Coma Scale, which is based on three
parameters: eye movement, motor assessment, and verbal
assessment. The scores range from 3 (poorest) to 15 (best).
Any stroke victim with a score less than 8 needs airway
protection with endotracheal intubation.
Patients with acute stroke are at risk for respiratory
compromise from aspiration, upper airway obstruction,
hypoventilation, and neurogenic pulmonary edema. The
combination of poor perfusion and hypoxemia will exacerbate and extend ischemic brain injury, and has been associated with worse outcome from stroke. The administration
of supplementary oxygen is mandatory.
A 12-lead ECG does not take priority over the CT scan,
but it may identify a recent acute MI or arrhythmias (atrial
fibrillation) as the cause of an embolic stroke. There is general agreement to recommend cardiac monitoring during
the initial evaluation of patients with acute ischemic stroke
to detect atrial fibrillation and potentially life-threatening
arrhythmias. Management of hypertension in the stroke
patient is controversial. For patients eligible for fibrinolytic
therapy, however, control of blood pressure is required to
reduce the potential risk of bleeding. If a patient who is
otherwise eligible for treatment with tissue plasminogen
activator (tPA) has elevated blood pressure, try to lower
it to <185/<110 mm Hg. Because the maximum interval
from onset of stroke until effective treatment of stroke with
tPA is limited, most patients with sustained hypertension
above these levels cannot be treated with IV tPA. Fibrinolytic administration is not recommended if the patient’s
neurological signs appear to be clearing spontaneously and
approaching baseline.
As with all medications, fibrinolytics have potential
adverse effects. The physician must verify that there are
no exclusion criteria, consider the risks and benefits to the
patient, and be prepared to monitor and treat any potential complications. The major complication of IV tPA for
stroke is symptomatic intracranial hemorrhage.
Hypertensive Crisis
Marked elevation of blood pressure to levels greater
than 200/120 mm Hg requires immediate attention. The
urgency and the method of treatment are not dictated solely
by the absolute level of blood pressure but also according
to the patient’s clinical status. The treatment is urgent if
the patient is encephalopathic, pregnant with toxemia, or
suffering from acute myocardial ischemia, aortic dissection,
or acute stroke. Malignant hypertension is a clinical diagnosis manifested by systolic blood pressure greater than
220 mm Hg and/or diastolic blood pressure greater than
130 mm Hg with hemorrhagic retinopathy, papilledema,
and other end-organ involvement, such as renal failure
and encephalopathy. Clinically, the patient is likely to have
pulmonary edema, in which case the treatment of choice
will combine a diuretic (IV furosemide 40 mg) with a
vasodilator (e.g., as nitroglycerin 1 mg/h and uptitrated
or nitroprusside 0.3–10 µg/kg/min). Other maintenance
therapies constitute thiazides (oral chlorothiazide 12.5 mg
once daily), ACE inhibitors (e.g., oral enalapril 10 mg twice
daily), central acting drugs (oral aldimine 250 mg twice
daily), and alpha (oral doxazosin 1–8 mg once daily), beta
(oral metoprolol 25 mg twice daily), and/or calcium blockers (oral amlodipine 5 mg once daily). The aim of urgent
Chapter 5
treatment is to lower the blood pressure by not more than
25% so as not to impair cerebral blood flow. Practically, the
drug regimen should contain IV furosemide 40 mg push
and IV nitroglycerin 20 mg/100 mg saline (beginning 2
cc/h rate, uptitrated as needed). Consider a beta blocker
(also exerting alpha-blocking effects) such as labetalol at
an initial IV dose of 20 mg injected over 2 minutes and
additional injections of 40 or 80 mg every 10 minutes as
needed up to a total dose of 300 mg. Another possibility is an agent with direct vasodilator properties, such as
nitroprusside with a starting dosage of 0.1 g/kg/min and
increased as necessary and as tolerated.
Shock
Shock is a syndrome of low blood pressure and inadequate end-organ perfusion. Its main etiologies are cardiogenic, septic, hemorrhagic, and anaphylactic. Cardiogenic
shock must be considered in a patient with a history of
heart disease who presents with chest pain and low blood
pressure with peripheral hypoperfusion. In such a patient,
the shock is most probably due to acute MI and/or acute
heart failure. As such, treatment will constitute revascularization with either PCI or coronary artery bypass grafting and inotropic drugs (e.g., IV dopamine 400 mg/500 cc
saline in an initial rate of 5 cc/h, or IV dobutamine 500
mg/500 cc saline, in an initial rate of 5 cc/h). Septic shock
is probable in a patient with fever, chills, and infection; the
patient must be treated with fluids, antibiotics, and glucocorticoids for adrenal insufficiency. Patients who have
lost blood must be treated with blood transfusion. Anaphylactic shock is due to drugs or toxins, and the immediate
treatment is SC adrenaline 0.1 mg and the usual supportive
treatment.
SPECIAL PROCEDURES
Endotracheal Intubation
The endotracheal tube confirms a patent airway, permits
suctioning of airway secretions, enables delivery of a high
concentration of oxygen, provides an alternative route for
the administration of some drugs, facilitates delivery of
a selected tidal volume, and, with the use of a cuff, may
protect the airway from aspiration. Endotracheal intubation attempts by unskilled providers can produce complications such as trauma to the oropharynx, interruption of compressions and ventilations for unacceptably
long periods, and hypoxemia from prolonged intubation
attempts or failure to recognize tube misplacement or displacement. Indications for emergency endotracheal intubation are the inability of the rescuer to adequately ventilate the unconscious patient with a bag and mask and
the absence of airway protective reflexes (coma or cardiac
arrest).
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Critical Care: Stuff You Really, Really Need to Know
57
During CPR, the rescuers should minimize the number
and duration of interruptions in chest compressions, with
the goal of limiting interruptions to no more than 10 seconds except as needed for interventions, such as placement
of an advanced airway. Interruptions needed for intubation
can be minimized if the intubating rescuer is prepared to
begin the intubation attempt as soon as the compressing
rescuer pauses in administering compressions. The compressions should be interrupted for only as long as the
intubating rescuer needs to visualize the vocal cords and
insert the tube. The compressing rescuer should be prepared to resume chest compressions immediately after the
tube is passed through the vocal cords. If more than one
intubation attempt is required, the rescuers should provide
a period of adequate ventilation and oxygenation and chest
compressions between attempts. If endotracheal intubation
is performed for the patient with a perfusing rhythm, use
pulse oximetry and ECG monitoring continuously during
intubation attempts and interrupt the attempt to provide
oxygenation and ventilation if needed.
Even when the endotracheal tube is seen to pass through
the vocal cords and tube position is verified by chest expansion and auscultation during positive-pressure ventilation,
rescuers should obtain additional confirmation of placement by using an end-tidal CO2 or esophageal detection
device. The most important caveats for rescuers performing CPR after insertion of the advanced airway are to be
sure the advanced airway is correctly placed and to not cease
CPR efforts.
Complications of endotracheal intubation are associated
with improper endotracheal tube positioning. Esophageal
and right main stem bronchus intubation should be suspected if hypoxemia, hypoventilation, or cardiac decompensation occurs. Abdominal distension, lack of breath
sounds over the thorax, and regurgitation of stomach contents indicate esophageal intubation. In emergency settings when standard endotracheal intubation cannot be performed, needle cannulation of the cricothyroid membrane
can be performed as a stopgap before providing a more
definitive airway.
Central Venous Catheterization
Central venous catheterization is the insertion of an
indwelling catheter to a large central vein, mostly the subclavian or internal jugular veins. It is mainly indicated for
better fluid therapy, drug administration, and parenteral
nutrition, and for monitoring of the central venous pressure. The only contraindication against its use is an existing
coagulopathy.
Postresuscitation Support
The management of successfully resuscitated patients
should focus on the treatment of the underlying disease
58 E MERGENCY D ERMATOLOGY
process and the maintenance of electrical, hemodynamic, and respiratory stability. All patients require careful repeated assessment and should be initially monitored in an ICU. Few randomized, controlled clinical
trials have dealt specifically with supportive care following cardiopulmonary–cerebral resuscitation from cardiac
arrest; nevertheless, postresuscitation care has significant
potential to improve early mortality caused by hemodynamic instability and multiorgan failure and later mortality/
morbidity resulting from brain injury.
The initial objectives of postresuscitation care are to
optimize cardiopulmonary function and systemic perfusion, especially perfusion to the brain, and to continue care in an appropriately equipped critical care unit.
Attempts are made to identify the precipitating causes
of the arrest, and measures are instituted to prevent
recurrence and improve long-term, neurologically intact
survival.
Induced Hypothermia
Both permissive hypothermia (allowing a mild degree of
hypothermia >33◦ C that often develops spontaneously
after arrest) and active induction of hypothermia may
play a valuable role in postresuscitation care. In two randomized, clinical trials,10,11 induced hypothermia resulted
in improved outcome in adults who remained comatose
after initial resuscitation from cardiac arrest. Complications associated with cooling can include coagulopathy
and arrhythmias, particularly with an unintentional drop
below target temperature. There was some increase in the
number of cases of pneumonia and sepsis in the
hypothermia-induction group. Cooling may also increase
hyperglycemia. These authors concluded that mild hypothermia may be beneficial to neurological outcome and
is likely to be well tolerated without significant risk of complications.
Glucose Control
The postresuscitation patient is likely to develop electrolyte
abnormalities that may be detrimental to recovery. Many
studies have documented a strong association between high
blood glucose after resuscitation from cardiac arrest and
poor neurological outcomes. Tight control of blood glucose using insulin reduced hospital mortality rates in critically ill patients who required mechanical ventilation. Signs
of hypoglycemia are less apparent in comatose patients,
so clinicians must monitor serum glucose closely to avoid
hypoglycemia when treating hyperglycemia. On the basis
of findings of improved outcomes in critically ill patients,
when glucose levels are maintained in the normal range, it
makes sense to maintain strict glucose control during the
postresuscitation period.
Organ-Specific Evaluation and Support
After ROSC, patients may remain comatose or have
decreased responsiveness for a variable period of time. If
spontaneous breathing is absent or inadequate, mechanical ventilation via an endotracheal tube or other advanced
airway device may be required. Hemodynamic status may
be unstable when there are abnormalities of cardiac rate,
rhythm, systemic blood pressure, and organ perfusion.
Clinicians must prevent, detect, and treat hypoxemia and
hypotension, because these conditions can exacerbate brain
injury. It is essential to determine the baseline postarrest
status of each organ system and support impaired organ
function as needed.
Respiratory System
Respiratory dysfunction is not uncommon after ROSC.
Some patients will remain dependent on mechanical ventilation and will need an increased inspired concentration of
oxygen. They should undergo a full physical examination
as well as a chest x-ray to verify appropriate endotracheal
tube depth of insertion and to identify any cardiopulmonary
complications of resuscitation. Mechanical ventilatory
support should be adjusted based on the patient’s blood
gas values, respiratory rate, and work of breathing. As the
patient’s spontaneous ventilation becomes more efficient,
the level of respiratory support may be decreased until
spontaneous respiration returns. If the patient continues
to require high inspired oxygen concentrations, providers
should determine if the cause is pulmonary or cardiac
and take measures accordingly. There is some debate as
to the length of time that patients who require ventilatory support should remain sedated. To date, there is little
evidence to guide therapeutic scheduling and inadequate
data to recommend for or against the use of a defined
period of sedation or neuromuscular blockade after cardiac arrest. Use of neuromuscular blocking agents should
be kept to a minimum because they preclude thorough
neurological assessments during the first 12–72 hours after
ROSC.
Sustained hypocapnia may reduce cerebral blood flow.
After cardiac arrest, restoration of blood flow results in
an initial hyperemic blood flow response, followed by a
more prolonged period of low blood flow. During this latter period of late hypoperfusion, there may be a mismatch
between blood flow and oxygen requirement. If the patient
is hyperventilated at this stage, cerebral vasoconstriction
may further decrease cerebral blood flow and increase cerebral ischemia and ischemic injury. There is no evidence that
hyperventilation protects the brain or other vital organs
from further ischemic damage after cardiac arrest.
In summary, although there are no data to support targeting a specific arterial PaCO2 level after resuscitation
from cardiac arrest, data extrapolated from patients with
Chapter 5
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Critical Care: Stuff You Really, Really Need to Know
59
brain injury support ventilation to reach normocarbic levels. Routine hyperventilation is detrimental.12
the posttresuscitation setting seems prudent if there are no
contraindications.
Cardiovascular System
Central Nervous System
Both the ischemia/reperfusion of cardiac arrest and electrical defibrillation can cause transient myocardial stunning and dysfunction that can last many hours but may
improve with vasopressors. Cardiac biomarker levels may
be increased in association with global ischemia caused by
absent or decreased coronary blood flow during cardiac
arrest and CPR. Increased cardiac biomarkers may also
indicate acute MI as the cause of cardiac arrest.
Hemodynamic instability is common after cardiac
arrest, and early death caused by multiorgan failure is associated with a persistently low cardiac index during the first
24 hours after resuscitation. Thus, after successful resuscitation, clinicians should evaluate the patient’s ECG, radiographs, and laboratory analyses of serum electrolytes and
cardiac biomarkers. Performing an ECG within the first 24
hours after arrest is useful to guide ongoing management.
Patients who are resuscitated following out-of-hospital cardiac arrest may have significant early but reversible myocardial dysfunction and low cardiac output, followed by later
vasodilation. Hemodynamic instability usually responds to
fluid administration and vasoactive support. Invasive monitoring may be necessary to measure blood pressure accurately and to determine the most appropriate combination
of medications to optimize blood flow and distribution. The
provider should titrate volume administration and vasoactive (e.g., norepinephrine), inotropic (e.g., dobutamine),
and vasodilator (e.g., milrinone) drugs that are given to
support blood pressure, cardiac index, and systemic perfusion. Both cardiac arrest and sepsis are thought to involve
multiorgan ischemic injury and microcirculatory dysfunction. Goal-directed therapy with volume and vasoactive
drug administration has been effective in improving survival from sepsis. The greatest survival benefit is due to
a decreased incidence of acute hemodynamic collapse, a
challenge also seen in the postresuscitation setting. Relative adrenal insufficiency may develop following the stress
of cardiac arrest, but the use of early corticosteroid supplementation in such patients to improve either hemodynamics or outcome is unproven and requires further evaluation.
Although SCA may be precipitated by cardiac arrhythmia,
it is unclear if antiarrhythmics are beneficial or detrimental in the postresuscitation period. Thus, there is insufficient evidence to recommend for or against prophylactic administration of antiarrhythmic drugs to patients who
have survived cardiac arrest from any cause. It may be reasonable, however, to continue an infusion of an antiarrhythmic drug that was associated with ROSC. Also, given
the cardioprotective effects of beta blockers in the context of ischemic heart disease, the use of beta blockers in
A healthy brain and a functional patient are the primary
goals of cardiopulmonary–cerebral resuscitation. Following ROSC, cerebral blood flow is reduced after a brief initial period of hyperemia (the “no-reflow phenomenon”) as a
result of microvascular dysfunction. This reduction occurs
even when cerebral perfusion pressure is normal. Neurological support for the unresponsive patient should include
measures to optimize cerebral perfusion pressure by maintaining a normal or slightly elevated mean arterial pressure
and reducing intracranial pressure if it is elevated. Because
hyperthermia and seizures increase the oxygen requirements of the brain, hyperthermia must be controlled and
therapeutic hypothermia should be considered.13
PROGNOSTIC FACTORS
The period after resuscitation is often stressful to medical staff and family members as questions arise about the
patient’s ultimate prognosis. Ideally, a clinical assessment,
laboratory test, or biochemical marker would reliably predict the outcome during or immediately after cardiac arrest.
Unfortunately, no such predictors are available. Determination of prognosis based on initial physical examination
findings can be difficult, and coma scores may be less predictive than individual motor and brainstem reflexes found
in the first 12–72 hours after arrest.
Five clinical signs that were found to strongly predict
death or poor neurological outcome, with 4 of the 5 predictors detectable at 24 hours after resuscitation are absent
corneal reflex at 24 hours, absent pupillary response at 24
hours, absent withdrawal response to pain at 24 hours, no
motor response at 24 hours, and no motor response at 72
hours. An electroencephalogram performed >24–48 hours
after resuscitation also has been shown to provide useful
predictive information and can help define prognosis.10
Other Complications
Sepsis is a potentially fatal postresuscitation complication.
Patients with sepsis will benefit from goal-directed therapy. Renal failure and pancreatitis, although often transient, should be ruled out.
MONITORING
Blood pressure
Blood pressure can be monitored either noninvasively or
invasively, and it is fundamental for hemodynamic assessment. When intraarterial monitoring is in place during the
60 E MERGENCY D ERMATOLOGY
resuscitative effort (in an intensive care setting), the clinician should try to maximize arterial diastolic pressures to
achieve an optimal coronary perfusion pressure.
Pulses
Arterial pulses should be palpated during chest compressions to assess the effectiveness of compressions. No studies
have shown the validity or clinical utility of checking pulses
during ongoing CPR. Carotid pulsations during CPR do
not indicate the efficacy of coronary blood flow or myocardial or cerebral perfusion during CPR.
Arterial Blood Gases
Arterial blood gas monitoring during cardiac arrest is not a
reliable indicator of the severity of tissue hypoxemia, hypercarbia (and therefore the adequacy of ventilation during
CPR), or tissue acidosis. It provides the foundation for the
assessment of respiratory function.
Oximetry
During cardiac arrest, pulse oximetry will not function
because pulsatile blood flow is inadequate in peripheral
tissue beds, which are also constricted. It is, however,
commonly used in emergency departments and critical
care units for monitoring patients who are not in arrest
because it provides a simple, continuous method of tracking
oxyhemoglobin saturation. Normal pulse oximetry saturation, however, does not ensure adequate systemic oxygen
delivery.
End-Tidal CO2 Monitoring
End-tidal CO2 monitoring is a safe and effective noninvasive indicator of cardiac output during CPR and may be an
early indicator of ROSC in intubated patients. CO2 continues to be generated throughout the body during cardiac
arrest. In the patient with ROSC, continuous or intermittent monitoring of end-tidal CO2 provides assurance that
the endotracheal tube is maintained in the trachea. Endtidal CO2 can guide ventilation, especially when correlated
with the PaCO2 from an arterial blood gas measurement.
Sedatives
Sedatives and analgesics used commonly in the care of critically ill patients often exhibit pharmacokinetics and pharmacodynamics that are significantly different than those
that are exhibited in studies of their use in other settings.
Knowledge of these differences is crucial to designing a
sedation protocol for the critically ill patient. Intravascular
catheters, endotracheal intubation, suctioning, immobility,
and underlying illnesses all may cause pain in the critically
ill patient. Most patients require IV narcotics at least initially (IV morphine 3 mg or IV dolestine 12.5 mg). Thus,
adequate sedation begins with adequate analgesia. Regional
pain control techniques, such as with epidural catheter–
administered anesthetics or opiates, can be highly effective
at achieving pain control in the postoperative patient. The
evaluation of sedation adequacy can be performed only at
the bedside and is facilitated by use of validated sedation
scales, along with a protocol for the systematic assessment
and administration of sedatives and analgesics. Most postarrest patients require larger doses of sedatives in the initial 48
hours. Thus, the level of sedation must be reassessed continuously and a protocol for downward titration of sedation
applied. If continuous administration is used, daily sedative
interruption is recommended to prevent drug accumulation, to allow the performance of a neurological examination, and to permit reassessment of the need for sedation.
An example of a sedative is oxazepam 10 mg thrice daily.
REFERENCES
1. 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005;112 Supplement I:IV-1–IV-45.
2. International Liaison Committee on Resuscitation. 2005
International consensus on cardiopulmonary resuscitation
and emergency cardiovascular care science with treatment
recommendations. Resuscitation. 2005;67:157–341.
3. Washington University School of Medicine Department of
Medicine, Green GB, Harris, IS, et al. (editors). The Washington manual of medical therapeutics. 31st ed. (spiralbound). Philadelphia: Lippincott, Williams & Wilkins,
2004;1–15;536–44.
4. Gabbott D, Smith G, Mitchell S, et al. Cardiopulmonary
resuscitation standards for clinical practice and training in the
UK. Resuscitation. 2005;64:13–19.
5. Wik L, Hansen TB, Fylling F, et al. Delaying defibrillation to
give basic cardiopulmonary resuscitation to patients with outof-hospital ventricular fibrillation: a randomized trial. JAMA.
2003;289:1389–95.
6. Van Alem A, Sanou B, Koster R. Interruption of CPR with
the use of the AED in out of hospital cardiac arrest. Med Ann
Emerg Med. 2003;42:449–57.
7. Eftestol T, Sunde K, Steen PA. Effects of interrupting precordial compressions on the calculated probability of defibrillation success during out-of-hospital cardiac arrest. Circulation.
2002;105:2270–3.
8. Van Alem AP, Vrenken RH, de Vos R, et al. Use of automated
external defibrillator by first responders in out of hospital
cardiac arrest: prospective controlled trial. BMJ. 2003;327:
1312.
9. Peberdy MA, Kaye W, Ornato JP, et al. Cardiopulmonary
resuscitation of adults in the hospital: a report of 14720 cardiac arrests from the National Registry of Cardiopulmonary
Resuscitation. Resuscitation. 2003;58:297–308.
10. Sandroni C, Nolan J, Cavallaro F, Antonelli M. In-hospital
cardiac arrest: incidence, prognosis and possible measures to
improve survival. Intensive Care Med. 2007;33:237–45.
Chapter 5
11. Boddicker KA, Zhang Y, Zimmerman MB, et al. Hypothermia improves defibrillation success and resuscitation outcomes from ventricular fibrillation. Circulation. 2005;111:
3195–201.
●
Critical Care: Stuff You Really, Really Need to Know
61
12. Stocchetti N, Maas AI, Chieregato A, van der Plas AA. Hyperventilation in head injury: a review. Chest. 2005;127:1812–27.
13. Berk JL, Sampliner JE, editors. Handbook of critical care. 3rd
ed. Boston: Little, Brown and Company; 1989;153–213.
CHAPTER 6
Acute Skin Failure: Concept, Causes,
Consequences, and Care
Robert A. Norman
Gwynn Coatney
PHYSICIANS AND health care professionals working at
hospitals and in acute care facilities strive to prevent and
treat organ failure on a daily basis. The skin is one organ
system that is usually overlooked when considering organ
failure. The concept of skin failure is not well circulated in
the medical world but is an important topic that should
be addressed. The potential for a severe prognosis and
increased morbidity and mortality is a significant reason
why skin failure needs to be addressed.
WHAT IS SKIN FAILURE?
Failure of any organ system occurs when its normal tasks
and functions can no longer be performed. The same goes
for the integument, which is the largest organ of the body.
The skin plays many important roles. It acts as a physical
barrier against trauma and aids in the prevention of foreign materials, including bacteria, from entering the body.
Conversely, this barrier also prevents loss of body fluids
and essential nutrients, such as protein and iron. Normally functioning skin also serves in temperature regulation, detection of sensation, toxin excretion, and vitamin D
synthesis and as an immune modulator. When this organ
loses the ability to maintain temperature control; when it
can no longer retain the balance of fluids, electrolytes, and
nutrition; and/or when it fails as a mechanical barrier, skin
failure has occurred.1
and mortality of the patient. The most common example
is the decubitus ulcer, also called a pressure ulcer or bed
sore.2
CAUSES OF ACUTE SKIN FAILURE
Acute skin failure has many etiologies (Table 6.1). The most
common and the best known may be thermal burns. Acute
medical conditions or illnesses can also lead to acute skin
failure. Hypoperfusion of the skin can occur when other
organ systems, such as the cardiovascular or renal system,
become severely dysfunctional or fail. Blood, along with
essential nutrients and oxygen, is then shunted to the core
organs, and the peripheral skin becomes impoverished of its
blood supply. The end result is that the skin and underlying
tissue begin to fail.
Common dermatologic conditions such as eczema and
psoriasis can develop into acute skin failure if the cases are
severe or if there is extensive involvement of the integument. Erythrodermic or generalized pustular psoriasis is
an example of what could potentially become a severe case.
ACUTE VERSUS CHRONIC AND END-STAGE
SKIN FAILURE
Acute skin failure has a rapid onset and occurs simultaneously with a critical illness or event. Any medical condition
that results in the patient suffering from severe hypotension, hypovolemia, or organ failure, could also develop
acute skin failure. Chronic skin failure has a slower, steadier presentation and occurs during an ongoing disease state.
This type of skin failure is more prevalent in elderly patients
with multiple comorbidities. End-stage skin failure occurs
at the end of life and is associated with increased morbidity
page 62
TABLE 6.1: Causes of Acute Skin Failure
No. Principle causes for acute skin failure
1. Erythroderma
a. Primary (idiopathic)
b. Dermatitis (atopic, seborrheic, contact dermatitis)
c. Psoriasis, pityriasis, rubra pilaris
d. Exfoliative drug eruption
e. Disorders of keratinization (lamellar ichthyosis, bullous
and nonbullous ichthyosiform erythroderma)
f. Cutaneous T-cell lymphoma
g. Graft versus host disease
2. Stevens–Johnson syndrome, toxic epidermal necrolysis
3. Acute generalized pustular psoriasis
4. Immunobullous disorders: Pemphigus vulgaris and
pemphigus foliaceus
5. Infections: Staphylococcal scalded skin syndrome,
febrile viral exanthemas
Chapter 6
TABLE 6.2: A Severity of Illness Score for Toxic
Epidermal Necrolysis (SCORTEN)
1. Age
2. Concurrent illness
3. Epidermal detachment
4. Serum urea-nitrogen level
5. Blood glucose level
6. Serum bicarbonate level
7. Heart rate
>40 y
Presence of malignancy
>30%
>28 mg/dL > 10 mmol/L
>252 mg/dL >14 mmol/L
<20 mEq/L < 20 mmol/L
>120 bpm
From (6, 7).
Significant dermatologic diseases such as toxic epidermal necrolysis (TEN), Stevens–Johnson syndrome (SJS),
cutaneous T-cell lymphoma, exfoliative drug reaction
eruptions, infections such as staphylococcal scalded skin
syndrome or viral exanthemas, pemphigus vulgaris, and
graft versus host disease can also cause acute skin failure.1,3
RISK FACTORS
There are several components that can increase the possibility of acute skin failure or make the prognosis more
severe.
With increased age the skin becomes thinner and has
decreased elasticity and increased fragility. Elderly skin also
has decreased vascularity that may result in slower repair
and healing. Additionally, sun damage and smoking effectuate premature aging of the skin.
The percentage of surface area in failure is directly proportional to the amount of fluid and nutrients lost. An
increased fluid and nutrition loss also elevates the risk of
infection and raises the risk of poor prognosis.
Patients who have incontinence of their bowel or bladder are more likely to develop skin failure. Constant exposure of feces and urine to the skin causes an increased need
for cleansing. When the skin is cleaned with soap or alcohol, the top layers are debrided; this debridement may cause
thinning and an increase in the skin’s pH, which makes the
skin more susceptible to bacterial infection and breakdown.
Multiple comorbidities or immunocompromised patients further complicate acute skin failure. In a patient
with concurrent skin failure and heart disease, there is an
increase in cardiac output and blood volume needed for circulation, which can ultimately lead to heart failure. A significant loss of fluids and electrolytes can precipitate renal
failure.4,5
MANAGEMENT
Acute skin failure is considered to be a dermatologic emergency, and should be managed in an intensive care setting
(Table 6.2). Some literature suggests that treatment should
be conducted in a burn unit. Special attention should be
paid to patients who are at an increased risk.
●
Acute Skin Failure: Concept, Causes, Consequences, and Care
63
TABLE 6.3: Definite Indications of Antibiotic Use
1. High bacterial count (single strain) from skin/catheter sample
of urine
2. Sudden hypothermia in a relatively stabilized patient
3. Confused mental status, anxiety, and excitement
4. Symptoms of infections pertaining to a particular system,
e.g., pneumonia/urinary tract infection
The body’s ability to regulate temperature is lost when
skin fails. Hyperthermia is seen in patients who have
decreased function or blockage of their sweat ducts. An
increase in dermal blood flow occurs with severely damaged skin, causing radiant heat expenditure resulting in
hypothermia. Hypothermia can be the initial sign of septic shock in the infected patient. Therefore, temperature
should be maintained at 30–32◦ C.
When the stratum corneum is destroyed, the amount of
fluid lost through this physical barrier is greatly increased.
In a patient with 50% body surface involvement, fluid loss
can exceed 4–5 L/day. It is important to quickly replace
intravascular fluid loss (Table 6.3). Normal saline is the
first-line treatment, but human albumin and fresh frozen
plasma are other treatment options. Urine output and
body weight should be measured daily to monitor fluid
balance.
Infection is common in acute skin failure and can lead to
sepsis and even death. Bacterial culture sensitivity should
be tested at the initial presentation and throughout the hospital course to treat with appropriate systemic antibiotics
(Table 6.4). Topical antiseptics may also be applied to the
affected areas.
There can be long-term complications as a result of
acute skin failure (Table 6.5), which is just another reason
why patients should be treated quickly and aggressively.
The underlying etiology should be treated specifically. For
TABLE 6.4: Long-Term Complications of Acute Skin Failure
No. Organ involved
Complications
1.
Eye
Ectropion, entropion, corneal,
scarring, symblepharon,
secondary sicca syndrome
2.
Mucosal involvement:
Esophagus
Urethra
Vagina
Dysphagia resulting from stricture
Stricture and phimosis
Synechiae
3.
Skin
Pigmentary changes (hypo- and
hyperpigmentation), contracture
4.
Hair
Scarring alopecia
5.
Nail
Beau’s lines, splinter hemorrhage,
distal onycholysis, dystrophy,
complete shedding of nail
64 E MERGENCY D ERMATOLOGY
TABLE 6.5: Important Parameters to be Monitored in Patients with Acute Skin Failure
Clinical
Biochemical
Hematological
Microbiological
Pulse rate
Blood and urine
Total and differential
white blood cell count
Bacteriology of
skin lesions
Respiratory rate
Sugar
Platelet count
Urine culture
Level of consciousness
Urea/creatinine
Albumin
Urine output
Serum electrolytes
Gastric emptying
Phosphorus
example, systemic steroids should be used to treat pemphigus vulgaris and biologic agents for psoriasis.6,7
TEN is a major cause of acute skin failure. SCORTEN
is a scoring system used to assess the risk factors associated with the morbidity and mortality of TEN (Table 6.6).
The majority of TEN cases are related to chemicals
systemically administered as drug therapy – in particular, antibacterial sulfonamides, anticonvulsants, allopurinol, pyrazolone derivatives, and, less frequently, other
nonsteroidal antiinflammatory drugs (NSAIDs).8 The
SCAR (severe cutaneous adverse reactions) study included
245 patients with TEN and SJS in Europe. The study
confirmed the “classical culprit” drugs: antibacterial
sulfonamides (cotrimoxazole); aromatic anticonvulsants
(phenobarbital, phenytoin, carbamazepine); some antimicrobials (aminopenicillins, quinolones, cephalosporins);
some NSAIDs (tenoxicam, piroxicam), chlormezanone,
and allopurinol.9 Although most of these drugs are therapeutic and the overall risk is low, if there are early signs of
SCAR, then these drugs are the likely suspects and should
be stopped and be avoided completely in the future. The
person should wear a medical alert bracelet with the name
of the drug.
CONCLUSIONS
The complications that stem from acute skin failure are
serious and potentially fatal. Other factors to consider are
the patient’s age and the presence of multiple comorbidities. Acute skin failure can be caused by many etiologies,
and it should be managed aggressively to ensure a positive
prognosis. Patients should be immediately hospitalized and
treated with the same level of care as patients suffering from
heart or kidney failure.
TABLE 6.6: Fluid Electrolyte Replacement and Nutrition in Patients with Acute Skin Failure
IV fluid
Nasogastric feeding
Human albumin (diluted in NS 40 g/L) 1 mL/kg
Body weight per % BSA
Initial 24 h +
Saline 0.7 mL/kg
1500–2000 mL (providing normal
1500–2000 calories)
Thereafter
To be guided by previous day’s output
Progressive increase of
nasogastric/oral supplementation
Gradual decrease of IV fluids
Increase by 500 cal/d, up to 3500–4000
cal/d
Body weight per % BSA
Electrolytes
Supplementation of potassium phosphate in
initial 24 h
Hypokalemia
(alkalosis ruled out)
Inj. potassium chloride 40 mmol/L in 5%
dextrose–saline/5% dextrose/NS, 6–8 nightly
Hyponatremia
NS (500 mL/d) supply normal daily
requirement. Further deficit can be replaced by
extra amount of NS
BSA, bovine serum albumin; IV, intravenous; NS, normal saline.
Milk, fruit juice, honey, potassium
chloride syrup
Chapter 6
REFERENCES
1. Irvine C. “Skin failure”-a real entity: discussion paper. J R Soc
Med. 1991;84:412–13.
2. Parish LC, Witkowski JA, Crissey JT. The decubitus ulcer in
clinical practice. New York: Springer Verlag; 1997. pp. 1–241.
3. Witkowski JA, Parish LC. The decubitus ulcer and destructive
behavior. Int J Dermatol. 2000;39:894–6.
4. Roujeau JC. Toxic epidermal necrolysis (Lyell syndrome):
more than “acute skin failure.” Intensive Care Med. 1992;
18:4–5.
5. Benbow M. Back to basics-skin and wounds. J Com Nurs.
2007;21:34–8.
●
Acute Skin Failure: Concept, Causes, Consequences, and Care
65
6. Col Vaishampayan SS, Brig Sharma YK, Col Das AL, Lt Col
Verma R. Emergencies in dermatology: acute skin failure.
MJAFI. 2006;62:56–9.
7. Inamadar AC, Palit A. Acute skin failure: concept, causes,
consequences and care. Indian J Dermatol Venereol Leprol.
2005;71:379–85.
8. Heimbach DM, Engrav LH, Marvin JA, et al. Toxic epidermal necrolysis: a step forward in treatment. JAMA.
1987;257:2171–5.
9. Roujeau JC, Kelly JP, Naldi L, et al. Medication use
and the risk of Stevens-Johnson syndrome or toxic
epidermal necrolysis. N Engl J Med. 1995;333:1600–
7.
CHAPTER 7
Cutaneous Symptoms and
Neonatal Emergencies
Daniel Wallach
Pierre-Henri Jarreau
EMERGENCIES ARE frequent in neonatal medicine as
the physiological fragility of the newborn induces rapid
deterioration of general condition in many circumstances,
including initially localized infections. In a broad sense,
one could argue that the majority of cutaneous abnormalities found in a newborn requires a rapid diagnosis1,2 for adequate management and relevant parental
information.
Among neonatal emergencies, a few situations imply
cutaneous symptoms, either as a predominant feature or
as one of the elements of a complex clinical situation. The
goal of this chapter is to provide dermatologists with the
clinical knowledge of the main cutaneous neonatal problems requiring rapid diagnosis or intervention.
Taking care of these babies, whatever their cutaneous
problem, generally requires a hospitalization in a neonatal
unit and thus involves a neonatal team. Indeed, the consequences of the initial condition as well as of the loss of
the cutaneous barrier may be severe and require supportive
care, which depends on neonatologists.
To facilitate the identification of these problems, we
will classify them according to the clinical presentation.
We must point out that, whatever the cutaneous condition, when called to see a neonate, the physician must have
always in mind infection as a possible diagnosis. Infection may be the cause of the cutaneous symptoms, or
appear as a complication of an initially noninfectious skin
disorder.
BULLOUS ERUPTIONS
Staphylococcal Infections
Newborns are exquisitely sensitive to the infection by
Staphylococcus aureus strains that produce exfoliatin because
of the immaturity of the epidermal barrier and of the
renal elimination of toxins. S. aureus infections are
acquired postnatally and must be prevented by adequate hygiene and antisepsis of the nurseries, mothers,
medical staff, and all persons in contact with newborns.
General hygiene of the facilities, “surgical” hand washing,
meticulous care of the nipple area of breastfeeding mothers, and nontoxic antiseptic care of the umbilicus (aqueous
chlorhexidine) are mandatory parts of this prevention.
Neonatal staphylococcal infection starts as a localized
superficial lesion located in the umbilical area, around folds,
and/or in the diaper or periorificial areas: yellow crusts,
erythema, and oozing, small pustules.
Bullous impetigo is the localized form of the epidermal
bullous disease caused by the exfoliatin secreted by some
phage II group S. aureus strains. Lesions appear as flat,
flaccid bullae, rapidly ruptured, leaving round erosions or
crusts. If untreated, these localized infections may lead to
the following types of complications:
●
cellulitis, fasciitis, abscesses, lymphadenitis;
●
osteomyelitis, arthritis, septic pleuritis, pneumonia, septicemia, by hematogenous spread;
●
a toxinic generalized skin disease called SSSS (staphylococcal scalded skin syndrome), resembling toxic epidermal necrolysis.
SSSS starts as a bright, scarlatiniform, erythematous rash,
predominating in periflexural and periorificial areas.
Rapidly, the superficial part of the epidermis is shed, as an
extensive peeling or superficial blistering, with a positive
Nikolsky sign (Figure 7.1). This desquamation phase lasts
2–4 days, and is followed by complete healing, without scarring. Complications may include dehydration, hypothermia, and generalized sepsis.
SSSS is caused by some strains of phage group II
S. aureus. The portal of entry is a superficial infection: cutaneous wound (umbilicus, circumcision, puncture),
nasopharynx, conjunctiva. Epidermolytic toxins are disseminated through the bloodstream and exert a proteolytic
activity on desmoglein 1, leading to an exfoliation at the
subcorneal level of the epidermis (similar to superficial
pemphigus).
page 66
Chapter 7
●
Cutaneous Symptoms and Neonatal Emergencies
67
lous diseases), resulting in an epidermal detachment. EB
includes numerous subtypes of variable severity, including
severe, lethal, or incapacitating forms. Each of these subtypes is due to a genetic defect in one of the many molecules
involved in the cohesion between the epidermis and the
dermis. They are classified by mode of inheritance, clinical features, histopathology, and more recently molecular
defect.
The Newborn with EB
FIGURE 7.1: Staphylococcal scalded skin syndrome.
Differential diagnosis includes all neonatal bullous eruptions. The onset after a few days helps differentiating
infection blisters form epidermolysis bullosa (EB). Burns,
ichthyosis bullosa, or toxic epidermolysis may be considered.
SSSS has a good prognosis, provided the following measures are taken:
●
intravenous antibiotics: methicillin, oxacillin, cloxacillin,
or vancomycin in case of resistance to β-lactams. Fusidic
acid, mupirocin, or retapamulin may be used for the topical treatment of localized staphylococcal infections.
●
isolation in an incubator;
●
nontraumatic skin care, including the use of emollients
(sterile petrolatum, paraffin oil); the shedding epidermis
must be conserved as a “biologic dressing.”
Epidermolysis Bullosa
EB is a group of rare genetic diseases characterized by
an increased fragility to mechanical trauma (mechanobul-
When no prior history is known, the birth of a child with EB
is a difficult problem that is better dealt with in a neonatal
intensive care unit (NICU), in cooperation with a reference
center.
Trauma- or friction-induced blisters are the hallmark
of EB. These blisters are initially located on the areas of
presentation in the case of vaginal delivery, and are induced
by handling by the obstetrician, midwife, and neonatal staff.
Later, hands, feet, and the diaper area will be the most
involved areas.
The child must be placed in an incubator (it is important
to avoid overheating), and the general principles of care are
similar to those for premature infants, whose skin is also
fragile.
A precise subtype diagnosis is difficult or impossible during the first week, and the course is difficult to predict. It is
advisable to be cautious in the indications given to the parents. In addition to the support by the medical staff, useful
information and psychological support may be provided
by groups such as the Dystrophic Epidermolysis Bullosa
Research Association (DEBRA).
A skin biopsy will be helpful to establish a precise diagnosis. The biopsy must be taken on a normal appearing,
recently rubbed area to induce splitting. Conventional histology, antigenic mapping, and electron microscopy by a
specialized center will allow a subtype diagnosis, which is
important both for the patient himself or herself and for
future prenatal diagnoses. Deoxyribonucleic acid (DNA)
mutations may be identified in the blood cells of the child
and his or her parents.
THE MAIN EB SUBTYPES
EB Simplex
The most common EB type, called the Koebner type, is an
autosomal dominant, relatively mild disease. It is caused by
mutations of keratins 5 and 14. The bullae are intraepidermal and heal without scarring. Even in the case of neonatal
onset, nails and mucosae are uninvolved, there is no extracutaneous manifestation, and the prognosis is good with
progressive improvement.
68 E MERGENCY D ERMATOLOGY
Variants of junctional EB include a form with pyloric
atresia, which may be revealed by polyhydramnios. Urologic complications may also be present. This form is due
to a defect in the α-6 β-4 integrin.
Dystrophic EB
Dystrophic EB is due to mutations of the COL7A1 gene,
coding for collagen VII, a major component of anchoring
fibrils. Blisters in the superficial dermis heal poorly, with
scars and many possible complications.
Dominant dystrophic EB (Cockayne–Touraine type) is
a relatively mild disease, although blistering may be present
at birth. Atrophic scars and milia are frequent (hands, feet,
knees).
Recessive dystrophic EB (Hallopeau–Siemens type) is
a severe disease. Extensive blistering since birth leads to
large nonhealing ulcerations, atrophic scars, and/or joint
contractures. On the hands and feet, repeated blistering
and abnormal scarring end in a “mitten-like” deformation,
functional limitation, and severe handicap. Oral ulcerations
and digestive involvement are frequent. Children face multiple nutritional deficiencies, growth failure, and ocular and
urinary complications and are susceptible to infection (and
later to squamous cell carcinomas). The management of a
child with recessive dystrophic EB requires a trained specialized multidisciplinary team.
Principles of Management
FIGURE 7.2: Superficial ulceration in junctional epidermolysis
bullosa.
The Dowling–Meara variant, which is more severe, is
characterized by a herpetiform pattern of the blisters (mimicking nonmechanical bullae). An autosomal recessive variant, clinically more severe and associated with muscular
dystrophy, is caused by mutations of the protein plectin.
Junctional EB
The Herlitz type of junctional EB is a rare, severe, often
lethal disease. It is an autosomal recessive disorder, due to
mutations of laminin 5, which induces splitting at the level
of the lamina lucida.
Bullae and large erosive areas heal very slowly after birth
(Figure 7.2). The formation of granulating tissue following
blisters around the nails is characteristic. There is a severe
mucosal involvement, with oral blisters; respiratory, digestive, and urinary lesions; and ocular complications. Failure
to thrive, anemia, and (later) severe dental problems cause
many distressing and life-threatening local and systemic
complications. Patients with Herlitz disease die early in
childhood from one of these complications or from sepsis.
No therapy is able to correct the skin fragility. Hopes of
genetic therapy stand in the future. Recently, hematopoietic stem cell therapy has been successfully performed in
severe forms, general medical and psychological support is
most important. Reference centers and specialized associations exist in many countries.
During the neonatal period, hospitalization in a NICU
is necessary for control of the general and cutaneous conditions. The main principles of management of a newborn
with EB are3 special attention to the avoidance of all trauma
to the skin, use of bland emollients and nonadhesive dressings, protection of all fragile areas, feeding with special bottles in case of oral lesions, and attention to all the numerous
possible complications, including pain, bacterial infection,
dehydration, and undernutrition.
OTHER NEONATAL BULLOUS DISORDERS
Other Skin Fragility Syndromes
In addition to the many subtypes of EB, other genetic disorders may start with a neonatal bullous eruption: peeling
skin syndrome and/or4 transient bullous dermolysis of the
newborn.5
Kindler syndrome, a rare disorder with poikiloderma
and photosensitivity in childhood, may induce traumatic
Chapter 7
●
Cutaneous Symptoms and Neonatal Emergencies
69
blisters in the neonatal period.6 It is due to mutations in the
gene coding for kindlin-1, a protein linking actin filaments
to the extracellular matrix.
Neonatal Syphilis
Congenital syphilis has disappeared where effective prophylaxis is performed in pregnant women. In other situations, it may still be observed. The first sign is usually
rhinitis, an unusual symptom in newborns. Many types of
cutaneous eruptions may be seen, including a characteristic
bullous eruption on the palms and soles. Congenital syphilis
is a systemic infection with hepatic, bone, and neurologic
manifestations. Spirochetes can be found in the lesions.
Serological tests are reactive. Parenteral penicillin G is the
first-line treatment.
FIGURE 7.3: Neonatal herpes simplex. (Photo courtesy of Alain
Taı̈eb, MD, Bordeaux, France.)
Congenital erythropoietic porphyria, or Gunther disease,
is due to the absence of uroporphyrinogen III synthase.
Children suffer from extreme photosensitivity, which may
induce blistering on exposed areas and skin fragility, starting in the neonatal period.
flu-like febrile illness before onset of labor. Infants appear
septicemic with a multisystemic involvement. Cutaneous
lesions are present at birth. A macular–papular generalized
rash, with petechiae, progresses to vesicles, then pustules.
Gram-positive rods can be found in the pustules. Immediate antibiotic treatment is needed, using ampicillin and an
aminoglycoside.
Autoimmune Bullous Diseases
Herpes Simplex Infection
Transient neonatal blistering may be caused by the
transplacental transmission of maternal autoantibodies.
The diagnosis is usually easy, but the affected mother may
(rarely) have an inactive disease.
The maternal disease is usually pemphigoid gestationis
(herpes gestationis), an autoimmune subepidermal bullous
disease associated with pregnancy.7 Newborns from mothers with pemphigus vulgaris may suffer from neonatal blisters and mucosal lesions.8
Neonatal herpes is usually acquired perinatally from an
infected mother. The more frequent cause is primary herpes simplex virus (HSV)2 infection, but HSV1 and recurrences may also infect the newborn. The dermatologist may
diagnose neonatal herpes by clinical examination showing
isolated or grouped 1- to 3-mm vesicles with a slight surrounding erythema (Figure 7.3) on the skin or, more rarely,
the oral mucosa.
The diagnosis may be rapidly confirmed by Tzanck
smear, polymerase chain reaction, or immunofluorescence.
The treatment is intravenous acyclovir, 20 mg/kg every 8
hours.
There are three forms of neonatal herpes simplex
infection:
Porphyria
VESICULAR/PUSTULAR ERUPTIONS
Neonatal Sepsis
Neonatal sepsis is a worldwide problem and a leading cause
of mortality in newborns. Prevention and treatment strategies have been discussed.9 Cutaneous symptoms are not
infrequent in neonatal sepsis, but the majority are nonspecific.10 Therefore, a diagnosis of sepsis must systematically be suspected and appropriate biological examinations
performed. The availability of superficial lesions, however,
may be helpful for the bacteriological identification of the
causing organism.
Listeriosis
Listeria monocytogenes is a rare cause of maternal–fetal infection. Affected mothers, contaminated by food, develop a
●
Superficial herpes simplex infection (50% of cases):
There is no extracutaneous dissemination, and the prognosis is good.
●
Encephalitis (40% of cases). Cutaneous lesions may not
be present. The prognosis is severe, with possible sequelae despite antiviral treatment.
●
Disseminated herpes (10%). Newborns appear septicemic, with fever, neurological signs, and multisystemic involvement (lung, liver, eye). Cutaneous lesions
are present in half the cases. Even with treatment, mortality is high and survivors often suffer from ocular and
neurological sequelae.
70 E MERGENCY D ERMATOLOGY
fungal filaments are easily found in the lesions. Parenteral
antifungal therapy and supportive care are necessary.
Scabies
FIGURE 7.4: Invasive candidal dermatitis.
Varicella
Congenital varicella, acquired in utero from a maternal
varicella between the 13th and the 20th week of pregnancy,
is rare.11 It may result in limb abnormalities and/or ocular and neurological involvement. The cutaneous lesions
are irregular scars (sometimes zosteriform), atrophic areas,
and/or hemorrhagic blisters.
Perinatal varicella is a severe disease, occurring when
the mother presents varicella between 5 days before and 2
days after delivery. The newborn has a disseminated, vesicular rash, as well as a visceral varicella (lung, liver). Specific immunoglobulins may prevent or lessen the severity
of neonatal varicella.12 Acyclovir and supportive therapy are
needed. The varicella vaccine should eradicate this severe
disease.
Congenital Candidosis
Newborns may have localized Candida infections: oral
thrush, perianal diaper dermatitis, and/or nail infection
with paronychia.
Congenital cutaneous candidosis is acquired in utero from a
candidal chorioamniotitis. It is manifest at birth or shortly
after, as a generalized rash, made of dozens of small erythematous papules that rapidly progress to vesicles and pustules, followed by superficial desquamation. Respiratory
infection can be found, but systemic dissemination is rare,
in contrast with systemic candidosis, which may include
skin lesions. A parenteral antifungal therapy is required if
there is evidence of pneumonia or birth weight is less than
1500 g.
Invasive fungal dermatitis is a severe candidal infection
occurring in only extremely premature babies (birth weight
<1000 g). The fungi (organisms other than Candida albicans may be responsible) invade the body through the skin,
because of the absence of an efficient epidermal barrier.
This disseminated dermatitis starts a few days after birth,
as an erythematous crusty eruption, with erosions and pustules (Figure 7.4). As in all forms of superficial candidiasis,
The incubation period of scabies is approximately 15 days,
and a newborn may be contaminated by the cutaneous contact of an infested individual. The newborn does not express
pruritus. The skin lesions are a papular–vesicular eruption,
with small nodules predominating around the axillae, vesicles, or pustules on the palms and soles. Burrows may be
seen by the naked eye, and dermoscopy may identify the
intraepidermal mite. The contaminating person is usually
rapidly found.
First-line treatment for neonatal scabies is a scabicide
product containing pyrethroids. Care must be taken in the
decontamination of the linen, the treatment of contact individuals, and the avoidance of repeated or toxic treatments.
Infantile acropustulosis is a rare pustulosis of infants,
predominating on the hands and feet. It must not be mistaken for scabies, but may follow an efficiently treated
scabies.
Incontinentia Pigmenti
All of the preceding vesicular–pustular conditions of neonates are of an infectious nature. Incontinentia pigmenti is
an X-linked dominant genetic disorder, occurring almost
only in girls.13 It is due to mutations of the NEMO gene,
located in X q 28. Inflammatory vesicles in a blaschkoid
pattern are the first clinical manifestation of incontinentia
pigmenti. Papular, keratotic, then pigmentary lesions may
follow or coexist. Eosinophils are found in the vesicles, and
there is at the same time a blood hypereosinophilia. Incontinentia pigmenti is usually a benign, limited disorder, but
may include neurological (epilepsy, mental retardation),
ocular, and dental abnormalities requiring specialized consultations. A genetic consultation is also advised.
OTHER NEONATAL ERUPTIONS
Macular–Papular Eruptions
Bacterial neonatal infections (neonatal sepsis) are multisystemic. A macular–papular rash may be observed, but is not
indicative of any etiological agent.10
Purpuras
Apart from traumatic purpura resulting from a difficult
delivery, purpura in a newborn is always an emergency. The
main causes are platelet abnormalities, coagulation defects,
and infections.
Protein C and protein S deficiency may cause neonatal purpura fulminans. Infections may include purpura
Chapter 7
●
Cutaneous Symptoms and Neonatal Emergencies
71
Subcutaneous nodules, starting shortly after birth, are
located on the upper back, shoulders, and arms. They
resolve in a few weeks, and their main complication is
hypercalcemia.
NEONATAL ERYTHRODERMA
FIGURE 7.5: Bluish nodular eruption (“blueberry muffin baby”)
during a cytomegalovirus infection. (Photo courtesy of Odile
Enjolras, MD, Paris, France.)
by many mechanisms, including thrombocytopenia and
extramedullary erythropoiesis.
TORCH Syndrome
TORCH is an acronym designating a clinical condition that can be caused by several congenital infections:
Toxoplasmosis, Other infections, Rubella, Cytomegalovirus, and Herpes.
Clinical manifestations include petechial purpura, jaundice, and cutaneous nodules of erythropoiesis (blueberry
muffin baby) (Figure 7.5).14 The systemic consequences of
the infections may be very severe.
Lupus Erythematosus
Neonatal lupus erythematosus (NLE) is due to the transplacental transfer of some antinuclear antibodies (anti-RoSSA, more rarely anti-LA–SSB). Mothers may be asymptomatic or suffering from a connective tissue disease. The
autoantibodies are pathogenic for the skin and the cardiac conducting tissue. Cutaneous NLE consists of annular
papulosquamous lesions, located on the upper part of the
face and scalp. They disappear in a few weeks. NLE may
also cause congenital heart block and, rarely, liver disease
and hematologic manifestations.
Nodular Eruptions
Subcutaneous fat necrosis of the newborn is a benign panniculitis occurring in newborns with some risk factors.15
Erythroderma, in other words, generalized erythema and
desquamation, can occur in newborns.16 This must be differentiated from toxinic erythema (SSSS), generalized mastocytosis (skin infiltration, bullae), and ichthyosis bullosa
(erythema, hyperkeratosis, bullae).
The main causes of neonatal erythroderma are immunodeficiencies (including Omenn syndrome); inflammatory
dermatoses such as psoriasis, seborrheic dermatitis (Leiner
disease), or atopic dermatitis; some metabolic disorders;
and inherited ichthyoses. Erythroderma is a state of subacute cutaneous insufficiency, and affected newborns are at
risk of superinfections as well as metabolic complications
due to proteic, aqueous, and ionic transepidermal losses.
They require intensive neonatal care, careful investigation,
and follow-up. Cutaneous management is based on emollients and prevention of infection.
Inherited ichthyoses are a group of genetic skin diseases
characterized by excessive desquamation. Some of these
disorders can be present at birth. The clinical presentation
is a neonatal erythroderma, or a collodion baby.
The collodion baby is a striking phenotype: The baby
seems to be surrounded by a shiny, erythematous envelope
resembling cellophane or collodion. Tension around the
eyes and the mouth gives rise to eclabion and ectropion
(Figure 7.6). The collodion-like envelope soon fissures and
desquamates. Collodion babies are at risk of dehydration,
hypothermia, and infection from an inefficient skin barrier
and they must be kept in incubators. Skin care is based
on abundant emollients and prevention of infection. Systemic toxicity of any topical must be considered. Collodion
babies must be differentiated from the desquamation of
postmature newborns, and from the collodion-like hyperkeratotic aspect of some ectodermal dysplasias. Although
the majority of collodion babies have variants of congenital ichthyosis,17 some cases rapidly recover, with perfectly
normal skin. It is impossible to predict the prognosis during
the first days or weeks after birth.
Netherton syndrome is characterized by a special form
of ichthyosis (ichthyosis linearis circumflexa), trichorrhexis
invaginata, and atopic dermatitis. This syndrome is due to
mutations of the gene SPINK 5, which codes for a protease inhibitor called LEKTI. Affected children may be
erythrodermic at birth (Figure 7.7). In this condition, the
epidermal barrier is greatly impaired and there is a risk of
hypernatremic dehydration, as well as systemic intoxication from absorbed topical drugs. The same risk exists, to
a lesser degree, in all erythrodermic infants and, as said, in
collodion babies.
72 E MERGENCY D ERMATOLOGY
FIGURE 7.6: Collodion baby. (Photo courtesy of Claudine
Blanchet-Bardon, MD, Paris, France.)
CONGENITAL CUTANEOUS TUMORS
Hemangiomas
Hemangiomas usually become visible after a few weeks. At
birth, they may be mistaken for capillary angiomas. White
vasoconstriction areas may herald the development of a
hemangioma.
Hemangioma-related emergencies may result from a
rapid increase in size, associated with thrombocytopenia (Kasabach–Merritt syndrome), from diffuse hemangiomatosis with visceral involvement, or from ulcerations
of periorificial hemangiomas.
Congenital hemangiomas18 can even be diagnosed prenatally. They realize violaceous superficial tumors (Figure
7.8). Some regress rapidly. If the diagnosis of hemangioma
cannot be ascertained clinically, a biopsy is necessary.
Hamartomas
Localized cutaneous malformations are visible at birth.
Epidermal nevi, melanocytic nevi, and other hamartomas,
FIGURE 7.7: Neonatal erythroderma of Netherton syndrome.
must be diagnosed rapidly. The two areas of concern are
the needed workup, the specialized medical–surgical management, and the psychological support to the parents.
Infantile myofibromatosis appears at birth as cutaneous
nodules that may be solitary or multiple. Skin lesions
may regress spontaneously, but visceral lesions may be
fatal.
Mastocytosis
Mastocytosis is a benign infiltration of the skin by mast
cells. Several forms exist, which may be present at birth.
Darier’s sign is a useful clinical clue: The gentle rubbing
of the lesion induces an urticarial papulation. The rubbing
must be done on a very small area, to avoid generalized
flushing.
Mastocytoma is a round elevated nodule, usually solitary.
Diffuse cutaneous mastocytosis presents as large, thick,
orange or brown plaques (Figure 7.9). Urtication or bulla
formation may be the consequence of pressure or friction
by clothes.
Chapter 7
●
Cutaneous Symptoms and Neonatal Emergencies
73
FIGURE 7.8: Congenital hemangioma.
FIGURE 7.9: Diffuse cutaneous mastocytosis.
Urticaria pigmentosa is the name given to papular mastocytosis, which develops later in infancy.
Usual locations are the head and neck and the perineal
area.
Congenital melanoma is a rare occurrence. It may present
as a nodule on a giant congenital melanocytic nevus.
Neoplastic Diseases
Langerhans cell histiocytosis (LCH) is a polymorphous disorder. It cannot be considered as an emergency, but it is
important to suspect LCH when a newborn has papular–
crusty, sometimes purpuric lesions in the folds, the scalp,
and/or the diaper area (Letterer–Siwe disease). Visceral
and/or bone involvement, as well as diabetes insipidus,
may be present. A nodular form of LCH is regressive
(Hashimoto–Pritzker syndrome).
Neuroblastoma may be present at birth. Cutaneous metastases appear as firm, bluish nodules (Figure 7.10), which
may blanch on palpation. Histological examination will
differentiate these lesions from leukemia or nonneoplastic
causes of “blueberry muffin” lesions.
Leukemia is rarely congenital. Purpuric and nodular
lesions appear in the context of a systemic leukemia. Biopsy
and blood examinations provide the precise diagnosis.
Rhabdomyosarcoma is a malignant tumor that can be congenital. It appears as a shiny, red to purple firm tumor.
FIGURE 7.10: Subcutaneous metastasis of neuroblastoma.
(Photo courtesy of Aı̈cha Salhi, MD, Algiers, Algeria.)
74 E MERGENCY D ERMATOLOGY
In all these cases of neonatal cutaneous tumors, the diagnosis relies on the histological examination of a biopsy,
which may be considered as urgent. Special stains may be
necessary.
APLASIA CUTIS
Aplasia cutis is a congenital absence of skin, on a limited area. The majority of cases are small, round atrophic
patches of the scalp, near the vertex, with no associated
anomaly.
There are in fact many other situations, including associations with EB (Bart syndrome), malformative syndromes,
and chromosomal defects.19
Some cases of aplasia cutis are large congenital ulcerations requiring careful wound care. Large ulcerations of
the scalp may involve the underlying structures, with the
risk of lethal hemorrhages of the venous system. Radiologic
imaging and surgery may be necessary.
PREMATURITY AS A CUTANEOUS EMERGENCY
The main function of the skin is to constitute a barrier
between the organism and the environment. This function
is carried out by the stratum corneum, which is formed
during the last trimester of gestation. Premature babies
(born before the 37th week) lack an efficient epidermal barrier and are at risk of dehydration, hypothermia, infection,
and systemic toxicity of topicals. The procedures of neonatal medicine, including the care in heat- and hydrationcontrolled incubators, aim at alleviating the consequences
of the functional insufficiency of the immature skin.20
REFERENCES
1. Eichenfield LF, Frieden IJ, Esterly NB. Textbook of neonatal
dermatology. Philadelphia: WB Saunders; 2001.
2. Taieb A, Enjolras E, Vabres P, Wallach D. Dermatologie
néonatale. Paris: Vigot Maloine; 2009.
3. Lin AN. Management of patients with epidermolysis bullosa.
Dermatol Clin. 1996;14:381–7.
4. Levy SB, Goldsmith LA. The peeling skin syndrome. J Am
Acad Dermatol. 1982;7:606–13.
5. Fassihi H, Diba VC, Wessagowit V, et al. Transient bullous
dermolysis of the newborn in three generations. Br J Dermatol. 2005;153:1058–63.
6. Fassihi H, Wessagowit V, Jones C, et al. Neonatal diagnosis
of Kindler syndrome. J Dermatol Sci. 2005;39:183–5.
7. Aoyama Y, Asai K, Hioki K, et al. Herpes gestationis in
a mother and newborn: immunoclinical perspectives based
on a weekly follow-up of the enzyme-linked immunosorbent
assay index of a bullous pemphigoid antigen noncollagenous
domain. Arch Dermatol. 2007;143:1168–72.
8. Campo-Voegeli A, Muñiz F, Mascaró JM, et al. Neonatal pemphigus vulgaris with extensive mucocutaneous lesions
from a mother with oral pemphigus vulgaris. Br J Dermatol.
2002;147:801–5.
9. Vergnano S, Sharland M, Kazembe P, et al. Neonatal sepsis:
an international perspective. Arch Dis Child Fetal Neonatal
Ed. 2005;90:F220–4.
10. Olivier-Martin M, Wallach D, Bordier C, et al. Les signes
cutanés des infections bactériennes néonatales. Arch Fr Pediatr. 1985;42:471–82.
11. Enders G, Miller E, Cradock-Watson J, et al. Consequences
of varicella and herpes zoster in pregnancy: prospective study
of 1739 cases. Lancet. 1994;343:1548–51.
12. Heuchan AM, Isaacs D. The management of varicella-zoster
virus exposure and infection in pregnancy and the newborn
period. Australasian Subgroup in Paediatric Infectious Diseases of the Australasian Society for Infectious Diseases. Med
J Aust. 2001;174:288–92.
13. Hadj-Rabia S, Froidevaux D, Bodak N, et al. Clinical
study of 40 cases of incontinentia pigmenti. Arch Dermatol.
2003;1399:1163–70.
14. Epps RE, Pittelkow MR, Su WPD. TORCH syndrome.
Semin Dermatol. 1995;14:179–86.
15. Mahé E, Girszyn N, Hadj-Rabia S, et al. Subcutaneous fat
necrosis of the newborn: a systematic evaluation of risk factors, clinical manifestations, complications and outcome of 16
children. Br J Dermatol. 2007;156:709–15.
16. Pruszkowski A, Bodemer C, Fraitag S, et al. Neonatal and
infantile erythrodermas: a retrospective study of 51 patients.
Arch Dermatol. 2000;136:875–80.
17. Paller AS. Disorders of cornification (ichthyosis). In: Eichenfield LF, Frieden IJ, Esterly NB, editors. Textbook of neonatal dermatology. Philadelphia:WB Saunders; 2001. pp. 276–
93.
18. Mulliken JB, Enjolras O. Congenital hemangiomas and
infantile hemangioma: missing links. J Am Acad Dermatol.
2004;50:875–82.
19. Frieden IJ. Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol. 1986;14:646–60.
20. Williams ML. Skin of the premature infant. In: Eichenfield
LF, Frieden IJ, Esterly NB, editors. Textbook of neonatal
dermatology. Philadelphia: WB Saunders; 2001. pp. 46–61.
CHAPTER 8
Necrotizing Soft-Tissue Infections,
Including Necrotizing Fasciitis
Ronni Wolf
Yalçin Tüzün
Batya B. Davidovici
SKIN AND SKIN structures are among the most frequent
sites of human bacterial infection and account for ∼10%
of hospital admissions in the United States.1
The terminology used for infections of skin and skin
structures is often confusing. “Primary” skin infections
occur in otherwise normal skin and are usually caused by
group A streptococci or Staphylococcus aureus. Infections are
called “secondary” when they complicate chronic skin conditions (e.g., eczema or atopic dermatitis).
A second classification system divides skin and skinstructure infections into “uncomplicated” or “complicated,” the latter defined as involving abnormal skin or
wound infections occurring in a compromised host or
requiring substantial surgical intervention.
A more important and, for our purposes, relevant distinction with essential management implications subdivides
soft-tissue infections into “non-necrotizing” and “necrotizing” processes. This chapter reviews only the necrotizing soft-tissue infections (NSTIs) – the ones that pose real
emergencies that are rapidly progressive, destructive, and
highly lethal.
NSTIs can be defined as infections of any of the layers
within the soft-tissue compartment (dermis, subcutaneous
tissue, superficial fascia, deep fascia, or muscle) that are
associated with necrotizing changes. NSTIs are typically
not associated with abscesses, although they can originate
from an untreated or inadequately drained abscess.
The incidence of NSTIs in the United States, as recently
established from insurance databases from various states,
is 0.04 cases per 1000 person-years.2 This number is
high enough to predict that surgeons, family physicians,
internists, and dermatologists will encounter at least one
patient during their practice, but too low for these doctors
to acquire any real degree of familiarity with the disease.
Distinguishing NSTIs from non-NSTIs and establishing
the diagnosis of these infections is probably the greatest
challenge in managing them. Early diagnosis and aggressive
surgical debridement of these often fatal and crippling diseases will save patients’ lives and reduce morbidity. It is
for this reason that familiarity with the clinical characteristics, diagnostic tools, and principles of management is so
important when dealing with affected individuals.
Necrotizing fasciitis (NF) is categorized as type 1, 2, or
3, depending on the causative organisms.3 Type 1 NF is
mostly a mixed infection from aerobic and anaerobic bacteria, including Group A β-hemolytic streptococci (GAS),
S. aureus, Klebsiella species, Enterococci, Escherichia coli, and
Clostridium and Bacteroides species. The infecting organisms are often introduced at sites of surgery or trauma,
and the lesions are often found in perineal and abdominal
areas.
Type 2 NF is caused by GAS, possibly with a coinfection
by S. aureus, and primarily affects the extremities. Type 3
NF is associated with Vibrio vulnificus, which enters the subcutaneous tissues via puncture wounds from fish or marine
insects.
Another similar classification1 distinguishes among the
following subgroups of NF:
1. Polymicrobial fasciitis (type I),
2. Fournier gangrene,
3. Synergistic necrotizing “cellulitis” with fasciitis and
myonecrosis,
4. Streptococcal gangrene (type II), and
5. Fasciitis caused by V. vulnificus and other vibrio species.
Myonecrosis is further subdivided into crepitant myonecrosis and noncrepitant myonecrosis.
It should be noted, however, that anatomical boundaries
are not necessarily respected by invasive pathogens and one
form of infection can rapidly progress to another (e.g., cellulitis can progress to fasciitis and myonecrosis and vice
versa).
page 75
76 E MERGENCY D ERMATOLOGY
CLINICAL PRESENTATION AND LABORATORY
AIDS REQUIRED FOR DIAGNOSIS
We will briefly describe an actual case that emphasizes the
essence of early diagnosis.
One of us (RW) was called for a consultation in the
rheumatology clinic to examine a 26-year-old woman with
systemic lupus erythematosus due to severe pain at the hip
area. The affected skin was erythematous and – we willl get
ahead of ourselves here – it had a giveaway color, something
between pink and violet, a color that, once you see, you
will never miss. She was febrile but appeared to be in good
physical condition, and had come for consultation independently. We prescribed ampicillin with clavulinic acie
and instructed her to return the following week. Instead,
she presented on the same evening to the emergency room
because of worsening of the pain that was now unbearable.
Because nothing in her clinical situation seemed to have
changed, the consultant dermatologist ordered an x-ray,
which showed no bone or joint involvement, so he discharged her with the same medication. She returned to the
emergency room on the following morning and died one
day later from septic shock (the result of cultures was GAS)
and multiorgan failure. What we want to emphasize in this
tragic case is the paucity of dermatologic symptoms and the
absence of systemic symptoms except for severe localized
pain. There were no signs of either sepsis or shock, when
the patient was first seen by us.
It is our experience that too many cases of NF are misdiagnosed as non-NSTIs, and vice versa. This is also the experience of others. In a large case series4 of NF, only 14.6% of
the patients were correctly diagnosed or suspected as having NF on admission. The majority of the patients were
diagnosed as having cellulitis (58.4%) or abscesses (18%).
Similar numbers were recorded on the case report forms of
42 cases of GAS NF at the Florida Department of Health.5
Only 9.5% were correctly diagnosed as having NF, and
4.8% were diagnosed as suffering from invasive GAS disease or toxic shock syndrome (also an acceptable diagnosis),
but 31% of the patients had an admitting diagnosis of cellulitis and 24% of sepsis. The reason for this misdiagnosis
is, in our opinion, the enormous dread of discovering that
our patient is suffering from “flesh-eating disease” together
with the erroneous expectation that the clinical signs should
be suitably dramatic.
Clinicians should be aware that the pathological process
involved in NF takes place very deeply – in other words, at
the level of the fascial planes and even deeper – thus sparing
the top layers of the skin at the earliest stages. This is unlike
cellulitis, which involves the dermis and subcutaneous tissues early on, and much different from erysipelas, the most
superficial infection. Consequently, clinical signs (e.g., the
color, hemorrhagic bullae, and necrotic skin ulcers) are
more prominent in the more superficial skin infections and
less noticeable in the deeper ones. Erysipelas would appear
TABLE 8.1: Signs and Symptoms of NF
Symptom/Physical finding
% of patients
Pain
Erythema
Swelling
Fever
Skin necrosis
Blistering
Crepitus
X-ray findings
>97%
∼100%
∼75%
40%–70%
30%–45%
20%–40%
12%–25%
∼20%
to the inexperienced clinician as being more serious than
cellulitis, and cellulitis more alarming than NF. It cannot
be emphasized enough that the very early stage of NF,
the time when we strive to make the correct diagnosis, is
characterized by mild symptoms that provide no clues of
the seriousness and grave prognosis of the disease. Most
of the patients we saw were febrile (but in apparent good
health) and came for consultation independently with no
need for special transportation. This experience is also the
experience of others.6 The affected dermal area characteristically had the typical rose–violet color. One symptom
that no report misses is the disproportionately severe pain
at the site of involvement. Another clue to diagnosis is the
tenderness extending beyond the apparent area of involvement. The explanation for this phenomenon is the rapid
spread of the infection along the deep fascia, faster than in
the epidermis.
An additional cause and possible explanation for misdiagnosis or delay in diagnosing NF is the search for specific findings that are either not as common as previously
thought, or, more important, are signs that become apparent only later in the evolution of the disease. These signs
include the presence of crepitus on physical examination or
soft-tissue air on plain x-ray, hemorrhagic and gangrenous
bullae and ulcers, and the appearance of compartment syndrome (one of the favorite signs of the orthopedic surgeons). Pathognomonic as all these signs may be, waiting
for them to emerge would lead to a regrettable and unfortunate postponement in arriving at the correct diagnosis. According to some large, retrospective case series4,6–8
and reviews,9 the most common symptom of NF is pain
(>97%), and the most common clinical findings on admission are erythema, tenderness, and warm skin on palpation
(>90%–100%). Much less common and inconsistent symptoms are fever and tachycardia (40%–70%), bullae/vesicle
formation (20%–40%), and discoloration (20%–40%). Still
less common are crepitations (12%–25%), x-ray findings
(∼20%), skin necrosis, and hypotension, which are also late
signs (Table 8.1).
Although we do not doubt the claims that crepitus, blistering, or radiographic evidence of soft-tissue gas are found
in more than 80% of patients on admission,10 we believe
Chapter 8
that these are not the early signs that the clinician should
look for. Indeed, it is not uncommon for NF patients to
progress with alarming rapidity through the early, intermediate, and late presentations within hours of initial insult, so
they present with “hard signs” on admission. These cannot
and should not be considered early signs. Indeed, although
the previously mentioned symptoms are the ones apparent
at admission, it does not mean that they are the earliest
ones.
KEYS TO EARLY DIAGNOSIS
●
Do not look for the “hard signs,” such as necrosis, crepitation, x-ray findings, or compartment syndrome. These
are late signs and, in any event, are present in the minority of patients.
●
Do not expect to see a severely ill patient with signs of
septic shock. NF patients are often in apparently good
health and walk into your clinic just like ordinary otherwise fit patients.
●
Look for severe disproportionate pain and the typical
color of the erythema: They are, in our opinion, the most
reliable signs that should raise suspicion of NF.
●
Tenderness usually extends beyond the area of skin
involvement.
TREATMENT
The treatment of NF involves the principles of treatment
of any kind of surgical infection: source control, antimicrobial therapy, support (hemodynamic, nutritional) and
monitoring. NF is an excellent example of the important
role of source control. When treatment is based only on
antimicrobial therapy and support, mortality approaches
100%.11,12 Antibiotics have not been shown to halt the
infection in NF when pre- and postantibiotic series are
compared.12 It is clear that early and complete debridement
is essential for effective treatment of NF. Concomitantly,
appropriate broad-spectrum antibiotic coverage combined
with adequate organ support and close monitoring helps
patients during the acute phase of the disease, but, again,
it is only the complete debridement of infected tissue that
controls the infection and allows for future recovery.
Wide debridement of all necrotic and poorly perfused
tissue at the time of initial presentation is clearly the most
important step. The debridement is extended until skin and
subcutaneous tissue cannot be elevated off the deep fascia
by a gentle forward pushing maneuver. Healthy, viable,
bleeding tissue should be present at the edges of the excision site, and aggressive resuscitation should accompany
the perioperative period. Poorly perfused tissue is a nidus
for continued bacterial proliferation. The anesthesiologist
plays a critical role in the initial management of hemodynamic instability. Because NF fuels the progression of the
septic state, one may not be able to completely stabilize the
●
Necrotizing Soft-Tissue Infections, Including Necrotizing Fasciitis
77
patient hemodynamically before surgery, and delay may
lead to a fatal outcome. After the initial debridement has
been done, management in an intensive care unit is recommended, and scheduled debridements should be performed
as necessary.
Physiologic support combined with close monitoring in
an intensive care unit setting is mandatory. Appropriate
nutritional (enteral or parenteral) support administered as
early as possible cannot be overemphasized. The magnitude of protein and fluid loss from the large wounds associated with NF is tremendous. In general, patients with
severe tissue loss should receive twice their basal caloric
requirements.7,11 Aggressive fluid resuscitation and blood
component therapy is often required during the perioperative period.
It is not uncommon to see patients with NF develop
organ failure, such as acute renal failure (∼30%), adult
respiratory distress syndrome (∼30%), multiorgan system dysfunction (20%), infectious complications, and
others,10 all of which require careful monitoring and
prompt treatment.
As for the role of antibiotics in NF, we refer to the Infectious Disease Society of America guidelines.13 Antimicrobial therapy must be directed at the pathogens and used in
appropriate doses until repeated operative procedures are
no longer needed, until the patient has demonstrated obvious clinical improvement, and until fever has been absent
for 48–72 hours.
ANTIMICROBIALS
Mixed infection: Ampicillin-sulbactam or piperacillintazobactam + clindamycin + ciprofloxacin. Alternatively,
meropenem, ertapenem, cefotaxime + metronidazole or
clindamycin
GAS infection (type II NF): Penicillin + clindamycin
S. aureus infection: Nafcillin, oxacillin, cefazolin, vancomycin (for resistant strains), clindamycin
Clostridium infection: Clindamycin or penicillin
Until recently, therapy directed against methicillinresistant S. aureus (MRSA) was not recommended in standard guides, presumably because of the rarity of this
pathogen as a cause of NF. Over the past few years,
community-associated infections caused by MRSA (CAMRSA), the majority involving skin and soft tissues, have
become common in multiple areas in the United States
and worldwide. CA-MRSA should no longer be regarded
as a strictly nosocomial pathogen.14 MRSA is now the most
common pathogen isolated in the emergency department
from skin and soft-tissue infections.15 Recently, 14 cases
of NF associated with CA-MRSA were identified among
843 patients whose wound cultures grew MRSA,16 and
wound cultures were monomicrobial for MRSA in 12 of
78 E MERGENCY D ERMATOLOGY
them. Although all these patients survived, serious complications were common, including prolonged stays in the
intensive care unit, the need for mechanical ventilation and
reconstructive surgery, septic shock, nosocomial infections,
and endophthalmitis. The main lesson from this and other
reports is that we should include antibiotics with good activity against CA-MRSA in the currently recommended therapy for NF.16,17 Vancomycin is still the preferred antibiotic
for empirical coverage and definitive therapy, but whether
it should remain so is questionable. It is a less effective antistaphylococcal agent than the penicillins, and increased use
will further exacerbate problems with vancomycin-resistant
enterococci and staphylococci.17 Newer effective antibiotics, such as linezolid and teicoplanin, represent appropriate empirical therapeutic options.14
Single-organism NF is also increasingly recognized as a
manifestation of Klebsiella infections18–20 probably due to
the emergence of the highly virulent K1 capsular serotype,
the predominant serotype of potentially lethal disseminated infection with this pathogen in Asia, including NF.18
Single-organism NF due to Klebsiella species is strongly
associated with predisposing conditions, such as diabetes
mellitus, and has a propensity for metastatic dissemination
resulting in multiple sites of infection.20
Hyperbaric oxygen as an adjunctive treatment has been
advocated by different groups that argue for a decrease in
the number of debridements and an associated decrease in
mortality.7,21,22 Results from this therapeutic strategy are
contradictory, and no real epidemiologically based studies
have been performed to elucidate the effect of this form of
therapy. Certainly, hyperbaric oxygen therapy should not
jeopardize standard therapy for NF. Hyperbaric oxygen
is not available at all institutions and is hardly standard
equipment of ordinary intensive care units; thus patients
would have to be transported to the chamber at least 3 times
per day, which may expose them to risk of contamination
and may limit the ability to perform close monitoring and
timely debridements while they are in the chamber.
Another adjuvant treatment that has been used is intravenous immunoglobulin (IVIG). The value of this form
of therapy is difficult to assess given the small number of
patients that had ever been treated with this method, the
differences in methodologies and, particularly, the diversity between batches of the different companies.23 The use
of IVIG has been advocated mainly for GAS infections.
Information on the efficacy of IVIG in GAS bacteremia
can be found in a publication of the Canadian Streptococcal Study Group.24 They compared survival in 21 consecutive patients with streptococcal toxic shock syndrome
who had been given IVIG to that of 32 control patients
who did not receive the therapy. Sixty-seven percent of the
treated patients survived compared with only 34% of the
control patients. A double-blind, placebo-controlled trial
from northern Europe showed no significant improvement
in survival for the IVIG group.25 We suggest adopting the
conclusion of the Infectious Disease Society of America13
“ . . . that additional studies of the efficacy of IVIG are necessary before a recommendation can be made . . . ” We vigorously disagree with those clinicians who suggest that this
therapy “may allow an initial non-operative or minimally
invasive approach.”26 No therapy should tempt the surgeon
to postpone surgery or to perform less mutilating and, consequently, less effective surgery.
PROGNOSIS AND FACTORS THAT
AFFECT OUTCOME
Many attempts have been made to understand the factors
affecting mortality from NF. The fortunate rarity of the
disease and the multiple factors that influence the outcome
(such as causative agent, site of infection, and host factors)
have paradoxically hampered the establishment of an effective scoring system. Objective estimation of the probability
of death from NF would have provided an explicit basis for
clinical decisions, aided in the understanding of the relative contribution of these specific prognostic criteria, and
reduced the reliance on clinical intuition.
The mortality rates for NF vary considerably, ranging
between less than 10% and as high as 75%. The larger,
more robust, retrospective case series have narrowed these
rates to between 25% and 40%.27 What is clear, however, is
that the prognosis has improved considerably over the past
two decades as a result of early recognition and improved
supportive multidisciplinary measures.
In a recently published retrospective analysis of 99
patients with NF treated in three tertiary care hospitals
in Ontario, Canada,28 the overall mortality was 20%. Sixteen patients underwent amputation or suffered organ loss.
There was a strong positive association between a patient’s
age and mortality, with the risk of death increasing by 4%
every year. Apart from age, streptococcal toxic shock syndrome and immunocompromised status were independent
predictors of mortality. There was also a significant association between diabetes and negative outcome. The anatomic
sites of infection did not reach a level of significance in predicting outcome, with the exception of perineal infection,
which was significantly associated with a negative outcome.
Interestingly, the hyperbaric oxygen therapy group had a
higher mortality rate than did the nonhyperbaric oxygen
therapy group.28
NSTI CAUSED BY V. VULNIFICUS
Although V. vulnificus infections had probably occurred in
ancient times (the first fatal infection was possibly reported
by Hippocrates in the 5th century BCE),29 it was not until
the reporting of the first case in 1987 (in Taiwan)30 that
an increased prevalence became apparent. Recent findings
suggest that the reason might be associated with global
warming and prolongation of warmer weather and warmer
Chapter 8
water temperature.31 V. vulnificus is considered one of the
most dangerous waterborne bacterial pathogens, with a
case fatality rate that may reach 50% for V. vulnificus septicemia. Notably, V. vulnificus is estimated to account for
95% of all seafood-related deaths in the United States.32
●
Necrotizing Soft-Tissue Infections, Including Necrotizing Fasciitis
79
rapidly progressive inflammation of the skin and soft tissues following recent exposure to contaminated seawater
or raw seafood, and possibly one of the associated predisposing diseases. Definitive diagnosis is made by identifying
the bacteria from cultures. Gram-negative bacteria can be
seen on Gram’s staining.
Microbiology and Epidemiology
V. vulnificus is a naturally occurring, gram-negative,
halophilic bacterium of the noncholera group that is a
free-living inhabitant of estuaries and marine environments
throughout the world. Vibrio species have been found in
warm coastal waters ranging in temperature from 9◦ C to
21◦ C in geographically diverse regions that include the
Gulf of Mexico, South America, Asia (Thailand, Taiwan,
Hong Kong), and Australia.33 The bacterium is frequently
found in oysters, crustaceans, and shellfish (according to
various reports, up to 50% of oysters and up to 11% of
crabs are cultured positive during summer).34
Clinical Manifestations
The disease manifestations caused by V. vulnificus depend
on the route of infection, with three recognized syndromes:
1) primary septicemia, which is classically linked to the consumption of raw oysters; 2) wound infection resulting from
cellulitis caused by direct inoculation of the microorganism, which may result in tissue necrosis and secondary bacteremia (usually involving the exposure of chafed skin to
salty water containing the microorganism or injuries associated with the cultivation and/or preparation of seafood);
and 3) gastrointestinal illness, characterized by vomiting,
diarrhea, or abdominal pain. Pneumonia and endometritis
have also been reported. Skin lesions appear within 24–
48 hours of exposure. The disease process begins with
localized tenderness followed by erythema, edema, and
indurated plaques. A purplish discoloration develops in the
center of the lesions and then undergoes necrosis, eventually forming hemorrhagic bullae or ulcers. These clinical manifestations occur in nearly 90% of patients and
are most common on the lower extremities. Noteworthy,
these symptoms are different from those described earlier
for NF because the infection usually starts superficially and
is accompanied by cellulitis. In a survey from Israel,35 for
example, 57 of 62 cases of NSTI caused by V. vulnificus
developed cellulitis, and only 4 had NF.
The disease occurs mostly in immunocompromised
host–associated diseases. In a recent study of 67 patients,36
27 (40%) had hepatic disease, 17 (25.4%) had chronic
renal insufficiency, and 12 (17.9%) exhibited adrenal insufficiency.
The diagnosis of NSTI caused by V. vulnificus is difficult because the symptoms of sepsis caused by V. vulnificus are not different from those of any other form of sepsis. This infection should be suspected in patients with a
Treatment
Soft-tissue infection by V. vulnificus represents a true surgical emergency. Early recognition and prompt aggressive
debridement of all necrotic tissue are critical for survival
and improve the rate of survival. The cause of death in
most cases is multiorgan failure, acute respiratory distress
syndrome, or overwhelming sepsis. With appropriate early
surgical intervention, mortality varies from 8.7% to 50%,
depending on a number of variables.36 Without surgical
intervention, the disease is usually fatal because antibiotics
alone are ineffective against the large soft-tissue bacterial
inocula resulting from the invasive nature of these infections and because of the widespread obliterative vasculitis,
vascular necrosis, and thrombosis of the supplying vessels
that hinder the penetration of antibiotics to the affected
area. As with other types of NSTIs and NF, debridement
must be aggressive, all necrotic tissue with overlying skin
should be excised deeply and beyond the necrotic area, and
all necrotic fascia and fat should be removed until healthy
viable tissue is evident. A second examination should be
done within 24 hours to assess the progression of the condition and check the need for further debridement.36
In addition to aggressive surgical debridement, efficient
and early presurgical antimicrobial treatment is essential
for management of V. vulnificus infection. Antimicrobial
use should be initiated as soon as the diagnosis is considered
likely. The combination of cefotaxime and minocycline
demonstrated a better outcome than monotherapy with
either drug alone.36 This combination is also better than
first- or second-generation cephalosporin. More recently,
the newer fluoroquinolones have been demonstrated to be
as effective as the combination cefotaxime plus minocycline
in vitro and in vivo.37 The combination of quinolone plus
cefotaxime showed a superior in vitro efficacy than either
drug alone or the combination of minocycline plus cefotaxime.37
All other measures to be taken are the same as for other
types of NF.
REFERENCES
1. DiNubile MJ, Lipsky BA. Complicated infections of skin and
skin structures: when the infection is more than skin deep.
J Antimicrob Chemother. 2004;53 Suppl 2:ii37–ii50.
2. Ellis Simonsen SM, van Orman ER, Hatch BE, et al. Cellulitis
incidence in a defined population. Epidemiol Infect. 2006;
134:293–9.
80 E MERGENCY D ERMATOLOGY
3. Salcido RS. Necrotizing fasciitis: reviewing the causes and
treatment strategies. Adv Skin Wound Care. 2007;20:288–
93.
4. Wong CH, Chang HC, Pasupathy S, et al. Necrotizing fasciitis: clinical presentation, microbiology, and determinants of
mortality. J Bone Joint Surg Am. 2003;85-A:1454–60.
5. Mulla ZD. Group A streptococcal necrotizing fasciitis: reducing the risk of unwarranted litigation. Am J Emerg Med. 2005;
23:578–9.
6. Wang YS, Wong CH, Tay YK. Staging of necrotizing fasciitis based on the evolving cutaneous features. Int J Dermatol.
2007;46:1036–41.
7. Childers BJ, Potyondy LD, Nachreiner R, et al. Necrotizing
fasciitis: a fourteen-year retrospective study of 163 consecutive patients. Am Surg. 2002;68:109–16.
8. Singh G, Sinha SK, Adhikary S, et al. Necrotising infections
of soft tissues–a clinical profile. Eur J Surg. 2002;168:366–71.
9. Cunningham JD, Silver L, Rudikoff D. Necrotizing fasciitis:
a plea for early diagnosis and treatment. Mt Sinai J Med.
2001;68:253–61.
10. Elliott DC, Kufera JA, Myers RA. Necrotizing soft tissue
infections. Risk factors for mortality and strategies for management. Ann Surg. 1996;224:672–83.
11. Anaya DA, Dellinger EP. Necrotizing soft-tissue infection:
diagnosis and management. Clin Infect Dis. 2007;44:705–
10.
12. Burge TS. Necrotizing fasciitis–the hazards of delay. J R Soc
Med. 1995;88:342P–343P.
13. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue
infections. Clin Infect Dis. 2005;41:1373–406.
14. Maltezou HC, Giamarellou H. Community-acquired
methicillin-resistant Staphylococcus aureus infections. Int J
Antimicrob Agents. 2006;27:87–96.
15. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillinresistant S. aureus infections among patients in the emergency
department. N Engl J Med. 2006;355:666–74.
16. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillinresistant Staphylococcus aureus in Los Angeles. N Engl J
Med. 2005;352:1445–53.
17. Chambers HF. Community-associated MRSA–resistance and
virulence converge. N Engl J Med. 2005;352:1485–7.
18. Kohler JE, Hutchens MP, Sadow PM, et al. Klebsiella pneumoniae necrotizing fasciitis and septic arthritis: an appearance in the Western hemisphere. Surg Infect (Larchmt).
2007;8:227–32.
19. Liu YM, Chi CY, Ho MW, et al. Microbiology and factors affecting mortality in necrotizing fasciitis. J Microbiol
Immunol Infect. 2005;38:430–5.
20. Wong CH, Kurup A, Wang YS, et al. Four cases of necrotizing fasciitis caused by Klebsiella species. Eur J Clin Microbiol
Infect Dis. 2004;23:403–7.
21. Jallali N, Withey S, Butler PE. Hyperbaric oxygen as adjuvant
therapy in the management of necrotizing fasciitis. Am J Surg.
2005;189:462–6.
22. Riseman JA, Zamboni WA, Curtis A, et al. Hyperbaric oxygen
therapy for necrotizing fasciitis reduces mortality and the need
for debridements. Surgery. 1990;108:847–50.
23. Kaul R, McGeer A, Low DE, et al. Population-based surveillance for group A streptococcal necrotizing fasciitis: clinical
features, prognostic indicators, and microbiologic analysis of
seventy-seven cases. Ontario Group A Streptococcal Study.
Am J Med. 1997;103:18–24.
24. Kaul R, McGeer A, Norrby-Teglund A, et al. Intravenous immunoglobulin therapy for streptococcal toxic shock
syndrome–a comparative observational study. The Canadian Streptococcal Study Group. Clin Infect Dis. 1999;
28:800–7.
25. Darenberg J, Ihendyane N, Sjolin J, et al. Intravenous
immunoglobulin G therapy in streptococcal toxic shock
syndrome: a European randomized, double-blind, placebocontrolled trial. Clin Infect Dis. 2003;37:333–40.
26. Muller AE, Oostvogel PM, Steegers EA, Dorr PJ. Morbidity related to maternal group B streptococcal infections. Acta
Obstet Gynecol Scand. 2006;85:1027–37.
27. Carter PS, Banwell PE. Necrotising fasciitis: a new management algorithm based on clinical classification. Int Wound J.
2004;1:189–98.
28. Golger A, Ching S, Goldsmith CH, et al. Mortality in
patients with necrotizing fasciitis. Plast Reconstr Surg.
2007;119:1803–7.
29. Baethge BA, West BC. Vibrio vulnificus: did Hippocrates
describe a fatal case? Rev Infect Dis. 1988;10:614–15.
30. Yuan CY, Yuan CC, Wei DC, Lee AM. Septicemia and
gangrenous change of the legs caused by marine vibrio, V.
vulnificus–report of a case.. Taiwan Yi Xue Hui Za Zhi.
1987;86:448–51.
31. Paz S, Bisharat N, Paz E, et al. Climate change and the
emergence of Vibrio vulnificus disease in Israel. Environ Res.
2007;103:390–6.
32. Oliver JD, Bockian R. In vivo resuscitation, and virulence
towards mice, of viable but nonculturable cells of Vibrio vulnificus. Appl Environ Microbiol. 1995;61:2620–3.
33. Strom MS, Paranjpye RN. Epidemiology and pathogenesis of
Vibrio vulnificus. Microbes Infect. 2000;2:177–88.
34. Tamplin M, Rodrick GE, Blake NJ, Cuba T. Isolation and
characterization of Vibrio vulnificus from two Florida estuaries. Appl Environ Microbiol. 1982;44:1466–70.
35. Bisharat N, Agmon V, Finkelstein R, et al. Clinical, epidemiological, and microbiological features of Vibrio vulnificus biogroup 3 causing outbreaks of wound infection and
bacteraemia in Israel. Israel Vibrio Study Group. Lancet.
1999;354:1421–4.
36. Kuo YL, Shieh SJ, Chiu HY, Lee JW. Necrotizing fasciitis
caused by Vibrio vulnificus: epidemiology, clinical findings,
treatment and prevention. Eur J Clin Microbiol Infect Dis.
2007;26:785–92.
37. Kim DM, Lym Y, Jang SJ, et al. In vitro efficacy of the
combination of ciprofloxacin and cefotaxime against Vibrio vulnificus. Antimicrob Agents Chemother. 2005;49:3489–
91.
CHAPTER 9
Life-Threatening Bacterial Skin Infections
Richard B. Cindrich
Donald Rudikoff
DERMATOLOGISTS are often called on to diagnose
severe life-threatening skin infections in the emergency
department, hospital wards, and in their clinical practices. The observational skills of the dermatologic specialist
enable him or her to differentiate conditions that are potentially fatal from those that may look horrific but are not life
threatening. This chapter provides essential information on
serious infections, many of which are not usually discussed
in depth in most dermatologic texts. These include periorbital (preseptal) and orbital cellulitis, malignant external
otitis, meningococcemia, Rocky Mountain spotted fever
(RMSF), Mediterranean spotted fever, anthrax, tularemia,
and infections with Vibrio vulnificus, Aeromonas hydrophila
and Chromobacterium violaceum. It is hoped that prompt
recognition of these infections by the clinician will reduce
morbidity and possibly be lifesaving.
PERIORBITAL (PRESEPTAL) CELLULITIS AND
ORBITAL CELLULITIS
Background
Eyelid infections presenting with erythema and edema are
not uncommon in children and adults and in some cases
can cause serious sequelae. Involvement of the orbit with
bacterial infection can result in severe damage to the eye,
cavernous sinus thrombosis, and death. Preseptal cellulitis
is an infection of the eyelids and surrounding skin anterior
to the orbital septum (Figure 9.1).1 This layer of fibrous tissue arises from the periosteum of the orbit and extends into
the eyelids.2 Infection posterior to the septum is referred
to as orbital cellulitis. Although less common than preseptal cellulitis, it is a much more worrisome condition with
the potential for major sequelae. It is essential when confronted with a patient with eyelid infection to distinguish
orbital cellulitis from preseptal infection and other entities that may present similarly. Whereas preseptal cellulitis
often can be managed in an outpatient setting, orbital cellulitis requires hospitalization, intravenous (IV) antibiotics,
and sometimes surgical intervention. Immediate ophthalmological consultation is essential and, because the process
may derive from sinus infection, otolaryngological consultation is often helpful.
Clinical and Laboratory Aids Required for Diagnosis
Distinction between preseptal and orbital cellulitis in
patients with periorbital inflammation is the major priority. Patients with preseptal cellulitis complain of pain,
symptoms of conjunctivitis, epiphora, and blurred vision
and display eyelid and periorbital erythema and edema
that may be so severe that they cannot open the eye.3
Although edema may frustrate examination, the visual acuity, light reflexes, and range of motion of the globe should
be assessed. Unlike preseptal cellulitis, orbital cellulitis
presents with some degree of ophthalmoplegia, pain on
eye movement, and/or proptosis. The latter condition may
also compromise the optic nerve causing vision loss, abnormal papillary reflexes, and disk edema. Computed tomography with contrast should be undertaken when physical
examination is impeded by obtundation or patient age to
rule out abscess formation, if orbital cellulitis is suspected.
FIGURE 9.1: Left preseptal cellulitis. Reproduced with permission from the BMJ Publishing Group. Br J Ophthalmol. 2007;
91:1723–4.
page 81
82 E MERGENCY D ERMATOLOGY
Orbital cellulitis can be caused by penetrating trauma but is
almost always a consequence of sinusitis. Most commonly,
the ethmoid sinus is involved in extension across the lamina papyracea. Blood cultures and complete blood counts
(CBCs) should be done in all patients but do not reliably differentiate between the two conditions. Leukocytosis with
left shift will be present in most patients with either condition. Bacteremia is infrequent but more common in young
children. Cultures should be obtained from the eyelid, or
any conjunctival or lacrimal sac discharge.3
Preseptal cellulitis occurs as a consequence of facial
infection, trauma, insect bites, or herpetic lesion. It also
may occur as a result of bacteremia in children younger
than 36 months. In this setting, prior to the introduction
and routine use of conjugated Hemophilus vaccine, the most
common pathogen was Hemophilus influenzae but it is now
Streptococcus pneumoniae. The intact orbital septum usually
prevents posterior spread of preseptal cellulitis in adults,
but in children such spread can occur. Clinical evidence
of trauma, insect bites, herpes infection, dacryocystitis, or
sinus infection should be sought in all patients presenting
with eyelid and periorbital inflammation.
Therapy
Oral antimicrobial coverage for Staphylococcus aureus and
group A Streptococci is usually sufficient in uncomplicated
cases of preseptal cellulitis in adults. Typical regimens
include oral amoxicillin/clavulanic acid, a first-generation
cephalosporin, or intramuscular ceftriaxone. Younger children should be admitted to the hospital and additionally receive antibiotic coverage for S. pneumoniae with an
agent such as cefuroxime. Local prevalence of methicillinresistant S. aureus and penicillin-resistant S. pneumoniae in
the community should be considered in deciding initial
antibiotic coverage pending the receipt of culture results.
An evidence-based literature review to determine whether
children with simple preseptal periorbital cellulitis should
be treated with IV or oral antibiotics failed to find any
evidence that either approach was superior.4 The authors
noted that, in one hospital series, four pediatric patients
with preseptal cellulitis developed intracranial, epidural
abscess or empyema.5
Suspected cases of orbital cellulitis should be admitted to
the hospital for IV antibiotic treatment. Consultation with
ophthalmology and otolaryngology should be obtained on
an emergency basis. Following culture collection, antibiotic
therapy should be initiated with coverage of Streptococcus
species, S. aureus, anaerobes, nontypable Hemophilus, and
Moraxella catarrhalis.
therapy is dependent on response and extent of infection.
If improvement does not occur in 24–48 hours, a resistant
organism or orbital infection should be suspected. Treatment should be continued for about 10 days.
For orbital cellulitis, IV antibiotics should be continued until the infection is well controlled and consideration given to oral therapy to complete a course of 3–4
weeks. Venous sinus thrombosis is a potential complication of orbital cellulitis as venous drainage of the orbit is
through the cavernous sinus.
MALIGNANT EXTERNAL OTITIS
Background
Malignant (necrotizing) external otitis is an invasive infection of the external auditory canal and skull base most
commonly occurring in elderly individuals with diabetes
mellitus (86%–90%) and in patients with acquired immunodeficiency syndrome.6,7 It is caused by Pseudomonas aeruginosa in more than 98% of cases. Case reports have implicated other bacteria in some cases including S. aureus,
Proteus mirabilis, and others. Aspergillus fumigatus has been
implicated in cases of fungal malignant external otitis.
Occasional pediatric cases of malignant otitis externa have
been reported, particularly in adolescents with diabetes and
children with immune dysfunction as a result of leukemia,
malnutrition, and/or solid tumors.8 Children with the disease may display fever, leukocytosis, and pseudomonas bacteremia and develop facial nerve palsy more often than
adults may. Rare cases have been reported in infancy.
Malignant external otitis may be complicated by facial
nerve palsy, meningitis, brain abscess, and dural sinus
thrombophlebitis and may be fatal.
Clinical and Laboratory Aids Required for Diagnosis
Patients with malignant otitis externa typically present with
ear pain and drainage, and frequently they will have failed
therapy with topical agents. They may also give a history of
recent irrigation for impacted cerumen. Pain may extend to
the temporomandibular joint and be exacerbated by chewing. A predisposing immunocompromising condition, diabetes most commonly, is usually present.
On physical examination, granulation tissue is noted
in the auditory canal at the bony cartilaginous junction.9
Drainage is present, but the tympanic membrane is usually
undamaged.
Therapy
Course and Prognosis
Preseptal cellulitis usually has an excellent prognosis if
recognized early and treated aggressively. Duration of
Following culture, therapy should be initiated with antibiotics covering Pseudomonas species. Until recently, oral
therapy with ciprofloxacin 750 mg twice daily with or
without the addition of rifampin has been advocated as
Chapter 9
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Life-Threatening Bacterial Skin Infections
83
the treatment of choice.10,11 Due to increasing use of
fluoroquinolones, resistance of Pseudomonas species to
ciprofloxacin has been increasing with anywhere from 20%
to 30% of isolates being reported as resistant.12–14 Hospital
admission and IV antibiotic therapy with a third-generation
cephalosporin such as ceftazidime with anti-Pseudomonas
activity is indicated when there is a history of recent fluoroquinolone use, high community rates of ciprofloxacinresistant Pseudomonas, or when clinical severity warrants
close observation. The use of hyperbaric oxygen has been
advocated to improve outcomes in malignant external otitis, but an analysis of published studies failed to find sufficient evidence in controlled studies for its use.15
Course and Prognosis
Osteomyelitis of the skull base with involvement of vital
structures is the most serious complication of malignant
otitis externa.16 Cranial nerve neuropathy, especially of the
facial nerve, may occur. The earliest series in the literature
reporting on elderly diabetic patients with late-stage disease who underwent extensive surgery as primary therapy
had a mortality rate of approximately 50%.17 Because of the
high mortality with surgery, the use of synergistic combinations of semisynthetic penicillins and aminoglycosides was
introduced to control pseudomonas; subsequently, thirdgeneration cephalosporins such as ceftazidime were shown
to have similar efficacy.18–20 Later, ciprofloxacin at a dosage
of 1.5 g/d used over an average of 10 weeks showed superior
efficacy with a reduction of mortality from approximately
30% to 2%–3%; however, this result was prior to recent
increases in ciprofloxacin resistance.10,18 Premature termination of treatment may result in recurrence rates of 15%–
20%.21 Prolonged treatment is more likely to be associated
with adverse drug reactions in patients receiving -lactam
antibiotics than in those treated with ciprofloxacin.22 In a
recent study, facial nerve involvement previously cited as
a poor prognostic indicator did not adversely affect survival.16,23
MENINGOCOCCEMIA
FIGURE 9.2: Necrotic purpuric bullae in a 5-year-old boy with
meningococcemia who developed purpura fulminans. Source:
DermAtlas, Johns Hopkins University; 2000–2009 (meningococcemia 1 031001), Andreas Eliades, MD.
and another 10%–20% are left with severe sequelae such as
hearing loss and limb amputation.25 Affecting primarily the
pediatric population, the highest rates of both meningitic
and nonmeningitic meningococcal disease occur in infants
younger than 1 year.26 Approximately one third of all cases
of sporadic meningococcal disease occur in adults, and one
half of these present without rash or meningitis.27 Given
the high morbidity and mortality of meningococcal infections, rapid institution of antibiotic therapy and supportive care are advocated by most authorities. Preadmission
parenteral antibiotics (benzylpenicillin, ceftriaxone, chloramphenicol) have been suggested for patients presenting
to a physician’s office with signs of invasive meningococcal
disease. Assuredly, no physician wants to miss the diagnosis
of meningococcemia. The diagnosis of patients presenting
with typical signs of acute meningitis is often straightforward. It is the patient who does not appear ill on initial presentation who represents a major diagnostic challenge.28
To not miss the diagnosis, it has been suggested that, in
any acutely febrile patient, it is prudent to ask, “Why is this
patient seeking help now?” then “Could this patient have
meningococcemia?”28
Background
Meningococcemia, with or without meningitis, is one of
the most serious emergencies in medicine. The causative
organism, Neisseria meningitidis, has the ability to cause outbreaks as well as sporadic cases of invasive meningococcal
disease with devastating consequences often progressing
rapidly to purpura fulminans, shock, and death. Large-scale
outbreaks occurred in the United States in the 1940s associated with military deployments, but disease rates have
remained relatively stable for the past 20 years, at 1.0–1.5
per 100,000 population.24 Despite advances in treatment,
approximately 10% of affected patients die from the disease,
Clinical and Laboratory Aids Required for Diagnosis
Early clinical clues to meningococcemia include a hemorrhagic (petechial or purpuric) eruption; a blanching macular or maculopapular rash appearing in the first 24 hours;
true rigors; severe pain in the extremities, neck, and back;
vomiting; headache; and rapid evolution of illness.28 The
lesions of acute meningococcemia are indurated, gun metal
gray patches of purpura that display an irregular (infarctive) pattern (Figure 9.2).29 These may occur anywhere on
the skin and can develop bullae and ulcerate. A transient
blanching erythematous maculopapular eruption may arise
84 E MERGENCY D ERMATOLOGY
before the appearance of purpura.29 In a study of children
and adolescents with invasive meningococcal disease, the
first classical sign to emerge was rash, which at the onset
was nonspecific and only developed into a petechial (and
then a largely hemorrhagic) eruption over several hours.30
In this study, fever was the first symptom noted in children younger than 5 years. Headache was the first symptom in patients older than 5 years; 94% developed fever at
some point, and irritability was a prominent symptom in
younger children.30 Three important features were identified as signs of early meningococcal disease in children
and adolescents: leg pain, cold hands and feet, and abnormal skin color (pallor or mottling).30 Eruption, meningism,
and impaired consciousness occurred later.
Therapy
The prompt initiation of IV antibiotic therapy is essential
in patients with suspected meningococcal disease. Recommended treatment regimens include a 5- to 7-day course
of: (1) penicillin G, 500,000 U/kg/d in six divided doses;
(2) ceftriaxone, 100 mg/kg/d in one or two divided doses;
or (3) cefotaxime, 200 mg/kg/d in three divided doses.31,32
Recently, intermediate resistance of some meningococci
to penicillin has been reported from Europe. In a Portuguese study, one quarter (24.6%) of the isolates showed
moderate resistance to penicillin.33 A study from Scotland
found an absence of “high-level” resistance to penicillin
among meningococci and an 8.3% prevalence of moderate
resistance.34 Although there is some indication that a small
number of strains in the United States display intermediate
resistance to penicillin, the U.S. Centers for Disease Control and Prevention (CDC) has not recommended routine
susceptibility testing of meningococcal isolates.35 Treatment of meningitis in children is aimed at the most likely
pathogen based on epidemiologic information.36 Because
of the significant prevalence of penicillin-resistant S. pneumoniae, empirical treatment of meningitis in children 1
month old or older should include vancomycin plus cefotaxime or ceftriaxone.36
Course and Prognosis
In general, the mortality rate for meningococcal septicemia
exceeds that of meningococcal meningitis. Reported mortality from meningococcemia ranges from 18% to 53%
whereas that of meningococcal meningitis has in the past
15–20 years hovered around 10%.31,37 Among adults with
single episodes of community-acquired meningitis, risk factors for death included older age (≥60 years), obtunded
mental state on admission, and seizures within the first
24 hours.38 In a study of 3335 meningococcal deaths in
the United States, 58% of deaths occurred among persons
younger than 25 years. Mortality was increased in infants,
young adults (15–24 years old), and older adults (older than
74 years).39 Neurological sequelae following meningococcal disease occurred in 10%–20% of patients.40
A number of treatment modalities have been used to
improve the prognosis of meningococcal disease. There is
controversy as to whether corticosteroids improve prognosis, but many groups use them routinely.
A subgroup analysis of patients with meningococcal
meningitis treated with corticosteroids showed a nonsignificant favorable trend in mortality.41
ROCKY MOUNTAIN SPOTTED FEVER
Background
RMSF is one of the most virulent human infections ever
identified; 5%–10% of individuals infected die, and many
others suffer sequelae such as amputation, deafness, or permanent learning disability.42 RMSF occurs throughout the
continental United States, Canada, Mexico, Central America, and parts of South America. During the period 1997–
2002, there were 2.2 cases per 1 million per year in the
United States, and more than one half (56%) of cases were
reported from only five states: North Carolina, South Carolina, Texas, Oklahoma, and Arkansas.43 Although cases
are reported throughout the year, most occur from May
through January with a peak in July, August, and September
(46% of 2298 cases in 2006).44 During 2006, more than half
of cases were reported from the South Atlantic region with
962 cases (42% of total U.S. cases) from North Carolina.
Arkansas and Tennessee accounted for 13% and 11.5% of
cases, respectively. RMSF is most common in boys and
men and Caucasians, and although children younger than
10 years were the group at highest risk in previous studies,
in 2003 the highest age-specific incidence was in persons
40–64 years old.45
Clinical and Laboratory Aids Required for Diagnosis
The initial symptoms of RMSF include sudden onset of
fever, chills, and headache, associated with malaise and
myalgias. Anorexia, nausea, vomiting, and photosensitivity are also commonly seen. Because eruption may not
be evident at the time a patient first presents for evaluation, clinicians should still maintain a high index of suspicion for the diagnosis in patients with a history of outdoor activities. History of a tick bite is elicited in only one
half of patients with RMSF. Sixty to 70 percent of patients
with RMSF present with the classic triad of fever (94%),
headache (86%), and eruption (85%) 1–2 weeks after tick
exposure.46 However, this occurs in only 3% of cases in
the first 3 days of illness.47 Fever usually exceeds 38.9◦ C
(102◦ F), and the majority of patients develop an eruption
within 3–5 days following its onset.46 Children with RMSF
present with fever (98%), eruption (97%), nausea and/or
vomiting (73%), and headache (61%).48 The eruption is
Chapter 9
FIGURE 9.3: Rocky Mountain spotted fever with red, partially
blanching papules on the palms. Source: DermAtlas, Johns Hopkins University; 2000–2009 (rmsf 2 010907), Bernard Cohen, MD.
maculopapular before the appearance of petechiae and may
be easily missed, especially in dark-skinned individuals.49
Blanching erythematous macules, 1–5 mm in diameter, initially arise on the wrists and ankles and spread to the palms
and soles (Figure 9.3).29,47 The eruption of erythematous
macules on the wrists, ankles, palms, and soles is followed by
centripetal spread to the arms, legs, and trunk (Figure 9.4).
In 24–48 hours, petechiae and purpuric macules develop
that may superficially resemble meningococcemia.29
Bilateral periorbital edema, suffusion of the conjunctivae, and edema of the hands and feet are highly sug-
●
Life-Threatening Bacterial Skin Infections
85
gestive of RMSF in the appropriate clinical setting. The
severe headache (which patients may describe as the worst
they have ever experienced) may mimic meningitis with
meningismus in 18% of patients.46,47,50 The headache is
usually frontal and is often associated with restlessness;
severe myalgias of the abdomen, back, and legs; nausea;
vomiting; and abdominal pain. Patients may display amnesia, psychiatric symptoms, and transient hearing loss.
CBC and a comprehensive metabolic panel should be
done when considering rickettsial disease. White cell count
in RMSF is usually normal, but increased numbers of
immature band forms are often seen. Thrombocytopenia,
mild elevations of hepatic transaminases, and hyponatremia
also can occur.
Blood cultures and examination of a peripheral smear
are useful in ruling out other conditions that mimic RMSF.
The presence of morula in the peripheral smear in either
monocytes or granulocytes suggests human monocytic
ehrlichiosis (HME) or human granulocytic anaplasmosis
(HGA), respectively. Leukopenia with elevations of liver
transaminases and thrombocytopenia further suggest HGA
and HME. HGA is transmitted through the Ixodes scapularis
tick, which does not transmit Rickettsia rickettsii, whereas
HME is transmitted to humans through the lone star
tick or Amblyomma americanum and possibly other tick
species. Blood cultures are useful in assessing bacterial
infections, particularly meningococcal infection the early
signs of which can be difficult to distinguish from RMSF.
Cerebrospinal fluid in RMSF usually shows a pleocytosis
(usually with <100 cells per milliliter) with neutrophilic
or lymphocytic predominance. Protein is elevated, but
glucose remains normal. Gram-negative diplococci with
neutrophilic predominance and low glucose clearly favor
meningococcal infection; however, there remains considerable overlap, and empiric coverage for meningococcus is
frequently unavoidable. Serological testing and immunohistochemical or polymerase chain reaction (PCR) analysis
of skin biopsy specimens can also confirm the diagnosis.
In a study of RMSF in children by Buckingham48 laboratory findings were nonspecific and similar to those that
might occur, for example, in viral syndromes such that “no
constellation of clinical and laboratory abnormalities has
adequate sensitivity for their absence to exclude the diagnosis of RMSF in a child.”48
Because of the rapid progression of infection, empiric
therapy should not be withheld awaiting laboratory confirmation.
Treatment
FIGURE 9.4: Rocky Mountain spotted fever. Diffuse petechiae,
purpura, and edema. Source: DermAtlas, Johns Hopkins University; 2000–2009 (rmsf 5 010907), Bernard Cohen, MD.
Doxycycline is the drug of choice for treatment of both
adults and children with presumptive or proven RMSF.
Even though the use of tetracyclines in young children has
been discouraged because of the potential for tooth discoloration, this effect is dose related and does not necessarily
86 E MERGENCY D ERMATOLOGY
preclude the use of this agent.51 One course of doxycycline
in young children for presumed RMSF, a potentially lifethreatening disease, has not been shown to cause clinically
significant staining of permanent teeth.52 Moreover, doxycycline effectively treats ehrlichiosis, which may be confused with RMSF. Chloramphenicol is the preferred agent
for treating RMSF occurring during pregnancy.53
Patients with RMSF should be admitted to the hospital
and observed closely and treated for altered mental status
or any organ dysfunction. Patients in more advanced stages
of disease warrant admission to an intensive care unit for
aggressive supportive measures.
Course and Prognosis
Appropriate treatment of patients with RMSF is often
delayed for a number of reasons including lack of tickexposure history; occurrence of illness at times of year when
tick activity is not at its peak; absence or delayed appearance
of eruption; symptoms other than the classic triad of fever,
eruption, and headache; and lack of headache.48,54–58 Of
interest, presentation to a health care provider early in the
course of the disease has been associated with delay in the
initiation of specific antirickettsial therapy.48,58 For example, in one study by Buckingham,48 children were seen by
medical providers after a median of 2 days of symptoms
but did not receive specific antirickettsial treatment until
after a median of 7 days of symptoms. In fact, 2 of the 3
children who died in that study, although seen early on,
were not given appropriate treatment. Also in that study,
more than one third of patients spent time in an intensive
care unit, 16% received mechanical ventilation, and 17%
received pressors.
Before the introduction of effective antirickettsial agents,
13% of children with RMSF died.51 Despite the availability
of specific therapy and improved supportive medical care,
the case fatality rate in children younger than 10 years is
still 2%–3%. Several clinical and laboratory variables have
been associated with fatal outcome including increased age;
male sex; neurological involvement; elevated levels of creatinine, aspartate aminotransferase, and bilirubin; decreased
levels of serum sodium; and decreased platelet count.59 The
development of acute renal failure increased the odds ratio
of dying 17-fold in one study.59 The presence of a deficiency of the enzyme glucose-6-phosphate dehydrogenase
(G6PD) may portend a more fulminant course because of
the development of hemolysis.60
Even with recovery, patients may suffer ongoing neuromotor impairment at the time of discharge from the hospital; this impairment may persist in some patients,61 particularly if neurologic compromise, especially coma, occurs
during the acute phase of the illness. Persistent sequelae
include dysarthria, difficulty reading, impaired memory,
deafness, and paresthesias. Gangrene can necessitate amputation of digits or entire extremities.
MEDITERRANEAN SPOTTED FEVER
Background
Mediterranean fever (Boutonneuse fever) has been described in many countries under a variety of names. It is
caused by Rickettsia conorii and its subspecies, and the vector is the brown dog tick Rhipicephalus sanguineus. Although
usually a benign, uncomplicated disease with recovery the
norm, it may sometimes be severe and fatal.62 The mortality rate is usually estimated at approximately 2.5%, but
a fatality rate of up to 5.6% has been reported in affected
hospitalized patients in Israel, France, and Portugal.63 The
disease tends to be more severe in the elderly population and in patients with cirrhosis, chronic alcoholism, and
G6PD deficiency.64 In Beja, a Portuguese southern district,
a case fatality rate of 32.3% was reported in hospitalized
patients with Mediterranean spotted fever.65 The risk of
dying was associated with diabetes, uremia, vomiting, and
dehydration. A subspecies of R. conorii (israelensis), the cause
of Israeli spotted fever, has been isolated from patients
in Sicily and Portugal and may be associated with more
severe disease. The disease has been reported throughout the Mediterranean basin, sub-Saharan Africa, India,
around the Black Sea, and in the eastern part of Russia close
to Japan. Diagnosis peaks in August in endemic areas of
France and Spain suggest that larvae and nymph forms are
important in disease spread. The peak activity of adult ticks
occurs several months earlier during the spring. Reports of
Mediterranean spotted fever throughout the year and from
colder areas removed from the Mediterranean imply that
R. sanguineus can survive in the microclimates of homes and
kennels.
Clinical and Laboratory Aids Required for Diagnosis
The incubation period of Mediterranean spotted fever is
approximately 7 days. Disease onset is abrupt and typically begins with high fever, flu-like symptoms, a black
eschar (tache noire) at the site of the tick bite, and a maculopapular eruption. The tache noir is said to be present
in approximately 74% of cases but is uncommon in the
Israeli form. Eruption is described as maculopapular but
may be purpuric in 10% of cases. Laboratory studies are
often nonspecific with thrombocytopenia, leukocyte count
abnormalities, both lymphopenia and leukocytosis, and elevated hepatic enzyme levels.
Early diagnosis of Mediterranean spotted fever can
be achieved using immunofluorescence or immunohistochemical studies of skin biopsy material or by PCR.66,67
Both techniques require experienced personnel and may
have limited availability.
Serologic studies provide retrospective confirmation
of the diagnosis. Antibodies to rickettsiae may not be
detectable until 7–10 days after infection is clinically manifest. An acute blood sample should be collected early in
Chapter 9
the course of the disease, and a second specimen should be
obtained 2 weeks later. If a fourfold increase in antibody
titer is not observed, collection of a third sample after 4–6
weeks should be considered. Specific diagnosis may not be
made until the patient has recovered or died.
Treatment
Treatment should be initiated as soon as the diagnosis is
suspected. Doxycycline is the drug of choice and is given
for a 7-day course of therapy or until the patient is afebrile
for 3 days. Doxycycline has been shown to effectively treat
Mediterranean spotted fever with a 1-day course of therapy.68 Doxycycline is contraindicated in pregnancy and not
usually recommended for use in children younger than
8 years with the exception of patients with RMSF. Chloramphenicol is also an effective antibiotic agent and had
previously been used in pregnancy. Aplastic anemia occurs
in 10 of 40,000 patients treated with chloramphenicol,
and gray baby syndrome (comprising abdominal distension, pallor, cyanosis, and vasomotor collapse usually leading to death) has been described in neonates treated with
this drug. Although there has been no report of an infant
exposed in utero having developed gray baby syndrome
or aplastic anemia, few obstetricians and pediatricians are
comfortable with its prescription. In vitro studies of clarithromycin and azithromycin have suggested effectiveness
of these antibiotics in treatment of R. conorii infection.
Clinical trials suggest that these agents provide a safe and
effective alternative for treatment of children younger than
8 years with Mediterranean spotted fever.69,70 Fluoroquinolines also have been shown in vitro to be effective
against R. conorii.71
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Life-Threatening Bacterial Skin Infections
87
ANTHRAX
Background
Anthrax is primarily a disease of wild and domestic animals (cattle, sheep, and goats) caused by the spore-forming
bacterium Bacillus anthracis. Human disease results from
exposure to infected animals or tissue from infected animals. This exposure occurs after cutaneous inoculation or
inhalation of spores or after ingestion of infected material.
B. anthracis can exist as a stable spore form for years and can
be weaponized as a bioterrorism agent. This weaponization
occurred in the United States in 2001 when powder containing anthrax was placed in letters and disseminated via
the U.S. Postal Service.
Although the cutaneous form of anthrax is usually considered the least severe presentation, it can result in fatality
if not adequately treated. A rare complication, malignant
edema, is characterized by severe edema, induration, multiple bullae, and shock.72 Involvement of the face, neck, and
chest may require intubation and corticosteroids to prevent
asphyxiation. In a series of 28 cases of cutaneous anthrax
reported in 2003 from Turkey, two patients (8%) died from
anthrax sepsis.73 A recent study from the Artibonite Valley of Haiti reported 87 cases of cutaneous anthrax over
a 4-year period.74 Seven of 87 patients (8%) died, 4 from
asphyxiation after facial and neck edema compressed the
trachea, causing airway obstruction. Two patients died
of symptoms associated with concurrent gastrointestinal
anthrax. Anthrax can cause a severe, usually fatal meningoencephalitis from both the cutaneous and inhalational
routes.72,75
Clinical and Laboratory Aids Required for Diagnosis
Course and Prognosis
In general, Mediterranean spotted fever has a good prognosis if appropriately treated. Risk factors for more severe
disease include diabetes, G6PD deficiency, older age, cirrhosis, and alcoholism. Delay in initiation of appropriate
antibiotic coverage is also frequently cited as a risk factor for poor prognosis; however, a retrospective study in
the Beja district of southern Portugal, which experienced
a 32.3% case fatality rate for hospitalized patients in 1997,
did not bear this out. Diabetes, vomiting, volume depletion,
and uremia were significantly correlated with risk of dying.
Treatment of severe illness induced by R. conorii may
require more than chemotherapeutic elimination of the etiologic agent. The multiorgan manifestations of endothelial
damage and increased vascular permeability may necessitate admission to an intensive care unit for monitoring of central pressures and airway management. Additional antibiotic coverage may be required to cover bacterial leakage from a compromised gut or from aspiration.
The diagnosis of anthrax is usually straightforward when
it occurs in a typical occupational or environmental setting involving exposure to infected animals or contaminated animal products, such as hides, wool, hair, or ivory
tusks.76 In the past, urban cases of anthrax were usually associated with imported products such as shaving brushes, and
recently two cases were reported in Connecticut in a drum
maker and his child after exposure to contaminated goat
hides imported from Guinea.77–79
The primary lesion of cutaneous anthrax is a painless
papule that usually develops approximately 7 days (range =
1–12 days) after inoculation of infected material.80 It most
commonly occurs on the head, neck, or arms and develops a central vesicle or bulla that becomes hemorrhagic
as the lesion enlarges. The classic black central eschar
is often surrounded by erythema and sometimes extreme
edema (Figure 9.5). The presence of a primary pustular
lesion should suggest another diagnosis. Multiple lesions
sometimes occur, and there may be tender regional lymphadenopathy and systemic symptoms of fever, chills, and
fatigue.80 Anthrax may occur on the eyelid and be associated
88 E MERGENCY D ERMATOLOGY
A
FIGURE 9.6: Facial cutaneous anthrax with massive edema.
Am J Trop Med Hyg. 2007; 77:806–11.
B
tularemia, the tache noir of rickettsial diseases, cat scratch
disease, ecthyma gangrenosum, orf, and staphylococcal or
streptococcal ecthyma.
When dealing with a patient with suspected cutaneous anthrax, universal precautions should be followed.
The American Academy of Dermatology recommendations include swabbing exudates using a dacron- or rayontipped swab (cotton should not be used) to obtain material
for Gram stain and culture.80 Vesicular fluid is optimal for
isolation of the organism. If only an eschar is present, the
edge should be lifted and swabs inserted to obtain fluid.
Two skin biopsies are advocated, one for histological examination including special stains and immunohistochemistry
and the other for culture.82 Treatment should be instituted while awaiting results. Serology and PCR assay may
be available through governmental agencies such as the
CDC.83
C
Treatment
FIGURE 9.5: Cutaneous anthrax in a 7-month-old infant. Progression of lesions: A. hospital day 5, B. hospital day 12, C.
2 months after discharge. Used with permission. JAMA. 2002;
c (2002). American Medical Association.
287:869–74. Copyright
All rights reserved.
with preseptal cellulitis, and severe edema resulting from a
primary lesion on the neck (bull neck) may result in asphyxiation (Figure 9.6).74,81
Cutaneous anthrax should be differentiated from insect
bites, brown recluse spider bite (almost always painful),
Uncomplicated localized cutaneous anthrax should be
treated with oral ciprofloxacin 500 mg twice daily or doxycycline 100 mg twice daily.84 Usual duration of treatment
is 7–10 days, but in the context of a bioterrorism attack, the
CDC recommends a 60-day course of treatment because of
the increased likelihood of exposure to aerosolized anthrax.
For children, the CDC recommends oral ciprofloxacin 10–
15 mg/kg every 12 hours, not to exceed 1 g/d or doxycycline. For children up to 8 years old (or those older
than 8 years weighing <45 kg), the CDC recommends
Chapter 9
a doxycycline dosage of 2.2 mg/kg every 12 hours. The
dosage of doxycycline for children older than 8 years and
weighing at least 45 kg is 100 mg every 12 hours. The
CDC has also recommended the use of ciprofloxacin and
doxycycline in pregnant woman although these agents traditionally have been avoided in pregnancy.
Cutaneous anthrax occurring on the head and neck and
cases with systemic involvement or severe edema should be
treated with the IV antibiotic regimens recommended for
inhalational anthrax. A multidrug regimen is recommended
in suspected cases of bioterrorism because antibiotic resistance may have been engineered into weaponized anthrax.
The initial treatment protocol recommended for inhalational bioterrorism-associated anthrax is ciprofloxacin
400 mg IV every 12 hours or IV doxycycline 100 mg every
12 hours plus one or two additional agents. IV therapy can
be switched to oral treatment when clinically warranted.
Additional agents that have activity against B. anthracis
include penicillin, ampicillin, imipenem, clindamycin, clarithromycin, rifampin, chloramphenicol, and vancomycin.
Inhalational anthrax and severe cutaneous disease in children are treated with IV ciprofloxacin 10–15 mg/kg every
12 hours (not to exceed 1 g/d in children) or IV doxycycline. Children younger than 8 years and those 8 years
old or older but who weigh less than 45 kg are treated
with IV doxycycline 2.2 mg/kg every 12 hours. Children
older than 8 years and who weigh more than 45 kg should
receive doxycycline 100 mg every 12 hours. One or two
additional antibiotics are added to this regimen in this
protocol.
Course and Prognosis
Prognosis of anthrax depends on the type of exposure.
Many sources quote a mortality rate of up to 20% in
untreated cutaneous anthrax, 25%–75% for gastrointestinal anthrax, and 80% or more for inhalational anthrax.
In one series, four patients (5.6% of patients) with cutaneous anthrax developed meningoencephalitis, and three
died.85 Less commonly cutaneous anthrax can progress to
septicemia and shock.86 Fulminant inhalational anthrax is
usually fatal, but initiation of antibiotics or anthrax antiserum therapy during the prodromal phase can improve
survival.87
TULAREMIA
Background
Tularemia is a zoonotic disease with worldwide distribution
caused by Francisella tularensis, a fastidious, gram-negative
organism.88,89 It has been speculated that tularemia was the
cause of the biblical plague of the Philistines.90 The Old
Testament warns in Leviticus 11:6 and 11:8, “And the hare
is unclean to you. Of their flesh ye shall not eat, and their
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Life-Threatening Bacterial Skin Infections
89
carcasses ye shall not touch.”91 Transmission to humans
occurs by several mechanisms, most commonly direct or
indirect inoculation of the skin from infected animal tissues,
body fluids, or pelts.92 The animals implicated in transmission of tularemia depend on the geographic area. In
the United States, jackrabbits, cottontail rabbits, beavers,
muskrats, meadow voles, and sheep are usually implicated. The disease may also be spread by arthropod vectors such as deerflies, mosquitoes, and several varieties of
ticks.
Interest in tularemia has been heightened in recent years
because of its potential for use as an agent of bioterrorism.
The organism is highly virulent in susceptible hosts. A low
infectious dose of 10–50 organisms can establish infection
in an open wound or if aerosolized and inhaled. The two
subspecies of F. tularensis commonly associated with human
disease are F. tularensis tularensis and F. tularensis holarctica.
The tularensis subspecies is found only in North America
and is the more virulent of the two.
The type of disease that develops reflects the route of
infection. Ulceroglandular disease, the most common presentation, follows exposure of broken skin to contaminated
animal material and occurs on the upper extremities in
more than 75% of patients.93 Lesions on the lower extremities, abdomen, back, or head usually result from exposure
to ticks or deerflies.
Clinical and Laboratory Aids Required for Diagnosis
Dermatologists are most likely to encounter patients
with ulceroglandular, glandular, or perhaps oculoglandular tularemia. A typical patient will present with the abrupt
onset of fever, chills, malaise, and fatigue after an incubation period of 1–10 days (average of 3 days).92 The most
common presenting complaint is of enlarged, tender, localized lymphadenopathy with overlying erythema. The initial
skin lesion may be present at the time of presentation or
shortly thereafter and is a painful, red papule that undergoes
necrosis leaving a tender ulcer with a raised border (Figure 9.7).94 Cutaneous ulcers range in size from 0.4 to 3.0
cm and are usually solitary. Multiple lesions can sometimes
occur and are usually caused by exposure to more than one
animal.93 The primary lesion may evolve over the course of
the disease. In a recent Swedish study, primary lesions were
described as “encrusted” in one third of cases and “ulcerous” or “pustular” each in about 20% of cases. “Papular”
primary lesions were noted in 13% and “macular” or “vesicular” lesions each occurred in approximately 3%–4% of
cases. Indeed, cases of tularemia have been initially misdiagnosed as herpes simplex or herpes zoster infection.95 Secondary skin eruptions including erythema nodosum have
been reported in patients with tularemia. In the previously
mentioned Swedish study, almost 30% of patients displayed
a secondary skin eruption apart from any primary lesions or
erythema overlying enlarged lymph nodes. Such eruptions
were most commonly papular or maculopapular. Erythema
90 E MERGENCY D ERMATOLOGY
The organism can be isolated from wound drainage,
lymph aspirates, sputum, and blood. Stringent precautions
should be taken when handling specimens to prevent infection in hospital and laboratory personnel. Francisella is a
biosafety level 3 pathogen, and the laboratory should be
warned if it is suspected. Relay of specimens to government health departments for processing may be the best
option for both expertise in culture and availability of PCR
or fluorescent antibody testing. Confirmation of infection
is usually made with increasing titers of antibodies in acute
and convalescent sera.
Treatment
FIGURE 9.7: Tularemia–cutaneous ulcer. From Oyston PCF,
et al. Tularaemia: bioterrorism defence renews interest in Francisella tularensis. Nat Rev Microbiol. 2004; 2:967–8.
nodosum occurred in 3% of patients, all girls and women.
Suppuration of involved lymph nodes may occur. In glandular disease, lymphadenopathy occurs in the absence of a
primary lesion.
Ulceroglandular tularemia must be differentiated from
other causes of ulceroglandular disease including Bartonella
henselae (cat scratch fever), Yersinia pestis (plague), Spirillum
minus (spirillary rat bite fever), and other bacterial adenitis.
Other diagnostic considerations are anthrax, herpes simplex, chancroid, syphilis, and mycobacterial disease.96
Oculoglandular disease resulting from direct or indirect
exposure of the conjunctivae to infectious material presents
with conjunctivitis, chemosis, lacrimation, photosensitivity, lid edema, and conjunctival ulceration accompanied by
tender lymphadenopathy in the preauricular, submandibular, and cervical regions. Pharyngeal disease occurs when
the primary exposure is within the oral cavity with contaminated foods or water. Typhoidal tularemia is distinct from
the other forms in that it is not accompanied by adenopathy and the portal of entry may not be identifiable. This
form usually affects persons with some degree of immune
compromise and may have a rapid and fulminant course. A
pneumonic form also exists in which the pulmonary findings are the most prominent feature.
Tularemia should be suspected when typical clinical
findings occur in a patient with an occupational or recreational exposure to animals in an endemic area. Diagnosis
outside of an endemic area requires a high index of suspicion.96 The incubation period is usually approximately
3–5 days, and onset of disease is often abrupt. Fever, chills,
malaise, sore throat, and headache are frequent, and pulse–
temperature dissociation may occur in 42% of cases. Persistent fever, greater than 101◦ F, is common over the course
of several days. Routine laboratory testing is nonspecific.
Leukocytosis may or may not be present. Thrombocytopenia, elevation of transaminases and creatine kinase, and
myoglobinuria may also be present.
Streptomycin is the preferred drug for treatment of
tularemia. Because it may not be readily available, gentamicin is commonly used with good results. -lactam antibiotics and macrolides are not effective and should not be
used. Fluoroquinolines provide effective coverage, as do
tetracyclines. A study from Spain showed ciprofloxacin to
be superior to both streptomycin and doxycycline in that it
had the lowest percentage of primary treatment failures;
however, this study was nonrandomized and retrospective. If the condition of the patient merits hospitalization,
IV therapy with streptomycin or gentamicin is indicated.
Stable patients may be treated with oral antibiotics with
ciprofloxacin or doxycycline, with ciprofloxacin being the
preferred oral agent for confirmed tularemia.
Course and Prognosis
Suppuration of large or flocculent lymph nodes is a common complication. Large nodes should be aspirated to prevent this complication. Another possible sequela to infection with tularemia is a prolonged period of fatigue that
may persist several weeks even following adequate antibiotic treatment.
Prior to the introduction of streptomycin in the 1950s,
patients often suffered from lingering symptoms and the
case mortality for ulceroglandular disease was about 5%.97
Death rates from all forms of tularemia in the antibiotic era
are about 4% but were as high as 33% prior to the use of
streptomycin.94
V. VULNIFICUS INFECTION
Background
V. vulnificus is not only the most virulent food-borne
pathogen in the United States but is a source of invasive, potentially life-threatening wound infections.98 Most
cases in the United States occur in individuals with cirrhosis who eat undercooked oysters from the Gulf of Mexico,
but cases of V. vulnificus have been reported from Japan,
Taiwan, Korea, Brazil, Mexico, Germany (from the Baltic
Chapter 9
Sea), Denmark, Spain, Israel, and Australia.99–109 A severe
outbreak occurred in Israel in fish market workers from
handling infected tilapia.108
V. vulnificus is present in shallow sea and estuarial waters
especially during the warm summer months. The gramnegative, comma-shaped organism is found in oysters, crustaceans, and shellfish.100
The main risk factors for developing V. vulnificus infection are consumption of raw or inadequately cooked oysters
or shellfish, exposure of a preexisting open wound to contaminated sea water, injury to the skin while in contact
with infected water, and handling contaminated marine
species (as in fish handlers). Wound infections are most
likely serious in persons with underlying chronic liver disease or other predisposing factors who engage in water
recreational activities. Also at risk are victims of natural
disasters such as tsunamis and flooding after hurricanes.
Eighteen wound-associated Vibrio cases were reported in
several states in victims of Hurricane Katrina of which 14
(82%) were V. vulnificus and 3 were V. parahaemolyticus.
Five (28%) patients with wound-associated Vibrio infections died, three from V. vulnificus and two from
V. parahaemolyticus.
Because early, specific antibiotic therapy, aggressive
wound management, and supportive measures can reduce
mortality, it is incumbent on physicians to be familiar with
the recognition of V. vulnificus infection.
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Life-Threatening Bacterial Skin Infections
91
FIGURE 9.8: Vibrio vulnificus infection with hemorrhagic cellulitis. Inset: Gram-negative rods seen on Gram stain. Falcon LM,
et al. Hemorrhagic cellulitis after consumption of raw oysters. N
Engl J Med. 2005; 353:1604.
and prompt initiation of antibiotic therapy are essential.
Soft-tissue infection with V. vulnificus has a propensity
to rapidly progress to necrotizing fasciitis. Clinical findings may include edema, patchiness, erythema, and tenderness. Hemorrhagic bullae or compartment syndrome may
already be apparent at the time of presentation.
Clinical and Laboratory Aids Required for Diagnosis
Infection with V. vulnificus should be suspected in any
patient presenting with cellulitis or sepsis after exposure to
brackish or salt water or with a history of recent ingestion
of raw or undercooked seafood, mainly raw oysters. The
presence of hemorrhagic bullae complicating cellulitis in
a patient with a history of liver disease or diabetes should
further suggest the diagnosis (Figure 9.8).110 A small study
comparing the clinical aspects of necrotizing fasciitis caused
by Vibrio with that caused by Streptococci pointed out
several significant differences. All cases of Vibrio infection
occurred during summer months in patients with underlying chronic liver dysfunction and were probably caused by
raw seafood consumption.111 In this study, Streptococcusinduced necrotizing fasciitis occurred in winter, and only
one patient had chronic liver disease. In patients with
Vibrio-induced disease, edema and subcutaneous bleeding
(ecchymosis and purpura) were seen early on, but cutaneous necrosis didn’t occur. In patients with streptococcal
disease, subcutaneous bleeding was rare and necrosis was
common.
Blood and wound cultures should be obtained immediately in all patients with suspected Vibrio infection. Gram
stain of exudative material may suggest the pathogen and
reinforce clinical suspicion. Progression of infection can
be rapid and fulminant, so that expediency in workup
Treatment
Prompt initiation of antibiotic therapy and surgical
debridement are the cornerstones in the management of
Vibrio infections. When there is suspicion of this pathogen,
antibiotic treatment should be started with a thirdgeneration cephalosporin and a tetracycline. The combination of third-generation cephalosporins, commonly ceftriaxone or ceftazidime, with tetracycline, minocycline, or
doxycycline have shown synergy. Recent studies with fluoroquinones have shown these agents to be as effective as
the cephalosporin–tetracycline combination in vitro and in
murine models. Because of the rarity of the infection, it
is unlikely that a blinded clinical trial will be carried out.
Surgical consultation should be obtained and appropriate
debridement of necrotic tissue done on an emergency basis.
Fasciotomy may be needed, and if infection has progressed
amputation may be required to remove the devitalized limb
and control systemic sepsis.
Course and Prognosis
Prognosis is significantly better with early intervention and
timely initiation of antibiotic coverage. Patients in whom
the severity of infection is not immediately recognized or
those who present later in the course of infection do not
92 E MERGENCY D ERMATOLOGY
do as well. Overall, 40% of V. vulnificus infections are fatal,
with case fatality rates of approximately 50% from primary
septicemia and 15%–20% for wound infections.112,113 Persons most at risk are those with chronic alcoholic liver
disease, hepatitis B or C, hemochromatosis, renal insufficiency, or adrenal insufficiency.100
infection were catalogued with 22 of 26 persons presenting
with nonlesional symptoms including eruption, malaise,
fever, rigors, headache, nausea, sore throat, or earache.
Many authors make note of an odd fishy or sweet, sickly,
foul odor.119,120
Therapy
A. HYDROPHILA INFECTION
Background
Aeromonas species are gram-negative rods usually found in
fresh or brackish water and soil, but also have been isolated
from chlorinated drinking water and even from hospital
water supplies.114,115 They cause disease in fish and other
cold-blooded aquatic animals, mammalian species, and
humans.116 Human infection occurs through contact with
contaminated fresh or brackish water and soil giving rise
to cellulitis within 8–48 hours. A. hydrophila is the species
most commonly associated with soft-tissue infection.
The clinical presentation is similar to that of V. vulnificus soft-tissue infection and similarly gives rise to sepsis
primarily in patients with underlying cirrhosis or malignancy.117
Clinical and Laboratory Aids Required for Diagnosis
The most important clue suggesting A. hydrophila infection
is a history of soft-tissue injury associated with exposure to
fresh water or soil. Posttraumatic wound infections caused
by Aeromonas may be clinically indistinguishable from cellulitis due to Streptococcus pyogenes or S. aureus, so limiting empiric therapy to these organisms will likely miss the
pathogen. Infection with A. hydrophila occurs in a variety
of settings. In recreational activities involving fresh water
(such as boating, swimming, or wading), abrasions or lacerations may become infected, and in commercial situations (such as in fisheries), wounds may be exposed to contaminated fresh water. Infections of burns with Aeromonas
have been reported after submersion or dousing of the
injured part with water and after rolling the victim in
soil to extinguish flames. Motor vehicle, machinery, or
boating accidents may also expose people to wound contamination with Aeromonas in a culture bed of devitalized
tissue. Although Aeromonas bacterial counts are often similar in marine environments to those in fresh water, infection
from sea water, for some unknown reason, usually doesn’t
occur. Aeromonas cellulitis also may develop in skin grafts
or flaps in which leeches were utilized to relieve venous
congestion.118 Aeromonas species are resident flora in the
foregut of leeches aiding them in the digestion of heme.
Initial evaluation should include Gram stain of exudates
or aspirates and bacterial culture. Depending on the extent
of the disease, leukocytosis and fever may be present. In
a study of a community outbreak of Aeromonas cellulitis
following a mud football tournament, 26 cases of soft-tissue
A combination of surgical and medical therapy is most
often required. The tendency of Aeromonas to form subcutaneous abscesses may not be clinically apparent, and early
surgical consultation is advised.119 Incision and drainage
may be curative in some cases. The Aeromonas species are
-lactamase producers and often resistant to penicillin,
ampicillin, carbenicillin, first-generation cephalosporins,
ticarcillin, vancomycin, and clindamycin.120 Susceptibility to piperacillin, ticarcillin–clavulanate, and tetracyclines is variable. Fluoroquinolones and trimethoprim–
sulfamethoxazole are usually effective, but reports of
decreasing susceptibility of strains emphasize the need to
follow response to therapy closely and adjust antimicrobial
therapy with the guidance of microbiological sensitivities.
Course and Prognosis
Aeromonas infection has a guarded prognosis. Bacteremia
and septicemia are more common in patients with underlying cirrhosis and malignancy and portend a worse outcome.
In contrast, cases of septicemia have been reported in otherwise healthy individuals.121 In a study from Taiwan, the
crude fatality rate of monomicrobial Aeromonas bacteremia
was 30% within 2 weeks after the onset of infection.117
Some patients with myonecrosis from Aeromonas infection
require limb amputation.122
C. VIOLACEUM INFECTION
Background
C. violaceum is a gram-negative rod that occurs as a ubiquitous saprophyte of soil and water in tropical and subtropical areas.123 It is an uncommon pathogen in humans
(<150 cases in the literature), but has a high fatality rate.
Cases have been reported from Asia, Australia, Africa, the
United States, and South America.123,124 Most cases in the
United States are reported from Florida. Human infection
usually begins with cellulitis and skin abscesses that rapidly
progress to sepsis and abscesses of internal organs. U.S.
cases have been related to wading in pools of rain water
or muddy ditches, walking barefoot, following trauma, and
swimming in fresh water.125
Clinical and Laboratory Aids Required for Diagnosis
C. violaceum infection can be rapidly fatal. The most
crucial factor in determining survival is the recognition
that the bacterium may be present and to cover for it
Chapter 9
FIGURE 9.9: Chromobacterium violaceum infection. Multiple
hemorrhagic and pustular blebs. Photo courtesy of Virat Sirisanthana, MD, Faculty of Medicine, Chiang Mai University, Chaing
Mai, Thailand. Used with permission.
empirically. The infection is found in tropical and subtropical regions and usually occurs in the summer months.
There is a predilection for patients with chronic granulomatous disease, deficiency of polymorphonuclear leukocyte G6PD, and neutrophil dysfunction; however, fulminant disease has been reported repeatedly in patients with
no apparent immune dysfunction.126 Localized infection
with regional lymphadenopathy occurs after contamination of damaged skin exposed to soil or stagnant water.
Systemic infection can occur following aspiration or ingestion of contaminated material.
The usual presentation is with fever, hepatic abscess,
and skin lesions, although preseptal and orbital cellulitis has
been reported as well as osteomyelitis, meningitis, and brain
abscess. Skin lesions may consist of multiple nodules, hemorrhagic and pustular blebs with surrounding erythema,
abscesses, cellulitis, and purpura scattered over the face,
body, and extremities (Figure 9.9).127,128 The palms and
soles may be affected (Figure 9.10). Ecthyma gangrenosum
also has been reported.129 Leukocytosis with left shift may
be the only laboratory abnormality. Liver enzymes, platelet
counts, and sedimentation rates may or may not be abnormal early in the course of infection. Culture of the organism confirms the diagnosis. Material from wound drainage,
blood, conjunctival exudates, and abscess drainage or aspirant should immediately be sent for culture and susceptibility testing.
●
Life-Threatening Bacterial Skin Infections
93
C. violaceum is generally known to be resistant to
first-generation cephalosporins and penicillins. Thirdgeneration cephalosporins, ureidopenicillins, tetracyclines,
and aminoglycosides have demonstrated mixed effectiveness. The organism is generally sensitive to trimethoprim sulfamethoxazole, gentamicin, ciprofloxacin, and
imipenem. The frequency of hepatic abscess formation has
prompted some authors to advocate ultrasound examination of the liver and spleen in all persons from whom C.
violaceum has been cultured followed by surgical drainage
of any abscesses visualized.
Course and Prognosis
Anyone found to be infected with C. violaceum should be
evaluated for underlying immunodeficiency.129 IV antibiotic therapy should be continued until all foci of infection
have been cleared. As the organism has been known to recur
following apparent resolution of infection, consideration of
an extended course of oral antibiotic therapy is appropriate.
Survival is dependent on the early recognition of the infection with initiation of effective antibiotic therapy. Recognition of the potential of this organism to form abscesses in
multiple sites is important. The fatality rate of all cases with
known outcome was 65% in 1998. Improvements in antibiotics and medical management have decreased the fatality
rate of 81% (from 1939 through 1979) to 41% (from 1980
through 1994).3 Under the best of circumstances, the prognosis with this infection remains guarded.
CONCLUSION
We have described the clinical presentation and treatment
of several infections with which the dermatologist and other
specialists should be familiar. Most of these are relatively
uncommon so physicians may not include them in their
differential diagnoses. For that reason, knowledge of their
often dramatic clinical presentations is essential as it will
allow early diagnosis and the initiation of prompt therapy,
which may be lifesaving.
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FIGURE 9.10: Chromobacterium violaceum infection. Pustular
blebs and purpura of the palm. Photo courtesy of Virat Sirisanthana, MD, Faculty of Medicine, Chiang Mai University, Chaing
Mai, Thailand. Used with permission.
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Bella F, Espejo E, Uriz S, et al. J. Randomized trial of 5-day
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Cascio A, Colomba C, Antinori S, et al. Clarithromycin versus
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Cascio A, Colomba C, Di Rosa D, et al. Efficacy and safety of
clarithromycin as treatment for Mediterranean spotted fever
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Raoult D, Gallais H, De Micco P, Casanova P. Ciprofloxacin
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Dixon TC, Meselson M, Guillemin J, Hanna PC. Anthrax. N
Engl J Med. 1999; 341:815–26.
Demirdag K, Ozden M, Saral Y, et al. Cutaneous anthrax in
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Peck RN, Fitzgerald DW. Cutaneous anthrax in the Artibonite Valley of Haiti: 1992–2002. Am J Trop Med Hyg.
2007; 77:806–11.
Meyer MA. Neurologic complications of anthrax: a review of
the literature. Arch Neurol. 2003; 60:483–8.
Swartz MN. Recognition and management of anthrax–an
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Test shaving brush of anthrax victim: Health department to
seek today for germ which killed Michael F. Farley. New York
Times. 1921 October 10.
Anthrax is spread by street vendors: Bellevue experts find
dreaded germs in cheap shaving brushes bought from peddlers. New York Times. 1922 January 22.
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Carucci JA, McGovern TW, Norton SA, et al. Cutaneous
anthrax management algorithm. J Am Acad Dermatol. 2002;
47:766–9.
Artac H, Silahli M, Keles S, et al. A rare cause of
preseptal cellulitis: anthrax. Pediatr Dermatol. 2007; 24:
330–1.
Shieh WJ, Guarner J, Paddock C, et al. The critical role of
pathology in the investigation of bioterrorism-related cutaneous anthrax. Am J Pathol. 2003; 163:1901–10.
Bode E, Hurtle W, Norwood D. Real-time PCR assay for a
unique chromosomal sequence of Bacillus anthracis. J Clin
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interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep.
2001; 50:909–19.
Maguina C, Flores Del Pozo J, Terashima A, et al. Cutaneous anthrax in Lima, Peru: retrospective analysis of 71 cases,
including four with a meningoencephalic complication. Rev
Inst Med Trop Sao Paulo. 2005; 47:25–30.
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86. Doganay M, Bakir M, Dokmetas I. A case of cutaneous
anthrax with toxaemic shock. Br J Dermatol. 1987; 117:659–
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87. Holty JE, Bravata DM, Liu H, et al. Systematic review: a
century of inhalational anthrax cases from 1900 to 2005.
Ann Intern Med. 2006; 144:270–80.
88. Eliasson H, Back E. Tularaemia in an emergent area in Sweden: an analysis of 234 cases in five years. Scand J Infect Dis.
2007; 39:880–9.
89. Tularemia transmitted by insect bites–Wyoming, 2001–
2003. MMWR Morb Mortal Wkly Rep. 2005; 54:170–3.
90. Trevisanato SI. The biblical plague of the Philistines now
has a name, tularemia. Med Hypotheses. 2007; 69:1144–6.
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92. Myers JP, Baird IM. Case report. Tularemia in Ohio: report
of two cases and clinical review. Am J Med Sci. 1981;
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93. Evans ME, Gregory DW, Schaffner W, McGee ZA.
Tularemia: a 30-year experience with 88 cases. Medicine
(Baltimore). 1985; 64:251–69.
94. Penn RL. Fransicella tularensis. In: Mandell GL, Douglas
RG, Bennett JE, editors. Principles and practice of infectious
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95. Byington CL, Bender JM, Ampofo K, et al. Tularemia with
vesicular skin lesions may be mistaken for infection with
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96. Guffey MB, Dalzell A, Kelly DR, Cassady KA. Ulceroglandular tularemia in a nonendemic area. South Med J. 2007;
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97. Weinberg AN. Commentary: Wherry WB, Lamb BH.
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98. Oliver JD. Wound infections caused by Vibrio vulnificus and
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100. Kuo YL, Shieh SJ, Chiu HY, Lee JW. Necrotizing fasciitis
caused by Vibrio vulnificus: epidemiology, clinical findings,
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in Korea: clinical and epidemiologic findings in seventy
patients. J Am Acad Dermatol. 1991; 24:397–403.
102. de Araujo MR, Aquino C, Scaramal E, et al. Vibrio vulnificus infection in Sao Paulo, Brazil: case report and literature
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104. Frank C, Littman M, Alpers K, Hallauer J. Vibrio vulnificus
wound infections after contact with the Baltic Sea, Germany.
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105. Ruppert J, Panzig B, Guertler L, et al. Two cases of severe
sepsis due to Vibrio vulnificus wound infection acquired in
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912–15.
106. Dalsgaard A, Frimodt-Moller N, Bruun B, et al. Clinical
manifestations and molecular epidemiology of Vibrio vulnificus infections in Denmark. Eur J Clin Microbiol Infect
Dis. 1996; 15:227–32.
107. Torres L, Escobar S, Lopez AI, et al. Wound infection due
to Vibrio vulnificus in Spain. Eur J Clin Microbiol Infect
Dis. 2002; 21:537–8.
108. Paz S, Bisharat N, Paz E, et al. Climate change and the
emergence of Vibrio vulnificus disease in Israel. Environ Res.
2007; 103:390–6.
109. Ralph A, Currie BJ. Vibrio vulnificus and V. parahaemolyticus necrotising fasciitis in fishermen visiting an estuarine tropical northern Australian location. J Infect. 2007;
54:e111–14.
110. Tyring SK, Lee PC. Hemorrhagic bullae associated with
Vibrio vulnificus septicemia. Report of two cases. Arch Dermatol. 1986; 122:818–20.
111. Fujisawa N, Yamada H, Kohda H, et al. Necrotizing fasciitis caused by Vibrio vulnificus differs from that caused by
streptococcal infection. J Infect. 1998; 36:313–16.
112. CDC. Fact Sheet: Vibrio Vulnificus. 2005 [updated 2005;
cited May 10, 2008]; Available from: http://www.cdc.gov/
nczved/dfbmd/disease listing/vibriov gi.html.
113. Bross MH, Soch K, Morales R, Mitchell RB. Vibrio vulnificus infection: diagnosis and treatment. Am Fam Physician.
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115. Millership SE, Stephenson JR, Tabaqchali S. Epidemiology
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11:169–75.
116. Zhiyong Z, Xiaoju L, Yanyu G. Aeromonas hydrophila
infection; clinical aspects and therapeutic options. Rev Med
Microbiol. 2002; 13:151–62.
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therapeutic implications of 104 episodes of monomicrobial
Aeromonas bacteraemia. J Infect. 2000; 40:267–73.
118. Lineaweaver WC, Hill MK, Buncke GM, et al. Aeromonas
hydrophila infections following use of medicinal leeches in
replantation and flap surgery. Ann Plast Surg. 1992; 29:238–
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119. Gold WL, Salit IE. Aeromonas hydrophila infections of skin
and soft tissue: report of 11 cases and review. Clin Infect Dis.
1993; 16:69–74.
120. Kienzle N, Muller M, Pegg S. Aeromonas wound infection
in burns. Burns. 2000; 26:478–82.
121. Adamski J, Koivuranta M, Leppanen E. Fatal case of
myonecrosis and septicaemia caused by Aeromonas
hydrophila in Finland. Scand J Infect Dis. 2006; 38:1117–
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122. Smith JA. Aeromonas hydrophila: analysis of 11 cases.
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123. de Siqueira IC, Dias J, Ruf H, et al. Chromobacterium violaceum in siblings, Brazil. Emerg Infect Dis. 2005; 11:1443–
5.
124. Huffam SE, Nowotny MJ, Currie BJ. Chromobacterium
violaceum in tropical northern Australia. Med J Aust. 1998;
168:335–7.
Chapter 9
125. Midani S, Rathore M. Chromobacterium violaceum infection. South Med J. 1998; 91:464–6.
126. Macher AM, Casale TB, Fauci AS. Chronic granulomatous disease of childhood and Chromobacterium violaceum
infections in the southeastern United States. Ann Intern
Med. 1982; 97:51–5.
127. Teoh AY, Hui M, Ngo KY, et al. Fatal septicaemia from
Chromobacterium violaceum: case reports and review of the
literature. Hong Kong Med J. 2006; 12:228–31.
●
Life-Threatening Bacterial Skin Infections
97
128. Sirisanthana V. Fever with hemorrhagic and pustular blebs
in 13 year old boy. Chiang Mai, Thailand: Department of
Pediatrics, Faculty of Medicine, Chiang Mai University;
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129. Brown KL, Stein A, Morrell DS. Ecthyma gangrenosum
and septic shock syndrome secondary to Chromobacterium
violaceum. J Am Acad Dermatol. 2006; 54(5 Suppl):S224–8.
CHAPTER 10
Bacteremia, Sepsis, Septic Shock,
and Toxic Shock Syndrome
Geeta Patel
Ryan Hawley
Noah Scheinfeld
IN THE EMERGENCY department, intensive care unit,
and primary care setting, dermatological conditions rank
as one of the most common disease presentations. It is
often a challenge for physicians to differentiate routine skin
ailments from more serious, life-threatening conditions
that require immediate intervention. This chapter highlights some dermatologic emergencies that plague physicians daily and initially may present with cutaneous manifestations. Septic shock and toxic shock syndrome (TSS)
are potentially fatal medical emergencies that manifest with
dermatologic signs, making a good understanding of dermatology a crucial step in rapid and early diagnosis of these
two emergencies. As part of a clinical continuum, the terms
bacteremia, sepsis, and septic shock have for many years
been confused due to the inaccurate usage of terminology associated with such infections. In 1991, the American College of Chest Physicians and the Society of Critical
Care Medicine convened a Consensus Conference to standardize terminology and provide a framework for physicians to accurately identify the body’s systemic response to
infection. These quantifiable definitions work on a clinical
continuum established by clinical and laboratory findings.
Unfortunately, to date there is no single definitive census
for the standard of care and defined illness; the 1992 consensus is commonly accepted and reputable for defining
disease for this topic and will be used as a guideline for this
chapter (Table 10.1).
be described as primary (direct invasion of blood stream,
as in intravenous [IV] drug use) or secondary (infection at
another site complicated by microorganisms invading the
bloodstream, as in pneumonia or soft-tissue infections).2 It
can present as:
●
Transient Bacteremia – short periods (minutes to hours)
of viable bacteria in blood usually with normal flora
pathogens. Common during toothbrushing, routine dental work, and menstruation. It is usually cleared by the
reticuloendothelial system.
●
Intermittent Bacteremia – recurrent episodes of viable
bacteria from extravascular abscesses, spreading cellulitis,
TABLE 10.1: Definitions from 1992 Consensus Conference
Term
Definition
Infection
Inflammatory response to the presence of
microorganisms or the invasion of normally
sterile host tissue by those organisms
Bacteremia
Presence of viable bacteria in blood
SIRS
Systemic inflammatory response to a variety of
severe clinical insults manifested by two or
more of the following conditions:
(1) temperature >38◦ C or <36◦ C; (2) heart
rate >90 bpm; (3) respiratory rate >20 breaths
per minute or PaCO <32 mm Hg; or (4) white
blood cell count >12,000/cu mm, <4,000/cu
mm, or >10% immature (band) forms
Sepsis
SIRS and documented or suspected infection
Severe sepsis
Sepsis associated with organ dysfunction,
hypoperfusion, or hypotension
Septic shock
Sepsis with hypotension despite adequate fluid
resuscitation along with the presence of
perfusion abnormalities
BACTEREMIA, SEPSIS, SEPTIC SHOCK, AND TSS
Bacteremia
Bacteremia refers to the presence of viable bacteria in
blood.1 To gain access to the circulation, bacteria and their
toxins must penetrate through protective mechanisms such
as anatomic barriers (skin), the nonspecific immune system,
and the specific immune system. Bacteremia can range from
a benign asymptomatic course to a more continual infection
that can progress to septic shock or TSS. Bacteremia can
Adapted from (1).
SIRS, systemic inflammatory response syndrome.
page 98
Chapter 10
TABLE 10.2: Community-Acquired and Hospital-Acquired
Bacteremia
Gram-negative
pathogens
Community-acquired E. coli
bacteremia
Bacteremia, Sepsis, Septic Shock, and Toxic Shock Syndrome
99
virulence and number of pathogens in the blood, and the
timing and nature of a therapeutic intervention.
Normal flora of:
Sepsis
Small and large
intestine
Sepsis can be a life-threatening infection and is characterized as a systemic response manifested by two of the
following with evidence of infection:1
and
K. pneumoniae Large intestine
hospital-acquired
bacteremia
P. aeruginosa
Small and large
intestine
Gram-positive
pathogens
S. aureus
Anterior nares, skin,
eye, upper respiratory
tract, large intestine
S. pneumoniae
Upper respiratory tract,
eye, oral cavity
E. faecalis
Small intestine
or body infections such as septic arthritis, peritonitis, or
an empyema.
●
●
Continuous Bacteremia – usually occurring when infection is intravascular, such as with infected endothelium
seen in infective endocarditis or with infected hardware
as with an indwelling catheter.
There is a continuous increase in the incidence of
bacteremia-associated mortality worldwide, mainly attributed to the increased usage of invasive devices and invasive procedures, increased usage of aggressive drug therapy
that results in immunodeficiency, increasing population of
critically ill patients due to advancements in life support,
and advances in the development of highly sensitive diagnostic tools.3 Bacteremia can be community acquired or
nosocomial in inheritance. Table 10.2 displays the most
common pathogens seen in patients with documented
bacteremia.
In studies documenting bacteremia, Escherichia coli
was the most frequently isolated pathogen among older
patients with community-acquired bacteremia. In contrast, Staphylococcus aureus was the most frequently isolated
pathogen among younger adults with community-acquired
bacteremia. S. aureus was the most common pathogen
causing nosocomial bacteremia, regardless of age.4 The
most common source of bacteremia is the urinary tract,
with suspected cases followed by pneumonia and central
venous catheter (femoral > subclavian) and wound infection.5 Many factors determine whether bacteremia will
progress to sepsis, septic shock, or TSS. Elderly patients
have an increased tendency to develop severe sepsis due to
bacteremia compared to younger patients.4,6 Some other
factors that can aid in the progression to sepsis or septic shock are the immunocompetence of the patient, the
◦
◦
●
Temperature >38 C or <36 C;
●
Heart rate >90 beats per minute; or
●
White blood cell count >12,000 mcL, <4,000 mcL or
>10% immature (band) forms.
Due to the potential for rapid progression to severe sepsis
or septic shock, sepsis is considered a true medical emergency, and thus rapid diagnosis is crucial to decrease morbidity and mortality. Sepsis is the leading cause of death in
critically ill patients and among the top 10 overall causes
of death in patients in the United States.7 Sepsis develops
in 750,000 people annually, with 435,000 cases progressing to septic shock and more than 215,000 cases leading
to death.8,9 There is a higher incidence in men than in
women and in nonwhite persons than in white persons.10
Although the median age of patients with a sepsis-related
hospital discharge diagnosis is approximately 60 years, the
incidence is high among infants (>500 cases/100,000 population per year), with low-birth-weight newborns experiencing particularly high risk.11 Sepsis incidence and sepsisrelated mortality decrease after the first year of life and
then increase steadily with increasing age.8 Approximately
80% of cases of sepsis progressing to severe sepsis in adults
occurred in individuals who were already hospitalized for
another reason.12,13
Sepsis is a clinical syndrome that can be caused by a variety of microorganisms (i.e., virus, bacteria, fungus, or parasites), although typically gram-negative and gram-positive
bacteria account for most cases. In 30%–50% of septic
cases, a definite microbial etiology was not found.13–15
It should be noted that sepsis is defined as an immune
response to microorganisms, and the number of organisms
necessary to launch such a response varies depending on
the patient’s immune response to bacterial antigens.
Septic Shock
Septic shock is the clinical extension of sepsis with the
addition of hypotension and secondary hypoperfusion of
tissue refractory to fluid administration, thus substantially
increasing the mortality rate.1 Sepsis is usually reversible,
whereas patients with septic shock often succumb despite
aggressive therapy. Septic shock represents the most severe
host response to infection. These patients do not display
normal hemodynamic response to administered fluid bolus,
and thus have persistent perfusion abnormalities, including tissue and organ hypoperfusion manifesting as lactic
100 E MERGENCY D ERMATOLOGY
acidosis, oliguria, and/or acute alteration in mental status.16
These findings should yield high suspicion for multiple
organ dysfunction syndrome (MODS), the most worrisome
consequence of septic shock and most likely to result in
mortality if not recognized and corrected early. Septic
shock is the major cause of death in intensive care units;
the mortality rate is as high as 50%–80% depending on
the patient population.8 Septic shock and MODS are the
most common causes of death in patients with sepsis.12 The
incidence has increased owing to an increased number of
patients who are immunocompromised, the increased use
of invasive devices, and the growing elderly population.
Septic shock is part of the continuum associated with
the systemic inflammatory response syndrome (SIRS).
Although any microorganism may cause septic shock, it
is most often associated with gram-negative bacteria such
as E. coli, Klebsiella pneumoniae, Pseudomonas, and Serratia.
Gram-positive bacteria such as S. aureus can also cause septic shock and, in past years, have led to outbreaks of TSS.
Lower respiratory infections, abdominal infections, urinary
tract infections, and soft-tissue infections are the nidus in,
respectively, 35%, 21%, 13%, and 7% percent of documented cases of septic shock.17,18 Common factors or conditions that are associated with septic shock include diabetes
mellitus, malnutrition, alcohol abuse, cirrhosis, respiratory
infections, hemorrhage, cancer, and surgery.19
tion.21,24 The disease is characterized by a fulminant onset,
often in previously healthy persons. The diagnosis is based
on clinical findings that include high fever (>38.9◦ C),
headache, vomiting, diarrhea, myalgias, and an erythematous eruption characterized as a sunburn. TSS often develops from a site of colonization rather than infection.25–27
Streptococcal TSS carries a mortality rate of 30% or
higher, despite aggressive and timely medical therapy.
Streptococcal TSS is epidemiologically distinct from other
invasive infections in that younger and healthier populations are commonly affected.22,28 Group A -hemolytic
streptococcal (GAS) TSS may often originate in the skin of
young, healthy patients at a site of local trauma. In 5%–10%
of cases, there may be accompanying necrotizing fasciitis.
Bacteremia has been shown to be a key component in a
large majority of severe GAS infections.29 TSS can occur as
a consequence of GAS sinusitis, cellulitis, peritonitis, and
tracheitis and as a complication of varicella infections.30,31
TSS is separated into two distinct categories: menstrual
and nonmenstrual. Both menstrual and nonmenstrual TSS
had higher incidence in white women. Although most cases
of TSS are related to menstruation, nonmenstrual cases
have increased and now account for approximately one
third of all cases. These nonmenstrual cases have been associated with localized infections, surgery, or insect bites.
Patients with nonmenstrual TSS have a higher mortality
rate than do those with menstrual TSS.27
Toxic Shock Syndrome
TSS is a rare, often life-threatening illness that develops
suddenly after an infection and can rapidly progress, affecting many organ systems and requiring prompt recognition
and medical treatment. It was first described in 1978 in
seven children with S. aureus infections.20 After an epidemic
in 1981, TSS has been typically associated with tampon use
in healthy menstruating women. Due to physician and public awareness, the incidence of TSS has since declined in
this population group, with the majority of documented
cases now reporting men, neonates, and nonmenstruating
women with TSS.21 A similar but more threatening TSSlike syndrome, streptococcal TSS, has emerged. It is associated with invasive and noninvasive Streptococcal infections
and has a rapidly progressive course and a high case-fatality
rate. TSS is the result of infection by Streptococcus pyogenes
or S. aureus bacteria.22,23 These pathogenic bacteria typically comprise a small percentage of the host’s normal flora
and usually do not cause severe disease. TSS occurs when
these bacteria have an optimal environment for replication and toxin production that can enter the bloodstream
and cause a severe immune reaction in immunosuppressed
and/or immunocompetent persons. The host’s immune
response to bacterial toxins causes the symptoms associated with TSS.
Staphylococcal TSS came to prominence in 1980–1981,
when numerous cases were associated with the introduction of superabsorbent tampons for use during menstrua-
PATHOPHYSIOLOGY
Sepsis is the endpoint of a multifaceted process that begins
with an infection. The initial host response is to mobilize
inflammatory cells, neutrophils and macrophages, to the
site of infection. These inflammatory cells then release circulating molecules that trigger a cascade of other inflammatory mediators that result in a coordinated host response.
If these mediators are not appropriately regulated, sepsis
will occur. In the setting of ongoing toxin release, a persistent inflammatory response occurs with ongoing mediator
activation, cellular hypoxia, tissue injury, shock, multiorgan failure, and (potentially) death. Much of the damage
inflicted on the septic host is attributable to microbial toxins and the host’s response to them.32–34
In sepsis and septic shock, microbial antigens contain
pathogen-associated molecular patterns that bind to the
host protein’s pattern recognition receptors, called Tolllike receptors (TLRs), directing the activation of antibodymediated immunity. Mutations associated with TLRs
have been implicated in hyporesponsive antibody-mediated
immunity, thus increasing certain patients’ susceptibility to
developing septic shock from gram-negative bacteria.35,36
One important microbial toxin in the pathogenesis
of sepsis is lipopolysaccharide (LPS). LPS is the major
structural component of the outer membrane of gramnegative bacteria. It is essential for cell viability for virtually all gram-negative bacterial pathogens.37 LPS has no
Chapter 10
intrinsic toxic properties by itself.38 The toxicity of LPS is
related to the host response to this antigen (such an antigen
is also termed a superantigen). Similar pathogen-associated
molecular pattern mediators (superantigens) exist in grampositive bacteria, lipoteichoic acid, that induce a potentially
harmful host response during sepsis.
LPS binds to LPS-binding protein, creating an LPS–
LPS-binding protein complex. This complex binds to the
receptor located on the CD14 molecule that is found on
monocytes, macrophages, and neutrophils. Peptidoglycans
of gram-positive bacteria and LPS of gram-negative bacteria bind to TLR-2 and TLR-4, respectively. Given their
central role in the recognition of microbes, TLRs are likely
to have a crucial role in sepsis: TLRs are on the one
hand essential for the early detection of pathogens, but on
the other hand cause excessive inflammation after uncontrolled stimulation. TLR-2 and TLR-4 binding activates
intracellular signal transduction pathways, which increase
transcription of cytokines such as tumor necrosis factor␣ (TNF-␣), interleukin-1 (IL-1), interleukin-6 (IL-6),
and interleukin-10 (IL-10).39,40 TNF-␣, IL-1, and IL6 are proinflammatory cytokines that activate an immune
response but also cause both direct and indirect host cellular injury such as endothelial damage and eventually capillary leakage. LPS and TNF-␣ probably promote intravascular coagulation initially by inducing blood monocytes
to express tissue factor, by initiating the release of plasminogen activator inhibitor type 1, and by inhibiting the
expression of thrombomodulin and plasminogen activator by vascular endothelial cells. IL-10 is an antiinflammatory cytokine that inactivates macrophages, as well as
altering of monocyte function, decreasing antigen presenting activity, and reducing production of proinflammatory cytokines, and is underexpressed in the Th2-mediated
immune response.35,40,41
In TSS, the staphylococcal and streptococcal toxins
are able to function as superantigens, which are proteins
that simultaneously bind nonspecifically to T-cell receptors (TCRs) and major histocompatibility complex (MHC)
class II molecules.42 Toxic shock syndrome toxin 1 (TSST1), the best characterized of the toxins, binds to the MHC
class II molecule.43 These toxins are known as superantigenic because they activate CD4 T-cell populations at a
level that is at least five orders of magnitude greater than
conventional antigens.44 Superantigens are not processed
by antigen-presenting cells. They bind directly to MHC
class II molecules expressed on antigen-presenting cells
and cross-link with a large number of T cells that bear
common V chains and their TCRs. High concentrations
of lymphokines and monokines result and induce TSS.
Immune activation induced by superantigens potentiates
the host response to other microbial mediators, including
bacterial endotoxin.45 The large numbers of effector CD4+
T cells resulting from this nonspecific proliferation begin
stimulating monocytes to secrete several cytokines, including TNF-␣ and IL-1. The secretion of these cytokines
●
Bacteremia, Sepsis, Septic Shock, and Toxic Shock Syndrome
101
(instead of the localized secretion that normally occurs during infection) is the major determinant for morbidity associated with staphylococcal and streptococcal TSS.
CLINICAL AND LABORATORY AIDS REQUIRED
FOR DIAGNOSIS
To diagnose bacteremia, sepsis, septic shock, or TSS as
early as possible, it is necessary to recognize historical, clinical, and laboratory findings that are indicative of infection
and organ dysfunction.17 A thorough physical examination is vital for the identification of the source of infection. Patients with bacteremia and often sepsis present a
diagnostic challenge to clinicians owing to nonspecific, and
sometimes nonexistent early clinical manifestations. The
diagnosis must rely on a strong clinical suspicion supported
by the presence of several of the signs of sepsis if possible.
Two populations in which a high index of suspicion for bacteremia and sepsis should remain despite lack of clinical features are infants/children and the elderly population.5,46,47
Criteria for establishing diagnosis are within the definitions
of bacteremia, sepsis, and septic shock, thus one must consider the diagnosis if a patient meets the criteria set forth
from the 1992 consensus.1
BACTEREMIA, SEPSIS, AND SEPTIC SHOCK
Symptoms that suggest the onset of sepsis are often nonspecific and include sweats, chills or rigors, breathlessness,
nausea and vomiting or diarrhea, and headache.48 Fever,
often accompanied by shaking chills, is the most common clinical manifestation of bacteremia and sepsis. In a
study reported by Kreger and colleagues49 and Vincent,50
fever (temperature > 37.6◦ C) was seen in 82% of patients.
Hypothermia (temperature < 36.4◦ C) was seen in 13% of
bacteremic patients. Although the most common sign of
bacteremic and septic patients is fever, a significant percentage of patients who present with bacteremia are also
found to be hypothermic. Age, renal insufficiency, corticosteroid or antipyretic administration, and malignancy
all increase the likelihood that a patient will not mount
a febrile response. Mental status changes may occur in
patients with bacteremia or sepsis. Changes may range from
mild anxiety or restlessness to profound confusional states.
Change in mental state is an important clinical finding in
elderly patients who may exhibit few other early signs of
disease. Tachypnea and altered mental status were more
common among patients older than 75 years than among
younger patients, whereas tachycardia and hypoxemia were
less common among older patients. The hemodynamic
instability of the young population with sepsis is of clinical
importance. This effect is due to younger patients’ ability
to regulate blood pressure via vasoconstriction, leading to
rapid onset of hypotension in this population.51
A number of dermatologic manifestations have been
described in patients with bacteremia, sepsis, septic shock,
102 E MERGENCY D ERMATOLOGY
TABLE 10.3: Tissue Involvement by Gram-Negative Microbial Pathogens
Name
Suggestive of:
Description
Histologic findings
Palpable purpura56,57,58
N. meningitidis;
H. influenzae; R. rickettsii;
S. aureus
>3 mm, elevated, nonblanching,
erythematous to violaceous plaques
or nodules; dependent areas such as
legs and feet are common areas;
appears 12–36 h after onset of
illness
Angiocentric inflammation with
endothelial cell swelling fibrinoid
necrosis and a neutrophilic cellular
infiltrate around and within blood
vessel walls
Deposits of immunoglobulins and
complement in blood vessel walls
Petechiae56,59,60,61
Infective endocarditis
2◦ to bacteremia;
N. meningitidis; E. coli;
other gram-negative
bacteria
<3 cm, range from erythematous to
violaceous; commonly found on
lower legs but can also be found on
the conjunctiva and palate; appears
12–36 h after onset of illness
Vascular thrombosis; perivascular
hemorrhage
Ecthyma
gangrenosum52,53,54,55
P. aureus; A. hydrophila;
gram-negative bacteria; V.
vulnificus
Painless, round, erythematous
macules; they become indurated and
progress to hemorrhagic bluish
bullae; lesions later slough to form a
deep gangrenous ulcer with a
gray–black eschar and a surrounding
erythematous halo; process evolves
rapidly over a period of 12–24 h;
usually found between umbilicus and
knees but may occur anywhere on
the body
Bacterial invasion of the media and
adventitia of vein walls deep in the
dermis
Acrocyanosis62,63
Septic shock DIC
Blueness of hands and feet with
preserved pinkness in mucous
membranes
Hemorrhagic
bullous64,65
V. vulnificus (contact with
seafood)
Erythematous painful swollen limb
(lower > upper) with bilateral
hemorrhagic plaques and bullae;
develops 36 h after onset
Cellulitis66,67
S. aureus
S. pyogenes
S. pneumoniae
Gram-negative bacilli
Not raised, and demarcation from
uninvolved skin is indistinct; tissue
feels hard on palpation and is
extremely painful; cellulitis extends
into subcutaneous tissues
Sparing of the intima and lumen
Minimal inflammation
Noninflammatory bulla, epidermal
necrosis, hemorrhage, and bacteria
in dermal vessels
DIC, disseminated intravascular coagulation.
and/or TSS. Skin may be the primary site of disease manifestation. To diagnose bacteremia, sepsis, or septic shock
from cutaneous lesions, one must look at the overall picture in addition to the definition of the infection established in the 1992 consensus. Cutaneous lesions that occur
as a result of bacterial infection can be divided into three
categories:
●
direct bacterial involvement of the skin and underlying
soft tissues (e.g., cellulitis, erysipelas, and fasciitis);
●
lesions that occur as a consequence of sepsis, hypotension, and disseminated intravascular coagulation (DIC;
e.g., acrocyanosis and necrosis of peripheral tissues); and
patterns of tissue involvement by gram-negative microbial
pathogen:52
1. Cellulitis and thrombophlebitis are associated with
intense local inflammation. Bacteria implicated in case
reports include Campylobacter fetus, Vibrio species, and
Aeromonas hydrophila. Only a few bacteria are present in
the affected tissues, however, making definitive diagnosis by Gram stain difficult as most biopsied lesions will
contain very few organisms. For this reason, much better
results may be obtained from culturing.
lesions secondary to intravascular infections (e.g.,
microemboli and/or immune complex vasculitis).
2. When the inflammatory response is impaired, usually by
neutropenia, ecthyma gangrenosum or bullous lesions
may occur; Pseudomonas aeruginosa is the most commonly
isolated microorganism.
Recognition of certain characteristic lesions can greatly
assist etiologic diagnosis. Musher distinguished three
3. In symmetrical peripheral gangrene associated with
DIC, fibrin thrombi are seen in small vessels, but neither
inflammatory cells nor bacteria are found.
●
Chapter 10
TABLE 10.4: Clinical Signs and Symptoms of Sepsis and
Septic Shock
System
Clinical symptoms
CNS68,69
Confusion
Focal signs, seizures, and cranial nerve
palsies are rare
Encephalopathy (may be associated with a
poor prognosis)
Endocrine
Cardiovascular
Pulmonary
Renal
GI
Hepatic
Diffuse weakness
Hypotension
Hypoglycemia or hyperglycemia
Adrenal insufficiency
Tachycardia
Hyperventilation
Oliguria
Nausea/Vomiting/Diarrhea
Ileus
Upper GI bleeding from stress ulcers
●
Bacteremia, Sepsis, Septic Shock, and Toxic Shock Syndrome
103
ecthyma gangrenosum are neutropenic at the time the
lesions develop and are associated with lesions of skin or
mucous membranes that rapidly worsen and evolve into
nodular patches marked by hemorrhage, ulceration, and
necrosis.52–55
Ischemic changes (dusky or pallid color, coldness, loss
of pulses) usually occur in the hands and feet, where they
may follow thrombosis of small to medium-size arteries.
Such ischemic changes are usually seen in septic shock.
Inflammation-induced coagulopathy and vasoconstriction
both contribute to their pathogenesis (Table 10.3).62,63
Table 10.4 displays other common clinical signs and
symptoms of sepsis and septic shock.
Laboratory Findings
Table 10.5 displays common laboratory findings seen in
sepsis and septic shock.
Jaundice
CNS, central nervous system; GI, gastrointestinal.
Although often considered pathognomonic for P. aeruginosa bacteremia, ecthyma gangrenosum also has been
observed in patients whose blood cultures grew Klebsiella,
Serratia, A. hydrophila, or E. coli. Almost all patients with
TOXIC SHOCK
History and physical examination are vital in the identification of a presumptive source of TSS. Whereas septic shock has hypotension and subsequent organ failure,
toxic shock is characterized as coinciding hypotension with
TABLE 10.5: Laboratory Findings in Sepsis and Septic Shock
Laboratory study
Findings
Comments
White blood cell count
Leukocytosis or leucopenia
Stress response, increased margination of
neutrophils in sepsis; toxic granulation may be
seen; occasionally, bacteria may be found in the
peripheral blood smear
Platelet
Thrombocytopenia
Look for evidence of fragmentation hemolysis in
the peripheral blood smear; thrombocytopenia
may or may not be accompanied by
disseminated intravascular coagulation
Glucose
Hyperglycemia or hypoglycemia
Acute stress response, inhibition of
gluconeogenesis
Clotting factors
Prolonged prothrombin time, activated partial
thromboplastin time, low fibrinogen levels, and
evidence of fibrinolysis
Coagulopathy often seen with systemic
endotoxin release
Liver enzymes
Elevated alkaline phosphatase, bilirubin, and
transaminases; low albumin
–
Blood cultures
Bacteremia or fungemia
The presence of positive blood culture does not
make the diagnosis, and its absence does not
exclude the diagnosis
Plasma lactate
Mild elevations (>2.2 mmol/L)
Hypermetabolism, anaerobic metabolism,
inhibition of pyruvate dehydrogenase
C-reactive protein
Elevated
Acute-phase reactant, sensitive but not specific
for sepsis
Arterial blood gas
Respiratory alkalosis (early); metabolic acidosis
(late)
Measurements of O2 content and mixed venous
O2 saturation useful in management
Serum phosphate
Hypophosphatemia
Inversely correlated with high levels of
inflammatory cytokines
104 E MERGENCY D ERMATOLOGY
TABLE 10.6: Major Criteria for Diagnosis of S. Aureus TSS
1. Fever: Temperature ≥38.9◦ C (102◦ F)
2. Eruption: Diffuse macular erythroderma (“sunburn” eruption)
3. Hypotension: Systolic blood pressure (BP) ≤90 mm Hg (adults) or less than fifth percentile for age (children <16 years old); or
orthostatic hypotension (orthostatic drop in diastolic BP by 15 mm Hg, orthostatic dizziness, or orthostatic syncope)
4. Involvement of at least three of the following organ systems:
a. Gastrointestinal (vomiting or diarrhea at onset of illness)
b. Muscular (severe myalgias or serum creatine phosphokinase level at least twice the upper limit of normal)
c. Mucous membranes (vaginal, oropharyngeal, conjunctival hyperemia)
d. Renal (blood urea nitrogen or creatinine level at least twice upper limit of normal or pyuria)
e. Hepatic
f. Hematologic (thrombocytopenia)
g. Central nervous system
5. Desquamation: 1–2 weeks after onset of illness (typically palms/fingers, soles/toes)
6. Evidence against alternative diagnosis: Negative results of cultures of blood, throat, or cerebrospinal fluid (if performed); no
increase in titers of antibody to the agents of Rocky Mountain spotted fever, leptospirosis, and rubeola (if obtained)
Probable Diagnosis:
• Desquamation and 3 other major criteria
• All 5 major criteria in the absence of desquamation
TSS, toxic shock syndrome.
organ failure. TSS caused by S. aureus and TSS caused by
S. pyogenes are both characterized by an acute illness with
fever, sudden-onset hypotension, rapidly accelerated renal
failure, and multisystem organ failure. Clinical definitions
of staphylococcal and streptococcal TSS are described in
Tables 10.6 and 10.7, respectively. Both types of syndrome
also have differences that can help differentiate them on
clinical appearance. Table 10.8 highlights those differences.
The presence of fever, vomiting, watery diarrhea, myalgias,
and conjunctival hyperemia are suggestive of S. aureus TSS
whereas soft-tissue infections such as cellulitis, abscess, or
necrotizing fasciitis with increased pain commonly occur
with streptococcal TSS. Both can form without an identifiable source of infection.
Staphylococcal TSS
Staphylococcal TSS should be suspected in any individual with a sudden onset of a fever (>38.9◦ C) with chills,
malaise, vomiting or diarrhea, myalgias, dizziness, syncope,
beefy edematous mucous membranes, and/or conjunctival
hyperemia.
In addition to signs and symptoms, there may be a
history of superabsorbant tampon use, recent surgery,
diaphragm contraception, or indwelling foreign body. On
physical examination, the patient appears ill and has a fever
>38.9◦ C. There may be clinical evidence of hypotension,
peripheral edema, and muscle tenderness. If an infected
wound is the source of TSS, the clinical presentation will
be out of proportion to the wound presentation. Skin
TABLE 10.7: Major Criteria for Diagnosis of S. Pyogenes TSS
1. Isolation of group A β-hemolytic streptococci
(a) from a normally sterile site (e.g., blood, cerebrospinal fluid, peritoneal fluid, tissue biopsy specimen)
(b) from a nonsterile site (e.g., throat, sputum, vagina)
2. Hypotension: systolic blood pressure <90 mm Hg in adults or lower than the fifth percentile for age in children
3. Two or more of the following signs:
• renal impairment: creatinine level >177 mol/L (≥2 mg/dL) for adults or two times or more the upper limit of normal for age
• coagulopathy: platelet count < ≤100,000/mcL or disseminated intravascular coagulation
• hepatic involvement: ALT, AST, or total bilirubin levels two times or more the upper limit of normal for age
• adult respiratory distress syndrome
• generalized erythematous macular eruption that may desquamate
• soft-tissue necrosis, including necrotizing fasciitis or myositis, or gangrene
An illness fulfilling criteria 1(a), 2, and 3 can be defined as a definite case. An illness fulfilling criteria 1(b), 2, and 3 can be defined as
probable case if no other cause for the illness is identified.
TSS, toxic shock syndrome; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Chapter 10
●
Bacteremia, Sepsis, Septic Shock, and Toxic Shock Syndrome
105
TABLE 10.8: Differences in Staphylococcal and Streptococcal TSS
Characteristics
Staphylococcal TSS
Streptococcal TSS
Predisposing factors
Site of infection
Tampons, burns, wounds
Superficial (i.e., impetigo, burns,
diaper rash, genital tract)
Varicella, wounds
Deep (i.e., blunt trauma, necrotizing
fasciitis, myositis, septic joint)
Abrupt onset of pain
Eruption
Vomiting/Diarrhea
Increased creatinine kinase
Bacteremia
Desquamation
Mortality
Rare
Very common
Very common
Rare
<5%
7–14 days
3%–5%
Common
Less common
Less common
Common in fasciitis
60%
Less common
5%–10%
TSS, toxic shock syndrome.
examination shows that there is a flexurally accentuated
diffuse nonpruritic, blanching macular–papular erythroderma, described as “sunburn.” The distribution always
involves the extremities, with erythematous palms and
soles. Erythema of the mucous membranes is commonly
observed as well. The eruption may be subtle and is often
missed in heavily pigmented patients or when the patient
is examined in a poorly illuminated room. The eruption
fades in approximately 3 days, but sheet-like desquamation
of the hands and feet occurs in all patients 5–12 days after
the eruption disappears. Some patients also may develop
reversible alopecia and nail shedding. In menstrual TSS,
edema and erythema of the inner thigh and perineum with
a normal uterine and adnexal examination may be noted.
In nonmenstrual TSS, another focus of infection may be
present.
Laboratory findings reflect dysfunction of several organ
systems. Laboratory abnormalities included as criteria
for diagnosing TSS are elevated creatinine phosphokinase, acute renal insufficiency, sterile pyuria, elevated
liver function tests, and thrombocytopenia. Some laboratory findings that are not included in the criteria for
TSS but can commonly be seen are electrolyte abnormalities (hypophosphatemia and hypocalcemia), leukocytosis, and decreased serum albumin and total protein due
to capillary leakage. The prothrombin, international normalized ratio, and partial thromboplastin times may be
elevated, with or without thrombocytopenia. Laboratory
abnormalities usually return to normal within 7–10 days
of disease onset. Cultures of material from the vagina or
cervix are usually positive for S. aureus. Blood cultures are
negative in 85% of patients with TSS, but must still be
obtained.
Streptococcal TSS occurs in all age groups without a
predisposing factor. A hallmark feature of S. pyogenes TSS
is pain that is severe and abrupt in onset. The pain is usually preceded by tenderness. Symptoms that remain the
hallmark in staphylococcal TSS (such as fever, chills, myal-
gias, vomiting, and diarrhea) are present in less than 20%
of streptococcal cases. Most cases present with fever and a
localized soft-tissue infection that can progress to necrotizing fasciitis or myositis and require surgical debridement or even amputation. Laboratory data on streptococcal TSS cases are similar to those on staphylococcal TSS.
Symptoms of streptococcal TSS are nonspecific. Physicians
should have clinical suspicion in children and in persons
with chronic underlying illness. Clues to suggest streptococcal TSS are localized severe pain as opposed to myalgia,
skin lesion, or history of trauma at site of pain.
THERAPY
Successful management of bacteremia requires elimination of the offending pathogen by the timely administration of antibiotics and removal of the source of infection.
Bacteremia should be treated if one obtains 2–4 positive
blood cultures; sensitivity is dependent on the volume of
blood cultured, with 30–40 mL per session being recommended for optimal results. One must draw at least 10 mL
of blood for culture by venipuncture with at least 10 mL
through each lumen of a central vascular catheter when
one is present. Empiric antimicrobial therapy of bacteremia
and sepsis depends upon localizing the site of infection to
a particular organ, which determines the pathogenic flora
in the septic process. The usual pathogens are determined
by the organ or infection site, are predictable, and are the
basis for the selection of appropriate empiric antimicrobial therapy. Coverage should be directed against the most
common pathogens and does not need to be excessively
broad or contain unnecessary activity against uncommon
pathogens. If multiple drugs are used initially, the regimen
should be modified and coverage narrowed based on the
results of culture and sensitivity testing.
When sepsis is identified, treatment should be started
immediately. To aid in uniform and consistent management, two sets of severe sepsis bundles were defined by
106 E MERGENCY D ERMATOLOGY
TABLE 10.9: Sepsis Bundles
Sepsis resuscitation bundle
1.
2.
3.
4.
Serum lactate measured
Blood cultures obtained before antibiotics administered
Improve time to broad-spectrum antibiotics
In the event of hypotension or lactate >4 mmol/L (36 mg/dL):
a. deliver an initial minimum of 20 mL/kg of crystalloid (or
colloid equivalent)
b. apply vasopressors for ongoing hypotension
5. In the event of persistent hypotension despite fluid
resuscitation or lactate >4 mmol/L (36 mg/dL):
a. achieve central venous pressure of 8–12 mm Hg
b. achieve central venous oxygen saturation of ≥70%
Sepsis management bundle
1. Administer low-dose steroids
2. Administer drotrecogin alfa (activated)
3. Maintain adequate glycemic control
4. Prevent excessive inspiratory plateau pressures
the 2002 Surviving Sepsis Campaign: the sepsis resuscitation bundle and the sepsis management bundle (Tables 10.9 and 10.10). The resuscitation bundle should be
implemented within the initial 6 hours after patient admission to the hospital. It is also recommended to implement the sepsis management bundle as soon as possible
but within the first 24 hours.70
For TSS, hemodynamic stabilization and antimicrobial therapy are the initial goals of treatment. Immediate
and aggressive management of hypovolemic shock is crit-
ical. Thus, fluid resuscitation with crystalloid or colloidal
solution is important in the mainstay of treatment. Tampons or other packing material should be promptly
removed. It is often difficult to determine initially whether
Streptococcus or Staphylococcus is the offending bacterium, so
coverage for both is necessary. Suggested regimens include
penicillin plus clindamycin, erythromycin, or ceftriaxone plus clindamycin. Patients with suspected methicillinresistant staphylococcal TSS should be treated with IV
vancomycin 1 g every 12 hours for 10–15 days, with dose
adjustment based on creatinine clearance. Patients with
streptococcal TSS require hospitalization for care, usually
initially in an intensive care setting. Patients with streptococcal TSS should be treated with both IV penicillin G,
3–4 million units every 4 hours, and IV clindamycin, 600–
900 mg every 8 hours for 10–15 days, followed by oral
therapy. Double antibiotic coverage is the standard of care
for streptococcal TSS because this infection is characterized by extremely large numbers of stationary bacteria and
penicillin alone is not effective in this scenario.
PROGNOSIS
Severe sepsis and septic shock are associated with casefatality ratios of approximately 30% and 50%, respectively.
Outcome is significantly (and most profoundly) influenced
by the patient’s underlying disease. Bacteremia with certain
microbes (e.g., S. aureus) may also be independently related
to mortality in multivariate analyses. Of the many studied
TABLE 10.10: Suggested Initial Drug Therapy Based on Presumed Source
Source
Antibiotic treatment
Comment
Community-acquired
pneumonia
Erythromycina and third-generation
cephalosporinb
OR
First- or second-generation cephalosporinc plus
aminoglycosided
Antipseudomonal -lactame plus aminoglycosided
Gram-negative bacteria cause 10%–20% of
community-acquired pneumonias requiring
hospitalization; H. influenzae, K. pneumoniae,
and others implicated; consider Legionella
species if patient is elderly or immunosuppressed
Hospital-acquired
pneumonia
Urinary tract infections
Intraabdominal or
biliary tract infections
Neutropenic patients
Unknown source
Ampicillina plus aminoglycosided
-Lactam inhibitor f plus aminoglycoside
OR
Imipenem plus aminoglycoside
Antipseudomonal -lactame plus aminoglycosided
Imipenem or -lactam inhibitor f plus
aminoglycosided
Must treat for more resistant organisms including
P. aeruginosa
Combination also covers enterococci
Use against enteric gram-negative bacteria and
anaerobes
Add vancomycin for Staphylococcus species if
intravascular catheter is present
Add vancomycin if gram-positive infection is a
consideration
Data from Stein JH, ed. Internal Medicine, 5th edition. St. Louis, Mosby-Year Book, 1998.
a
b
c
d
e
f
Others: Ampicillin 1–2 g every 4–6 h; erythromycin 0.5–1 g every 6 h; ticarcillin clavulanate 3.1 g every 4–8 h; vancomycin 1 g every 12 h.
Cefotaxime 1–2 g every 6–8 h; ceftriaxone 1–2 g every 24 h; ceftazidime 1–2 g every 8 h.
Cefazolin 1 g every 8 h; cephalothin 1–2 g every 4–6 h; cefuroxime 1 g every 8 h.
Gentamicin, tobramycin 3–5 mg/kg/d divided every 8 h; amikacin 15 mg/kg/d divided every 8 h. Must adjust for renal dysfunction.
Piperacillin, mezlocillin, ticarcillin 3 g every 4 h; ceftazidime 1–2 g every 8 h; imipenem 500 mg every 6 h.
Ticarcillin clavulanate 3.1 g every 4–6 h; piperacillin/tazobactam 3 g every 4–6 h.
Chapter 10
biologic markers, plasma IL-6 levels and a high IL-10/
TNF-␣ ratio may correlate best with risk of dying. None
of these measurements warrants routine use.
The mortality rate in patients with staphylococcal TSS
is 5%–15%, whereas that for streptococcal toxic shock syndrome may be 5 times higher.
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46. King C. Evaluation and management of febrile infants in the
emergency department. Emerg Med Clin N Am. 2003; 21:89–
99.
47. Martin GS, Mannino DM, Moss M. The effect of age on the
development and outcome of adult sepsis. Crit Care Med.
2006; 34:15–21.
48. Sprung CL, Peduzzi PN, Shatney CH, et al. The impact of
encephalopathy on mortality and physiologic derangements
in the sepsis syndrome. Crit Care Med. 1988; 16:398–405.
49. Kreger BE, Craven DE, Carling PC, McCabe WR. Gramnegative bacteremia. III. Reassessment of etiology, epidemiology and ecology in 612 patients. Am J Med. 1980; 68:332–43.
50. Vincent JL. Clinical sepsis and septic shock - definition, diagnosis and management principles. Langenbecks Arch Surg.
2008; 393:817–24.
51. Iberti TJ, Bone RC, Balk R, et al. Are the criteria used to
determine sepsis applicable for patients 75 years of age? Crit
Care Med. 1993; 21:S130.
52. Musher D. Cutaneous and soft-tissue manifestations of sepsis
due to gram-negative enteric bacilli. Rev Infect Dis. 1980;
2:854–66.
53. El Baze P, Ortonne JP. Ecthyma gangrenosum. J Am Acad
Dermatol. 1985; 13:299–300.
54. Huminer D, Siegman-Igra Y, Morduchowicz G, Pitlik SD.
Ecthyma gangrenosum without bacteremia. Report of six
cases and review of the literature. Arch Intern Med. 1987;
147:299–310.
55. Gucluer H, Ergun T, Demircay Z. Ecthyma gangrenosum.
Int J Dermatol. 1999; 38:298–305.
56. Brogan PA, Raffles A. The management of fever and
petechiae: making sense of rash decisions. Arch Dis Child.
2000; 83:506–7.
57. Crowson AN, Mihm MC Jr, Magro CM. Cutaneous vasculitis: a review. J Cutan Pathol. 2003; 30:161–73.
58. Macke SE, Jordon RE. Leukocytoclastic vasculitis. A cutaneous expression of immune complex disease. Arch Dermatol.
1982; 118:296.
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hospitalized for suspected sepsis. J Pediatr. 1985; 107:855–
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disease in children with fever and petechiae. Pediatrics. 1984;
74:77–80.
61. Van Deuren M, van Dijke BJ, Koopman RJ, et al. Rapid diagnosis of acute meningococcal infections by needle aspiration
or biopsy of skin lesions. BMJ. 1993; 306:1229–32.
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of thirty-six cases. Br J Dermatol. 1973; 88:221–9.
63. Jackson RT, Luplow RE. Adult purpura fulminans and digital necrosis associated with sepsis and the factor V mutation.
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3 causing outbreaks of wound infection and bacteraemia in
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65. Fujisawa N, Yamada H, Kohda H, et al. Necrotizing fasciitis caused by Vibrio vulnificus differs from that caused by
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complications of sepsis. Ann Neurol. 1993; 33:94–100.
69. Sprung CL, Peduzzi PN, Shatney CH, et al. Impact of
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Care Med. 1990; 18:801–5.
70. Gao F, Melody T, Daniels DF, et al. The impact of compliance with 6-hour and 24-hour sepsis bundles on hospital
mortality in patients with severe sepsis: a prospective observational study. Crit Care. 2005; 9:R764–70.
CHAPTER 11
Staphylococcal Scalded Skin Syndrome
Eleonora Ruocco
Adone Baroni
Sonia Sangiuliano
Giovanna Donnarumma
Vincenzo Ruocco
STAPHYLOCOCCAL scalded skin syndrome (SSSS) is
the term used to define a potentially life-threatening, blistering skin disease caused by exfoliative toxins (ETs) of certain strains of Staphylococcus aureus. The syndrome belongs
to a wide spectrum of staphylococcal infections that range
in severity from localized bullous impetigo to a generalized
cutaneous involvement characterized by extensive blistering with superficial denudation and subsequent desquamation of the skin. SSSS is so-named because of its staphylococcal etiology and its remarkable resemblance to the
clinical picture of scalding.
HISTORY
The original description of the syndrome dates back to
1878, when Ritter von Rittershain, director of an orphanage in Prague, reported approximately 300 cases of dermatitis exfoliativa neonatorum. A relationship between the
disease and staphylococci was perceived at the beginning
of the 20th century, but only in the early 1950s did the
link between bullous impetigo and phage group 2 staphylococci become evident. Lyell’s report on toxic epidermal
necrolysis (TEN) in 1956 drew attention to the similarities
between this drug-induced condition and the appearance
of extensive scalding, but also led to a period of confusion between nonbacterial (immune-mediated) TEN and
bacterial (staphylococcal) toxin-mediated scalded skin syndrome.1 In the early 1970s, the development of a murine
model of the staphylococcal disease clarified the situation.2
Nowadays, SSSS is clearly distinguished from other diseases of generalized epidermal necrolysis and the term
Ritter’s disease is still used to describe generalized SSSS in
newborns.
EPIDEMIOLOGY
SSSS, which may be present in epidemic form as well as
sporadically, is primarily a disease of infancy and early
childhood with most cases occurring in children younger
than 6 years. The median age of onset is 1 year 10 months.
There has been one case report of congenital SSSS in a
neonate with sepsis, born to a mother with staphylococcal
chorioamnionitis.3 Occasionally, adults with chronic renal
insufficiency or who are immunosuppressed can be affected.
Because the toxins responsible for the lesions are excreted
renally, infants, who have naturally immature kidneys, and
adults with renal failure are obviously the most common
candidates for this disease.
Besides decreased toxin clearance, lack of immunity to
the toxins may also play a role. Outbreaks of SSSS have
often occurred in neonatal nurseries as a consequence of
asymptomatic carriage of a toxigenic strain of S. aureus
by health care workers or parents. In fact, standard infection control measures, such as the use of chlorhexidine
hand washing, may not be always sufficient for prevention,
because the presence of potentially pathogenic staphylococci in the nasal cavities of a healthy adult carrier can be
a point source for infection.
Interestingly, a male-to-female predominance of SSSS
has been documented (2:1 in sporadic cases; 4:1 in epidemics).4
ETIOLOGY
The cause of SSSS is related to bacteria belonging to
the genus Staphylococcus. This genus encompasses spherical
gram-positive bacteria, irregularly grouped in cluster-like
formations. They are immobile and asporogenic microorganisms, and, from a metabolic perspective, are facultative aerobes–anaerobes (Figure 11.1, A and B). This genus
includes bacteria that are pathogens for both humans and
other mammals. Traditionally, staphylococci are subdivided into two groups according to their ability to coagulate plasma (Figure 11.1, C and D). S. aureus, which is
pathogenic for humans, belongs to the coagulase-positive
page 109
110 E MERGENCY D ERMATOLOGY
A
B
C
D
E
FIGURE 11.1: Etiology of staphylococcal scalded skin syndrome (SSSS). Panel A: Staphylococci grown in medium. Grampositive cocci grouped in typical clusters. Panel B: Electron
microscopy of a Staphylococcus species. Panels C and D: Coagulase test. A suspension of Staphylococcus aureus provokes
coagulation of plasma contained in test tube (positive test, panel
C). A suspension of Staphylococcus epidermidis does not provoke coagulation of plasma contained in test tube (negative test,
panel D). Panel E: Isolation of S. aureus in Chapman’s medium.
The high NaCl content allows the growth of Staphylococcus
species, but not other microorganisms. Only S. aureus causes
the phenol red (indicator of pH) to change from red to yellow,
through the fermenting of mannitol. (Photo courtesy of Maria
Antonietta Tufano, Naples, Italy.)
group; the coagulase-negative group comprises 32 species
that have been isolated in humans. The latter constitute
the normal flora of the skin and mucosa, although some
of them can cause infections in neonates, elderly persons,
and immunodepressed subjects. S. aureus owes its name
to the carotenoid pigment produced during multiplication
that gives its colonies a yellow–orange color. To isolate
S. aureus in samples contaminated by a mixed flora, a selective medium containing 7% NaCl is needed as this inhibits
the multiplication of most microorganisms but not of
S. aureus. If mannitol (Chapman’s medium) is added to
the NaCl medium, the sugar is fermented by S. aureus but
not by the other staphylococci, thus allowing differentiation of the species (Figure 11.1E). S. aureus is a ubiquitous
microorganism that permanently colonizes the epidermis
around the nostrils in 20% of the population, is usually
associated with transient flora, and can occasionally cause
infections. S. aureus infections underlie several clinical patterns that differ considerably according to the site of infection and the means of transmission (direct extension or
metastatic or hematogenous diffusion). S. aureus, in particular, is the most frequent etiological agent in common
skin infections, such as folliculitis, furuncle, and carbuncle
that arise in the sebaceous glands and hair follicles where
the microorganism produces lipolytic enzymes that allow
both the degradation of the sebum (and as a result of the
lipid components with antibacterial activity) and the use of
the lipids themselves as a source of metabolic energy. The
pathogenic action of S. aureus depends both on a series of
factors that favor multiplication in vivo and on the production of numerous toxins and isoenzymes.
The strains of S. aureus responsible for the onset of SSSS
are producers of epidermolytic or exfoliative toxin (ET)
and are often penicillin resistant.5 Although most toxigenic
strains of S. aureus are identified by group 2 phage (types 71
and 55), toxin producers have also been identified among
phage groups 1 and 3.2 The frequency of isolation of strains
of toxin-producing S. aureus varies from place to place, but
is generally less than 10%. ET is produced by the microorganism in two antigenically distinct forms, both capable
of causing the disease (ET-A and ET-B). ET-A, a thermostable protein, is encoded by a chromosomally located
gene; ET-B, which is encoded by a gene located in the
plasmids, is a thermolabile protein.6,7
PATHOGENESIS
More than 30 years ago it was shown that the blisters in
SSSS are caused by an ET released by virulent strains of
S. aureus dwelling in distant foci of infection, such as the
pharynx, nose, ear, or conjunctiva. It was surmised that
ET, produced by staphylococci, and released into circulation, reached the skin and caused blistering and shedding
of the epidermis at sites that were distant from the infection. In fact, the formation of superficial epidermal blisters
and extensive skin exfoliation, similar to those observed
in patients with SSSS, were experimentally obtained in
neonatal mice into which purified staphylococcal ET was
injected. It was also noted that the presence of ET in the
blood induced the production of protective neutralizing
antibodies and, as a consequence, lasting immunity, which
could account for the fact that adolescents and adults are
rarely affected by SSSS. Subsequently, it was discovered
that two major serotypes of this toxin, ET-A and ET-B, are
responsible for the pathogenic changes of the syndrome.8
ET-A is the predominant ET isoform in Europe and the
United States, whereas ET-B is the most frequent isoform
in Japan. ET-B–producing S. aureus is, however, the predominant strain isolated in generalized SSSS.
After the initial identification of the toxins, the mechanism by which ETs cause intraepidermal separation
remained unknown for more than 3 decades. Early studies
reported that ETs were mitogenic in human and murine
lymphocytes, suggesting that the toxins act as superantigens and stimulate certain V T lymphocyte clones nonspecifically via major histocompatibility complex class II
molecules. Histopathological observations of the cutaneous
lesions in SSSS patients, however, have generated controversy regarding the superantigen theory of ETs because the
Chapter 11
SSSS skin lesions fail to show evidence of intense T-cell
recruitment into the epidermis, where the blisters occur.
In addition, patients exhibit only a loss of cell–cell adhesion, but no induced keratinocyte necrosis as would be
expected with superantigen-stimulated T cells. Furthermore, because purified recombinant ET-A produced in a
non–toxin-producing strain of S. aureus was unable to stimulate human and murine T cells, it was suggested that the
superantigen activity of ETs was probably due to contamination by other mitogenic exotoxins.7
The potency of ETs as serine proteases also has
been examined. Comparison of the deduced amino acid
sequences of ET-A and ET-B (they comprise 242 and 246
amino acids, respectively, and share approximately 40%
amino acid homology) showed that they share primary
amino acid homology with staphylococcal V8 protease,
which belongs to a family of trypsin-like serine proteases.
The crystal structure analyses of ET-A and ET-B
revealed that their three-dimensional structures resemble
those of known glutamate-specific serine proteases, including the presence of the catalytic triad, a putative active site
comprising histidine, aspartic acid, and serine.7
Both ET isoforms cleave human and mouse desmoglein
1 (dsg 1), a desmosomal intercellular adhesion molecule,
at one position after glutamic acid residue 381, between
extracellular domain (EC) 3 and EC 4 This cleavage site is
located in the putative calcium-binding site of dsg 1, and
the removal of the calcium ions blocks the cleavage of dsg 1
by both ET-A and ET-B. The importance of this site was
demonstrated by the replacement of the catalytic serine195 of ET-A with a cysteine or glycine residue, which
resulted in a loss of exfoliating activity after injection into
neonatal mice.6
These findings suggest that the serine protease activities
of ET-A and ET-B are involved in intraepidermal blister
formation in patients with SSSS.7 ET cleaves dsg 1 by the
key-in-lock mechanism that is common to many proteolytic
enzymes with limited substrate specificities. This remarkable mechanism efficiently targets one molecule, dsg 1,
which allows Staphylococcus to grow below the epidermal
barrier but superficially enough to be contagious through
skin contact;8 however, neither the enzymatic activities of
ETs nor their specific substrates were recognized at the
time. To determine whether ET-A cleaves dsg 1 directly,
the toxin was incubated in vitro with baculovirus recombinant ECs of human dsg 1, human dsg 3, mouse dsg 1-␣
(one of three mouse dsg 1 isoforms), and mouse dsg 3. ET-A
was shown to cleave human and mouse dsg 1-␣ in a dosedependent fashion, but not dsg 3. ET-B also was found to
cleave the ECs of human and mouse dsg 1-␣ specifically
and directly.9 A major breakthrough in understanding the
mechanism of ET-mediated blistering came in 2000, when
similarities were noted between SSSS and an autoimmune
blistering skin disease, pemphigus foliaceus (PF).10 In PF
patients, immunoglobulin G (IgG) autoantibodies disrupt
●
Staphylococcal Scalded Skin Syndrome 111
TABLE 11.1: Similarities between Pemphigus Foliaceus (PF)
and Staphylococcal Scalded Skin Syndrome
Clinical features: scaly and crusted superficial erosions
Skin (not mucous membranes) are involved
Site of cleavage: just below the stratum corneum
The crucial point where cleavage occurs is a Ca2+ binding
domain in the extracellular region of desmoglein 1
Identical appearance of experimentally induced lesions in
neonatal mice injected with either PF immunoglobulin G
antibodies or staphylococcal exfoliative toxins
the intercellular adhesion of keratinocytes and cause
epidermal blistering. The target molecule for IgG autoantibodies in PF is dsg 1. The extracellular region of dsg contains five cadherin repeats separated by putative calciumbinding domains. In humans, four dsg isoforms (dsg 1, 2,
3, 4) with tissue- and differentiation-specific distribution
patterns have been identified. In all desmosome-bearing
tissues dsg 2 is present, whereas dsg 1 and dsg 3 are found
predominantly in stratified squamous epithelia. In humans,
dsg 1 is expressed throughout the epidermis, but most
intensely in superficial layers. The expression of dsg 3 is
restricted to the basal and immediate suprabasal layers,
although in human oral mucous membranes, dsg 1 and dsg
3 are expressed throughout the epithelia, with dsg 1 expression being much lower than that of dsg 3. The expression of
dsg 2 and dsg 4 in the human epidermis is restricted to the
basal layer and just below the cornified layer, respectively.
In PF, blisters are observed exclusively in the superficial
epidermis, where dsg 1 is predominantly expressed with no
coexpression of other dsg isoforms.7
Five important clues from PF studies indicated that the
substrate of the ETs might be dsg 1 (Table 11.1). These
clues suggested that the ETs, such as PF IgG, might target
dsg 1. If dsg 1 were cleaved specifically by the ETs, then,
just as in PF, “desmoglein compensation” would account
for the localization of the blisters in SSSS in the superficial epidermis and for the absence of the blisters in the
mucous membrane. The dsg compensation theory rests
on the following two observations: anti–dsg 1 or anti–dsg
3 autoantibodies inactivate only the corresponding dsg,
and functional dsg 1 or dsg 3 alone is usually sufficient
for cell–cell adhesion. Anti-dsg 1 IgG autoantibodies in
serum from patients with PF cause superficial blisters in
the skin; no blisters form in the lower epidermis or mucous
membranes because dsg 3 maintains cell–cell adhesion in
those areas. In SSSS, the ETs produced by S. aureus act
as dsg 1–specific molecular scissors and cleave dsg 1 but
not dsg 3, resulting in superficial epidermal blisters only,
because, in the upper epidermal layers, the cohesive function of the impaired dsg 1 cannot be compensated by other
dsgs isoforms, as occurs elsewhere. Therefore, although
pemphigus and SSSS are unrelated diseases, the identical
112 E MERGENCY D ERMATOLOGY
Dsg1
Dsg3
Desmocollins
Intercellular
space
Cell
membrane
Plakoglobin
Desmoplakin
Keratin
dsg 1
Exfoliative toxins
(SSSS)
Subcorneal
blister
CLEAVAGE
SITE
Anti–desmoglein 1 lgG
antibodies
(PF)
FIGURE 11.2: Identical cleavage site in staphylococcal scalded skin syndrome (SSSS) and pemphigus
foliaceus (PF). IgG, immunoglobulin G; dsg 1, desmoglein 1.
histopathology of the superficial type of the IgG-mediated
disorder (PF) and lesions in neonatal mice treated with
staphylococcal ETs clearly indicates that staphylococcal
ETs act on the same autoimmune target of PF (i.e., dsg 1),
thus provoking identical specific cleavage within the superficial layer of the epidermis (Figure 11.2). Interestingly
enough, about 2 centuries ago, astute clinicians realized
that staphylococcal bullous diseases were clinically similar
enough to pemphigus to name SSSS (along with its localized form, bullous impetigo) in infants “pemphigus neonatorum.”8
CLINICAL FEATURES
The onset of SSSS may either be acute with fever and
rash or be preceded by a prodrome of malaise, irritability, and cutaneous tenderness, often accompanied by purulent rhinorrhea, conjunctivitis, or otitis media. The typical
rash presents as a faint, orange–red, macular exanthem,
localized initially on the head (Figure 11.3A) and spreading within a few hours to the remainder of the body,
with peculiar periorificial and flexural accentuation. Edema
of the hands and feet may be observed. At this stage,
cutaneous tenderness is a distinctive feature as proven by
the easy disruption of skin after firm rubbing or pressure (Nikolsky sign) (Figure 11.3B). Within 24–48 hours,
the macular exanthem gradually turns into a blistering
eruption; in particular, a characteristic tissue-paper-like
wrinkling of the epidermis heralds the appearance of large,
flaccid bullae. Blistering usually starts in the axillae and
groins and on periorificial areas. Subsequently, the entire
body is affected. One or two days later, the bullae rupture and their roofs are sloughed, leaving behind a moist,
glistening, red surface along with varnish-like crusts. At
this stage, the clinical appearance closely resembles that
of extensive scalding (Figure 11.3C). The patient becomes
irritable, sick, and feverish, with “sad man” facies, perioral
crusting, lip fissuring, and mild facial edema. Mucous membranes are usually spared by bullae and erosions, but generalized mucous membrane erythema, especially intense in
the conjunctiva (under which there may be hemorrhage),
is often observed. Days later, due to generalized shedding
of the epidermis, scaling and desquamation progressively
occur. The skin returns to normal in 2–3 weeks. Scarring
is not usually a feature.
An abortive form of SSSS, known as scarlatiniform variant (staphylococcal scarlet fever), also may be seen. The
early erythrodermic picture evolves into a desquamative
condition with the absence of a blistering stage. This clinical form is often associated with occult bone and joint infections or contaminated wounds.
PATHOLOGY
Under light microscopy SSSS is characterized by intraepidermal cleavage with clefts appearing in the granular layer
Chapter 11
A
●
Staphylococcal Scalded Skin Syndrome 113
B
C
FIGURE 11.3: Clinical features of staphylococcal scalded skin
syndrome. Panel A: Orange–red exanthema initially localized on
the head. Panel B: Nikolsky sign: erosion following firm rubbing
of the skin. (Photo courtesy of Carlo Gelmetti, Milan, Italy.) Panel
C: Extensive sloughing of the skin closely resembling that of
vast scalding. (Photo courtesy of Giovanni Angelini, Bari, Italy.)
or just beneath the stratum corneum and leading to the formation of bullous cavities (Figure 11.4). Few or no inflammatory cells are present within the blister. A few acantholytic cells are often seen either adjoining the cleavage
plane or free-floating in the bulla. A scanty lymphocytic
infiltrate may surround superficial blood vessels in the dermis. In fresh lesions, no bacterial organisms can be seen
on Gram stain of the biopsy specimens, whereas older
lesions can become superinfected thus obscuring an SSSS
diagnosis.
DIAGNOSIS
The diagnosis of SSSS is mainly clinical and should be
taken into consideration in any child who develops a generalized, tender erythema, most prominent on periorificial
(in particular perinostril and periocular) areas, associated
with Nikolsky sign. Suspected SSSS is supported by the
confirmation of staphylococcal infection in different sites
(conjunctiva, nasopharynx, ear). Cultures taken from intact
bullae are negative because fresh lesions do not harbor
staphylococci. In the full-blown disease, shock is a typical
feature, whereas postural dizziness may be an important
diagnostic clue in the early stages or mild cases.
FIGURE 11.4: Histology of staphylococcal scalded skin syndrome: subcorneal bullous cavity (hematoxylin and eosin,
×200). (Photo courtesy of Carlo Gelmetti, Milan, Italy.)
The main differential diagnosis is that of TEN, which
usually affects adults and is uncommon in children. In
this severe drug-induced reaction, the skin changes are
widespread and severe mucosal involvement is common
(erosive mucositis is part of the clinical presentation in
TEN), whereas SSSS extends from the face and flexures
and does not affect mucosae with erosions. Histologically,
TEN shows subepidermal splitting, also in frozen sections, with full-thickness necrosis of the epidermis, whereas
SSSS is characterized by subcorneal cleavage with a viable
appearance of the epidermis. The two conditions can be
rapidly differentiated by means of exfoliative cytology. A
Tzanck smear taken from a fresh bulla shows necrotic
keratinocytes with inflammatory cells in TEN and viable
acantholytic or normal keratinocytes without inflammatory
cells in SSSS, but accurate interpretation requires an experienced observer. Other differential diagnoses comprise
Leiner and Kawasaki diseases. Leiner disease, the erythrodermic form of seborrhoeic dermatitis in newborns, lacks
blisters or erosion, but yellowish scales are present all over
the body. Prolonged fever, heart involvement, and generalized lymphadenopathy characterize Kawasaki disease. Slide
latex agglutination, double immunodiffusion, and enzymelinked immunosorbent assay tests – which can identify the
staphylococcal toxins responsible for the intraepidermal
114 E MERGENCY D ERMATOLOGY
splitting – are all useful in confirming a SSSS clinical
diagnosis.
COURSE AND PROGNOSIS
The disease in newborns (Ritter’s disease) is usually selflimiting, with rapid resolution of the skin blisters and complete recovery in a couple of weeks, but there is a mortality of 2%–3% due to progression of the staphylococcal
infection (sepsis) or exfoliation complications (serious fluid
and electrolyte disturbances). In children, with appropriate treatment, complications (cellulitis, pneumonia) are
uncommon and the prognosis is usually good, with a low
mortality risk (about 5%). In adults, SSSS carries a less
favorable prognosis because of basic medical problems such
as immunosuppression or kidney failure. Adults are much
more likely than children to develop staphylococcal sepsis,
which brings the mortality rate to more than 50%, despite
appropriate antibiotic therapy.
FUTURE PERSPECTIVES
The increasing frequency of methicillin-resistant S. aureus
(MRSA) strains raises the possibility that antibioticresistant, ET–producing staphylococci can become
pathogens in future cases of SSSS. The development of
innovative, alternative therapies may rapidly become an
urgent necessity. Structural identification of the dsg 1
binding site of staphylococcal ETs and the generation
of neutralizing antibodies that efficiently inhibit the
reaction between enzyme and substrate will provide a
novel therapeutic option for SSSS caused by MRSA.7
ACKNOWLEDGMENTS
We are greatly indebted to Prof. Maria Antonietta Tufano
(Naples), Prof. Carlo Gelmetti (Milan), and Prof. Giovanni Angelini (Bari) for their courtesy in providing us
with Figures 11.1 (MAT); 11.3A, 11.3B, and 11.4 (CG);
and 11.3C (GA).
MANAGEMENT
REFERENCES
Patients with SSSS require hospitalization because, besides
the appropriate systemic antibiotic therapy, intensive general supportive measures are needed. The mainstay of
treatment is to eradicate staphylococci from the focus of
infection, which in most cases requires intravenous (IV)
antistaphylococcal antibiotics (e.g., methicillin, flucloxacillin). Subsequently, parenteral therapy may be replaced
with 1-week oral treatment with a -lactamase–resistant
antibiotic (e.g., dicloxacillin, cloxacillin, cephalexin).
Second-line therapies include IV macrolide (erythromycin
or clarithromycin)11 or vancomycin.12 Due to the disrupted
cutaneous barrier function, which may lead to dehydration
and electrolyte imbalance, IV replacement of fluids and
lacking electrolytes is recommended for prompt recovery.
In each case, oral fluid intake and careful monitoring of
urinary output should be encouraged. If required, analgesics should be used. The superficial nature of the erosions
in SSSS paves the way to rapid reepithelialization following appropriate topical therapy. The therapy consists of
nonirritant, nonsensitizing antiseptics (e.g., 1:1000 diluted
aqueous potassium permanganate solution) on denuded,
moist areas and bland, lubricating emollients on itching,
tender, scaling areas. Newborns with SSSS should be kept
in incubators to maintain body temperature. In neonatal
care units, as well as in hospital-acquired cases of SSSS, it
is of the utmost importance to identify health care workers who are possible carriers of toxigenic staphylococci.
Useful prevention measures encompass strict enforcement
of chlorhexidine hand washing, oral antibiotic treatment
for infected workers, and the use of intranasal mupirocin
ointment to eradicate persistent nasal carriage of toxigenic
strains of S. aureus.2
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Fitzpatrick’s dermatology in general medicine. 5th ed. Vol. 2.
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49:21–31.
8. Stanley JR, Amagai M. Pemphigus, bullous impetigo, and the
staphylococcal scalded-skin syndrome. N Engl J Med. 2006;
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exfoliative toxin B specifically cleaves desmoglein 1. J Invest
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10. Amagai M, Matsuyoshi N, Wang ZH, et al. Toxin in bullous
impetigo and staphylococcal scalded-skin syndrome targets
desmoglein 1. Nat Med. 2000; 6:1275–7.
11. Sturman SW, Malkinson FD. Staphylococcal scalded skin
syndrome in an adult and a child. Arch Dermatol. 1976;
112:1275–9.
12. Strauss G, Mogensen AM, Rasmussen A, Kirkegaard P.
Staphylococcal scalded skin syndrome in a liver transplant
patient. Liver Transpl Surg. 1997; 3:435–6.
CHAPTER 12
Life-Threatening Cutaneous Viral Diseases
Aron J. Gewirtzman
Brandon Christianson
Anne Marie Tremaine
Brenda L. Pellicane
Stephen Tyring
Presentation and Clinical Features
during childhood and is commonly asymptomatic, whereas
HSV-2 infections are routinely found in postpubertal individuals who engage in sexual contact. Both HSV-1 and
HSV-2 are associated with recurrent infections in patients
with low immunologic status.
The classic HSV presentation is indurated erythema followed by grouped vesicles on an erythematous base. These
vesicles eventually become pustules, which rupture and
eventually crust. Sometimes the affected skin may become
necrotic and result in a punched-out ulcerative appearance.
Clinical manifestations, however, can vary and include
acute gingivostomatitis, herpes labialis, ocular herpes, herpes genitalis, zosteriform herpes simplex, herpetic whitlow, eczema herpeticum, meningitis, encephalitis, visceral
infections, and neonatal herpes. For mucocutaneous infections, the mainstay of therapy has been the synthetic purine
nucleoside analogues acyclovir, valacyclovir, famciclovir,
and penciclovir. In emergency situations intravenous (IV)
acyclovir should be used.
Herpes simplex virus (HSV) is not typically associated
with life-threatening or emergency situations; rather, HSV
is better known as an acute, self-limited infection that
may recur in certain individuals. In rare instances, fatal
and highly morbid complications can arise. Neonates and
immunocompromised persons generally make up the vast
majority of patients with these poor outcomes, but in
extremely rare cases some immunocompetent patients suffer severe complications.
HSV can be divided into two subgroups (HSV-1 and
HSV-2) based on molecular and immunologic characteristics. HSV-1 typically causes lesions in the oral mucosa
and produces gingivostomatitis and pharyngitis in primary
infections. Primary infections of HSV-2 most commonly
cause genital lesions and produce acute vulvovaginitis and
progenitalis. Infection with HSV-1 is generally acquired
Neonatal HSV. HSV in a neonate is considered a pediatric emergency, and antiviral therapy should be initiated as soon as there is clinical suspicion.1 HSV is known
to infect approximately 1 in 3200 deliveries.2 Transmission to the neonate can occur by intrauterine (5%), intrapartum (85%), or postpartum (10%) infection.3–7 The risk
of neonatal herpes is greatest if a woman has a primary
occurrence at delivery, lower if she has a recurrent episode,
and lowest if there is a history of HSV but no lesions
at delivery.2 Although cesarean section has proven to be
effective in decreasing the chances of HSV transmission to
the neonate from a mother actively shedding virus from
the genital tract, the majority of transmitted infections
arise from mothers who do not have lesions at the time of
delivery. Approximately 60%–80% of women who deliver
VIRAL DISEASES frequently have cutaneous manifestations, most of which are self-limited and of little consequence; however, there are occasions when a viral
cutaneous disease may be accompanied by systemic manifesttions that can be life threatening. In general, healthy
children and adults are at little risk for these severe complications. Persons at highest risk for systemic involvement
include patients who are immunosuppressed, as well as
neonates, extremely elderly persons, and the undernourished population. Because many viruses have some form
of cutaneous exanthem, almost any virus known to have
systemic involvement can be considered a dermatological
emergency. This chapter focuses mainly on those viruses
in which the cutaneous findings would be likely to prompt
dermatological investigation in an emergency situation.
HERPES SIMPLEX VIRUS
page 115
116 E MERGENCY D ERMATOLOGY
TABLE 12.1: Herpes Simplex Virus in Neonates
Incidence8
Mortality
without
treatment8,11
Skin, eye, and
mouth infections
45%
Central nervous
system
Disseminated
multiorgan
infection
Type of neonatal
HSV infection
Presentation12
Therapy1
Onset1,13
0%
Discrete vesicles and
keratoconjunctivitis to spastic
quadriplegia, microcephaly, and
blindness
IV acyclovir 20 mg/kg
every 8 h for 14–21 days
10–11 days
35%
50%
Seizures, lethargy, irritability,
tremors, poor feeding,
temperature instability, bulging
fontanelle, or pyramidal tract signs
60 mg/kg/d in three
divided doses for 21 days
is advised
16–19 days
20%
80%
Irritability, seizures, respiratory
distress, jaundice, bleeding
diatheses, shock, and vesicular
exanthema
60 mg/kg/d in three
divided doses for 21 days
is advised
9–11 days
HSV, herpes simplex virus; IV, intravenous.
an HSV-infected infant have no evidence of genital HSV
infection at the time of delivery, no past history of genital
herpes, nor a sexual partner reporting a history of genital
HSV.2,8–10
In neonates, HSV can manifest in three different types
of infections (Table 12.1).
Neonatally disseminated HSV infection and central nervous system (CNS) HSV disease both have high mortality rates without treatment. In those individuals who do
survive without treatment, significant neurologic impairment is common.8,11 Although skin, eye, and mouth HSV
neonatal infections typically do not cause mortality, without antiviral therapy, approximately 75% of infections will
eventually develop into CNS or disseminated disease.8
HSV in Immunocompromised Patients. Immunocompromised individuals such as those with human immunodeficiency virus (HIV), recipients of organ transplantations,
pregnant women, or patients with any other disease/state
that affects T-cell function should also be monitored for
dissemination and/or CNS involvement in HSV infections.
These patients have been associated with higher mortality
rates and worse recurrent episodes of HSV.
Herpes Simplex Encephalitis. Herpes simplex encephalitis (HSE) is the most commonly identified cause of acute,
sporadic viral encephalitis in the United States, comprising
10%–20% of all cases.14 It is estimated to have an incidence
of approximately 1 case per 250,000 population per year.15
Mortality in untreated patients is in excess of 70%, and
only 2.5% of all patients recover full neurological function.
The pathology of HSE varies and may occur in a primary
or recurrent infection. Not all cases have skin lesions, and
differentiation from other encephalitides can be very difficult. HSV DNA in the cerebrospinal fluid confirmed by
polymerase chain reaction is the most sensitive noninvasive
test for early diagnosis.16 HSE manifests as an acute onset of
fever and focal (temporal) neurologic symptoms.17 Patients
typically complain of headache, nuchal rigidity, weakness,
sensory abnormalities, aphasia, visual field defects, or cranial nerve palsies.18
Eczema Herpeticum. Eczema herpeticum is a potentially
life-threatening dermatologic emergency that involves a
herpetic superinfection of a preexisting skin disease. It is
most commonly seen in individuals who have disruptive
skin diseases (typically atopic dermatitis) or are immunocompromised (secondary to medication for the skin disease). It is commonly seen in children of all ages and all
ethnic groups, with those in the first 2–3 years of life having the highest incidence.19 Without rapid antiviral therapy, complete dissemination can occur, leading to fulminant hepatitis and possible death.20,21
Eczema herpeticum is similar to the classic skin lesions
of HSV except that there are multiple clusters of vesicles in
areas of previous skin disease involvement along with systemic symptoms (fever and malaise). Vesicles spread and
result in punched-out erosions causing significant pain.
Lesions may be discrete or confluent, and tend to occur
in crops, resulting in many lesions at different stages.22
Other signs and symptoms may include pruritus, vomiting, anorexia, diarrhea, lymphadenopathy, and/or secondary bacterial infection.23,24
Visceral Infections. The most common sites of visceral
infections are the esophagus, lung, and liver; the infections usually result from viremia. Of these, lung and liver
infections have the worse prognoses. Lung HSV infections frequently present as a focal necrotizing pneumonitis
and are more common in severely immunocompromised
patients. Mortality is considered to be greater than 80%.
Chapter 12
HSV hepatitis also has a high association with mortality
(near 80%) and can present with fever, abdominal or right
upper quadrant pain, nausea and vomiting, abrupt elevations of bilirubin and serum aminotransferase levels, and
leukopenia.25 HSV hepatitis has been seen in immunocompetent and immunosuppressed persons.
Prevention and Treatment
IV acyclovir is highly recommended for all cases of neonatal HSV. Treatment of neonatal HSV with IV acyclovir
is described in Table 12.1. For maximum benefit, antiviral
therapy must be administered before widespread dissemination or significant replication of the virus in the CNS has
occurred.13 It is also recommended that dosing intervals
for IV acyclovir be increased in premature infants due to
their high creatinine clearance.26 In rare cases, IV acyclovir
has been associated with neutropenia and nephrotoxicity.
Therefore, neutrophil counts and kidney function should
be monitored in neonates when receiving IV acyclovir.1
With acyclovir therapy the mortality of disseminated HSV
and CNS HSV is reduced to 29% and 4%, respectively.1
Preventing maternal primary infection is of the utmost
importance because primary infection has the highest rate
of transmission to the infant. To prevent maternal infection, condoms or suppressive oral acyclovir in late pregnancy has been beneficial for persons who are in sexual
contact with partners who have genital herpes.
Immunocompromised patients should be treated with
systemic antiviral therapy such as acyclovir. For patients
who may have acyclovir-resistant HSV, foscarnet can be
used, but it is generally reserved for patients with extensive mucocutaneous infections because of its high cost and
toxicity.27 Cidofovir has also been proven to work as a topical medication for HSV lesions and may also be used in
acyclovir-resistant patients.
Prompt treatment is of the utmost importance to prevent the high mortality associated with HSE. It is recommended that HSE patients be treated with IV acyclovir at
30 mg/kg/d divided into 3 doses for 14–21 days.28 Even
in presumed HSE, IV acyclovir is recommended until an
alternative diagnosis is made, and continued when the diagnosis of HSE is confirmed.29
For all visceral HSV infections, IV acyclovir is recommended. In some cases liver transplant plus high-dose acyclovir therapy has been used to treat fulminant HSV hepatic
failure.30,31
VARICELLA ZOSTER VIRUS
Presentation and Clinical Features
Primary Varicella. Varicella zoster virus (VZV) presents
as chickenpox (varicella) as a primary infection and shingles (herpes zoster) when the virus is reactivated. Varicella
●
Life-Threatening Cutaneous Viral Diseases 117
is generally a self-limited disease, usually of childhood,
that causes outbreaks of vesicles and pustules classically
described as “dewdrops on a rose petal.” Lesions progress
from a vesicle into a pustule that then produces an itchy
scab. Classically, all of these stages are present simultaneously, as the lesions develop in successive crops. Varicella is
common, as greater than 95% of adults in the United States
have antibodies to the virus. In healthy children, the mortality rate is quite low, estimated at two deaths per 100,000
cases.32 In immunocompromised patients and neonates,
however, complications such as pneumonitis, thrombocytopenia, liver function impairment, and CNS involvement
are more common and must be recognized and treated
promptly.
Neonatal varicella is mostly caused by maternal chickenpox acquired during the last 3 weeks of pregnancy. Death
may occur due to complications of generalized neonatal
varicella in up to 20% of neonates if the mother develops
a rash between days 4 and 5 antepartum to day 2 postpartum.33 Whereas neonatal chickenpox occurring within the
first 4 days after birth tends to be mild, a fatal outcome has
been reported in 23% of cases occurring between 5 and
12 days of age.33
Primary varicella in adults is frequently more severe than
in children. Fewer than 5% of cases of varicella occur in
adults, yet 55% of varicella-related deaths occur in this age
group, usually due to pneumonia and consequent respiratory failure.32,34
Herpes Zoster. Herpes zoster has a lifetime incidence
between 10% and 25%, with the elderly population being at
greater risk than the general population. Like varicella, herpes zoster is rarely life threatening in immunocompetent
people. The disease is recognized by dermatomal pain and
vesicular rash. Pain may be intense and can last for months
after the rash heals (postherpetic neuralgia). Herpes zoster
is generally limited to a single dermatome or a few adjacent dermatomes, but may disseminate, particularly in
patients with immunosuppression due to HIV, hematological malignancy, organ transplantation, or chemotherapy.
Disseminated zoster results from hematogenous spread of
the virus resulting in involvement of multiple dermatomes,
as well as potentially systemic involvement. Dissemination
is life-threatening due to the potential to cause encephalitis,
hepatitis, or pneumonitis.
Disseminated herpes zoster may present with visceral
symptoms including hepatitis, pancreatitis, gastritis, or
abdominal pain. Occasionally, these complaints are seen
even without skin involvement at all, or can be the presenting feature before a rash develops.35,36 CNS involvement may be seen in the form of cranial nerve palsies or
encephalitis in up to one third of patients with disseminated
zoster.37
Although the incidence of shingles among recipients
of solid organ transplants is approximately 9%,32 the
118 E MERGENCY D ERMATOLOGY
complications of dissemination in these patients are particularly grave. A review of the literature of disseminated
varicella infection in adult renal allograft recipients found
a mortality rate of 34%.38 Use of mycophenolate mofetil
(a drug commonly used to prevent organ transplant rejection) has been associated with increased susceptibility to
VZV infection.39
Of note, disseminated herpes zoster is not limited to
immunocompromised persons. Although rare, there have
been reported cases of disseminated cutaneous herpes
zoster without any apparent immunosuppression. It has
been proposed that significant age-related depression in
cellular immunity can contribute to dissemination of herpes zoster; therefore, elderly patients should be recognized
as a group in which dissemination risk is higher than the
average immunocompetent host.40
Prevention and Treatment
A live, attenuated varicella zoster vaccination has been
approved by the U.S. Food and Drug Administration
(FDA) for prevention of varicella in children since 1995,
and a similar vaccine to prevent herpes zoster outbreaks in
adults received approval in 2006. Curtis and colleagues41
reported a case of disseminated zoster in an elderly woman
with a history of recurrent breast cancer undergoing
chemotherapy that occurred 8 days following vaccination.
This was the first known report of dissemination attributed
to zoster vaccination with the Oka strain in a chemotherapy patient. Dissemination of varicella zoster following
vaccination has been reported as the defining illness in a
16-month-old patient who was later diagnosed with
acquired immune deficiency syndrome (AIDS).42 Similarly,
a novel deficiency in natural killer T cells was discovered following VZV dissemination after vaccination of an
11-year-old girl.43 These multiple reports of disseminated
infection resulting from the vaccine strain in immunocompromised patients point to the need for careful medical
history-taking prior to vaccination to avoid vaccinating
patients who are immunosuppressed. Disseminated zoster
following vaccination in a patient with no known history
of immunodeficiency should prompt a thorough workup.
The most effective method to protect immunocompromised persons is to ensure that their potential susceptible
contacts have been vaccinated.34
Treatment for classic herpes zoster may be given orally,
either with acyclovir (800 mg 5 times a day for 7 days),
valacyclovir (1 g 3 times a day for 7 days), or famciclovir
(500 mg 3 times a day for 7 days). The treatment of choice
for disseminated zoster is IV acyclovir 10 mg/kg every 8
hours for 7 days.40 Likewise, IV acyclovir should be given
for primary varicella in immunocompromised populations.
To prevent severe neonatal chickenpox, passive immunization (i.e., with varicella immune globulin) is indicated.33
SMALLPOX (VARIOLA MAJOR) AND VACCINIA
Presentation and Clinical Features
Smallpox was, historically, one of the most lethal viruses
known to man until it was eradicated in 1980 by a worldwide
vaccination effort.44 The last reported case of smallpox was
in 1977; therefore, a significant percentage of the world’s
population is susceptible to smallpox infection.32 Unfortunately, in the modern era, the potential use of smallpox
as a weapon of bioterrorism makes this virus of continued
interest to dermatologists.
Smallpox is spread by the respiratory route and has a
prodromal phase of high fever, headache, and backache.
Skin lesions are classically distributed in a centrifugal pattern with greater involvement of the face and extremities
than of the trunk. Lesions begin as erythematous macules,
which then evolve in synchrony (as opposed to chickenpox)
into papules, pustules, and then crusts with the entirety of
the rash lasting approximately 2 weeks. The mortality rate
caused by smallpox averages approximately 30%.45
Prevention and Treatment
As just stated, smallpox was eradicated due to vaccination.
The vaccinia virus is used to vaccinate against smallpox and
produces a localized exanthem at the site of inoculation.
The virus is inoculated through multiple punctures into the
upper dermis. Persons with severe cell-mediated immunodeficiency should not receive the vaccination because of
potential complications of encephalitis, generalized vaccinia (a self-limited eruption), progressive vaccinia, or accidental infection. Vaccinia necrosum is characterized by failure of the vaccination site to heal, followed by progressive necrosis and ulceration that may or may not spread
to distant sites (skin, bones, and viscera).46 Untreated progressive vaccinia can be fatal and should be treated with
systemic vaccinia immune globulin and sometimes thiosemicarbazone.47 Generalized and progressive vaccinia are
uncommon complications in the absence of immunosuppression, and thus most cases occur in patients with undiagnosed immunodeficiency. Transmission of vaccinia following vaccination is possible, although the transfer rate is low
if the vaccination site is kept covered until it heals. Vaccination against smallpox is no longer commonplace, although
the possibility of reinstituting a vaccination program is
being considered due to the high susceptibility of the
world’s population and potential use as biological warfare.
PARVOVIRUS B19
Presentation and Clinical Features
Parvovirus B19 (PVB 19), a small single-stranded DNA
virus from the family Parvoviridae, is a virologic pathogen
Chapter 12
that often causes asymptomatic infection but may become
life threatening in certain circumstances. The common dermatologic manifestations associated with PVB 19 infection
include erythema infectiosum, papular purpuric “glovesand-socks” syndrome, and nonspecific findings such as
reticular erythema, petechiae, and/or purpura, and maculopapular eruptions.
Erythema infectiosum, otherwise known as fifth disease,
is common in the pediatric population and is characterized
by the classic “slapped-cheek” facial erythema and the fine
reticulated (lacy) erythema involving the trunk and extremities. Papular purpuric “gloves-and-socks” syndrome is a
disease seen in adulthood, and it presents with the hallmark
symmetric, sharply demarcated erythema and edema of the
hands and feet that evolves into petechiae and purpura over
time.
Although PVB 19 infections are often mild and selflimited, patients who are immunosuppressed, have hematologic diseases, or are pregnant are at risk for serious
complications. PVB 19 infects erythroid progenitor cells
and temporarily halts red blood cell production, thereby
causing a transient aplastic crisis. Individuals with hematologic conditions such as sickle cell anemia, thalassemia,
autoimmune hemolytic anemia, and other similar conditions are at increased risk for developing an aplastic crisis.
Often the crisis is transient and self-resolving, but the risk
of a fatal complication increases in this subset of patients.
Immunocompromised individuals lack the ability to mount
an immune response to the virus and may have a course
complicated by lingering cutaneous eruptions, persistent
anemia, myocarditis, pericarditis, acute heart failure, acute
liver failure, meningitis, and encephalitis.48
Maternal parvovirus infection during pregnancy can
lead to vertical transmission of the virus to the unborn fetus.
The incidence of maternal PVB 19 infection during pregnancy is 1%–2%, with vertical transmission occurring in
33%–51% of cases,49–51 and fetal loss occurring in approximately 10% of all cases.52,53 Fetal infection can result in
miscarriage or nonimmune hydrops fetalis. The incidence
of fetal morbidity and mortality is inversely related to gestational age, thus infection during the first trimester is the
most dangerous.
●
Life-Threatening Cutaneous Viral Diseases 119
contagious; thus no measures can be taken to avoid infecting others.49,54
CYTOMEGALOVIRUS
Presentation and Clinical Features
Cytomegalovirus (CMV, human CMV [HCMV], or human herpesvirus [HHV]-5) is a large double-stranded
virus from the herpesvirus family. Most commonly, CMV
mononucleosis is mild and asymptomatic, with no impact
on the immune system. Immunocompromised individuals,
such as those with HIV or a malignancy, or those who
have had an organ transplant, may exhibit complications
with CMV infection. Blood transfusion recipients and newborns are other patient populations that may have a lethal
outcome from a CMV infection.
CMV infections are a frequent cause of morbidity and
mortality among immunocompromised patients. The virus
itself may not directly lead to the death of a patient, but it
further lowers the patient’s immune system, thus making
him or her much more susceptible to other deadly diseases.
For example, patients with HIV may die from a coinfection
with CMV and Pneumocystis carinii (now renamed Pneumocystis jiroveci). Prognosis depends on the extent and interval of immunosuppression. CMV infection may increase
the rate of organ rejection by inducing autoantibodies.55
Patients with postperfusion syndrome (CMV mononucleosis acquired via blood transfusion) exhibit fever, malaise,
hepatosplenomegaly, and jaundice; these patients carry a
poor prognosis.56
Newborns can acquire CMV in utero (transplacentally),
after exposure to genital secretions in the vaginal canal,
or through breastfeeding.57 Severe clinical manifestations
of congenital CMV infection most often occur when the
mother sustains a primary CMV infection rather than reactivation of a recurrent infection. The disease tends to be
more severe if the infection is acquired earlier in gestation. The dermatologic manifestations of CMV infection
include petechiae, purpura, jaundice, and “blueberry muffin” syndrome. Even if a newborn is born without overt
symptoms, he or she is at risk for long-term complications
such as hearing loss and/or mental retardation.
Prevention and Treatment
The treatment for PVB 19 is mostly symptomatic, and
immunocompetent patients do very well. Immunocompromised patients, pregnant women, and persons with
hematologic disease must be closely monitored by their
respective specialists. High-dose IV immunoglobulins have
been shown to eliminate the virus from the bone marrow. Intrauterine transfusion can correct fetal anemia and
reduce fetal death. Prevention is difficult because, when
a patient presents with a rash, he or she is no longer
Prevention and Treatment
Immunocompromised patients should be treated concurrently with antiviral therapy (ganciclovir) and passive
immunization with hyperimmune globulin (HIG). Little
can be done in terms of prevention of CMV infection.
Transplant centers use ganciclovir and HIG after organ
transplant to prevent an infection. A live attenuated CMV
vaccine (Towne strain) appears to be prophylactic against
infection but it is not yet commercially available.
120 E MERGENCY D ERMATOLOGY
In pregnancy, prevention of CMV infection starts
with hygienic behavior for seronegative women. Pregnant
women with primary CMV infection can prevent transmission to the fetus by using CMV HIG. The effect of HIG
on newborns is unknown, but there is evidence to suggest
that it may also be effective. The efficacy of ganciclovir in
pregnancy is unknown, and there is concern about possible teratogenic effects on the fetus. Ganciclovir, however,
can be used safely and effectively in newborns. Pregnancy
termination is an option if fetal infection is diagnosed via
ultrasonography or amniocentesis.58
MEASLES (RUBEOLA)
Presentation and Clinical Features
The first sign of measles infection is usually high fever
(approaching 40◦ C at its peak) beginning approximately
10–12 days after exposure and lasting 1–7 days. Other
associated symptoms include coryza, conjunctivitis, and
cough. Approximately 2–3 days later, a cutaneous exanthem appears, consisting of an erythematous rash composed of macules and papules (usually beginning on the
face and upper neck) that coalesce and spread to the trunk
and eventually to the extremities, hands, and feet. Often
there is a diagnostic enanthem of bluish-gray areas on the
tonsils (Herman spots) and punctate blue–white lesions surrounded by an erythematous ring on the buccal mucosa
(Koplik spots).59 The exanthem lasts for 5–6 days, then
fades, whereas the enanthem occurs a few days prior to the
exanthem and lasts 2–3 days.
For most persons, measles is an unpleasant mild or moderately severe illness. In poorly nourished young children,
however, especially those who do not receive sufficient
vitamin A, or whose immune systems have been weakened by HIV/AIDS or other diseases, severe complications
including blindness, encephalitis, severe diarrhea (which
can cause dehydration), pneumonia, and mortality from
such complications can result.60,61
Encephalitis is estimated to occur in 1 of 800–1000
cases (although death and brain damage is limited to a
small minority of cases), whereas pneumonia may occur
in 5%–10% of cases. More uncommon is subacute sclerosing panencephalitis, which can develop in approximately 1
of 100,000 cases and cause mental and motor deterioration,
seizures, coma, and death.32
Overall, the case fatality rate in developing countries
is generally in the range of 1%–5%, but may be as high
as 25% in populations with high levels of malnutrition
and poor access to health care. In January 2007, the
World Health Organization/United Nations Children’s
Fund (WHO/UNICEF) reported that implementation of
measles mortality reduction strategies (including vaccinations and early treatment strategies) had reduced measles
mortality by 60%, from an estimated 873,000 deaths worldwide in 1999 to 345,000 deaths in 2005.62,63
Prevention and Treatment
The best weapon we have against measles is vaccination to
prevent disease. The measles vaccine is a live attenuated
vaccine that first became available in 1963. In the United
States, it is generally given as part of either the measles,
mumps, rubella (German measles) (MMR) or MMR plus
varicella (MMRV) vaccines. The vaccine is given in two
shots, the first at 12–15 months and the second at 4–6
years of age.64 After the second shot, approximately 99% of
people become immune to the disease. Because it is a live
vaccine (like the varicella vaccine), immunocompromised
patients should not be vaccinated.
Severe complications of measles can usually be avoided.
General nutritional support and the treatment of dehydration with oral rehydration solution are necessary. Should
eye and ear infections or pneumonia result, antibiotics may
be prescribed. In developing countries, persons diagnosed
with measles should receive two doses of vitamin A supplements given 24 hours apart to help prevent eye damage and
blindness. More important, vitamin A supplementation has
been shown to reduce the number of deaths from measles
by 50%.65
GERMAN MEASLES (RUBELLA)
Presentation and Clinical Features
Rubella tends to be milder than rubeola. Often called 3-day
measles because of the duration of its classic rash, it is recognized by mild constitutional symptoms followed by an
erythematous eruption that begins on the face and spreads
from head to foot. Unlike measles, the rash of rubella is
nonconfluent and tends to have a lesser degree of erythema.
Additionally, petechiae of the palate may be present. In general, rubella is uncomplicated, but infection during pregnancy can lead to congenital rubella syndrome (CRS), an
important cause of severe birth defects.66 When a woman
is infected with the rubella virus early in pregnancy, she has
a greater than 50% chance of passing the virus on to her
fetus, which may cause fetal demise or CRS, whereas infection later in pregnancy has a lower risk of CRS.67 Common birth defects that may occur due to CRS are ocular defects, cardiovascular defects, CNS defects, deafness,
microcephaly, mental retardation, and intrauterine growth
retardation.
An uncommon but important systemic complication,
particularly in adult women, is encephalitis. Rubella encephalitis occurs in approximately 1 in 6000 cases, and is
fatal in approximately 20% of these cases.68
Chapter 12
Prevention and Treatment
The currently used rubella vaccine is a live attenuated strain
that was developed in 1979 and is given as part of the MMR
or MMRV vaccine. The vaccine schedule includes a first
shot at 12–15 months and a second at 4–6 years of age.64 As
it is a live virus vaccine, immunosuppressed patients should
not be vaccinated. Treatment for rubella infection is supportive.
KAPOSI SARCOMA
Presentation and Clinical Features
Kaposi sarcoma (KS) is a vascular neoplasm with several distinct subtypes. Classic KS is an indolent disease in middleaged to elderly men, generally of Southern and Eastern European origin. African cutaneous KS, which affects
middle-aged Africans in tropical Africa, tends to be locally
aggressive. African lymphadenopathic KS is an aggressive
disease that affects young patients, usually younger than
10 years. KS is also seen in patients who are immunosuppressed, either by AIDS or by lymphoma or immunosuppressive therapy.46
Lesions of KS are reddish, violaceous, or bluish-black
macules and patches that spread and coalesce to form
nodules or plaques. They often appear on the toes or
soles in the earliest stages. Regardless of the epidemiologic form, the prognosis of KS depends on the severity of
visceral involvement. The gastrointestinal (GI) tract, particularly the small intestine, is the most frequent site of
internal involvement in classic KS, although it may also
affect the lungs, heart, liver, lymph nodes, and bone. Visceral involvement in classic KS occurs in approximately
10% of patients.69 African cutaneous KS frequently has
bone involvement as well as leg swelling caused by lymphedema. African lymphadenopathic KS, as the name suggests, involves the lymph nodes, which often precede the
appearance of skin lesions. In AIDS-associated KS, 25%
of patients have cutaneous involvement only, whereas 29%
have visceral involvement only.46 If AIDS is left untreated,
more than 70% of patients with AIDS-associated KS will
develop visceral involvement.
Due to its indolent course, patients with classic KS usually die of unrelated causes, often many years after initial diagnosis. In contrast, African cutaneous KS is aggressive and has early nodal involvement; this form of KS
often results in death within 1–2 years. Despite often being
widespread, AIDS-related KS tends not to be fatal, as most
patients die of intercurrent infection.
Prevention and Treatment
KS lesions are radiosensitive, but they can also be locally
excised and/or treated with cryotherapy, laser ablation,
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Life-Threatening Cutaneous Viral Diseases 121
and intralesional injections (interferon, vincristine, vinblastine, and actinomycin D have all been reported). For disseminated, progressive, or symptomatic disease, systemic
treatment options include interferon-␣ and chemotherapy
including pegylated liposomal anthracyclines and paclitaxel.70 Highly active antiretroviral therapy (HAART) in
patients with AIDS has been shown both to decrease the
incidence of KS as well as to treat existing lesions.70,71
The fact that KS lesions tend to regress when a patient
is on HAART leads to the assumption that improvement in immune function is responsible for the regression. Therefore, removal of the iatrogenic cause in patients
with immunosuppression-related KS may result in KS resolution without therapy. There are no current preventative therapies for KS besides HAART in AIDS patients or
removal of iatrogenic stresses on the immune system.
MOSQUITO-BORNE VIRUSES
Presentation and Clinical Features
Mosquitoes have been called the world’s deadliest animals
as diseases spread by these insects are responsible for more
deaths than all mammals, amphibians, reptiles, birds, and
fishes combined. Three such life-threatening viral diseases
of concern to dermatologists include dengue, yellow fever,
and West Nile virus.
Dengue causes fever as well as headache, retroorbital
pain, myalgia, and arthralgia that may be followed by a
skin eruption in up to 80% of patients during the remission of the fever. The rash classically consists of a mild
macular eruption over the nape of the neck and face lasting up to 5 days. Petechiae or purpura as well as involvement of the palms and soles followed by desquamation and
proximal spread to the arms, legs, and torso are also common.32,66 This eruption is helpful diagnostically, as prior
to the eruption the differential can include malaria, yellow
fever, and influenza.32 Dengue is associated with two lifethreatening complications: hemorrhagic fever and shock
syndrome. Hemorrhagic fever consists of a sudden temperature elevation lasting 2–7 days followed by bleeding from
sites of trauma as well as the GI tract and urinary tract. The
average case fatality is approximately 5%32 but, in severe
cases of dengue, hemorrhagic fever mortality may reach
50%.66 Occasionally, shock syndrome may follow hemorrhagic fever. In these cases, circulatory and respiratory failure may occur, resulting in death in approximately 2% of
cases.
Yellow fever has two disease phases. The first (acute
phase) presents with fever, muscle pain (especially backache), headache, anorexia, and nausea and/or vomiting.
Most patients improve after 3–4 days.72 Approximately
15% of patients will enter a toxic phase consisting of fever
reappearance, jaundice, and abdominal pain. Hemorrhage
122 E MERGENCY D ERMATOLOGY
from the GI tract, mouth, nose, and eyes may occur. Liver
and kidney failure may occur, and mortality can be as high
as 40% in this toxic phase because of hepatorenal failure.66
Dermatological findings in yellow fever include icteric skin
(hence the name “yellow” fever) as well as hemorrhages or
petechiae of the skin and mucous membranes.
West Nile virus can cause fever, headaches, GI symptoms, and (in up to 50% of cases) a skin eruption characterized by punctate, erythematous macules and papules
most pronounced on the extremities.32,66 Common serious
complications include meningitis, encephalitis, and flaccid paralysis, although less than 1% of infections result
in severe neurological illness. Persons at greatest risk for
neurological disease are thoses older than 50 years.
Prevention and Treatment
Vaccination is available for yellow fever and is recommended every 10 years for persons visiting endemic countries.66,73 There are no currently available vaccines for
dengue or West Nile virus. The best form of prevention
is to avoid mosquito bites. Using insect repellent; getting rid of mosquito breeding sites by emptying standing
water from flower pots, buckets, or barrels; staying indoors
between dusk and dawn (when mosquitoes are most active);
and using screens on windows to keep mosquitoes out are
all effective techniques. There are no antiviral treatments
for the mosquito-borne viruses. Treatment for dengue and
yellow fever is symptomatic, consisting of rehydration, rest,
analgesia, and antiemetics, whereas therapy for West Nile
virus is the same as for patients with meningoencephalitis.66
MARBURG AND EBOLA VIRUSES
Presentation and Clinical Features
The filoviridae viruses, Marburg and Ebola, cause severe
hemorrhagic fever in human and nonhuman primates. The
classic rash that may bring these infections to dermatological attention is a nonpruritic centripetal rash composed of
macules and papules with varying degrees of erythema.74
The rash occurs approximately 2 weeks after exposure and
tends to desquamate by day 5 or 7 of the illness. Hemorrhagic manifestations include GI tract bleeding, bleeding into the oropharynx and lungs, petechiae, hemorrhage
from puncture wounds, and massive gingival bleeding.74
Mucosal bleeding and persistent vomiting are ominous
symptoms in these diseases. Mortality due to Marburg and
Ebola ranges between 30% and 90%, depending on the
strain of the virus.75,76
Prevention and Treatment
There is no virus-specific treatment for either Marburg or
Ebola virus; therefore, supportive therapy is the standard of
care. Therapy should attempt to maintain effective blood
volume and electrolyte balance that present due to hemorrhage.74 Additionally, shock, cerebral edema, renal failure,
coagulopathy, and secondary bacterial infection are commonplace and must be managed appropriately. Isolation
is recommended to prevent spread of the disease to additional patients. When available, patients should be placed
in a negative pressure room if experiencing symptoms of
cough, vomiting, diarrhea, or hemorrhage.77
ONCOGENIC VIRUSES
Several viruses have the potential to be life threatening due
to their oncogenic potential. Although these viruses are
unlikely to require treatment on an emergent basis, recognizing some of the pathologies associated with these viruses
is important.
Human papilloma viruses (HPV; there are >100 currently identified) are responsible for common warts and
condyloma acuminata, and are encountered by dermatologists on a daily basis. Most warts are benign, but they can
convert to malignant carcinomas, as is the case in patients
with epidermodysplasia verruciformis.78 Papilloma viruses
are also found associated with human penile, uterine, and
cervical carcinomas and are likely to be their cause. Of the
multiple types of HPV, certain strains have been identified
as having high oncogenic potential. Some of these strains,
namely HPV 16 and 18 (along with nononcogenic types
6 and 11) have been targeted in a quadrivalent vaccine to
prevent cervical cancer (Gardasil).79
Epstein–Barr virus (EBV) is a herpes virus that is
strongly associated with cancer. It infects primarily lymphocytes and epithelial cells. EBV causes infectious
mononucleosis, which itself is a benign self-limited disease
characterized by fever, sore throat, swollen lymph glands,
and occasionally hepatosplenomegaly. A pink, measleslike rash can occur and is more likely if the patient is
given ampicillin or amoxicillin (approaching 70%–100%
of patients who receive these medicines)80 for a throat
infection, which may prompt dermatological consultation.
EBV is associated with multiple tumors, including Burkitt
lymphoma (particularly in the tropics), nasopharyngeal
cancer (particularly in China and Southeast Asia), B-cell
lymphomas in immune suppressed individuals (such as in
organ transplantation or HIV), and Hodgkin lymphoma
(EBV has been detected in approximately 40% of affected
patients).81–83
HHV-8 is widely known to be the viral cause of KS.
It has also been associated with hematologic malignancies,
including primary effusion lymphoma, Castleman disease,
and various atypical lymphoproliferative disorders.69,84
Hepatitis B may come to dermatological attention if a
patient develops Gianotti–Crosti syndrome, a cutaneous
manifestation that is not specific to hepatitis B (it can also be
associated with EBV among other diseases). This cutaneous
Chapter 12
eruption is characterized by monomorphous pale, pinkto flesh-colored or erythematous papules or papulovesicles distributed symmetrically and acrally over the extensor surfaces of the extremities, buttocks, and the face, with
the trunk, knees, elbows, palms, and soles rarely involved.46
Hepatitis B is thought to be associated with hepatocellular
carcinoma (HCC), one of world’s most common cancers.
There is a strong correlation between HBsAg (hepatitis B
virus surface antigen) chronic carriers and the incidence of
HCC. In Taiwan, it has been shown that 72% of patients
with HCC are carriers of HBsAg.85 Fifty-one percent of
deaths of HBsAg carriers are caused by liver cirrhosis or
HCC compared to 2% of the general population.
SUMMARY
Most cutaneous viral diseases are self-limited in immunocompetent individuals. Due to the growing number
of immunocompromised patients (whether because of
HIV/AIDS or iatrogenic causes), life-threatening manifestations of these viral diseases are increasingly common.
Although many of these diseases are classically seen in
developing countries, air travel and the global economy
have brought these infections to the attention of physicians and patients in developed nations as well. Doctors
and health care workers must be careful not to overlook
the potential for life-threatening complications of viral skin
diseases. Vaccination when available is usually the best
strategy for prevention of illness. On infection, prompt
treatment is necessary to prevent avoidable morbidity and
mortality.
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Life-Threatening Cutaneous Viral Diseases 125
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CHAPTER 13
Life-Threatening Cutaneous Fungal
and Parasitic Diseases
Marcia Ramos-e-Silva
Carlos Gustavo Costanza
Sueli Coelho Carneiro
CUTANEOUS FUNGAL and parasitic diseases are frequent and usually do not threaten the physical integrity of
the patient. There are, however, some that may acquire
a severe clinical picture and may even cause death. Some
of the most important and/or dangerous of these lifethreatening cutaneous fungal (as systemic candidosis,
paracoccidioidomycosis, sporotrichosis, zygomycosis, and
histoplasmosis) and parasitic diseases (Chagas disease,
schistosomiasis amebiasis, and leishmaniasis) are discussed
in this chapter.
FUNGAL INFECTIONS
Systemic Candidosis
First observed by Langenbeck in 1839, the genus Candida
suffered several taxonomic modifications until its present
classification. It presents about 200 species of fungi and
shelters the most important yeasts that infect mankind.
Many species are opportunistic pathogens; however, the
majority do not infect humans.1
Although the last decade has observed an increase of
infections by the non-albicans Candida species (such as C.
tropicalis, C. glabra, C. krusei, C. dubliniensis, and C. parapsilosis), C. albicans remains the dimorphic yeast responsible for
70%–90% of all infections of this type.2,3 It is frequently
found as a saprophyte of humans colonizing the mucosa of
the digestive system, and by contiguity, the vaginal mucosa
of the majority of mammals.
The term “candidiasis” or “candidosis” (more frequent
in Canadian and UK literature) has a generic connotation
and encompasses a wide spectrum of clinical manifestations.
Factors related to the host’s immunity, mainly the cell
immunity, and characteristics of the microorganism’s virulence will determine the spectrum of the disease, which
varies from superficial infection of the mucous membranes
and skin, to visceral and systemic infections.1,2
Neutropenia, hematological neoplasias, cancers in solid
organs, transplants, and other situations of immunosupression are the main substrata for installation of systemic candidosis. Additional aggravating factors to those scenarios
are extensive hospital internments, prolonged use of broadspectrum antibiotics, hemodialysis, multiple gastrointestinal (GI) procedures, parenteral feeding, and medium- to
long-term intravascular catheters.3–5
Systemic candidosis is a severe infection, associated with
great mortality (approximately 40%–60%)1,3,5,6 caused
mainly by difficulties in its diagnosis, leading to a delay in
its recognition. The clinical manifestations are unspecific,
and tools for diagnosis are not sensitive enough.
The most relevant clinical finding is persistent fever,
despite the use of appropriate antibiotics for the supposed
bacterial picture. The remaining manifestations are inherent to the organs affected and to septic syndrome.
Dermatological lesions affect approximately 10%–13%
of patients. Despite C. albicans ruling absolute as the cause
of systemic disease, C. tropicalis is isolated with greater frequency in cases of systemic candidosis with dermatological
manifestations. It is speculated that a greater tropism by
cutaneous tissue occurs in the latter.7,8
Newborns present more frequent dermatological alterations when compared to adults with systemic candidosis.
A 35.8% rate of cutaneous manifestations associated
with systemic candidosis has been observed.7 In the present
study, 52.6% of the patients with dermatological manifestations had onset of dermatitis concurrently with fever and,
of these, four patients (40%) presented a triad of fever,
cutaneous eruption, and myalgia.
The cutaneous lesions are varied and multiple: macules, nodules, and erythematous plaques, some purple, with
a central lighter hue, affecting especially the trunk and
extremities. In some cases, numerous vesicles can mimic
herpes zoster. Also worthy of mention are reports of cellulite lesions and gangrenous ecthyma-like lesions. Some
page 126
Chapter 13
FIGURE 13.1: Candida albicans – culture. (Photo courtesy of
Mycology Laboratory – HUCFF/UFRJ.)
authors blame the purple lesions on the frequent thrombocytopenia found in those patients.7,9,10
Systemic candidosis is a disease of difficult diagnosis.
Within some clinical coherence, biopsies of suspect cutaneous lesions and affected organs may suggest the diagnosis; however, the usual stains and immunofluorescence
methods fail in identifying the species.
The dermatopathological findings can identify spores
and/or hypha, mainly in the upper dermis, surrounding
small vessels with varied degrees of vascular damage from
dilations, thrombus, red cell extravasation, and even vasculitis.7
The gold standard is hemoculture, but cultures from
other suspect sites can help in the diagnosis (Figures 13.1
and 13.2). The lack of sensitivity (only 50% of the affected
patients) and a delay in identifying the agent (approximately
1 week) make the method unacceptable for a basis to begin
therapy. Furthermore, the method has little capacity to
identify the species of Candida, crucial for an appropriate
treatment, because some species are naturally less sensitive
●
Life-Threatening Cutaneous Fungal and Parasitic Diseases
FIGURE 13.2: Candida albicans – germ tubes. (Photo courtesy
of Mycology Laboratory – HUCFF/UFRJ.)
or resistant to commonly employed systemic antifungals
(Table 13.1).11
Serological tests, using several resources (radioimmunoassay, enzyme-linked immunosorbent assay [ELISA],
latex agglutination (LA), and reversed passive latex agglutination [RPLA] assay) aimed at identifying fungus antigens
and metabolites, as well as detecting serum antibodies, are
difficult to interpret and have low sensitivity.
New methods for biomolecular identification with
amplification of deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR) are promising. Recent publications praise the systems called “real-time” PCRs
R
R
(TaqMan system
and LightCycler system
), promising
immediate results, with optimal sensitivity and specificity.
Those tools still present prohibitive costs, require standardization, and are not available in the majority of clinical
laboratories.6,12,13
The fast and adequate institution of antifungal therapy is primordial for the reduction of mortality rates.
TABLE 13.1: Susceptibility of Candida Species
Candida spp.
Amphotericin B
Fluconazole
Itraconazole
Voriconazole
Caspofungin
C. albicans
C. tropicalis
C. parapsilosis
C. glabrata
C. kruzei
C. lusitaniae
S
S
S
S to I
S to I
S to R
S
S
S
S-DD to R
R
S
S
S
S
S-DD to R
S-DD to R
S
S
S
S
S to I
S
S
S
S
Sa
S
S
S
Note: Interpretation based on the use of the National Committee for Clinical Laboratory Standards (CLSI) M27-A
methodology.
S, susceptible; S-DD, susceptible-dose dependent; I, intermediate; R, resistant.
a
MIC90 (the minimum inhibitory concentration required to inhibit the growth of 90% of organisms) is higher than in
other Candida species, but clinical significance is unknown (breakpoints not yet defined).
Data adapted from (3).
127
128 E MERGENCY D ERMATOLOGY
TABLE 13.2: Empirical Therapy for Candida Bloodstream Infections
Setting
First choice
Alternatives
Non-neutropenic patient and no
previous exposure to azoles
Fluconazole 800 mg IV (1st dose), then
400 mg/d IV
Amphotericin B deoxycholate 1 mg/kg/d IV
Or Caspofungin 70 mg IV (1st dose), then
50 mg/d IV
Or Voriconazol 6 mg/kg IV q12h on day 1, then
4 mg/kg q12h IV
R
Non-neutropenic patient and
previous exposure to azoles
Amphotericin B deoxycholate 1 mg/kg/d IV
Or Caspofungin 70 mg IV (1st dose) then
50 mg/d IV
Liposomal Amphotericin B (AmBisome )
3 mg/kg/d IV
Neutropenic patient
Amphotericin B deoxycholate 1 mg/kg/d IV
Caspofungin 70 mg IV (1st dose) then
50 mg/d IVa
R
Or Liposomal Amphotericin B (AmBisome )
3 mg/kg/d IV
Severe sepsis or septic shock
Caspofungin 70 mg IV (1st dose) then
50 mg/d IVa,b
R
Liposomal Amphotericin B (AmBisome )
3 mg/kg/d IV
Or Voriconazole 6 mg/kg IV q12h on day 1,
then 4 mg/kg q12h IVa,b If no previous azole
exposure
a
b
c
Few clinical data are available on the use of azoles and echinocandins in neutropenic patients with documented invasive candidosis. In vitro,
azoles are fungistatic; echinocandins are fungicidal. In some experimental models (e.g., Candida endocarditis, disseminated candidosis in
neutropenic animals), azoles are less efficacious than amphotericin B or echinocandins.
Amphotericin B deoxycholate is not recommended in critically ill patients with severe sepsis/septic shock: risk of acute nephrotoxicity or of
R
underdosing due to infusion-related toxicity. Caspofungin (Cancidas
) is first choice or alternative, respectively, in this setting.
According to susceptibility testing. Some experts would add voriconazole to the list of first choice agents for the treatment of C. glabrata infections.
Data adapted from (3).
It is worthwhile to treat, when possible, the predisposing underlying factors, such as the removal of deep vein
accesses.
The choice of the employed agent will depend on factors
such as 1) the patient’s state (hemodynamically stable, sepsis/shock, predisposing factors to renal inadequacy, etc.);
2) use of previous antifungal medication before the current
picture; 3) isolation of specific microorganisms with known
resistance to certain agents (Table 13.2).
For decades, amphotericin B deoxycholate, a polyenic
antibiotic of broad-spectrum fungicide action, was used as a
treatment of choice for invasive candidosis. Unfortunately,
that drug is ill-tolerated, presenting immediate adverse
reactions (related to the speed of its infusion; fever, shivers,
hypoxemia, and hypotension) and late effects (nephrotoxicity; reduction of glomerular filtration rate and depletion
of potassium, magnesium, and bicarbonate).
Lipid-based formulations were created to minimize
undesired effects from amphotericin B deoxycholate,
mainly nephrotoxicity. The high cost and scarcity of effective results in comparative studies led the lipid-based formulations to be used for second-line treatment of systemic
candidosis.3,14–16
With the emergence of triazolic compounds (fluconazole and itraconazole), fluconazole became the most
employed medication in the treatment of non-neutropenic
and hemodynamically stable patients. It presents a
wide action spectrum and good bioavailability; however,
C. krusei and C. glabrata present respectively resistance and
low sensitivity to fluconazole. The azolic compounds, acting on enzymes of the cytochrome P450 system, interact
with several drugs.3,14–16
Already available in intravenous (IV) formulations, itraconazole has variable bioavailability and low serum concentration when compared to other tissues (liver, lungs,
and bones) and has a higher interaction with other medications.14,15,17
The second generation of triazolic compounds (voriconazole, posaconazole, and ravuconazole) is in advanced
study phases. These compounds present an expanded spectrum with smaller risks of interactions with several drugs.
Voriconazole and posaconazole are already available in
venous and oral formulations, and initial comparative studies showed promising results.3,14–16,18
The echinocandins (caspofungin, micafungin, and
anidulafungin), a recent class of antifungals with parenteral action, have fungicide action on different species
of Candida, including samples resistant to fluconazole and
amphotericin B. Different from the remaining antifungals, the echinocandins act on the fungal cell wall. Caspofungin and, later, micafungin were approved by the U.S.
Food and Drug Administration with good action spectrum and minimal collateral effects being reserved for
patients with severe sepsis or systemic shock and averting risks of renal damage from amphotericin B deoxycholate.14,15,17
Chapter 13
Investigations encompassing combinations of antifungal agents are scarce and, in certain cases, disappointing. In
vivo studies showed antagonism between the simultaneous
use of amphotericin B and azoles. The classic association
between amphotericin B deoxycholate and 5-fluorocitosin
did not show a clear advantage as in the cases of cryptococcosis in immunodepressed patients. In contrast, the combination of caspofungin and meropenem, an ultra–broadspectrum antibiotic in hospital use, showed a significant
superiority to monotherapy.3,19
Paracoccidioidomycosis
Paracoccidioidomycosis was first described in Brazil by
Adolfo Lutz, in 1908, and, later, investigated by Afonso
Splendore and Floriano Almeida, in 1912 and 1930, respectively, both with relevant contributions. Lutz–Splendore–
Almeida disease and South American blastomycosis are
less common names for paracoccidioidomycosis, a term
acknowledged by the United Nations since 1971.20–22
Paracoccidioidomycosis is a deep mycosis, the isolated agent of which is the dimorph fungus Paracoccidioides
brasiliensis, the causative agent of the granulomatous process, predominantly chronic, and implicated on rare occasions in acute and subacute diseases. It is characterized by
polymorphism of the lesions and can affect virtually any
organ, especially the lymph nodes, lungs, nasal mucosa, and
GI tract, besides suprarenal glands and the central nervous
system (CNS).21
The geographic distribution of the fungus is directly
related to the climate, being found predominantly in tropical and subtropical regions with acid soils. It is an endemic
disease in Latin America, with great incidence in South
American countries, mainly Brazil, Venezuela, Colombia,
Ecuador, and Argentina, without reports of autochthonous
cases either in Chile or in the Antilles. There are few cases
of the disease in Central America, with predominance in
Mexico.
The infection happens in general in the first two decades
of life; however, it can remain latent for many years until
generating the disease.
Incidence before age 12 is similar in both sexes, with
greater risk for the acute and subacute forms of paracoccidioidomycosis. After age 12, there is greater predominance
in men (young or middle-aged men, and men who work in
rural areas [who are at greater risk of developing the disease
in the chronic form]).
The extremely low percentage of women affected during
childbearing age can be explained by the assumed inhibition of -estradiol by the transformation of the mycelia
into hyphae, infecting forms of P. brasiliensis, after finding
receivers of that hormone in the cytoplasm of the fungus.
The greatest risk factor for infection is represented by
activities involving handling of polluted soil. Tabagism
and alcoholism are frequently associated with the disease.
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Life-Threatening Cutaneous Fungal and Parasitic Diseases
129
TABLE 13.3: Classification of the Clinical
Forms of Paracoccidioidomycosis
Paracoccidioidomycosis disease
Acute/subacute form (juvenile type)
Chronic form (adult type)
Unifocal
Multifocal
Residual form or sequel
Data adapted from (23).
Different than other systemic mycoses, paracoccidioidomycosis is rarely related to immunodepressive diseases. There have been reports of this mycosis in patients
with acquired immune deficiency syndrome (AIDS), neoplasias, and (more rarely) transplants.
The most important infection modality is through the
respiratory tract, by inhalation of the spores of the fungus,
although there is a report of the disease by direct cutaneous
and mucosal inoculation. Starting from the penetration site,
the fungus can multiply and disperse into neighboring tissues, reaching the regional lymph nodes or disseminating
hematogenically.
Varied clinical forms can be observed in paracoccidioidomycosis, from located benign to disseminated and
progressive disease, often with a fatal outcome. Genetic,
hormonal, nutritional, and immunologic factors are
involved in the development of the infection and its clinical
manifestations.21
The classification proposed by the consensus on paracoccidioidomycosis of 2006, developed by the Brazilian
Society of Tropical Medicine and adapted at the International Colloquium on Paracoccidioidomycosis (held in
February 1986) is shown in Table 13.3.23
After penetration of P. brasiliensis into the host, a paracoccidioidomycosis infection results that may resolve spontaneously, progress to a disease, or remain latent, according
to the patient’s immunity. The main types of paracoccidioidomycosis disease are the acute/subacute forms (juvenile type) and the chronic type. The acute/subacute form
is responsible for approximately 5% of the cases of paracoccidioidomycosis, prevailing in children and teenagers of
both sexes, presenting rapid evolution. We highlight occurrence of lymph-node involvement, hepatosplenomegaly,
intraabdominal masses, jaundice, ascites, osteoarticular and
cutaneous lesions (approximately 50% of the cases), in addition to rare lung involvement (<5% of the cases).
The chronic form prevails in 90% of the cases of the
disease, affecting adults older than 20 years, and can be
divided into unifocal or multifocal, according to the number of organs or systems affected, in direct relation to the
degree of cellular and humoral immunity.
The oral cavity involvement (Figure 13.3) is predominantly caused by contamination from lung secretions,
although a direct inoculation of the fungus can also occur.
130 E MERGENCY D ERMATOLOGY
FIGURE 13.3: Paracoccidioidomycosis – oral lesion.
FIGURE 13.5: Paracoccidioidomycosis – lymph-node enlargement.
The most affected sites are lower lip, mucous membrane,
and sublingual area. The lesions can extend to the pharynx, tonsils, and larynx. The typical presentation is erythematous ulcerated lesions, with granulomatous bases, intermixed with hemorrhagic spots, called moriform stomatitis
of Aguiar-Pupo (Figure 13.4).
The characteristic cutaneous lesions are ulcers or vegetations, but crusted papules, erythematous plates, and nodules may be present. They are located more frequently in
the central face area, limbs, and trunk. Cervical lymph-node
involvement (Figure 13.5) tends to suppurate, resembling
scrofuloderma.
Visceral commitment is varied and always present.
Lungs (Figure 13.6), adrenals, liver, spleen, GI tract, genitourinary tract, CNS, and bones can also be affected.
The residual form or sequel is observed in advanced
stages of the disease, where the chronic inflammatory process generates fibrosis and functional restrictions of the
affected organs, with lung fibrosis being the preferred
one.
In view of a clinical and epidemiologic suspicion of paracoccidioidomycosis, methods for isolation and identification of the fungus are required, in addition to serological
techniques that help in the diagnosis and follow-up.22
The direct mycological examination of fresh or Giemsastained material shows rounded cells, of double contour,
well refringent, varying from 5 to 25 µm in diameter
(Figure 13.7). Simple or multiple gemulations can be
observed, both by direct examination as in histopathology.
FIGURE 13.4: Paracoccidioidomycosis – stomatitis of Aguiar
Pupo.
FIGURE 13.6: Paracoccidioidomycosis – x-ray showing lung
involvement.
Chapter 13
FIGURE 13.7: Paracoccidioides brasiliensis – direct examination of cutaneous biopsy in potassium hydroxide (KOH) and
Parker ink. (Photo courtesy Mycology Laboratory – HUCFF/UFRJ.)
A typical finding is multiple gemulation in the form of
a rudder wheel, with multiple gemulation around the
fungus.21,24
Cultures are made in Sabouraud or blood agar, with an
approximate 20-day duration,24 and they are different if the
culture is maintain at 37◦ C or 25◦ C (Figure 13.8).
At histopathology, we observe a granulomatous pattern,
rich in giant and epithelioid cells, some containing different amounts of fungi. The finding of a parasitic element
with double walls with simple or multiple gemulation is a
positive diagnosis. P. brasiliensis can be visualized by hematoxylin and eosin (H&E) stain, but special colorations are
required for fungi; periodic acid–Schiff (PAS) and Gomori
methenamine–silver (GMS) stains are required when the
amount of parasites is low.
Currently, several serological techniques for identification of antigens of P. brasiliensis, mainly gp43 and gp70,
FIGURE 13.8: Paracoccidioides brasiliensis – cultures at 37 ◦ C
and 25 ◦ C showing dimorphism. (Photo courtesy of Mycology
Laboratory – HUCFF/UFRJ.)
●
Life-Threatening Cutaneous Fungal and Parasitic Diseases
131
are available from reference services. Double immunodiffusion, counterimmunoelectrophoresis, indirect immunofluorescence, ELISA, and immunoblot are examples that,
besides aiding in the diagnosis, present relevant roles in
the segment, with important information on the prognosis
and activity of the disease.
The titer of specific anti-P. brasiliensis antibody is correlated to the severity in the clinical forms, being higher
in the acute/subacute forms of the disease. Cases of falsenegative serologies can be justified for located forms of the
disease, immunodepressed hosts, or AIDS patients. Falsepositive results are found in patients with histoplasmosis
and aspergillosis.23
For its simplicity, acceptable cost, and good sensitivity
and specificity, double immunodiffusion was considered the
main technique for diagnosis of paracoccidioidomycosis by
consensus of the Brazilian Society of Tropical Medicine.
Other more complex tests are subject to clinical suspicion or initial alterations that predict the involvement of
CNS, lung, GI, osteoarticular, or adrenal dysfunction.
The treatment of paracoccidioidomycosis should obligatorily encompass support measures for clinical complications associated with local and systemic involvement of
the mycosis, in addition to specific antifungal therapeutics.
Most of the systemic antifungal drugs available present
action against P. brasiliensis, such as amphotericin B, sulfamides (sulfadiazine and sulfamethoxazole/trimethoprim),
terbinafine, and azolic antifungals, (ketoconazole, fluconazole, itraconazole, and voriconazole).
In mild-to-moderate cases, itraconazole is the option of
choice. For its low cost and availability at the public health
services, the association of sulfamethoxazole/trimethoprim
is widely used in Brazil. Terbinafine has in vitro activity,
against P. brasiliensis, similar to itraconazole, and was used
successfully in the treatment of the disseminated disease,
in a dosage of 500 mg/day, with a 2-year follow-up.22,25 In
patients with severe forms of the disease, amphotericin B
or IV sulfamethoxazole/trimethoprim is used.
IV fluconazole can be considered in an attack dosage
(400–800 mg/day for 1 month) for cases of neuroparacoccidioidomycosis because of its good penetration into the
CNS.21 Voriconazole, a second-generation triazolic compound available in oral and IV formulations, is an alternative therapeutic option of great potential.
Treatment is long, related to the severity of the disease
as well as to the type of drug employed, and should be maintained until reaching cure criteria based on clinical, mycological, radiological, and serological parameters. Clinical
cure means resolution of the signs and symptoms referring to the disease, healing of the tegumentary lesions, and
regression of adenopathy and recovery of body weight. The
demonstration of the agent’s elimination or its nonviability represents the mycological cure. The stabilization of the
radiological findings and regression, characteristically slow
of the lung images, predict radiological cure.26 Serological
132 E MERGENCY D ERMATOLOGY
cure occurs when double immunodiffusion shows negative
titers or stabilization of the values less than or equal to 1:2
observed in two samples collected in a 6-month interval
after the period of specific treatment.23
Every patient presents a potential risk of a late reactivation; for that reason, after observing the criteria for cure,
and after treatment interruption, patients should be followed half-yearly in the first year with clinical and serological tests, if necessary.21,23
Vaccines containing antigen gp43 DNA demonstrated
capability to generate protective immunity against P.
brasiliensis and to be a potential weapon in the prevention
of future cases.27,28
Visceral and Disseminated Sporotrichosis
The first case of sporotrichosis was reported in 1896 by
Benjamin Schenck, who was at that time a medical student. He isolated the suspect organism and forwarded it
to Erwin Smith, a mycology teacher, who concluded that it
belonged to the Sporotrichum genus. Later, in 1900, Hekton
and Perkins classified the pathogenic fungus as Sporothrix
schenckii.29,30
Although it is found worldwide, S. schenckii is more
prevalent in the tropics and in hot areas of temperate
regions. This dimorph fungus is present in decaying vegetation, sphagnum moss, and soil. Commonly, contamination
occurs by cutaneous inoculation of the organism, preceded
by local trauma.
Another less common contamination modality, but
related to more severe forms of the disease, is through
inhalation of fungal conidia, generating primary lung
lesions (diffuse fibrosis, abscesses, and lymph-node enlargement) with posterior hematogenic dissemination.31
Farmers, gardeners, horticulturists, and forest workers
are most susceptible to the infection. Sporotrichosis can
be transmitted by scratches and bites from digging animals
that carry the microorganism in their paws and teeth.32
Recently, an epidemic of sporotrichosis in cats occurred
with a consequent increase of reports of infections transmitted by those sick animals.33,34
Classified among the subcutaneous mycoses, most
reports of sporotrichosis are restricted to the skin and
subcutaneous tissue. Osteoarticular, visceral, and disseminated lesions are uncommon and present greater morbidity. Osteoarticular manifestations are the most frequent
among the cases of extracutaneous disease. The immune
conditions of the host and the contamination route are the
factors of greater relevance for the severity of the disease.
Kong and colleagues35 demonstrated the possibility of
virulence factors associated with different genotypes of S.
schenckii being contributors to the distinct forms of presentation of sporotrichosis.
Patients with AIDS, chronic alcoholics, and malnourished, transplanted, or immunodepressed patients in
FIGURE 13.9: Sporotrichosis – cutaneous lesion patient with
lymphoma. (Photo courtesy of Nurimar Fernandes, MD, PhD, and
Hugo Alves, MD, Rio de Janeiro, RJ, Brazil.)
general are most susceptible to the disseminated forms
(Figures 13.9 and 13.10). Patients with AIDS present a
special risk for developing more severe forms. The diagnosis of cutaneous or lymphocutaneous sporotrichosis in an
AIDS patient justifies the search for disseminated lesions
FIGURE 13.10: Sporotrichosis – cutaneous lesion with multiple
myeloma.
Chapter 13
FIGURE 13.11: Sporothrix schenckii – cultures at 25 ◦ C. (Photo
courtesy of Mycology Laboratory – HUCFF/UFRJ.)
in other organs, including the CNS. Disseminated lesions
may result in arthritis, mastitis, meningitis or multiple cerebral abscesses, orchitis, pyelonephritis, and bone infections.
Cutaneous manifestations can arise in the process of disease dissemination and are characterized by painful nodules
that evolve into ulcers. Papules, pustules, and other elementary lesions are occasionally observed.30
Due to the few reported cases and similarity of their clinical manifestations to other more common diseases such as
tuberculosis, paracoccidioidomycosis, cryptococcosis, and
sarcoidosis, the diagnosis of visceral sporotrichosis is frequently delayed.
Culture is the gold standard for diagnosis. Aspirates,
scrapings, and biopsies of suspect lesions, cutaneous or not,
can serve as substrata. Cultures of synovial liquid and/or
liquor can be adequately accomplished. The culture is initially white, acquiring a darker color later (Figure 13.11). In
89% of cases, isolation of S. schenckii is obtained in approximately 8 days. The growth of the fungus can occur later,
sometimes taking up to 4 weeks. Microscopy of the culture
shows conidia in a flower head arrangement (Figure 13.12).
Direct examination does not help due to the very small
amount of fungal cells, commonly present in the examined
materials.
A histopathologic study can disclose an unspecific granulomatous reaction with pseudoepitheliomatous hyperplasia and intraepidermal abscesses. Rarely, in PAS or silver
stain, oval and cigar-shaped organisms are observed, with
diameters of 3–5 mm inside the granuloma. The asteroid
bodies are observed in 40% of the rare cases in which these
microorganisms are found. They can be seen in other granulomatous reactions, however, extracellular structures
made of spiculae of eosinophilic material involved by a center containing yeasts (Splendore-Hoeppli phenomenon)
are specific of the asteroid bodies in sporotrichosis.30,31,36
The test of late reaction with sporotrichin is of little use
in cases of visceral infections or in dealing with patients with
●
Life-Threatening Cutaneous Fungal and Parasitic Diseases
133
FIGURE 13.12: Sporothrix schenckii – culture microscopy
microculture in potato-dextrose agar (PDA) stained in blue.
(Photo courtesy of Mycology Laboratory – HUCFF/UFRJ).
inadequate immune response, in addition to the incapacity
of differentiating previous exposure. Serological examinations did not prove useful in the diagnosis of sporotrichosis
and are not widely available.
The cutaneous and cutaneolymphatic lesions are
responsive to the therapy using a saturated solution of
potassium iodide (SSKI), triazoles (especially itraconazole),
terbinafine, and even local heat application.37
With the exception of osteoarticular lesions, with reasonable response to itraconazole, the remaining extracutaneous infections (visceral and disseminated) fail to
respond to commonly used medications. Present guidelines for management of sporotrichosis are summarized in
Table 13.4.31
In cases of disseminated or visceral disease, administration of amphotericin B is mandatory, preferably in lipidic
formulations. After a favorable response, the parenteral
medication can be replaced with itraconazole for a minimum of 12 months. In patients with AIDS, itraconazole can
be used indefinitely, as collateral prevention, in a dosage of
200 mg/dia. Surgical treatment combined with amphotericin B can be recommended in localized visceral cases,
mainly in pulmonary sporotrichosis.
Among the second-generation triazoles, voriconazole
showed less antifungal activity against S. schenckii than did
itraconazole and without indications in cases of sporotrichosis. Posaconazole presents activity against isolated S.
schenckii samples, but no comparative study has been published so far.
In a published Mexican study38 the production of
melanin by Sporothrix was demonstrated. This fact might
positively influence the discovery of effective therapeutic
interventions. Herbicides directed to melanin biosynthesis, such as tricyclazole, are available for agricultural use.31
134 E MERGENCY D ERMATOLOGY
TABLE 13.4: Summary of Recommendations
Lymphocutaneous/
Cutaneous
Itr 200 mg/d
Itr 200 mg b.i.d.; or terbinafine 500 mg b.i.d.; or SSKI
with increasing doses; or fluconazole 400–800 mg/d;
or local hyperthermiaa
Osteoarticular
Itr 200 mg b.i.d.
Lipid AmB 3–5 mg/kg/d; or deoxycholate AmB
0.7–1 mg/kg/db
Pulmonary
Lipid AmB 3–5 mg/kg/d, then Itr 200 mg b.i.d.; or Itr
200 mg b.i.d
Deoxycholate AmB 0.7–1 mg/kg/d, then Itr 200 mg
b.i.d.; surgical removalc
Meningitis
Lipid AmB 5 mg/kg/d, then Itr 200 mg b.i.d.
Deoxycholate AmB 0.7–1 mg/kg/d, then 200 mg
b.i.d.d
Disseminated
Lipid AmB 3–5 mg/kg/d, then Itr 200 mg b.i.d.
Deoxycholate AmB 0.7–1 mg/kg/d, then 200 mg/
b.i.d.e
Pregnant women
Lipid AmB 3–5 mg/kg/d or deoxycholate AmB
0.7–1 mg/kg/d for severe disease; local hyperthermia
for cutaneous disease
Children
Itr 6–10 mg/kg/d (400 mg/d maximum) for mild
disease; deoxycholate AmB 0.7–1 mg/kg/d for severe
disease
f
SSKI with increasing doses for mild disease.g
AmB, amphotericin B; b.i.d., twice per day; Itr, itraconazole; SSKI, saturated solution of potassium iodide.
a
Treat for 2–4 weeks after lesions resolve.
b
Switch to Itr after favorable response if AmB used. Treat for a total of at least 12 months.
c
Treat severe disease with an AmB formulation followed by Itr. Treat less severe disease with Itr. Treat for a total of at least 12 months.
d
Length of therapy with AmB is not established, but therapy for at least 4–5 weeks is recommended. Treat for a total of at least 12 months. May
require long-term suppression with Itr.
e
Therapy with AmB should be continued until the patient shows objective evidence of improvement. Treat for a total of at least 12 months; may
require long-term suppression with Itr.
f
It is preferable to wait until after delivery to treat non–life-threatening forms of sporotrichosis.
g
Treat severe disease with an AmB formulation followed by Itr.
Data adapted from (31).
Zygomycoses
The term “zygomycosis” characterizes any disease caused
by fungi of the Zygomycetes class, and includes two groups
of pathogenic microorganisms of medical importance: the
order of the Mucorales and that of the Entomophthorales.39
Several species of genera Rhizopus (Figures 13.13 and
13.14), Mucor, and Absidia may cause the disease.
Mucorales cause an aggressive disease called mucormycosis, which is angioinvasive, rapidly destructive, and in most
cases fatal.
Although Entomophthorales, responsible for entomophthoromycoses, are known for causing mucocutaneous and
FIGURE 13.13: Rhizopus sp. – culture. (Photo courtesy of
Mycology Laboratory – HUCFF/UFRJ.)
subcutaneous, painless, and chronic infections, recently a
change in the profile of virulence and geographic distribution of those fungi was found that can cause clinical syndromes that are indistinguishable from those caused by the
Mucorales, making a differentiation between the two orders
impossible, based solely on epidemiologic observation or
even at histopathologic examination.40
FIGURE 13.14: Rhizopus sp. – culture microscopy. (Photo courtesy of Mycology Laboratory – HUCFF/UFRJ.)
Chapter 13
TABLE 13.5: Factors Predisposing Patients to Zygomycosis
Diabetes mellitus
Diabetic ketoacidosis
Poorly controlled diabetes mellitus
Chronic metabolic acidosis
Renal failure
Chronic salicylate poisoning
Deferoxamine therapy
Iron overload
Immunosuppression
Neutropenia (due to malignances or chemotherapy)
Corticosteroid therapy
Organ or hematopoietic cell transplantation
Human immunodeficiency virus infection
Skin or soft tissue breakdown
Burn
Trauma
Surgical wound
Miscellaneous
Intravenous illicit drug use
Neonatal prematurity
Malnourishment
Prolonged use of broad-spectrum antimicrobial agents
Data adapted from (39).
Despite the majority of zygomycosis cases being caused
by Mucorales, the term zygomycosis is preferable to
mucormycosis, for being more encompassing and designating disease even when the cultures are not available and
identification of the fungus is not made.
Recent studies show that zygomycosis is an emerging
non-Aspergillus mycosis of relevant significance, in part due
to the constant increase of cases of diabetes and growing use
of immunosuppressive drugs available from the progress of
modern medicine.
Inhalation, ingestion, and cutaneous exposure to
microorganisms are the main infection sources, and the
predisposing factors are listed in Table 13.5.39
Diabetes mellitus with metabolic acidosis is implicated
in the most cases (36%–88%), although zygomycosis has
been observed in metabolically controlled diabetes patients.
The average survival rate in diabetic patients with
zygomycosis is approximately 60%. The relative treatment
facility of acute complications, compared with the remaining immunocompromising conditions, helps to explain the
lower mortality rate in cases of zygomycosis associated with
diabetes mellitus.
The excess of iron (by transfusion or by dyserythropoiesis) in addition to therapy with deferoxamine for treatment of excessive albumin and/or iron in patients in dialysis
is an important risk factor for angioinvasive zygomycoses.
Some recent studies show, that 78% of patients in dialytic regime and with zygomycosis were treated with deferoxamine.41 The more common presentation of the disease
was the disseminated (44%), followed by the rhinocerebral
form (31%).
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Life-Threatening Cutaneous Fungal and Parasitic Diseases
135
Zygomycosis associated with deferoxamine therapy
presents great mortality, approximately 80%,39 and in
immunosuppressed patients it is frequently fatal (68%–
100%). A prolonged neutropenia represents the greatest
risk factor of this group, approximately 15% of all cases of
zygomycosis.
Pulmonary disease is the most common presentation
in neutropenic patients, with the disseminated form more
common in individuals with greater immunosuppression.
Systemic steroids are another factor favoring zygomycosis,
whether by action of macrophages and neutrophils or by
steroid-induced diabetes. Patients with AIDS are known to
be at risk; however, the majority of cases of zygomycosis
in human immunodeficiency virus (HIV)-infected persons
are also associated with IV drug abuse.42
Temporary local trauma and burns can also lead to accidental inoculation of fungus spores, generating cutaneous
disease even in immunocompetent hosts. The use of broadspectrum antibiotics and topical preparations with antibacterial effect in burned patients seems to increase the risk
of cutaneous fungal infection significantly, including cutaneous zygomycosis.43
Other predisposing factors include abuse of illicit IV
drugs, premature neonatality, malnutrition, sites of IV
catheter insertion, and extensive therapy with broadspectrum antimicrobials.
Recent reports of prolonged use of voriconazole for
prophylaxis and treatment of invasive fungal infections
revealed great risk for several forms of zygomycosis.39,44
Based on the clinical presentations and involvement
sites, zygomycoses can be classified as rhinocerebral, pulmonary, cutaneous, GI, disseminated, and miscellaneous,
as involvement of CNS without alteration of the paranasal
sinuses, endocarditis, and pyelonephritis.
Primary cutaneous commitment varies among edemas,
pustules, plates, bullae, nodules, ulcerations, gangrene-like
ecthyma lesions, necrotizing fasciitis, osteomyelitis, and
dissemination of the infection.39 Cutaneous manifestations
of hematogenic dissemination frequently result in painful
erythematous lesions, cellulite-like, with central necrosis
and eschar, resulting from the angioinvasive action of the
fungus.39
There is a certain correlation between the predisposing
factor and the clinical site or form of the disease, as can be
seen in Table 13.6.
In case of a clinical suspicion, the diagnosis of zygomycosis can be made thru histopathologic examination of
the supposedly committed tissues, in which characteristic broad, hyaline, ribbon-like, wide-angled branching,
pauciseptate irregular fungal hyphae accompanying tissue
necrosis and angioinvasion of the fungi are found. The tissue invasion by hyphae is essential for the diagnosis. The
samples can be stained routinely by H&E, but the fungal
elements are better observed by special stains such as the
GMS, PAS, or calcofluor white stain. Perineural invasion
136 E MERGENCY D ERMATOLOGY
TABLE 13.6: Relationship between Predisposing Condition and Site of Infection
Predisposing condition
Predominant site of infection
(in decreasing order of frequency)
Diabetic ketoacidosis
Iron overload and deferoxamine
Neutropenia
Corticosteroids and immunosuppression
Trauma, catheter/injection sites
Malnourishment
Prolonged broad-spectrum azole use
Rhinocerebral and pulmonary
Disseminated and rhinocerebral
Pulmonary and disseminated
Pulmonary, disseminated, or rhinocerebral
Cutaneous/subcutaneous
GI
Pulmonary, disseminated, GI, or rhinocerebral
GI, gastrointestinal.
Data adapted from (44).
is seen in 90% of tissues containing such elements for sampling. The inflammatory response can be absent, or there
may be neutrophils or granulomas.39
Large hyaline, nonseptated or irregularly septated,
thick-walled hyphae (coenocytic hyphae) can be observed
directly in samples from a bronchoalveolar wash and also
from other materials prepared with potassium hydroxide (Figure 13.15). Direct immunofluorescence can be
employed with samples prepared for maceration by potassium hydroxide and use of calcofluor white, blank fluor, or
UVITEX.
The differentiation between zygomycoses (mucormycosis/entomophthoromycosis) can be made by some
histopathologic peculiarities: broad fungal hyphae with
sparsely found septum surrounded by eosinophilic granular
material (Splendore–Hoeppli phenomenon) and peripheral
eosinophilia, which are not usually seen in Mucorales, favoring the suspicion of Entomophthorales.39
Hemocultures in all forms of zygomycoses are frequently negative, even when fungal hyphae are observed
at histopathologic examination, but it is important that
the physician endeavors to exhaustively try to identify the
FIGURE 13.15: Zygomycosis – direct examination – kenocytic
hyphae in KOH and Parker ink. (Photo courtesy of Mycology Laboratory – HUCFF/UFRJ.)
agent, aiming at better guiding his or her therapy, because
the differentiation of Mucorales/Entomophthorales with
other filamentous fungi at histopathologic examination is
difficult.
Contamination of clinical samples by Zygomycetes is common due to the small size of the sporangiospores, facilitating their airborne dissemination. In any case, isolation of
Mucorales/Entomophthorales from sterile sites or repeatedly
positive nonsterile cultures in patients with significant risk
factors should be considered highly suspect.
Different techniques of molecular serological examinations are appearing, but are not being recommended as
routine procedures because of lack of studies and few satisfactory results.
Despite the growing clinical suspicion of the cases of
zygomycoses, based on the best knowledge of the predisposing factors, more than half of the mucormycosis diagnoses are obtained postmortem.
The treatment of patients with zygomycosis by Mucorales is frustrating; therefore, an early diagnosis should
be the objective in patients with high risk, and treatment should be initiated as soon as possible. A multifactor approach should be initiated as early as possible. They
are appropriate antifungal therapy, surgical debridement,
and correction or resolution of the predisposing factors,
such as control of comorbidities and adjuvant therapies for
improving the host’s immune response.
Despite frequent use of amphotericin B deoxycholate
(1–1.5 mg/kg/d), lipidic amphotericin B formulations represent the first line of treatment because it is potentially the
least toxic and it has better clinical response than do high
doses. Those compounds should be used in initial doses
of 5 mg/kg/d, increasing to significant doses and for an
extended time, not less than 6–8 weeks.44
Among the azolic compounds, itraconazole has action
in some strains of Mucorales; however, it has been implicated as a risk factor for zygomycosis in prolonged use.
Of the second-generation imidazoles, voriconazole is not
effective in vitro. It has also been frequently implicated
in cases of zygomycosis with long-term use after prophylaxis for other systemic fungal infections. Posaconazole and
Chapter 13
ravuconazole have in vitro action against agents of
mucormycosis. There are promising reports regarding the
use of posaconazole as monotherapy or in combination with
lipidic formulations of amphotericin B.44
Caspofungin and micafungin seem to be ineffective as
monotherapy, but present a synergic effect when used with
amphotericin B.44
Zygomycosis (mucormycosis) is rapidly progressive, and
an antifungal therapy alone is inadequate to control the
infection. The numerous agents of zygomycosis have a
wide spectrum of susceptibility to drugs used, and some
can be highly resistant to amphotericin B. Additionally,
thrombosis and tissue necrosis resulting from angioinvasion generate an environment with poor penetration by
systemic agents into the sites affected by the infection.39
Even if the causative agent is susceptible and the drug
does penetrate the affected site appropriately, tissue necrosis is not prevented with the death of the microorganism.39
Surgical debridement is crucial and highly recommended,
and should be initiated quickly and repeated several times,
which may cause deformities.
Correction of the metabolic disturbances and reversal of the immunosuppression are essential for the treatment of zygomycosis. In patients with diabetic ketoacidosis,
the hyperglycemia and the acidosis should be corrected as
soon as possible. Immunosuppressors, especially systemic
steroids, should be discontinued, if possible, or at least have
their doses significantly reduced.
The main role of iron metabolism in the pathogenesis of
zygomycosis suggests the possibility of using iron chelate
as therapeutic adjuvant. In contrast to deferoxamine, other
oral iron chelates did not allow an iron offer to the microorganism and did not favor the growth of the same in vitro.44
Ibrahim and colleagues45 demonstrated the protecting
action of deferasirox in mice.
Despite cytokines not being recommended as routine,
granulocyte-macrophage colony-stimulating factor and
granulocyte colony-stimulating factor as adjuvant therapy
have been considered in cases of conventional therapy
failure.
The use of hyperbaric oxygen therapy finds support in
the hypothesis that the high oxygen pressure might improve
the capacity of the macrophages to fight the infection.44
HISTOPLASMOSIS
Histoplasma capsulatum var. capsulatum infection is a common infection in areas of the United States and Latin America where it is endemic, but some cases have also been
reported from Europe. In the United States, most cases
have occurred within the Ohio and Mississippi River valleys
(moderate climate, humidity, and soil characteristics). Bird
and bat excrement enhances the growth of the organism in
soil by accelerating sporulation. Air currents carry the conidia for miles, exposing individuals who were unaware of
contact with the contaminated site. Histoplasmosis causes
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Life-Threatening Cutaneous Fungal and Parasitic Diseases
137
FIGURE 13.16: Histoplasmosis – lesion on the tongue in a
patient with AIDS.
progressive infection in immunocompromised individuals
and in persons with underlying chronic lung disease. Certain forms of histoplasmosis cause life-threatening illnesses
and result in considerable morbidity, whereas other manifestations cause either no symptoms or minor self-limited
illnesses.46
In some cases of immune depression (Figures 13.16 and
13.17), disseminated histoplasmosis appears in the eyes,
oral cavity, larynx, CNS, GI tract, and, more rarely, the
nasosinusal region.47
Laboratory diagnosis is made by direct examination in
which, with special staining, small round intracellular fungal structures may be observed (Figure 13.18). The small
round forms, similar to Leishmania, can also be seen in
histopathological preparations. At 25◦ C, the colonies have
a cotton aspect and are a white to beige color, whereas at
37◦ C they are leveduriform (Figures 13.19 and 13.20). In
microscopy, hyaline, septated, and branched hyphae; thick
and spiculated walled, round macroconidia; and oval microconidia are observed (Figure 13.21).
The treatment is indicated only in patients with chronic
pulmonary disease and in those with severe forms of acute
pulmonary illnesses or in those with the disseminated form
of infection with mild to moderately severe manifestations.
In patients with AIDS, the treatment may fail because the
absorption is variable, resulting in the inability to achieve
therapeutic concentrations in blood.48,49
PARASITIC DISEASES
American Trypanosomiasis or Chagas Disease
Trypanosomiasis is a tropical and mainly rural parasitic disease of blood and various organs. There are two different
entities: African, caused by trypanosomes of the Trypanosoma brucei group (T. gambiense and T. rhodesiense),
transmitted by tsetse flies, also called sleeping sickness; and
Chagas disease, also known as American trypanosomiasis.50
Chagas disease, described in 1909 by Carlos Chagas, occurs in rural areas, in wattle and daub houses in
138 E MERGENCY D ERMATOLOGY
FIGURE 13.19: Histoplasma capsulatum – culture at 25◦ C.
(Photo courtesy of Mycology Laboratory – HUCFF/UFRJ.)
FIGURE 13.17: Histoplasmosis – disseminated lesions and herpes infection on the left side of the lip in a patient with AIDS.
FIGURE 13.20: Histoplasma capsulatum – culture at 37◦ C.
(Photo courtesy of Mycology Laboratory – HUCFF/UFRJ.)
FIGURE 13.18: Histoplasma capsulatum – direct examination – Giemsa stain. (Photo courtesy of Mycology Laboratory –
HUCFF/UFRJ.)
FIGURE 13.21: Histoplasma capsulatum – culture microscopy.
(Photo courtesy of Mycology Laboratory – HUCFF/UFRJ.)
Chapter 13
FIGURE 13.22: Trypanosoma cruzi. (Photo courtesy of Luis
Rey, MD, Rio de Janeiro, RJ, Brazil.)
tropical zones of the Americas. It is also called Trypanosomiasis americana and is caused by Trypanosoma cruzi, a parasite of humans and domestic or wild animals. The transmission is through a sting by the vector animal, the triatominae
(“barbeiro”). Age, sex, and race do not influence the incidence of the disease, despite the acute phase being more
frequent in children.51
Chagas disease is produced by a hemoflagellated protozoan, Trypanosoma cruzi (Chagas, 1909) (Figure 13.22),
affecting humans and various domestic or wild mammals
that act as reservoirs. It is transmitted by bloodsucking
invertebrates of the order Hemiptera, genera Triatoma,
Panstrongylus, and Rhodnius, called reduviid, assassin, or
kissing bugs and “barbeiro” in Brazil (Figure 13.23).
Transfusional and congenital infections are also possible,
although rare.50
FIGURE 13.23: Chagas disease – reduviid bug. (Photo courtesy
of Luis Rey, MD, Rio de Janeiro, RJ, Brazil.)
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Life-Threatening Cutaneous Fungal and Parasitic Diseases
139
FIGURE 13.24: Chagas disease – Romaña sign. (Photo courtesy of João Dias, MD, and Luis Rey, MD, Rio de Janeiro, RJ,
Brazil.)
Two cycles of circulation of the parasite are known in
nature: the wild and the domestic. The wild cycle occurs
among marsupials, rodents, monkeys, mice, rabbits, and
the triatomid. The domestic cycle results from contamination of animals that live in the vicinity of human dwellings.
The trypomastigote form circulates in the peripheral blood
of vertebrates; undergoes transformation in the organism
of the vector to the epimastigote form; and multiplies,
becoming metacyclic trypomastigotes in the digestive
system of the triatomine.51 The main species of this
arthropod is Triatoma infestans (Argentina, Bolivia, Brazil,
Chile, Paraguay, Peru, and Uruguay), Rhodnius prolixus
(Colombia, Guyana, Venezuela, and Central America),
and Panstrongylus megistus (Brazil). Transmission occurs
through the feces of triatominae, which habitually defecate
while feeding.52–54
Acute Chagas disease is more frequently seen in children
and begins with inflammatory lesions at the inoculation site
of the parasite in the skin or conjunctiva, called Romaña
sign (Figure 13.24). The inoculation chagoma is a macular or papulonodular lesion, erythematous-violet, hard and
painless, that can ulcerate, but tends to regress in 3 weeks.
Other signs of disease are satellite lymphadenitis, fever,
indisposition, cephalea, myalgia, hepatosplenomegaly, and
maculopapular, morbilliform, or urticariform cutaneous
rashes (schizotrypanis).
The following phases may present megaesophagus
megacolon and affection of the heart, with myocarditis,
arrhythmias, and complete blocking.50,53,55
During the acute phase, direct examination of Giemsastained blood smears, imprints of skin, or lymph-node
biopsy can easily show the parasite.50 The search for
anti-T. cruzi immunoglobulin M antibodies by indirect
immunofluorescence and PCR and (in the chronic phase)
140 E MERGENCY D ERMATOLOGY
serological tests with indirect hemagglutination, indirect
immunofluorescence, and ELISA are useful.56 They can
also be demonstrated by blood culture in NNN medium
or by animal inoculation.50
Xenodiagnosis of Brumpt is also helpful. For this an
uninfected reduviid bug is allowed to bite and feed on
the forearm of the suspect patient; 30–60 days later, the
insect’s feces are examined for the infective form. During
the chronic phase, the Machado–Guerreiro complement
fixation test using antigens of cultured T. cruzi is most
useful. ELISA, hemagglutination, indirect immunofluorescence, and PCR can also diagnose the disease.50
The therapeutics are unsatisfactory, and treatment does
not change the serological reactions or degradation of
cardiac function in chronic phases, despite possibly curing the patient in the acute phase. The two main drugs,
benznidazole and nifurtimox, are active against circulating and tissue forms and should be administered for 30–
90 days.51,55,57
For patients with stable chronic disease, the treatment
includes antiarrhythmics and control of the affected systems. Prevention of the disease requires sanitary education
and use of insecticides.51,57
Schistosomiasis
Schistosomiasis is one of the most important helminthic
infections because of its wide geographical distribution and
extensive pathological effect. It is a systemic disease, and its
causative agents are human trematodes or flukes. These
trematodes affect approximately 200 million people worldwide, mainly in the tropical and subtropical latitudes; sometimes entire communities are affected. Most infected persons experience few, if any, signs and symptoms, and only
a small minority develop significant disease.58,59
Schistosomiasis or bilharziasis is an infection caused by
five types of blood flukes of the genus Schistosoma. Humans
are infected by the cercarial stage of the parasites released
from freshwater snails in ponds, canals, lake edges, and
streams. Penetration of intact skin occurs rapidly, and the
schistosomes migrate into the portal system to mate and
then to a part of the venous system to lay eggs. High infection rates persist among both the rural and urban poor.
Rural living, poor housing and water supplies, and low educational level are major factors in schistosomiasis occurrence among agricultural populations.60
In Brazilian urban areas, prevailing living conditions in
shantytowns and labor migrations from and periodic return
movements to rural areas were predictive of schistosomiasis. The risk of the establishment of new transmission foci
exists in both rural and urban areas, conferred by and affecting poorer people.61–63
In sub-Saharan Africa there is high prevalence of
parasitic worm infections, such as schistosomiasis. The
hypothesis of whether a helminth infection increases the
susceptibility of the host to acquire de novo infection with
FIGURE 13.25: Schistosomiasis – vulval granuloma. Reproduced from Parish et al. (2001).60
an immunodeficiency virus after mucosal exposure, which
is the predominant route of HIV transmission in humans,
has been tested by Chenine and colleagues.64 They quantified the amount of a clade C simian–human immunodeficiency virus needed to infect rhesus macaques that had
acute Schistosoma mansoni infections compared with control
animals exposed to virus alone. The schistosome-infected
monkeys also had significantly higher levels of initial virus
replication and loss of a certain subset of memory T cells,
both predictors of a more rapid progression to immune
dysfunction. Research suggested that worm infections may
increase the risk of individuals with viral exposures becoming infected with HIV-1 and also suggested that control
programs for schistosomiasis and perhaps other parasitic
worm infections may also be useful in helping to reduce
the spread of HIV/AIDS in developing countries where
helminths are endemic.
Contrary to previous reports that indicated no transmission of schistosomiasis at altitudes higher than >1400 m,
John and colleagues65 found that schistosomiasis transmission can take place at an altitude range of 1487–1682 m
above sea level in western Uganda.
Eggs laid in bladder and pelvic and rectal venous plexuses
return to the local water supply to complete the cycle
through the snail population. Cercarial penetration of the
skin may produce an itch eruption, which may be followed
by myalgia, headache, and abdominal pain.
Abdominal pain, diarrhea, malabsorption, and (occasionally) intestinal obstruction and rectal prolapse; cirrhosis of the liver associated with portal hypertension,
splenomegaly, and esophageal varices; recurrent hematuria
and eventually bladder calcification; and obstructive uropathy and renal failure are late manifestations of the disease.
Periovular or schistosomotic granuloma may rarely occur
on the skin or vulva (Figure 13.25). Migration of eggs to
the lungs may cause massive chronic fibrosis.
Detection of the characteristic ova in the stools, in urine,
or on biopsy (Figure 13.26) or with an ELISA make the
Chapter 13
FIGURE 13.26: Schistosomiasis – biopsy of vulval granuloma
showing egg and inflammatory infiltrate. Reproduced from
Parish et al. (2001).60
diagnosis. Treatment of patients is made with praziquantel
given as a single dose.61–63
Amebiasis
Amebiasis is an intestinal parasitic disease that may sometimes affect the skin, especially perianal and genital. It is
caused by a common and worldwide intestinal unicellular
parasite, Entamoeba histolytica, the only human pathogenic
species of this genus. The invasive form found in the tissues is a 20- to 40-µm elongated cell, with pseudopods on
its surface.50,66
E. histolytica is the pathogenic ameba that can cause invasive intestinal and extraintestinal disease. The most frequent manifestations of invasive amebiasis are colitis and
liver abscesses. E. histolytica invades the colonic mucosa,
and the patient suffers from bloody diarrhea. It is one of
the most common parasitic infections worldwide, and the
possibility of amebiasis must always be considered in a
patient who complains of bloody diarrhea and has recently
returned from a developing country. In industrialized
counties where the E. histolytica endemicity is generally low,
invasive disease may occur in men who have sex with men.67
In tissues, the trophozoites – with a basophilic and
elongated cytoplasm, single eccentric nucleus, and central
spherical karyosome – are difficult to observe. In cutaneous
and mucosal lesions, they are more easily seen in biopsies
of the borders rather than the center of the ulcer.50
E. histolytica is a pathogenic ameba that recent studies
indicate is an increased risk for invasive amebiasis among
persons with HIV.68 The infestation by this species is a public health concern because it has the potential to become
endemic and to cause severe disease, such as acute dysenteric symptoms (malaise, fever, abdominal pain, and frequent loose stools containing blood and mucus); granulomatous masses in the bowel wall (amoeboma); liver abscess;
and pleura, lung, and pericardium involvement.56
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Life-Threatening Cutaneous Fungal and Parasitic Diseases
141
Vegetative forms of amebae should be sought in fresh
stools or in scrapings from bowel ulcers at sigmoidoscopy.
Ultrasound, computed tomography, or aspiration diagnoses suspected liver abscess. The effective treatment is
made with metronidazole.56
Patients can be rapidly cured in 7–20 days with metronidazole, 20–40 mg/kg/day, divided in three daily doses, for
up to 8 days. Tinidazole, in a single daily dosage, 2 g for
adults and 50–60 mg/kg for children, for 3–5 days, also
shows good and fast results. IV or intramuscular dehydroemetine hydrochloride, the drug of choice in the past, is
cardiotoxic. Diiodohydroxyquinoline, paromomycin, and
diloxanide furoate can also be used. Severe dysentery associated with mucosal or cutaneous involvement requires support measures.50,66
Mucocutaneous Leishmaniasis
Leishmaniasis is an anthropozoonosis of worldwide distribution, being considered a public health problem in
88 countries, distributed in four continents, in the Americas, Europe, Africa, and Asia. On the American continent
there are records of cases from the extreme southern part of
the United States to north of Argentina, with the exception
of Chile and Uruguay.20,56,57,66,69
Leishmania belongs to the Trypanosomatidae family of
protozoa. It is a mandatory intracellular parasite of the
mononuclear phagocyte system, with two main forms: a
flagellated or promastigote, observed in the digestive tube
of the vector insect, and another aflagellated or amastigote, found in the tissues of vertebrate hosts. Currently in
the Americas, there are 11 known dermotropic species of
Leishmania causative of disease in humans and eight species
described only in animals, all belonging to the subgenera
Viannia and Leishmania. The three main species are: L.(V.)
braziliensis, L.(V.) guyanensis, and L.(L.) amazonensis.57,69
The vectors are insects called Phlebotominae, belonging to the order Diptera, family Psychodidae, subfamily Phlebotominae, genus Lutzomyia, also known popularly as sandflies, and, depending on the geographical location in Brazil,
as mosquito palha, tatuquira, and birigui, among others. The
reservoirs can be forest animals (such as rodents and marsupials), synanthropic and domestic (canidae, felidae, and
equidae, considered accidental hosts of the disease).57
The transmission occurs through a sting by the infected
transmitter insects without distinction regarding sex, race,
or age, without person-to-person transmission. The majority of cases occur in men between 20 and 40 years old.
The disease incubation period in humans may vary from
2 weeks to 2 years, with an average of 2–3 months.57,66
Epidemiological analyses have suggested changes in the
transmission pattern of the disease passing from a sylvestral animal zoonosis to a disease of rural zones, in practically
barren and periurban areas. There are three epidemiological profiles: sylvestral, in which the transmission occurs in
areas of primary vegetation (zoonosis of sylvestral animals);
142 E MERGENCY D ERMATOLOGY
occupational, associated with irregular forest exploration
and forest slashing (anthropozoonosis); and rural or periurban, in areas around cities or colonized regions, where the
vector undergoes an adaptation to the peridomicile (zoonosis of residual woods and/or anthropozoonosis).57
The transmission cycles differ according to the geographic variations, involving several types of parasites, vectors, reservoirs, and hosts. L. (L.) amazonensis is present
in primary and secondary forests of the “Legal Amazonia”
(Amazonas, Pará, Rondônia, Tocantins, and Maranhão),
and also in the states of the Northeast Region (Bahia),
Southwest (Minas Gerais and São Paulo), Midwest (Goiás),
and South (Paraná) of Brazil. It causes localized cutaneous
ulcers and, occasionally, some individuals can develop a
classical diffuse cutaneous leishmaniasis. L. (V.) guyanensis is
found in onshore forests and is apparently restricted to the
North Region of Brazil (Acre, Amapá, Roraima, Amazonas,
and Pará) and Guyana, Suriname, and French Guiana. It
causes single or multiple cutaneous ulcers, with the latter resulting from simultaneous stings of several infected
phlebotoma or secondary lymphatic metastases. Mucous
involvement is rare. In endemic areas, besides young males,
a great number of children can be affected. L. (V.) braziliensis is a widespread species, occurring from Central America
and all over Brazil to the North of Argentina. In the areas
of modified environments, transmission occurs in the surroundings of the dwellings, affecting individuals of both
genders and all age groups, with a tendency to concentrate the cases in a single focus. The lesions that are characterized by cutaneous ulcer (single or multiple) or the
main complication, which is the hematogenic metastasis
to the mucous membranes of the nasopharynx, with tissue
destruction, can occur in the eyelids or in areas usually covered by clothes, suggesting that the transmission with great
frequency occurs inside human dwellings.57,69
When introduced into the skin, promastigotes meet
the immune system cells, as T and B lymphocytes,
macrophages, Langerhans cells, and mastocytes. Through
a not entirely clarified mechanism, the parasite adheres
to the surface of the macrophages and Langerhans cells,
passing into the intracellular media and changing into the
amastigote form, characteristic of parasitism in mammals.
The leishmania develop defense mechanisms capable of
subverting the microbicidal capacity of the macrophages,
surviving and multiplying until cell rupture occurs, when
they are freed to infect other macrophages and propagate the infection. The location of the amastigote in the
interior of macrophages makes the control of the infection become dependent on the immune response mediated
by the cells. The main effecting cell is the macrophage
itself, after its activation by T-helper lymphocyte cells.
Even with the diversity of Leishmania species, the spectrum of clinical manifestations of the disease depends not
only on the species involved, but also on the infected individual’s immunologic state. With cutaneous leishmaniasis, the cutaneous test with leishmanin, the intradermal
FIGURE 13.27: Leishmaniasis – ulcer on the side of the neck
with a visible lymph-node enlargement.
reaction of Montenegro (IDRM), and other in vitro tests
are positive. Cutaneous leishmaniasis can be caused by all
dermotropic species of Leishmania. There are clinical differences, however, such as those observed in lesions caused
by L. (L.) amazonensis that present more infiltrated borders,
with great amounts of parasites, whereas in those caused by
the subgenus Viannia, few macrophages and parasites are
present.57,66,69
An infection is called unapparent when characterized by
positive serological and IDRM tests in apparently healthy
individuals, living in areas of mucocutaneous leishmaniasis
without previous clinical history. Lymph-node leishmaniasis is characterized by localized lymph adenopathy without
tegumentary lesion. Cutaneous leishmaniasis presents as a
rounded or oval painless ulcer, of few or several millimeters,
located in exposed sites of the skin, with an erythematous
and infiltrated base, with well-delimited and raised borders, reddish background, and coarse granulations (Figure 13.27). Vegetating lesions also occur, either papillomatous or verrucous, as well as lesions with associated
bacterial infection (Figure 13.28). The lesions tend to cure
spontaneously with atrophic, depressed scars, with hypoor hyperpigmentation and fibrosis in variable periods, but
Chapter 13
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Life-Threatening Cutaneous Fungal and Parasitic Diseases
143
FIGURE 13.28: Leishmaniasis – vegetating lesion on the lip.
Reproduced from Ramos-e-Silva et al. (2002).69
FIGURE 13.29: Leishmaniasis – amastigote inside a macrophage.
may remain active for several years and coexist with later
emergence of mucous lesions. The disseminated mucocutaneous leishmaniasis form is relatively rare, being observed
in up to 2% of the cases. The two species recognized as
causes of this syndrome are L. (V.) braziliensis and L. (L.)
amazonensis. There is emergence of multiple papular lesions
with an acneiform aspect, on several segments of the body,
mainly in face and trunk, followed by hematic or lymphatic
dissemination of the parasite, sometimes within 24 hours,
causing distant lesions from the site of the sting. Concurrent mucous affection has been observed in up to 30% of
the patients, and systemic manifestations can also appear,
as fever, general indisposition, muscle pains, weight loss,
and anorexia, among others. Finding the parasite in the
disseminated form is uncommon when compared to the
diffuse form. The titers of serous anti-Leishmania antibodies are high, and the response to the IDRM is variable. In individuals co-infected by HIV, ulcerated lesions
prevail. The diffuse cutaneous form is severe, albeit rare,
and occurs in patients with lack of energy and specific deficiency in the cellular immune response to Leishmania antigens. In Brazil, it is caused by L. (L.) amazonensis. The
response to the therapeutics is poor or absent, and IDRM
is usually negative. It is estimated that 3%–5% of cutaneous cases develop a painless mucous lesion, destructive
of the upper respiratory tract due to hematic or lymphatic
dissemination. Patients with multiple cutaneous, extensive
lesions with more than 1 year of evolution and located
above the waist are the group with greater risk of developing metastases in the mucous membrane. The etiologic
agent causative of mucosal lesions, in Brazil, is mainly L.
(V.) braziliensis. IDRM is strongly positive; however, it has
difficult parasitological confirmation due to the scarceness
of parasites, presents difficult therapeutic response, has a
higher complication frequency, is mainly infectious, and
may result in death in 1% of the cases.66
The clinical–epidemilogical diagnosis is complemented
by positive IDRM. Direct demonstration of the parasite
is the procedure of first choice because it is faster, less
expensive, and easy to execute (Figure 13.29). The probability of finding the parasite is inversely proportional to the
time of evolution of the cutaneous lesion, being rare after
a year. The isolation in cultivation in vitro is a method
that allows the subsequent identification of the species
of Leishmania involved. The intradermal test, IDRM, or
leishmanin test is based in the response of retarded cellular hypersensibility. Patients with mucous disease usually
present an exacerbated IDRM, with several centimeters of
hardening, vesiculation in the center of the reaction, possibly with ulceration and local necrosis. In diffuse cutaneous
forms, IDRMs are usually negative. Other methods, such
as detection of circulating antibodies and PCR, can also be
used.56,69
The drugs of first choice in the treatment of leishmaniasis are the pentavalent antimonials, considered as leishmanicide drugs, because they interfere in the bioenergetic
processes of the amastigote forms of Leishmania. In the
case of unsatisfactory response with pentavalent antimonials, the second choice of drugs are amphotericin B and
pentamidines. The cure criterion is clinical, being recommended a regular follow-up for 12 months. Cure is defined
by epithelization of the ulcerated lesions and total regression of the infiltration and erythema, up to 3 months after
the end of treatment. Recurrence is defined as reappearance of the lesion in any part of the body in the period of
up to 1 year after clinical cure, discarding the possibility
of reinfection. The prophylactic measures are use of insect
repellents; use of fine-mesh mosquito nets, as well as the
screening of doors and windows; and environmental handling through cleaning of backyards and land areas.56,57,66
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20:122–34.
CHAPTER 14
Life-Threatening Stings, Bites,
and Marine Envenomations
Dirk M. Elston
BITES AND STINGS
Major causes of death related to arthropod bites and stings
include anaphylaxis, reactions to venom, and vector-borne
disease. This chapter addresses each of these causes.
ANAPHYLAXIS
Background
Anaphylaxis related to insect stings is estimated to occur in
3 of every 100 adults.
Clinical and Laboratory
Skin tests can be used to verify a history of sting allergy.
Radioallergosorbent testing (RAST) is less sensitive, but
does not carry a risk of anaphylaxis during the testing. It is
important to note that neither the size of a skin test reaction
nor the RAST level is a reliable predictor of the severity
of subsequent sting reactions.1 In vitro methods of testing also include western blot and in vitro basophil activation tests that measure histamine and sulphidoleukotrien
released (Cellular Antigen Stimulation Test [CAST]) or
activation markers on the cell surface detected by means of
flow cytometric analysis (Flow CAST).2 Basophil activation
tests using either CD63 or CD203c show promise in the in
vitro diagnosis of patients with bee or wasp venom allergy.3
Patients with mastocytosis who develop severe hypotension after wasp or bee stings typically do not demonstrate
specific immunoglobulin E (IgE). Similar patients have
been described with no skin lesions to suggest mastocytosis. In some patients, serum tryptase elevations suggest subclinical mastocytosis, and bone-marrow biopsy may reveal
systemic mastocytosis.4
Cardiac medications such as beta-blockers and
angiotensin-converting enzyme inhibitors may increase
the severity of anaphylactic reactions, placing the patient
at greater risk for a bad outcome.5 In contrast, previous
large local reactions to insect stings does not increase the
risk of subsequent anaphylaxis.6 In a study of 115 patients
with a history of an anaphylactic reaction to a wasp sting
and specific IgE to Vespula and/or Polistes, the mean age
was higher in patients with no cutaneous symptoms and
cardiovascular involvement was more frequent in males,
but the clinical pattern was not predicted by a history of
atopy.7 Vespids remain the major cause of insect-related
anaphylaxis. In a retrospective review of 98 adult patients
with anaphylactic reactions to vespids, 18 patients (18%)
suffered a reaction to wasp venom while at work. The
rest of the reactions occurred during leisure time. Most
(94%) of the patients with work-related anaphylaxis had a
personal history of atopy, whereas only 22% of those with
sting-induced anaphylaxis outside of the workplace had an
atopic diathesis. Previous systemic reactions had occurred
in 17% of the patients. Gardening was the occupation
most closely associated with a risk of vespid-induced
anaphylaxis. Vespula IgE was detected in all patients, and
Polistes IgE was detected in 78%.8
Among patients with bumblebee allergy, two groups
have been identified, patients with IgE that is highly crossreactive with honeybee venom and patients, frequently
stung only by bumblebees, who require immunotherapy
with purified bumblebee venom.9
Children with insect-induced anaphylaxis have a higher
incidence of honeybee allergy than adults have, but severe
systemic reactions are less common than in adults. Those
patients with moderate to severe systemic reactions have a
30% chance of a similar reaction years later. Fortunately,
the long-term immune tolerance induced by immunotherapy is greater in children than adults.10
Membranous winged insects other than wasps and
bees can also cause anaphylaxis – most notably, the fire
ants Solenopsis invicta and Solenopsis richteri. A diverse
array of other ant species belonging to six different subfamilies (Formicinae, Myrmeciinae, Ponerinae, Ectatomminae, Myrmicinae, and Pseudomyrmecinae) have also
been associated with anaphylactic reactions.11 Although
hymenopterids remain the major cause of arthropodinduced anaphylaxis, other arthropods, such as the European pigeon tick (Argas reflexus) have also been implicated.
This tick has demonstrated the potential for both IgEmediated sensitizations and anaphylactic reactions.12
page 146
Chapter 14
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Life-Threatening Stings, Bites, and Marine Envenomations
147
Therapy
Although intramuscular injections of epinephrine remain
the standard type of epinephrine therapy for vespid-related
anaphylaxis, rapidly disintegrating sublingual epinephrine
tablets show promise for oral treatment of anaphylaxis.13 Biphasic reactions are common, and patients need
extended observation after their initial response to therapy.14 Desensitization improves quality of life and is preferred by patients.15 All patients with sting-related anaphylaxis should be referred to an allergist to discuss
the option of desensitization. Venom immunotherapy is
thought to be 75%–98% effective in preventing future
episodes of anaphylaxis. Rush regimens of hymenoptera
venom immunotherapy have been shown to be safe and
effective.16
Course and Prognosis
Risk factors for fatal anaphylactic reactions include preexisting cardiovascular disease and a high mast-cell load as
evidenced by clinical evidence of mastocytosis or an elevated baseline serum tryptase level.17 Patients with vespid
allergy who also have mastocytosis are at greater risk for
life-threatening sting reactions, but most tolerate venom
immunotherapy well with few systemic symptoms.18
REACTIONS TO VENOM
Background
A wide variety of reactions to arthropods relate directly
to the venom. Manifestations vary from disseminated
intravascular coagulation (DIC) to rhabdomyolysis.
Clinical and Laboratory
Rhabdomyolysis with acute renal failure has been described
after fire ant bites.19 Life-threatening facial edema has been
reported after exposure to pine caterpillars.20 Neurologic
symptoms are common after centipede bites, but are usually self-limited. Acute myocardial infarction in a previously healthy young man has been reported after a centipede bite.21
Death from scorpion envenomation relates to the
potency of the toxin, the age of the patient, and preexisting conditions such as heart disease. In some studies,
all fatalities involved children younger than 10 years.22 In
Bangkok, a strip of Teflon tape is wrapped around each piling supporting a house to prevent scorpions from climbing
the pilings and entering the house. It has reduced infant
mortality related to scorpionism.
Tityus zulianus is a major cause of scorpionism in Latin
America. Mesobuthus tamulus (the Indian red scorpion) is
often associated with fatal envenomation. The toxin produces an autonomic storm and has been associated with
FIGURE 14.1: Brown recluse spider.
bilateral cerebellar infarction.23 Prazosin reverses the autonomic storm characteristic of Indian red scorpion envenomation and is superior to antivenin.24
Brown spiders of the genus Loxosceles include Loxosceles reclusa, the brown recluse spider (Figure 14.1). All spiders in this genus are capable of producing dermonecrotic
reactions and may also produce DIC. A generalized vasculitic exanthem has also been described following Loxosceles reclusa envenomation.25
Brown recluse spiders have three sets of eyes (rather than
the usual four) and a characteristic violin-shaped marking
on the dorsum of the cephalothorax. Sphingomyelinase D
is the primary dermonecrotic factor. The toxin depletes
clotting factors VIII, IX, XI, and XII and prolongs the
activated partial thromboplastin time in a dose-dependent
manner.26 The venom induces rapid coagulation and occlusion of small capillaries, causing subsequent tissue necrosis. Enzyme-linked immunosorbent assay methods can be
used for the diagnosis of loxoscelism with noninvasive tissue
sampling.27 Both tissue swabbing and hair pluck techniques
have been used.
Immunologic studies have demonstrated crossreactivity between L. boneti and L. reclusa venoms, and
between anti-L. gaucho and anti-L. laeta venoms. In contrast, the venom of the South American L. laeta shows little
cross-reactivity with North American Loxosceles antivenoms. The lack of cross reaction limits the worldwide
distribution of spider antivenin.28
Widow spiders are widely distributed throughout the
world. Genetically, widow spiders can be divided into two
large groups. The geometricus clade includes Latrodectus
rhodesiensis from Africa, and the more widespread L. geometricus. The mactans clade contains all other Latrodectus
species in Africa, the Middle East, the Iberian Peninsula,
Australia, New Zealand, and North and South America.29
The venom of black widow spiders (Figure 14.2) is
more toxic than that of brown widow spiders, and black
widow spiders are found throughout the continental United
148 E MERGENCY D ERMATOLOGY
FIGURE 14.2: Black widow spider.
States and southern Canada. The venom contains latrotoxins that act by depolarizing neurons, resulting in increasing intracellular calcium and release of neurotransmitters.
Female black widow spiders can be as much as 20 times
larger than the males and have much more potent venom.
The female can be identified by the red hourglass pattern
on the ventral aspect of her large, shiny, roughly spherical abdomen. Alpha-latrotoxin induces release of acetylcholine, norepinephrine, dopamine, and enkephalin. The
result is abdominal rigidity that may mimic an acute surgical abdomen.
Widow spiders are named for their cannibalistic behavior. The female mates, then kills. Some female spiders do
not even wait until mating is complete before taking the
first bite from their mates. Some male Latrodectus spiders
have developed strategies to prolong their survival long
enough to maximize their chance of passing on their genes.
Female redback spiders (Latrodectus hasselti) have paired
sperm-storage organs that are inseminated during two separate copulations. If a male can survive to copulate twice, he
ensures the transmission of his genes. Males have developed
a reflexive abdominal constriction during courtship that
increases their chance of survival from cannibalistic injury
inflicted during the first copulation.30 It is hardly romantic, but effective nonetheless. In a study of redback spider
envenomation, the median duration of symptoms was 48
hours, with severe pain lasting more than 24 hours occurring in more than half of the patients. Systemic signs and
symptoms occurred in more than one third of the patients.
Local diaphoresis and pain are characteristic features. The
Australian funnel web spider (Atrax and Hadronyche spp.)
pose a significant risk in Australia. They are not related
to the funnel web spiders (Tegenaria agrestis) of the Pacific
Northwest. In a prospective Australian study of 750 spider
bites with expert identification of the spider, clinically significant effects occurred in 44 bites (6%), including 37 of 56
redback spider bites. The major symptom was pain lasting
more than 24 hours. One severe neurotoxic envenomation
by an Australian funnel web spider required antivenin therapy.31 Brazilian Phoneutria “armed spiders” have a limited
range, but are an important cause of life-threatening bites
in Brazil. Antivenins are available for both the neurotoxic
Australian funnel web spider and the Brazilian armed spider, but relatively few data exist regarding efficacy.
Lonomia caterpillars in South America cause a hemorrhagic diathesis. No antivenin exists. Tick paralysis in
North America is typically associated with Dermacentor
ticks. Tick paralysis typically occurs in children who present
with rapidly progressive ascending paralysis. Symptoms
resolve rapidly when the tick is removed, but Dermacentor
ticks (Figure 14.3) tend to attach to the scalp where they
are hidden by the hair. As a result, tick paralysis carries a
death rate of approximately 10%. Ixodes tick paralysis is a
common cause of death in Australian dogs, but is less likely
to affect humans.
Therapy
Although in vitro data and rabbit studies suggest that dapsone and tetracyclines32 could be of benefit in the treatment
of brown recluse spider bites, a “real life” delay in the onset
of therapy negates any beneficial effect of dapsone therapy.
In a rabbit model, the only therapy that showed a trend
toward less thrombosis was intralesional triamcinolone.33
The primary treatment for black widow spider envenomation is the administration of antivenin, although antispasmodics such as valium and calcium gluconate play some
role. The antivenin is horse serum, and serum sickness can
result from subsequent use.
Redback spider antivenin is effective at controlling local
symptoms, but did not demonstrate a conclusive effect
against systemic toxicity.34 It should be noted that redback
antivenin is routinely given intramuscularly, which may not
be as effective as the intravenous route.35
FIGURE 14.3: Male (left) and female (right) Dermacentor andersoni.
Chapter 14
FIGURE 14.4: Erythema migrans of Lyme disease.
VECTOR-BORNE DISEASE
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Life-Threatening Stings, Bites, and Marine Envenomations
149
lifestyle common to subtropical areas of the developed
world. An outbreak of dengue along the United States–
Mexican border demonstrated this effect. Disease transmission was greater on the Mexican side of the border, even
though the vector was more abundant on the U.S. (Texas)
side.36
Whereas mosquito-borne illness predominates in much
of the world, tick-borne illness is more common in North
America, Northern Europe, and even parts of Africa.
Amblyomma ticks carry Ehrlichia chaffeensis, the agent of
human monocytic ehrlichiosis, as well as RMSF and southern tick–associated rash illness (southern Lyme disease),
as well as African tick bite fever. Dermacentor variabilis is
the major North American vector for RMSF. Dermacentor andersoni also carries RMSF and serves as a vector for
Colorado tick fever, Q fever, and tularemia. RMSF carries a high mortality rate if antibiotic therapy is delayed.
In endemic areas, it is best to “treat now and ask questions
later” for any patient with fever and a headache, regardless
of a history of tick bite. Spotless fever is particularly prone
to misdiagnosis, and treatment should never be delayed
because of the absence of dermatitis.
Rhipicephalus ticks are common brown dog ticks in both
North America and Europe. They are important vectors
for RMSF as well as canine ehrlichiosis, Boutonneuse fever,
babesiosis, and Congo–Crimean hemorrhagic fever virus.
Ixodes ticks carry Lyme disease, babesiosis, anaplasmosis
(human granulocytic ehrlichiosis), and viral encephalitis.
Trombiculid mites are important vectors of scrub
typhus in East Asia, and rickettsial pox is transmitted by
Liponyssoides sanguineus (the house mouse mite). Body lice
are important vectors for Bartonella endocarditis among
homeless persons in urban areas.37–39 Fleas are important vectors of plague, bacillary angiomatosis, and endemic
typhus.
Background
Arthropod-borne diseases remain a serious threat throughout most of the world. Malaria remains the single most
important vector-borne disease and kills thousands every
year. Other important vector-borne diseases worldwide
include viral encephalitis, viral hemorrhagic fevers, African
and New World types of trypanosomiasis, and leishmaniasis. In the United States, mosquitoes are more likely to carry
West Nile virus, St. Louis encephalitis, equine encephalitis,
or dengue. North American ticks are important vectors of
Lyme disease (Figure 14.4), Rocky Mountain spotted fever
(RMSF), ehrlichiosis, Colorado tick fever, relapsing fever,
tularemia, and babesiosis.
Clinical and Laboratory
Persons in the developing world are at particular risk for
transmission of arthropod-borne diseases, partly because of
sophisticated vector-control programs in developed countries and partly because of the indoor, air-conditioned
Therapy
Most tick-borne diseases respond readily to tetracycline,
with viral fevers and babesiosis being notable exceptions.
Antibiotic prophylaxis after tick bites is controversial.
Although it is not indicated after most tick attachments, an
argument can be made for prophylaxis in highly endemic
areas with ticks that are heavily engorged, evidence that
they have been attached long enough to transmit disease.
Primary prevention of vector-borne disease requires a
multifaceted approach including infrastructure measure for
control of important vectors, use of screens and mosquito
netting, and personal protection with repellents. Prompt
tick removal also plays an important role in disease prevention. Secondary prevention of disease and morbidity
can be accomplished with malaria chemoprophylaxis, prophylactic antibiotics after a tick bite, or early treatment of
illness. Although malaria chemoprophylaxis may be reasonable for visitors to an area, it is not feasible for the
150 E MERGENCY D ERMATOLOGY
entire indigenous population. Malaria-carrying anopheline
mosquitoes feed mostly at night, emphasizing the importance of screens and mosquito netting. Screening can be
impregnated with pyrethroids to improve their effectiveness. Because the mosquitoes that carry dengue typically
bite during the day, vector control, repellents, and protective clothing play important roles in disease prevention.40,41
Infrastructure changes to control mosquito vectors
include draining stagnant water, stocking water with fish
or turtles to eat larvae, spraying with insecticide, and using
gas or electric mosquito traps. Most mosquito traps generate carbon dioxide. Although some use chemical attractants such as octenol and butanone in areas with Aedes
mosquitoes, it should be noted that some Culex mosquitoes
are repelled by octenol.42–44
N,N-diethyl-3-methylbenzamide (DEET) remains the
most commonly used repellent, although picaridin is gaining market share. Although DEET has a long safety record,
rare cases of bullous dermatitis, anaphylaxis, and toxic
encephalopathy have been reported.45–48 For children,
the American Academy of Pediatrics recommends slowrelease products that require less frequent application. The
Academy notes that such products plateau in efficacy at
concentrations of 30% and that there is no published evidence to support the use of higher concentrations in children. It should be noted that many extended duration products formulated for children have concentrations of 10% or
less and that these appear to be perfectly adequate in most
instances.
Wherease DEET products can generally be applied to
both exposed skin and clothing, permethrin products are to
be applied to fabric. The combination of DEET repellent
and permethrin-treated clothing is effective against a wide
range of biting arthropods.49,50
Picaridin has been used in Europe and Australia and is
now available in North America. In tests, it has shown good
efficacy against a range of mosquitoes. A soybean oil–based
product (marketed as Bite Blocker for Kids in the United
States) shows reasonable efficacy against some mosquitoes
and may be a good choice for persons who wish to avoid
chemical repellents. Neem oil products perform reasonably
well against various mosquitoes, whereas citronella has limited efficacy.51,52
Permethrin-treated clothing offers significant protection against ticks and chiggers, with good substantivity
through a number of wash cycles.53–55 In southwest Asia
and North Africa, some ticks are attracted by permethrin,
but this has not been reported in other areas.56
Deer fencing, border beds, insecticidal sprays, and even
fire ants help keep residential and recreational areas free of
ticks.57,58 Area sprays of insecticides are more effective if
leaf debris is removed. Removal of leaf debris also reduces
tick numbers by means of dehydration.59,60 Various other
methods have been employed, including deer-feeding stations outfitted to deliver topical acaricides to the deer. This
approach is more cost effective than adding a systemic acaricide to the deer corn.61–63
MARINE ENVENOMATIONS
Background
Marine animals contain some of the most potent toxins
known. Most minor envenomations result in severe pain.
As the toxins tend to be heat labile, immersion in hot, but
not scalding, water is the preferred form of therapy. This
section focuses on the more severe life-threatening envenomations.
Clinical Features
Chironex fleckeri, the Pacific box jellyfish or sea wasp, is
responsible for many deaths as a result of shock and drowning. Confirmation of envenomation can be made by identification of the jelly or by means of tape stripping nematocysts from the skin.64 Other jellies cause painful eruptions
but are much less likely to result in serious reactions. Important jellies around the world include Physalia physalis (the
Portuguese Man o’ War, endemic to the southern waters
of the Atlantic), Physalia utriculus (the Pacific bluebottle jellyfish), as well as Cyanea and Chrysaora sea nettles. These
may cause severe allergic reactions in some individuals, but
generally lack the severe toxicity associated with Chironex
fleckeri. All jellyfish produce serpiginous patterns of stings
that follow the course of the tentacles attached to skin.
Sponge dermatitis is related to calcium and silica spicules
that become embedded in the skin and is rarely life threatening. In contrast, sponge diver’s disease is not caused by
the sponge at all, but rather by sea anemones attached to
the base of the sponge. In addition to local symptoms similar to jellyfish stings, systemic symptoms may occur, such
as nausea, vomiting, and headache. More severe reactions
are possible in predisposed individuals.
Life-threatening envenomation by mollusks may occur
with the blue-ringed octopus and with some cone shells.
The blue-ringed octopus is a small cephalopod (about
10 cm long) found in waters off the coast of Australia. The
distinctive blue rings may cause some foolish divers to get
too close to the mollusk, but most envenomations occur
completely by accident. Cone shells are marine gastropods
with pretty shells and highly potent venom. The mortality rate from cone shell envenomation may approach 20%.
The shells are approximately 10 cm in length and tend to be
found in shallow water, mostly in tropical and subtropical
waters.
Death has been reported after penetrating chest injury
from stingrays. The death may occur as a direct result of the
injury or by means of venom-induced myocardial necrosis.65 Envenomation by stonefish and lionfish is becoming
more common as these fish move from tropical waters to
Chapter 14
a much more cosmopolitan distribution. Stings commonly
result in pain, erythema, bulla formation, and tissue necrosis. Systemic symptoms may be life threatening, but death
is more likely a result of drowning related to disorientation
following the sting. Catfish spine injuries may be associated
with local pain, severe bleeding, and systemic symptoms,
but are rarely fatal.
Treatment
As with other bites and stings, knowledge and avoidance
are the best means of preventing injury. Drowning is the
most common cause of death from marine envenomation,
and the swimmer should be removed from the water immediately. Supportive treatment for shock may be necessary
in severe envenomations. Initial treatment for most marine
envenomations includes soaking the site in hot, but not
scalding, water to denature as much of the venom as possible. Sea wasp antivenin is available, but data on other systemic agents (such as calcium channel blockers) are mixed.
Physicians in coastal areas should consult current recommendations for treatment of local venomous species.
Course and Prognosis
The prognosis depends on the potency of the toxicity,
comorbidities such as cardiac disease or hypertension, and
prompt removal from the water to prevent drowning.
ACKNOWLEDGMENTS
Images were produced while the author was a full-time
federal employee. They are in the public domain.
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Chapter 14
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153
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CHAPTER 15
Severe, Acute Adverse Cutaneous Drug
Reactions I: Stevens–Johnson Syndrome
and Toxic Epidermal Necrolysis
Ronni Wolf
Batya B. Davidovici
ADVERSE CUTANEOUS drug reactions (ADRs) are frequent, affecting 2%–3% of all hospitalized patients. Fortunately, only approximately 2% of ADRs are severe, and
few are fatal.
Stevens–Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) are acute, severe, life-threatening diseases with a mortality rate reaching 30%. Only prompt
recognition, diagnosis, and referral to an intensive care unit
or burn care unit might improve the prognosis and save the
patient’s life.
HISTORICAL BACKGROUND
In his classic 1866 treatise “On Disease of the Skin,” Ferdinand von Hebra precisely described and gave the name to
erythema multiforme (EM).1 In 1922, two American physicians, Stevens and Johnson, described two patients, boys 7
and 8 years old, who had “an extraordinary, generalized
eruption with continued fever, inflamed buccal mucosa,
and severe purulent conjunctivitis”2 that was later given
the name “Stevens–Johnson syndrome.” In 1950, Thomas
divided EM into two categories: erythema multiforme
minor (von Hebra) and erythema multiforme major, also
known as SJS.3 In 1956, Alan Lyell wrote the most highly
cited article ever to appear in The British Journal of Dermatology: He described four patients with a scalding disease,
which was later given the name toxic epidermal necrolysis
(TEN), or the Lyell syndrome or Lyell disease.4,5 These
severe, acute, life-threatening ADRs were not classified
and defined according to their clinical appearance and/or
linked to their etiology and prognosis until around 1993.6
DEFINITION AND CLASSIFICATION
EM was initially described as an acute self-limited skin
disease, symmetrically distributed on the extremities with
typical concentric “target” lesions and often recurrent.1
The terminology “EM minor” was later proposed to separate the mild cutaneous syndrome from more severe forms
with involvement of several mucous membranes (“EM
major”). SJS for years had been considered an extreme variant of EM, and TEN as being a different entity. In 1993,6 a
group of experts proposed a new classification in which they
separated SJS from the EM spectrum and added it to TEN,
thereby creating a new spectrum of drug-related severe diseases, for example, SJS/TEN. Two disease spectra were
created: 1) EM consisting of EM minor and EM major,
and 2) SJS/TEN. The former are often recurrent, postinfectious disorders (especially herpes and mycoplasma) with
low morbidity and almost no mortality. The latter are usually severe drug-induced reactions with high morbidity and
poor prognosis.
According to the new “consensus definition and classification,”6 categorization of these diseases is determined
essentially by the percentage of skin detachment and by
the characteristic appearance of the typical individual “EMlike” or “target” lesions.
The clinical pattern of the individual skin lesion was
classified into the following four types:
1. Typical targets – individual lesions less than 3 cm in diameter with a regular round shape, well-defined border,
and at least three different zones (i.e., two concentric
rings around a central disk). One ring consists of palpable edema, paler than the center disk.
2. Raised atypical targets – round, edematous, palpable lesions, similar to EM but with only two zones and/or a
poorly defined border.
3. Flat atypical targets – round lesions characteristic of EM
but with only two zones and/or a poorly defined border
and nonpalpable with the exception of a potential central
blister.
page 154
Chapter 15
●
Severe, Acute Adverse Cutaneous Drug Reactions I
155
TABLE 15.1: Original Classification
TABLE 15.2: Proposed New Classification
EM
SJS/Overlap/TEN
EM
SJS/Overlap/TEN
Typical targets
Raised atypical targets
Flat atypical targets
Macules with/without blisters
Raised typical targets
Raised atypical targets
Flat typical targets
Flat atypical targets
Macules with/without blisters
EM, erythema multiforme; SJS, Stevens–Johnson syndrome;
TEN, toxic epidermal necrolysis.
4. Macules with or without blisters – nonpalpable, erythematous, or purpuric macules with an irregular shape and
size and often confluent. Blisters often occur on all or
part of the macule.
The involved body surface area (BSA) should measure the
extent of detached and detachable epidermis (which is often
much less than the area of erythema) at the worst stage of
the disease.
These authors then proposed the following consensus
classification (five categories):
1. EM – detachment <10% of BSA, localized typical targets or raised atypical targets.
2. SJS – detachment <10% of BSA, widespread erythematous or purpuric macules or flat atypical targets.
3. Overlap SJS/TEN – detachment between 10% and 30%
of BSA, widespread purpuric macules or flat atypical targets.
4. TEN with spots – detachment >30% of BSA, widespread
purpuric macules or flat atypical targets.
5. TEN without spots – detachment >10% of BSA, large
epidermal sheets and no purpuric macules.
They went on to suggest a practical algorithm in the definition and categorization of these diseases based on their classification. The first question that the clinician needs to ask
is: “What is the percentage of detachment?” The second
question is: “What is the nature of the discrete lesions?”
They also suggested that their purely descriptive clinical
classification might indicate a causative agent, namely, that
SJS, TEN, and overlap are drug induced, whereas the diseases in the EM group are caused by infectious agents.
Because the involved area of detachment is defined as
such at the worst stage of the disease, it cannot always be
delineated when the clinician first sees the patient. Consequently, the most – and often the only – reliable means of
classifying the cases is through observing the pattern of the
individual lesions.
We recently proposed a small modification of the current classification to enable the clinician to pinpoint quickly
and precisely the type of lesion to implement the appropriate treatment without delay.7
EM, erythema multiforme; SJS, Stevens–Johnson syndrome; TEN,
toxic epidermal necrolysis.
We have noticed that patients of the SJS/TEN group
occasionally have typical targets that are flat and are missing the palpable ring around the center. We therefore suggested adding an additional type of lesion to the nomenclature, namely, a flat typical target, and calling the original
typical target a raised typical target. The new classification will thus contain five types of lesions, instead of four
(Tables 15.1 and 15.2).
As to the questions “Why a new classification?” and
“Why an additional type of lesion that, at first glance, seems
only to complicate the existing classification and make it
more cumbersome?” we contend that our proposed modification gives the classification better leeway, incorporating all the variations characteristic of these lesions. We also
believe that the new addition makes the classification more
compact, easier to understand, and (not less important) easier to remember. How can extending a classification make
it more compact? In our proposed modified classification,
all the lesions that are found in the EM group are raised,
whereas all lesions that characterize the SJS/TEN group
are flat, which makes the classification easy to remember
and to use. Accordingly, if a patient is found to have raised
lesions (raised typical or raised atypical targets), we are
directed toward a diagnosis of postinfectious EM. In contrast, if a patient has flat lesions (flat typical targets, flat
atypical targets, or macules with or without blisters), we
should immediately consider the diagnosis of drug-induced
SJS/TEN.
CLINICAL PATTERN
The initial symptoms of TEN (i.e., before the appearance of frank mucocutaneous sloughing) include fever (all
cases) as well as conjunctivitis (32% of cases), pharyngitis
(25% of cases), and pruritus (28% of cases). These signs
usually last 2–3 days and can resemble an upper respiratory infection. There is speculation that the fever is caused
by drugs, release of pyrogens from epidermal necrosis, or
both, but that it is not due to infection. Mucous membranes (in increasing order of frequency: oropharynx, eyes,
genitalia, anus) are commonly affected 1–3 days before the
skin lesions appear.8 The cutaneous lesions begin with a
burning and painful eruption initially not typical. This
156 E MERGENCY D ERMATOLOGY
B
A
FIGURE 15.1: A, B, and C. 78-year-old man with toxic epidermal necrolysis (TEN) that appeared 5 days after he had
been treated with cefuroxime for an upper respiratory infection. (Photos courtesy of S. Halevy, MD, Soroka University
Medical Center, Ben Gurion and University of the Negev, BeerSheva, Israel.)
C
eruption extends symmetrically from the face and upper
part of the body to the entire body, predominantly on the
trunk and proximal limbs. The initial lesions are poorly
defined macules with darker centers. Maximal extension
of lesions usually occurs in 2 or 3 days, but can be manifest in a few hours. There is a sheet-like loss of epidermis and the appearance of flaccid blisters that spread with
pressure. The Nikolsky sign is positive over large areas
involved by confluent erythema. Traumatized sites leave
a dark red oozing dermis. The entire skin surface may
be involved, with up to 100% of epidermal sloughing.
Widespread painful mucosal erosions result in impaired
alimentation, photophobia, and painful micturition. (See
Figures 15.1A–15.1C.) Keratitis and corneal erosions are
less frequent, but they are known to occur. Asthenia, skin
pain, and anxiety are extreme. Gastrointestinal or tracheobronchial epithelium can be involved via a process of
necrosis resulting in profuse diarrhea or respiratory dis-
tress, respectively, and causing high morbidity.9,10 Prerenal
azotemia is common. Fluid losses are massive and accompanied by electrolyte imbalance. During the first days, skin
lesions are usually colonized by Staphylococcus aureus; they
are later invaded by gram-negative rods. Thermoregulation is impaired, and energy expenditure is increased.11,12
Alteration of immunologic functions increases the risk of
sepsis.
Reepidermization begins after a few days, and most of
the skin surface is reepithelialized in 3 weeks. Pressure areas
and mucosal lesions often remain eroded and crusted for
an additional 2 weeks. Scarring may occur in areas of pressure or infection. Disturbances in pigmentation are characteristically present and lead to a patchwork of pigmented
and hypopigmented areas. Ocular sequelae are frequent
and severe, affecting approximately 40% of survivors.13,14
Abnormal nail regrowth, phimosis, and vaginal synechiae
may be present as well.14
Chapter 15
DIFFERENTIAL DIAGNOSIS
The preceding classification is intended to help physicians
to differentiate EM from SJS/TEN; however, there are several other dermatoses that must be differentiated from these
diseases.
Although the clinical presentation and patient history
make the diagnosis of the classical form of SJS (with its target lesions and mucosal involvement) and of TEN obvious,
other conditions should be considered in the differential
diagnosis, particularly in the early stages of disease when
the full-blown picture may not be fully apparent. These
simulators include staphylococcal scalded skin syndrome
(SSSS); linear immunoglobulin A (IgA) bullous dermatosis;
paraneoplastic pemphigus and acute graft versus host disease (GVHD); drug-induced pemphigus and pemphigoid,
urticarial vasculitis, or lupus erythematosus; Sweet syndrome, particularly the recently described variant of neutrophilic dermatosis of the dorsal hands. Linear IgA bullous
dermatosis, SSSS, and drug-induced pemphigus usually do
not show mucosal membrane involvement. All other diseases – except SSSS, Sweet syndrome, and acute GVHD –
are not accompanied by fever.
In any event, two biopsy specimens are recommended:
one for routine, formalin-fixed hematoxylin and eosin processing, and the other for immediate frozen sections. Epidermis must be present to make the diagnosis, as epidermal necrosis is the pathognomonic finding in this
entity.
LABORATORY CHANGES
Blood abnormalities are also almost always present. Anemia and lymphopenia are found in virtually all patients,
neutropenia in 30% of patients (indicating a poor prognosis), and thrombocytopenia in 15% of patients.15 The
peculiarity of the anemia lies in its regenerative character,
with concomitant medullary erythroblastopenia and blood
reticulocytopenia. It does not appear to be secondary to
the inflammatory process, because the regenerative capacity returns before the peak of the inflammatory phase. Lymphopenia is also commonly present (90% of patients) due
to depletion of CD4+ helper T lymphocytes.16,17 Disseminated intravascular coagulation (DIC) has been reported,
and some authors advocate prophylactic treatment with
heparin.18
Approximately 30% of patients have elevated transaminase enzymes19 and elevated levels of amylase and lipase
without other evidence of pancreatic involvement.20
Proteinuria is present in more than one half of patients,
but usually at a level less than 1 g per 24 hours.
Renal tubular enzyme secretion and microalbuminuria
are increased in all patients, but the glomerular filtration
rate remains normal. This profile is suggestive of both
●
Severe, Acute Adverse Cutaneous Drug Reactions I
157
proximal tubule involvement and secondary effects of
glomerular structure.21
CAUSATIVE DRUGS
Drugs are clearly the leading causative factor and are associated with nearly 90% of TEN cases and more than 50%
of SJS cases.22
Recent studies suggested a strong association between
human leukocyte antigen (HLA) alleles and susceptibility
to drug hypersensitivity.23 The genetic associations can be
drug specific, such as HLA-B∗ 1502 being associated with
carbamazepine-induced SJS/TEN, HLA-B∗ 5701 with abacavir hypersensitivity, and HLA-B∗ 5801 with allopurinolinduced severe cutaneous adverse reactions. A genetic association can also be phenotype specific (e.g., B∗ 1502 is
associated solely with carbamazepine–SJS/TEN, and not
with either maculopapular eruption of hypersensitivity
syndrome).24 Furthermore, a genetic association can also
be ethnicity specific; carbamazepine–SJS/TEN associated
with B∗ 1502 is seen in Southeast Asians, but not in whites,
which may be explained by the different allele frequencies.25
More than 100 drugs have been associated with the
development of SJS/TEN in single case reports or retrospective studies. In 1995, results of the first prospective case–control study to assess the relative risk for different drugs for being associated with SJS/TEN were
published.26 In this study, sulfonamides were the most
strongly associated with TEN (crude relative risk, 172;
95% confidence interval, 75 to 396) followed by antibiotic
drugs (in descending order of frequency: cephalosporins,
quinolones, aminopenicillins, tetracyclines, macrolides),
imidazole antifungals, anticonvulsants (phenobarbital,
phenytoin, valproic acid, carbamazepine, and lamotrigine),
then nonsteroidal antiinflammatory drugs (especially oxicam), allopurinol, and others.
TREATMENT
Both SJS and TEN are life-threatening diseases, so the
management of patients must be prompt. Early diagnosis
with the early recognition and withdrawal of all potential
causative drugs is essential to a favorable outcome. Morbidity and mortality decrease if the culprit drug is withdrawn no later than the day when blisters or erosions first
occurred.27
The patient must be transferred to an intensive care unit
or a burn center. Prompt referral reduces risk of infection,
mortality rate, and length of hospitalization.28–30
The main types of symptomatic treatment are the same
as for burns, and the experience of burn units is helpful for the treatment of TEN: environmental temperature
control, careful and aseptic handling, sterile field creation,
158 E MERGENCY D ERMATOLOGY
avoidance of any adhesive material, and maintenance of
venous peripheral access distant from affected areas.
Intravenous (IV) fluid replacement must be initiated
immediately on admission and use macromolecules or
saline solutions. The rate and amount of fluid and electrolyte administration must be adjusted daily. The early
fluid requirement of TEN patients is two thirds to three
fourths of that of patients with burns covering the same
area.31
Like most other authors, we do not advocate the use
of prophylactic antibiotics. Catheters should be changed
and cultured regularly, and bacterial sampling of the skin
lesions must be performed at least every 48 hours.
Early initiation of massive oral nutrition by nasogastric tube to minimize protein losses promotes healing
and decreases the risk of stress ulcer. The environmental temperature should be increased to 30◦ C, and heat
shields, infrared lamps, and an air-fluidized bed should be
provided.
Thromboembolism and DIC are important causes of
morbidity and death: Effective anticoagulation with heparin is recommended for the duration of hospitalization.27
Like patients with major burns, TEN patients suffer
severe pain as well as emotional instability and extreme
anxiety, which should be treated appropriately.32
Pulmonary care includes aerosols, bronchial aspiration,
and physical therapy. Intubation and mechanical ventilation are nearly always necessary if the trachea and bronchi
are involved.
The SJS/TEN disease spectrum remains an important cause of severe visual loss in a significant number of
patients. Therefore, daily examination by an ophthalmologist and vigorous treatment are mandatory. Antiseptic or
antibiotic eyedrops and eye ointments, with or without corticosteroids, should be instilled every 2 hours. Lid–globe
adhesions should be cautiously removed with a glass rod
twice daily to avoid occlusion of the fornices, taking care
not to strip pseudomembranes which may lead to bleeding
and increased conjunctival scarring.33
There is no consensus about topical care. Topical antiseptics (0.5% silver nitrate or 0.05% chlorhexidine) are
usually used to paint, bathe, or dress the patients. Silver
sulfadiazine, which is popular in burn units, should be
avoided because sulfonamides are frequently implicated in
the etiology of TEN and can cause hemolysis in glucose6-phosphate dehydrogenase–deficient patients. Although
most surgeons in burn units advocate large operative
debridement of nonviable epidermis followed by immediR
ate wound cover with biologic dressings such as Biobrane
34
or xenograft, dermatologists are more conservative, leaving in place the epidermis that has not yet peeled off.
Dressings may be gauzes with petrolatum, silver nitrate, or
polyvidone iodine; hydrogels; Hydrone; Vigilon (semipermeable dressings); SoftSorb; and others, which can also be
impregnated with silver nitrate.
CORTICOSTEROIDS AND OTHER
“DISEASE-MODIFYING” DRUGS
For years, corticosteroids have been the mainstay therapy
for TEN and SJS in most32,35–42 (although not all43,44 )
dermatological centers, including ours, in the belief that
they suppress the intensity of reaction, control the extension of the necrolytic process, decrease the involved area,
reduce fever and discomfort, and prevent damage to internal organs when given at an early stage and in a sufficiently
high dosage. There are no randomized clinical trials on
the use of corticosteroids in the treatment of these lifethreatening diseases.
The early approach to treatment was followed by a
complete turnabout at the beginning of the 1980s when
the management of SJS/TEN shifted to specialized burn
centers and was taken over by nondermatologists, mostly
surgeons, who rejected the use of steroids almost out
of hand. They regarded them as being hazardous and a
potential iatrogenic source of decreased host resistance,
increased morbidity and complications (e.g., sepsis, leukopenia, thromboembolism, gastrointestinal ulcerations),
prolonged recovery, worse and deteriorated prognosis,
reduced survival and, for all intents and purposes, a contraindicated mode of therapy.45–50
In the absence of well-controlled trials, many dermatology departments adopted the concept of large burn units to
avoid the use of steroids, in our opinion more as a matter
of practicing “defensive medicine” and being on the safe
(rather than on the effective) side.
The simple fact is that burns and TEN are two separate disease entities, and, although there is an “acute skin
failure” in both conditions, they differ in terms of etiology and pathomechanism. Specifically, burns are a onetime, acute event that affects the skin from the outside,
whereas TEN is a more complex, probably immune (T
lymphocyte)-mediated process that reaches the skin from
within. Above all, unlike thermal burns, in TEN, the disease
continues to progress and becomes more intensified over a
period of several days after its first appearance; therefore,
it would make good sense to turn to aggressive diseasemodifying drugs that are capable of halting disease progression, reduce the extent of skin detachment, decrease
the inflammatory cytokines and, consequently, the symptoms, discomfort, organ damage (less relevant for burns),
and perhaps mortality. The important role of burn units in
the treatment of these patients notwithstanding, we think
it has been a mistake to ignore our collective clinical experience and own good judgment and be swayed by the stand
taken by plastic surgeons who view TEN and thermal burns
as similar entities.
It is our hope that, with the introduction of new
immunomodulating drugs, the pendulum will swing again
in the opposite direction (i.e., toward advocating diseasemodifying agents). The first step in this long journey
Chapter 15
has already been taken with the introduction in 1998 of
IV immunoglobulins (IVIG) in the treatment of TEN
patients.
Following the observation that antibodies present in
IVIG block Fas-mediated keratinocyte apoptosis in vitro,
and in light of the fact that the Fas–Fas ligand pathway of apoptosis is considered the first or pivotal step in
the pathogenesis of TEN,51 Viard and colleagues52 tried
this treatment in their patients. In their initial article, all
10 patients benefited from this therapy, an observation that
was confirmed in several additional studies,53–59 but contradicted by at least one prospective noncomparative study
based on 34 patients from a single referral center.60
In a recent study from a plastic surgery and burn center from Italy,61 the experience using IVIG together with
the local conservative approach (the change to conservative
approach by plastic surgeons is noteworthy) was related
to previous treatments, which consisted of an aggressive
approach with a wide debridement. The group treated with
IVIG and conservative local approach showed a reduction
in mortality rate from 75% to 26%.
The recommended approach today is early treatment
at a total dose of 3 g/kg over 3 consecutive days (1 g/
kg/d for 3 days).61,62 It is of note that there are significant batch-to-batch variations concerning Fas-inhibitory
activity of IVIG, which might also explain some of the
variability in the response-rate of TEN patients to this
therapy.
We hope that, with the meteoric advances being made
in biologic therapy and the continuing development of target monoclonal antibodies against cytokines and receptors,
new therapies will emerge that will more selectively and
specifically target the underlying processes, thus avoiding
treatment-related side effects. Until these new therapies
are available for clinical use, we advocate treating TEN
patients with what we have here and now, namely, IVIG
and corticosteroids.
PROGNOSIS
In 2000, a mathematical tool called SCORTEN (Severityof-Illness Score for Toxic Epidermal Necrolysis) was developed to asses severity of illness and predict mortality.63 .
SCORTEN should be computed within the first 24 hours
after admission and again on Day 3.64 The score is the
sum of 7 easily measured clinical variables: 1) age (>40); 2)
tachycardia (>120 bpm) ; 3) the presence of malignancy;
4) initial surface of epidermal detachment (>10%); 5)
serum urea (>10 mmol/L); 6) serum glucose (>14 mmol/L;
>252 mg/dL); and 7) bicarbonate (<20 mmol/L [mEq/L]).
One point is given for each variable if positive and zero if
negative. Computing the sum of the scores for each parameter results in a SCORTEN ranging from 0 to 7, with
the mortality increasing sharply with each additional point
(Table 15.3).
●
Severe, Acute Adverse Cutaneous Drug Reactions I
159
TABLE 15.3: Mortality and
Severity-of-Illness Score for
Toxic Epidermal Necrolysis)
SCORTEN
Mortality
0–1
2
3
4
≥5
3.2%
12.1%
35.3%
58.3%
90.0%
SCORTEN, Severity-of-Illness Score
for Toxic Epidermal Necrolysis.
The scoring system that was developed with a French
patient cohort has been validated in a U.S.-based patient
cohort65 and is proving to be a valuable tool for predicting
patient outcome.
CONCLUDING REMARKS
“Any substance that is capable of producing a therapeutic effect can also produce unwanted or adverse effects.”66
ADR had occurred since the beginning of ancient medicine.
To our great fortune, the most severe ADRs described here
in SJS/TEN are rare. Despite their low incidence they are
still frequent enough that primary care physicians and dermatologists will probably be involved with the management
of at least one affected individual during their practice, but
they are too infrequent to acquire any real degree of familiarity with them.
Because there is no specific and definitely effective treatment for SJS/TEN, prompt recognition and diagnosis and
early identification and withdrawal of all potential causative
drugs and prompt referral to a burn unit are generally
agreed-upon steps and, for the time being, the best we can
do for our patients to most significantly influence outcome
and prognosis. Beyond that, however, considerable controversy exists. Evidence both pro and con exists for the use
of IVIG, systemic corticosteroids, and other measures.
In this chapter, we present practical and comprehensive
information on the two most severe acute cutaneous drug
eruptions – SJS and TEN – concentrating on their definition, classification, clinical appearance, management, and
prognosis. It is intentionally clinically oriented and covers what is most relevant to the clinicians in their practice,
omitting the theoretical aspects of the pathogenesis of the
diseases, unless they are relevant to diagnosis or treatment.
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CHAPTER 16
Severe, Acute Adverse Cutaneous Drug
Reactions II: DRESS Syndrome and Serum
Sickness-Like Reaction
Ronni Wolf
Batya B. Davidovici
DRUG RASH WITH EOSINOPHILIA
AND SYSTEMIC SYMPTOMS
Epidemiology and Causative Drugs
Background
Drug rash with eosinophilia and systemic symptoms
(DRESS) syndrome, formerly termed “drug hypersensitivity syndrome” (HSS), is a severe, potentially fatal adverse
drug reaction characterized by skin rash, fever, lymph-node
enlargement, and single- or multiple-organ involvement,
characteristically occurring in a delayed fashion between 3
and 8 weeks after starting treatment with the culpable drug
for the first time.
Phenytoin HSS was first described in 1939,1 1 year after
phenytoin had been introduced in the treatment of convulsive disorders. Similar reactions were reported during the
following years, initially to various anticonvulsant drugs2,3
and later to many other drugs.4–6 Consequently, the name
of this reaction was changed to the more widely inclusive HSS, instead of anticonvulsant-, sulfone-, or dapsonehypersensitivity syndrome. The word “hypersensitivity”
itself, however, is ambiguous and uninformative insofar as
it may apply to any idiosyncratic reaction that fits one phase
of the classic Gell and Coombs classification. Therefore, a
more informative, precise, and clinically relevant term was
proposed, “drug rash with eosinophilia and systemic symptoms” or DRESS.7 The suitability of the term DRESS has
recently been questioned because eosinophilia need not
necessarily be present in this syndrome, and a return to
“drug-induced HSS” has been suggested.8
DRESS is characteristically defined by a triad of symptoms consisting of fever, skin eruption, and internal organ
involvement. In this context, it should be mentioned that
serum sickness (SS) or serum sickness-like reaction (SSLR),
which have many features in common with DRESS syndrome, are distinct diseases that have another pathogenesis
and, as such, should be distinguished from DRESS syndrome (Table 16.1).
The true incidence of DRESS syndrome is unknown
because its variable presentation confounds uniform diagnosis. It is estimated to occur in between 1 in 1000 and
1 in 10,000 exposures with drugs such as anticonvulsants
and sulfonamides.9 In a record linkage study, the risk for
developing DRESS syndrome within 60 days of the first or
second prescription in new adult users of phenytoin or carbamazepine was estimated to be 2.3–4.5 per 10,000 exposures, respectively.10
The aromatic anticonvulsants (phenylhydantoin, phenobarbital, carbamazepine)9,11–14 and sulfonamides15 are
the most common causes of DRESS syndrome, but a large
variety of other drugs have been associated with it, notably
among them lamotrigine16,17 (see Figure 16.1), allopurinol,18,19 nonsteroidal antiinflammatory drugs, captopril,
antibiotics, tuberculostatic drugs, calcium channel blockers, mood stabilizers, neuroleptics, dapsone, terbinafine,
methyldopa, minocycline, and antiretroviral drugs.20,21
TABLE 16.1: Comparison between DRESS Syndrome and
SS/SSLR
Symptom
DRESS
syndrome
SS/SSLR
Rash
Exanthematous
(mostly)
Urticarial (mostly)
Onset of symptoms
Fever
1–8 weeks
Present
>2 weeks
Present
Internal organ
involvement
Present
Absent
Arthralgia
Absent
Present
Lymphadenopathy
Present
Present
DRESS, drug rash with eosinophilia and systemic symptoms; SS/SSLR,
serum sickness/serum sickness-like reaction.
page 162
Chapter 16
FIGURE 16.1: A 43-year-old man with lamotrigine-induced drug
rash with eosinophilia and systemic symptoms (DRESS). Note
the typical periorbital edema.
Clinical and Laboratory Aids Required for Diagnosis
DRESS syndrome occurs most frequently on first exposure
to the drug, with initial symptoms starting between 1 and 8
weeks afterward.22 The syndrome may occur within 1 day
upon rechallenge in previously sensitized individuals.
The syndrome commonly begins with a fever shortly
followed by a maculopapular rash and varying degrees of
lymphadenopathy. Body temperature ranges from 38◦ C to
40◦ C, with spikes that usually generate the concern of an
underlying infection. The spiking fever often persists for
as long as weeks despite discontinuation of the offending
drug.23
An eruption occurs in approximately 70%–100% of
patients.8 In most cases, the cutaneous eruption starts as
a macular erythema that often evolves into a red, symmetrical, pruritic, confluent, and papular rash. Pustules, either
follicular or nonfollicular, may also be present. The upper
trunk and face are initially affected, with later involvement
of the lower extremities. Facial and periorbital edema is a
frequent occurrence, and can lead to such gross distortion
of the patients’ features that they can become unrecognizable. Notably, there is usually no mucosal involvement, a
feature that helps to distinguish DRESS from other forms
●
Severe, Acute Adverse Cutaneous Drug Reactions II
163
of severe drug eruptions, such as Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).
As for internal organ involvement, again there is a large
degree of variability among patients with regard to both the
target organs involved and the severity of the involvement.
It is important to emphasize, however, that the severity of
cutaneous changes does not necessarily reflect the severity of internal organ involvement. Therefore, meticulous
assessment is necessary for patients suspected of DRESS
syndrome and internal organ involvement. It is also important to bear in mind that internal organ involvement may
not develop for 1–2 weeks into the reaction, and even not
until 1 month later.
The liver is the most frequently involved internal
organ, with tender hepatomegaly and sometimes with
splenomegaly. Liver involvement can range from mild elevations in serum transaminase levels24 to granulomatous
hepatitis or fulminant hepatic necrosis.25–28 The degree of
hepatitis is related to the interval between the onset of the
syndrome and the discontinuation of the drug.29 Prompt
recognition of the syndrome and withdrawal of the drug
are therefore of utmost importance to the prognosis.
The kidney is another organ frequently involved, and
the nephrotic condition can range from mild hematuria,
to nephritis, to acute renal failure, usually following acute
granulomatous interstitial nephritis, even despite discontinuation of the offending drug.30,31
Rarer manifestations of DRESS syndrome are colitis,
pneumonitis, pancreatitis, myocarditis, encephalitis, arthritis, and myositis.8,32 Thyroiditis with autoantibodies has
also been reported. Its acute hyperthyroid phase may be
missed by the clinician because of fever, tachycardia, and
malaise, which are part of DRESS syndrome, and may
thus be identified only several months later when hypothyroidism develops.33
Lymphadenopathy is perhaps the most frequent finding
associated with DRESS syndrome. In the early stages of
the disease, lymph-node histology shows benign hyperplasia, but histological changes may progress to reveal atypical lymphoid cells. In rare cases, pseudolymphoma or lymphoma may develop if the drug is not discontinued.34
Notably, no single symptom, including fever or peripheral eosinophilia, is necessarily present in all cases of
DRESS, and cutaneous lesions apparently are, in fact, the
most often reported signs. The clinical pattern of skin
changes is, however, quite variable, ranging, according to
the present definition, from a faint generalized exanthematous eruption to SJS or TEN. The same is true for the
other associated symptoms, organ dysfunction, and laboratory abnormalities.8,32,35
In 2006, a Japanese consensus group proposed a set of
criteria for diagnosis of DRESS (or, as suggested by them,
drug-induced hypersensitivity syndrome, DIHS).21 That
group established 6 diagnostic criteria for DIHS/DRESS
to which they subsequently added a 7th:36 1) maculopapular
164 E MERGENCY D ERMATOLOGY
rash developing more than 3 weeks after starting therapy;
2) prolonged clinical symptoms 2 weeks after discontinuation of the causative drug; 3) fever higher than 38◦ C; 4)
at least one leukocyte abnormality (i.e., leukocytosis >11
× 108 /L), atypical lymphocytosis >5%, or eosinophilia
>1.5 × 108 /L); 5) liver abnormalities (alanine aminotransferase >100U/L), which can be replaced with other organ
involvement, such as the kidney; 6) lymphadenopathy; and
7) human herpesvirus 6 (HHV-6) reactivation. The diagnosis is confirmed by the presence of all seven of these
criteria (typical DIHS) or of the first five (atypical DIHS).
The most novel and innovative of the proposed criteria is
undoubtedly HHV-6 reactivation. The authors state that
their series of more than 60 patients diagnosed by clinical
findings had consistently shown that HHV-6 reactivation
can be detected in the vast majority of patients who satisfy the other six criteria and show clinical manifestations
consistent with the classical triad, but not in patients with
other types of drug eruption, such as papulomacular rash,
SJS, and TEN. Moreover, HHV-6 was rarely detected in
patients with a tendency toward milder disease. Without
entering into any debate about the appropriateness of this
criterion, the fact that it usually appears 2–3 weeks after the
onset of rash means that it can be used for studies and late
analyses, but not when we first see our patient and have to
make urgent decisions. The same holds true, of course, for
their second criterion.
We especially espouse two features of this newly suggested classification: 1) it narrows the wide definition of
cutaneous rash, in particular by excluding cases with cutaneous manifestations of SJS and TEN, a characteristic that
we had emphasized long ago,20,35 and 2) it provides cutoff
points for delineating hematological and other laboratory
abnormalities.
Although most authors agree that the existence of
DRESS as a clinically distinctive and unique entity is unarguable,8,37 its diagnosis is complicated because, in addition to its highly variable presentation, it is a diagnosis by
exclusion. Its main features, such as rash, fever, and organ
involvement, can also be attributed to a wide range of other
causes, most notably infections (with which it is also often
associated). The similarity between DRESS and infection
diseases is of particular importance considering our efforts
to avoid prescribing for patients with DRESS additional
drugs because they can cross-react with other drugs or initiate drug neosensitization38 during DRESS, whereas we
usually use drugs such as analgesics/antipyretics and antibiotics in the case of infections.
Treatment
DRESS is potentially life threatening. The mortality
rate is estimated at nearly 10%, although complete
recovery can be achieved.39 DRESS syndrome must be
promptly recognized and all potential culprit drugs withdrawn.
Skin care may include the use of topical steroids to alleviate symptoms. The main principles of therapy for extensive
rash or erythroderma are the same as those for major burns:
warming of the environment, correction of electrolyte disturbances, high caloric intake, and prevention of sepsis.
As for the controversy about the use of systemic corticosteroids, unlike their position on the administration of
these medications to patients with SJS/TEN, most authors
do not regard them as either hazardous or contraindicated and suggest their use “when internal organ involvement exists.”40,41 Because internal organ involvement is a
prerequisite for this syndrome (remember, the requisite
triad of fever, rash, and internal organ involvement!), however, systemic steroids should be considered in most cases
of DRESS syndrome, particularly in patients with severe
organ damage. Furthermore, corticosteroids are known for
their beneficial effects in diseases with blood eosinophilia
(e.g., hypereosinophilic syndrome), where eosinophils are
responsible for organ damage, and thus might be expected
to be of benefit in DRESS, insofar as eosinophil accumulation is also thought to account for the internal organ
involvement in this disease.
SERUM SICKNESS AND SERUM SICKNESS-LIKE
REACTION
Background
SS, first described in humans by von Pirquet and Schick in
1905, is a type III hypersensitivity reaction (of the classic
Gell and Coombs classification) resulting from the administration of foreign protein or of heterologous serum, usually equine, serving as an antitoxin.42
The syndrome includes fever, cutaneous eruptions
(mostly urticaria), edema, arthralgias, and lymphadenopathy. Although fatalities from this reaction are rare, it has
been traditionally included in the group of severe adverse
cutaneous reactions to drugs43 because it requires hospitalization (and, often, intensive care) and might cause extensive organ damage.
During the first 4 decades of the 19th century, it was
not uncommon for up to 50% of patients to develop this
reaction after treatment with horse serum as an antiserum
to diphtheria, tetanus, rabies, or other organisms. It has
almost disappeared in these settings with the advent of
effective immunization procedures, antimicrobial therapy,
and the development of specific human immune serum
globulins. More recently, SS has made a comeback with the
introduction of targeted immune modulators – commonly
referred to as biological response modifiers or simply “biologics.” It is also commonly seen with the use of antivenom
therapy used to treat envenomations by snakes, spiders,
scorpions, and so forth. The SSLR that is similar to classic SS may result from the administration of a number of nonprotein drugs, such as antibiotics (particularly
cefaclor and minocycline), psychiatric drugs, analgesic/
Chapter 16
antiinflammatory drugs, antineoplastic drugs, and many
others.
Clinical and Laboratory Aids Required for Diagnosis
Early recognition and accurate diagnosis are the keys to
the management of SS because treatment is highly effective in reversing all symptoms. Recognition and diagnosis,
however, are made more difficult by a lack of diagnostic
and laboratory criteria and by the protean manifestations
of this reaction.
An attempt was recently made to gather signs and
symptoms and produce diagnostic criteria for SS.44 Four
major criteria were established: 1) more than 7 days since
initial drug (thymoglobulin) administration, 2) persistent
high fevers (>101◦ F), 3) persistent arthritis/arthralgias,
and 4) positive heterologous antibodies on enzyme-linked
immunosorbent assay. Rash was considered a minor criterion. These criteria are, however, in disagreement with
earlier studies, in which cutaneous rash appeared in more
than 90% of patients.45–48 The clinical manifestations of
SS begin at 4–21 days (usual range 7–10 days) after initial exposure to the causative antigen. Symptoms usually
include fever, a cutaneous eruption (morbilliform, urticaria,
or the combination of these two reaction patterns) in more
than 90% of patients, arthralgias in up to 50%, lymphadenopathy, and myalgias. Headache and gastrointestinal
complaints may occasionally occur as well. Less common
manifestations include arthritis, nephritis, neuropathy, and
other organ involvement.
The diagnosis is made on the basis of clinical findings
because there are no pathognomonic laboratory tests specific for the diagnosis of SS or SSLRs in the acute setting. The erythrocyte sedimentation rate is noncontributory because it may be elevated, normal, or low. Leukopenia or leukocytosis may be present, and SS is one of the
few illnesses in which plasmocytosis may be detected in the
peripheral blood smear. The urine analysis may show proteinuria, hematuria, or hemoglobinuria. Serum creatinine
and transaminases may be transiently elevated. Circulating immune complexes may rise and fall before symptoms
and signs appear. Serum concentrations of C3, C4, and
total complement are depressed because of the formation of
immune complexes, but they tend to rapidly return to normal.49 Direct immunofluorescence microscopy of lesional
skin from patients with SS had demonstrated immunoreactants in seven of nine subjects, with immunoreactants being
confined to the walls of dermal blood vessels and consisting of immunoglobulin M, C3, immunoglobulin E, and
immunoglobulin A. Immunoglobulin G was not identified
in any of the specimens.46
Therapy
We, like others,44 recommend the administration of highdose steroids for 3–5 days, followed by a prednisone taper,
●
Severe, Acute Adverse Cutaneous Drug Reactions II
165
depending on the severity of the disease and its activity.
Typically, there is a noticeable improvement in the fevers
and arthralgias within the first 48 hours of treatment, and
resolution of symptoms is seen over approximately 8–10
days 50 Some groups consider plasmapheresis the firstline therapy for SS.51,52 Like others,44 however, we think
that plasmapheresis should be reserved for steroid-resistant
cases.
Vasculitis
Vasculitis is inflammation of vessel walls. It has many
causes, although they result in only a few histologic patterns of vascular inflammation. Vessels of any type in any
organ can be affected; this fact results in a wide variety
of signs and symptoms. These manifold clinical manifestations, combined with the etiologic nonspecificity of the histologic lesions, complicate the diagnosis of specific forms of
vasculitis. The difficulty in diagnosis is problematic because
different vasculitides with indistinguishable clinical presentations have different etiologies, associations with specific
diseases, involvement in certain organs, prognoses, and
treatments. To make things even more complicated, there
are many classifications and no agreed-upon diagnostic criteria for the various categories of vasculitis, particularly the
small-vessel vasculitides.
Drugs cause approximately 10% of vasculitic skin lesions
and should be considered in any patient with small-vessel
vasculitis.53–55 Withdrawal of the offending agent alone is
often sufficient to induce prompt resolution of clinical manifestations, obviating the need for systemic corticosteroids
or more powerful forms of immunosuppression.
For more details on this topic, readers are directed to
Chapter 23 in this book, which is devoted entirely to purpura and vasculitis of any kind.
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18. Hamanaka H, Mizutani H, Nouchi N, et al. Allopurinol
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19. Sommers LM, Schoene RB. Allopurinol hypersensitivity
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44. Lundquist AL, Chari RS, Wood JH, et al. Serum sickness
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Chapter 16
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Severe, Acute Adverse Cutaneous Drug Reactions II
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CHAPTER 17
Severe, Acute Complications of
Dermatologic Therapies
Ronni Wolf
Jasna Lipozenčić
Batya B. Davidovici
ALTHOUGH PHYSICIANS from other specialties, like
the population at large, still consider cutaneous maladies as
being mainly aesthetic, skin deep, and insignificant, they are
generally aware that treating these diseases often requires
a variety of potent systemic drugs and not only topical
treatments. These powerful medications may cause many
adverse reactions, some of them severe, acute, or even life
threatening.
“There are no really ‘safe’ biologically active drugs. There
are only ‘safe’ physicians.”1 A “safe” physician must, first and
foremost, be well informed about adverse reactions at the
time of prescribing a drug, during the follow-up period,
and especially when one of these rare catastrophes suddenly
occurs. Because the diversity of severe adverse reactions to
dermatologic therapies is almost endless, we focus on new
drugs and the less known adverse effects.
TARGETED IMMUNE MODULATORS/BIOLOGICS
Targeted immune modulators (TIMs) – commonly referred to as biological response modifiers or simply “biologics” – are a relatively new category of medications used in
the treatment of certain types of immunologic and inflammatory diseases, including dermatologic diseases, most
notably psoriasis.
Overall, TIMs appear to have a good tolerability profile, although some rare but acute serious adverse events,
such as infections, hematologic events, neurologic events,
infusion reactions, congestive heart failure, nephrotic syndrome, and others, are of concern. The following sections
describe adverse events associated with TIMs.
patients and usually during or within 2 hours after infusion.2 They can, in most cases, be easily managed.
Clinical manifestations of acute infusion reaction
include fever, chest pain and/or discomfort (e.g., tightening pressure), hypotension or hypertension, palpitations, urticaria, and hyperemia. Although such a reaction
might very well be a harrowing experience to the uninformed, most of the symptoms improve substantially or
resolve completely after stopping the infusion or slowing its rate. The Division of Clinical Immunology Infusion Center at Mount Sinai Medical Center has developed a protocol for the treatment of initial severe acute
reactions3,4 that recommends stopping the infusion and
starting an infusion of normal saline. The airway must
be maintained, and oxygen is given. Epinephrine (0.1–
0.5 mL, 1:1000) is administered subcutaneously and can
be repeated every 5 minutes for three doses. Intravenous
(IV) hydrocortisone (100 mg) or IV methylprednisolone
(20–24 mg) is also given, followed by IV diphenhydramine
(25–50 mg) and oral acetaminophen (650 mg). It should be
noted that epinephrine and diphenhydramine have a rapid
onset of action and, in cases of severe reactions, should
be given before steroids, which have a slower onset of
action.
Although those authors3,4 recommend restarting TIM
infusion at a slower rate after resolution of the symptoms, and that a “prophylaxis protocol” be followed for
retreatment of patients who experienced severe reactions,
we believe that there is no logical justification to do so,
especially in view of the facts that we are treating a benign
disease and that there are many other alternative medications from which to choose.
Infusion Reactions
As is the case with any foreign protein–derived agent,
infusion with chimeric antibodies that contain murine
antibodies, such as infliximab (containing 25% murine proteins), can lead to either acute or delayed infusion reactions. Overall, these reactions occur in up to 10%–20% of
Infections
Following U.S. Food and Drug Administration (FDA)
approval and the more widespread use of TIMs (particularly, anti–tumor necrosis factor-␣ [TNF-␣] for rheumatic
page 168
Chapter 17
disease and inflammatory bowel disease [IBD]), postmarketing surveillance data from the FDA MedWatch database
revealed a disturbing number of reports of serious infections in patients treated with these agents.5 The FDA has
issued black box warnings about an increased risk of infections for all TNF-␣ inhibitors, stating that “Serious infections, including sepsis and pneumonia, have been reported
in patients receiving TNF-␣–blocking agents. Some of
these infections have been fatal.”
The true incidence of infections and the effect of TNF␣–blocking agents on these numbers cannot be ascertained
with accuracy, particularly in view of the fact that rheumatologic patients have a higher risk for infection than do
nonrheumatologic patients, and that they are also usually
receiving other disease-modifying drugs that are associated
with considerable risk of infections. We will discuss several
of the most significant infections reported so far, without
entering into the issue of the quantitative effect of antiTNFs to their incidence.
Tuberculosis. At the forefront of interest concerning serious infections and the use of TNF-␣ inhibitors are
mycobacterial infections, particularly Mycobacterium tuberculosis.
An estimated one third of the world’s population (outside the United States, where the disease is uncommon) has
latent tuberculosis infection (LTBI), which can potentially
progress to disease and further spread of the epidemic. In
LTBI, the person has a small number of “latent” M. tuberculosis bacilli that are contained in granulomas in their bodies. These organisms are viable and are possibly in a slow
state of replication. These bacilli will never cause disease
in most infected persons, but the ones who do reactivate
disease suffer considerable morbidity and mortality and are
also the major source of transmission of the disease, fueling the continued epidemic. Even though TB is usually
not rapidly fatal, the disease may show a fulminant course
in immunocompromised patients, and may also have an
atypical pattern and presentation. In a review of 70 TB
cases associated with infliximab therapy reported to the
FDA,6 more than half of the patients had extrapulmonary
TB (lymph-node disease, peritoneal disease, pleural disease, meningeal disease, etc.), and approximately one quarter had disseminated TB. In contrast, among cases of TB
in immunocompetent patients, approximately 18% were
manifested as extrapulmonary disease, and disseminated
disease accounted for less than 2%. TNFs have a central
role in the host defense against M. tuberculosis. The human
immune response is highly effective in controlling primary
infection resulting from exposure to M. tuberculosis. TNF␣ is involved in the killing of mycobacteria by activating
macrophages and preventing the dissemination of infection
by stimulating granuloma formation. Physicians should be
aware of the increased risk of reactivation of TB among
patients who are receiving anti-TNFs and, in particular,
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Severe, Acute Complications of Dermatologic Therapies
169
of the unusual clinical manifestations of the disease, of the
high mortality rates in this group (12%),7 and its sometimes fulminant course. Both infliximab and adalimumab
have black box warnings on their product labels citing this
risk, and discussion with the FDA is ongoing regarding an
update to the package labeling for etanercept.8 The Centers
for Disease Control and Prevention (CDC) recommends
TB screening with tuberculin skin test for all patients being
treated with any TNF-␣ inhibitor. Although other biologic
medications that are not anti-TNFs (such as alefacept or
efalizumab) have not been reported to cause reactivation
of LTBI, they are immunosuppressive, and the majority of
advisors from the medical board of the National Psoriasis
Foundation perform baseline TB testing before initiating
therapy with either agent.8 Physicians should also bear in
mind that a negative skin purified protein derivative (PPD)
skin test and negative chest x-ray are not always reliable in
patients with concomitant immunosuppression.9 Indeed,
anergy to PPD testing has been reported to be as high as
50% in rheumatic arthritis patients, compared with 7% in
controls.10 When active TB is suspected, treatment with
TIMs should be immediately stopped until the diagnosis
has been ruled out or the infection has been treated with
anti-TB agents. In contrast, TB following therapy with
anti-TNFs may be initially refractory to treatment because
of lingering TNF-␣ blockers in the system.11
Other Bacterial Infections. There are no reliable postlicensure data on the rates of serious bacterial infections
in patients treated with TNF-␣ inhibitors because infections with commonly acquired organisms are less likely to
be reported to the authorities. Nonetheless, the clinician is
certain to encounter serious bacterial infections, including
those requiring a critical care setting, in individuals exposed
to TNF-␣ antagonists. There are no specific guidelines
for the recognition or treatment of suspected infections in
these patients, but a heightened awareness and suspicion
on the part of the clinician for these infections and rapid
evaluation and treatment cannot be emphasized enough.
Histoplasmosis and Other Fungal Infections
Host responses to pulmonary inoculation with the fungus
Histoplasma capsulatum are similar to pulmonary mycobacterial infection. Histoplasmosis is the most prevalent
endemic mycosis in the United States, and approximately
250,000 individuals are infected per year. As with TB, 90%–
95% of exposed immunocompetent hosts will develop
latent asymptomatic disease, but reactivation and dissemination, which can be severe and fatal, may occur in the
context of therapy with immunosuppressants.12
There were no cases of histoplasmosis in clinical trials with etanercept and infliximab, but two cases were
documented in phase I trials with adalimumab. By May
2002, 22 cases of histoplasmosis were reported to the FDA
170 E MERGENCY D ERMATOLOGY
MedWatch database. Of these 22, 19 were associated with
infliximab and three with etanercept. Five of the 22 resulted
in death. All 22 cases occurred in the United States, and
most resided in the Ohio and Mississippi River valleys.
The majority of the cases presented with disseminated disease. Typical presenting symptoms included fever, dyspnea, malaise, weight loss, and intestinal pneumonitis.12
Cases of histoplasmosis are uncommon outside the United
States. Currently no reliable serologic or skin testing is
available for screening for latent histoplasmosis infection.
Due to this lack of a diagnostic tool, and because manifestations of infection can mimic any other infection, a high
index of suspicion, particularly of physicians in endemic
areas, is crucial for early diagnosis.
Pneumocystis carinii pneumonia (PCP; now renamed
Pneumocystis jiroveci) is a common opportunistic infection
in immunocompromised persons. As of June 2002, there
have been 44 cases of PCP in the United States following the use of infliximab, and five cases of PCP following
etanercept, with six fatal cases among them.13
Case reports and case series of other severe fungal infections have also been reported in association with the use
of TNF-␣ inhibitors. These include disseminated cryptococcal infections, disseminated sporotrichosis, invasive pulmonary aspergillosis, systemic candidiosis, and others.12,14
In summary, disseminated fungal infections should be
carefully considered in the differential diagnosis of patients
who present to the emergency room or intensive care setting with a serious febrile illness in the setting of anti-TNF
therapy, especially in areas of high disease prevalence.
indicated a strong trend toward an increase in the percentage of patients with worsening clinical status with increasing infliximab dose, largely due to an increase in deaths or
hospitalization for CHF at weeks 14 (primary endpoint)
and 28.17
In an examination of case reports18 of all patients who
developed new or worsening CHF while receiving TNF␣ antagonist therapy, investigators obtained a total of 47
reported cases from the FDA’s MedWatch system. After
receiving TNF-␣ antagonist therapy, 38 patients developed
new-onset CHF and 9 patients experienced CHF exacerbation. Of the 38 patients with new-onset CHF, 19 (50%)
had no identifiable risk factor, and 10 patients were younger
than 50 years. After TNF-␣ antagonist therapy was discontinued and heart failure therapy was started in these
10 patients, 3 had complete resolution of heart failure, 6
improved, and 1 died, an outcome that supports a causal
relationship between TNF-␣ therapy and CHF.
There are currently no concrete guidelines for the evaluation and treatment of patients with suspected CHF. It
is generally agreed upon that infliximab (>5 mg/kg) is
contraindicated in patients with severe CHF. Likewise,
patients who develop new-onset CHF while on anti-TNF
therapy should immediately stop medication, undergo a
prompt evaluation, and receive appropriate treatment. We
currently advise against the reinstitution of anti-TNF therapy in such patients with dermatological diseases. As for
patients with well-compensated mild CHF, each patient’s
risk versus benefit should be considered before therapy is
begun.
Congestive Heart Failure
Serious Neurological Events
Worsening or exacerbation of congestive heart failure
(CHF) is inarguably a serious, life-threatening, and frightening adverse effect. The question is, to what extent, if at
all, are TNF-␣ antagonists involved in this event?
It is known that worsening CHF has been associated
with elevated serum levels of TNF-␣. Indeed, initial data
from animal models and from preclinical and pilot studies were encouraging, showing some anecdotal efficacy of
TNF-␣ antagonist therapy in the treatment of CHF.15,16
Two larger, multicenter, randomized, placebo-controlled
clinical trials (i.e., RECOVER [Research into Etanercept
Cytokine Antagonism in Ventricular Dysfunction] and
RENAISSANCE [Randomized Etanercept North American Strategy to Study Antagonism of Cytokines]) failed
to show any significant difference in composite clinical
function score for anti–TNF-␣ therapy versus placebo.
Both studies were terminated early because interim analysis did not show any benefit of etanercept on morbidity or
mortality. For the RENAISSANCE study, the key finding
was a trend toward higher mortality in etanercept-treated
subjects, a concern heightened by the apparent dose–
response relationship.15,16 A phase II trial with infliximab
Seizure Disorder. Seizure disorder following anti-TNF
therapy is rare, having been reported in 29/170,000 patients
who had been exposed to infliximab, in 26/104,000 exposed
to etanercept, and in none exposed to adalimumab.13,19 In
view of these data, it was suggested that preexisting seizure
disorder does not seem to be a contraindication to antiTNF therapy for rheumatic patients.13,19 We, however,
think that dermatologic patients should nevertheless have
an alternative therapy.
Demyelination
As is the case for TNF-␣ antagonists and CHF, the fact that
patients with multiple sclerosis (MS) show elevated TNF␣ levels in serum and cerebrospinal fluid (CSF) prompted
researchers to try this form of therapy for patients with MS.
To this end, a TNF-␣ blocker named lenercept, which was
developed and studied specifically for patients with MS,
resulted in an increase in MS exacerbations and a shortened time to flare.20 An open-label, phase I safety study of
infliximab carried out on two patients with MS showed a
worsening of the disease.21
Chapter 17
Demyelinating disorders have been described in postmarketing surveillance and in published case reports for all
three TNF-␣ blockers.13,14,19 The incidence of demyelinating disease, however, does not appear to be increased in
patients on anti-TNF therapy compared with the background rate in the general population.13,14,19 Nonetheless, it has been recommended that, for the sake of safety,
these agents should be avoided in patients with preexisting demyelinating conditions until more data are available
on the relationship between TNF-␣ blocker and demyelination.13,14,19 In this context, it is important that physicians are aware of the signs and symptoms of demyelinating diseases, such as weakness, paresthesias, visual disturbances, confusion, and gait disturbances. Obviously, therapy with TNF-␣ inhibitors should be immediately stopped
if a patient develops any suspicious neurological signs, and
the patient should be sent for evaluation.
Serious Hematological Events
Although extremely rare, serious and acute hematological dyscrasias, such as aplastic anemia and pancytopenia,
have been described in association with the use of TNF␣ inhibitors. There are no current recommendations for
regular monitoring of blood counts, but physicians should
be aware of the possibility of hematological adverse events.
If one occurs, TNF blockers should be stopped and the
patient should be checked for evidence of other underlying disease or other causative medications before ascribing the event as potentially related to the TNF blockade.13,19,22
Efalizumab, an immunosuppressive recombinant
humanized immunoglobulin G1 (IgG1) isotype monoclonal antibody that binds to human CD11a, is another
biological therapy utilized in the treatment of psoriasis.
Four cases of hemolytic anemia have been reported with
efalizumab. Two cases that were reported during clinical trials required discontinuation of therapy and blood
transfusions. There is no descriptive information about
the other two cases. A precaution regarding immunemediated hemolytic anemia was added to the package
insert for efalizumab.23,24 Eight cases of thrombocytopenia (0.3%) were reported in a combined safety database of
2762 patients who received it, all eight being consistent
with an immune-mediated process. Three individuals were
asymptomatic and three required hospitalization, including
one with heavy uterine bleeding. Five of the eight patients
were treated with systemic steroids. Postmarketing cases
of thrombocytopenia have also been reported. Prescribing information for efalizumab advocates monitoring for
signs and symptoms of thrombocytopenia along with baseline and periodic assessments of platelet counts.23,24 The
reporting of one case of efalizumab-induced autoimmune
pancytopenia resulted in the recommendation of close
monitoring of all blood cell counts.23
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171
Miscellaneous
Vasculitis. Rare cases of vasculitis associated with antiTNF therapy have been reported, some of them severe.
The causal relationship between the drug and the vasculitis remains uncertain, however, because the possibility of
rheumatoid vasculitis cannot be excluded.25,26
Hepatotoxicity. Although TNF-␣ inhibitors have no confirmed liver toxicity, rare cases of serious liver disease suspected of having been induced by these drugs have been
reported.27,28
Autoantibodies and Drug-Induced Lupus. TNF-␣ inhibitors can lead to the formation and increased titers of
autoantibodies and antinuclear antibodies. The formation
of these antibodies is not associated with any specific clinical
syndrome. In contrast, a clinical syndrome of systemic lupus
erythematosus (SLE) occurs rarely (approximately 0.2%)
and seems to be associated with TNF-␣ inhibitors. The
outcome of the disease has been favorable, with the disease being reversible on cessation of the drug. No patient
thus far has reportedly developed neurological or renal disease.13,14
Recently, the manufacturer of efalizumab (Raptiva) has
voluntarily withdrawn the drug from the market because
of the association of efalizumab with an increased risk of
progressive multifocal leukoencephalopathy (PML).
Since the approval of Raptiva (efalizumab) in October
2003, the FDA has received reports of three confirmed
cases and one possible case of PML in patients 47 to 73
years of age who were using Raptiva for the treatment of
moderate to severe plaque psoriasis. Two of the patients
with confirmed PML and one patient with possible PML
died. All four patients were treated with Raptiva continuously for more than three years. None of the patients
were receiving other treatments that suppress the immune
system while taking Raptiva.
METHOTREXATE
Since the mid-1950s, methotrexate (MTX) has become the
gold standard by which other systemic psoriasis medications are measured.29 MTX has been safely prescribed to
thousands of patients with psoriatic and rheumatoid conditions with great therapeutic benefit. Indeed, the fact that
58% of surveyed dermatologists used MTX to treat patients
with severe psoriasis in 198730 indicates that dermatologists feel comfortable with this form of therapy. A significant number of dermatologists are, however, still unwilling
to treat psoriasis with MTX, reflecting a persistent bias
against it. The good benefit/toxicity ratio, low cost,
extensive experience over decades, and relatively good tolerability of MTX notwithstanding, it is, like the majority
of cancer medications, a toxin and an antimetabolite and,
172 E MERGENCY D ERMATOLOGY
as such, it can cause acute toxicity. In this section we focus
on some acute, serious adverse reactions of MTX.
be needed, it is suggested to start empirical antimicrobial
treatment and, in some cases, IV corticosteroids until there
is evidence of clinical and radiological improvement.
Pancytopenia
Bone-marrow toxicity (specifically, pancytopenia) is certainly the most serious, acute, and, therefore, frightening side effect of MTX, with an estimated incidence of
1.4%.31 MTX-induced bone-marrow suppression develops suddenly, rapidly, and without warning signs. It seems
unlikely, therefore, that a more frequent monitoring schedule would substantially avoid its occurrence. Although
it usually occurs late into treatment,32 there are several
reports on early occurrence, even after one or two doses
of MTX.31,33 The outcome is grave, with a reported mortality rate ranging from 17%31 to as high as 44%,33 most
commonly resulting from infections and bleeding disorders.
Physicians need to be alerted to this potentially lifethreatening complication, if not to avoid it, then at least
to recognize it as early as possible and promptly take the
appropriate measures.
Pulmonary Complications
Although the major safety concern of MTX is its hepatotoxicity, it is less known that pulmonary toxicity is only
slightly less common and not less serious: It is the reason for withdrawal of MTX in 1 in 108 patient-years
compared with 1 in 35 patient-years for hepatotoxicity.
The prevalence of MTX-induced pneumonitis is reported
to be 0.3%–7.5%,34 and more than 120 cases have been
reported in the English language literature since its first
description in 1969.34 Pneumonitis following MTX is a
serious, potentially fatal hypersensitivity reaction and is far
less predictable than hepatic and hematological toxicity.
A review of 123 published cases of MTX-induced pneumonitis showed a mortality rate of 13%.34 Although most
patients with MTX pneumonitis have the subacute type
with progression over several weeks, a life-threatening,
acute type with rapid progression over only a few days
has also been reported.34,35 Differentiation between MTX
pneumonitis and acute respiratory infection is not always
easy, despite the accepted diagnostic criteria.36 A suggested
management approach34,35 for a patient with suspected
MTX-related lung pathology consists of MTX discontinuation, supportive therapy, and (most important) a comprehensive diagnostic procedure to exclude infection. It
should consist of extensive cultures of sputum, blood, and
bronchoalveolar lavage (BAL) fluid and serological testing
for common respiratory viruses, Mycoplasma, Rickettsia, and
Legionella. Microscopic examination of BAL fluid is recommended to exclude P. jiroveci, fungi, and mycobacteria.
Because excluding infection might sometimes be difficult
and time consuming in cases where rapid treatment might
CYCLOSPORINE A
Cyclosporine A (CsA) has a range of side effects that is the
subject of much concern. It may seem surprising that this
drug is generally well tolerated and, ironically, the good
tolerability itself can represent a hazard, because patients
are not likely to be aware of any signs of its chronic toxicity.
Nephrotoxicity and Hypertension
The major safety concerns of CsA are nephrotoxicity, hypertension, and the potential risk of malignancy.
There are three different forms of CsA nephrotoxicity: 1)
reversible acute renal dysfunction, 2) hemolytic-uremic–
like syndrome, and 3) irreversible chronic nephrotoxicity.
CsA-induced acute nephrotoxicity is a hemodynamically mediated phenomenon characterized by the absence
of permanent structural changes and by reversibility with
decrease or discontinuation of the drug. It is a dose-related,
clinically asymptomatic increase in serum creatinine, which
can occur even when drug blood levels are in the therapeutic range. In these patients, renal histology is usually normal
or shows only nonspecific changes, such as vacuolization or
the presence of giant mitochondria in tubular cells.37
Recurrent or de novo hemolytic-uremic syndrome is
rare, generally multifactorial, and seldom related exclusively to CsA.37,38 It occurs mainly in bone-marrow
and solid-organ–transplanted patients and has not been
reported in patients on CsA therapy for dermatological diseases.39
Chronic CsA nephrotoxicity is an insidious condition
associated with an irreversible and progressive renal interstitial fibrosis, followed by decrease in renal function.37 It
is a clinicopathologic entity related to long-term exposure
to CsA, and is never acute.
Neurotoxicity
Observations of acute neurotoxicity in conjunction with
high concentrations of CsA in blood were reported soon
after CsA’s introduction into clinical practice in 1979.40
Subsequently, severe neurotoxicity resulting from CsA
treatment was frequently reported in bone-marrow and
solid organ recipients, but also in patients with dermatological41 or autoimmune diseases.42 Neurotoxicity had
been less well known, but with growing experience, central nervous system side effects are now reported in up to
40% of patients treated with CsA.43–45 The most commonly noted neurologic finding is tremor, appearing in
20%–40% of patients treated with the drug.43,44 This side
effect is not particularly distressing for most patients and
Chapter 17
tends to diminish with time. Visual hallucinations are less
frequently reported, and cortical blindness is extremely rare
and reversible in most (although not all) patients.44 A mild
encephalopathy due to CsA was reported in up to 30% of
patients, and cessation or reduction in dose is usually followed by relief of symptoms.43,44 Severe encephalopathy,
altered level of consciousness, psychosis, and coma have all
been reported as well.43,44
Seizures were reported to occur in 1.5%–6% of CsAtreated patients. Most patients suffer a single seizure, without recurrence after dose reduction, although rare cases
with status epilepticus have been reported.43
In summary, CsA induces neurological side effects in
up to 40% of patients. The symptoms can be mild (e.g.,
tremor, headache, and neuralgia), moderate (e.g., visual disturbances and cortical blindness), or severe (affecting up to
5% of patients; e.g., altered level of consciousness, confusion, seizures, and coma). These side effects are almost
always reversible on reduction or cessation of treatment;
however, permanent changes have also been reported.
Physicians should be aware of these acute side effects of
the drug.
RETINOIDS (ISOTRETINOIN)
Isotretinoin (13-cis-retinoic acid) is a synthetic oral retinoid
that has high efficacy against severe, recalcitrant, and nodulocystic acne.
Isotretinoin, a vitamin A derivative, interacts with many
of the biologic systems of the body and, as such, has a
diverse pattern of adverse effects, not unlike that seen in
hypervitaminosis A. The side effects involve the mucocutaneous, musculoskeletal, metabolic, gastrointestinal, hepatobiliary, ophthalmic, and central nervous systems, as well
as headaches. Most of the adverse effects are mild and temporary and resolve after the drug is discontinued: Some rare
complications persist; these will be discussed here.
In a recent retrospective analysis of 1193 suspected pediatric adverse drug reactions (ADRs) reported to Health
Canada (1998–2002),46 41 reports included a fatal outcome
of which isotretinoin was responsible for two, making it
second (together with six other drugs) to olanzapine, with
3 fatal cases. Of 14 cases that were defined as “recovered
with sequelae,” isotretinoin with three cases was alone in
first place.
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Severe, Acute Complications of Dermatologic Therapies
173
necessary.”47 This warning notwithstanding, the issue is
still not entirely clear. Although studies (mostly sponsored)
conclude that the existing reports do not meet the required
criteria for establishing causality between the ingestion of
isotretinoin and suicide or major depression, and furthermore claim that the risk of depressed mood is no greater
during isotretinoin therapy than during other therapy of an
age-matched acne group, the link between psychiatric disorders and isotretinoin remains a controversial issue.47–50
Intracranial Hypertension
Severe headache is the most frequently reported adverse
effect of isotretinoin.51,52 About one fourth of the cases are
caused by pseudotumor cerebri. Although this side effect is
almost always reversible and leaves no sequelae, it can have
a devastating outcome (there are cases of irreversible blindness), if not recognized early enough and treated appropriately.
Ocular Side Effects
These are common although rarely serious. Fraunfelder
and colleagues53 described a number of cases of optic neuritis, cortical blindness, corneal ulcers, and glaucoma that
were possibly associated with isotretinoin.
Gastrointestinal and Hepatobiliary Side Effects
Gastrointestinal together with hepatobiliary side effects are
the second most commonly reported adverse reactions after
psychiatric disorders.46
Although IBD is described as a possible ADR in the
product information of isotretinoin, this association has
been given little attention in the literature. There are many
cases of IBD reported to the FDA and World Health Organization (101 reports on isotretinoin and ulcerative colitis,
and 35 reports on isotretinoin and Crohn disease), and cases
of IBD are significantly more often reported in association
with isotretinoin than with other drugs, thus supporting an
association between the drug and the condition.54
Derangements of lipid metabolism leading to increased
triglyceride and cholesterol levels are well-known side
effects of retinoid therapy and are usually harmless,
although the rare cases of marked hyperlipidemia associated with pancreatitis are always serious and of major concern.50,55,56
Psychiatric Disorders
Grave side effects attributed to isotretinoin are depression, psychosis, suicide, and suicide attempts. On February 25, 1998, the FDA mandated a change in the label
warning to include, “Psychiatric disorders: Accutane may
cause depression, psychosis and rarely, suicide ideation,
suicide attempt and suicide. Discontinuation of Accutane
therapy may be insufficient; further evaluation may be
IV IMMUNOGLOBULIN
IV immunoglobulin (IVIG) is a blood product consisting
primarily of intact IgG molecules, which are derived from
pooled normal human plasma of between 1000 and 15,000
donors per batch. Its dermatological uses are Kawasaki
disease, therapy-resistant dermatomyositis, toxic epidermal
174 E MERGENCY D ERMATOLOGY
necrolysis, and the blistering diseases, particularly pemphigus. Examples of conditions for which the evidence consists
mainly of case series or reports include atopic dermatitis,
chronic immune urticaria, scleromyxedema, erythema multiforme, and others.
Several serious, acute, and potentially fatal adverse
effects are known to be associated with IVIG therapy. Fortunately, these side effects are rare.
Acute Renal Failure
One of the most significant concerns of IVIG therapy is its
association with acute renal failure. Interestingly, it is not
the immunoglobulins that mostly cause renal insufficiency,
but the sugar that is added to some of the products to stabilize the solution and minimize aggregate formation. Up to
90% of the IVIG-associated renal adverse events have been
linked to sucrose-containing preparations.57,58 The pathomechanism is osmotic nephrosis. Sucrose is a disaccharide that is enzymatically cleaved into glucose and fructose
when it is ingested orally; however, the cleaving enzyme is
not present in the blood or kidney, so, when given IV, the
sucrose molecule remains intact and is excreted through
the kidney. During this process, the sucrose is taken up
(pinocytosed) into the proximal tubular cells, causing an
osmotic gradient and leading to the entrance of fluid into
the cells and to cell damage (“osmotic nephrosis”).
An extensive review of the literature58 comparing a
group of patients with IVIG nephrotoxic effects published
as case reports (Group A) with patients whose data were collected by the FDA (Group B) provides a useful picture of the
demographic and clinical data of this side effect. In Group
A, 45% of the patients had preexisting renal disease. Most
(90%) of the patients in Group B and 72% of the patients
in Group A received sucrose-containing IVIG products
(a difference that might stem from the tendency to report
unusual cases). Acute renal failure onset was between 1 and
10 days following IVIG administration. A high percentage
of patients required hemodialysis (i.e., 31% in the published
cases and 40% in the FDA report). The duration of the
renal failure ranged from 3 to 45 days and was reversible in
about 85% of the cases, with return of serum creatinine levels to baseline. Death occurred in 10%–15% of all patients
in both groups despite treatment. All deaths involved
patients with severe underlying medical conditions (pneumonia, cardiac disease, and SLE): The extent to which renal
failure contributed to their deaths was undetermined.
General guidelines have been established to minimize
the incidence of acute renal failure from IVIG.59,60 Patients
should be adequately hydrated prior to any infusion. If their
clinical condition permits, they can skip the morning dose
of a diuretic on the days of infusion. The recommended
dose of IVIG should not be exceeded, and recommended
infusion rates should be strictly followed. Urine output
should be monitored during the infusion. Periodic monitoring of the serum creatinine level is indicated in high-risk
patients. The infusion should be discontinued if deterioration in renal function is detected. The need for dialysis
therapy is determined on an individual basis.
Stroke
Stroke is a rare but potentially fatal side effect of IVIG therapy. One review of a series of 16 cases61 and an additional 13
case reports59 provided the clinical features of this unusual
occurrence. Most patients had received an IVIG dose of
2 g/kg/cycle. All of them had received IVIG at the recommended infusion rate or slower. Most patients developed
stroke within 24 hours of completing an infusion, indicating a direct temporal relationship to the administration
of IVIG. Slightly more than one half of the patients were
receiving their first cycle of IVIG, suggesting that factors
intrinsic to certain patients may have put them at higher
risk for stroke than others. Common risk factors for stroke
were present in most of the patients.
Currently, there is no clear understanding of the pertinent pathophysiology of this serious and sometimes fatal
side effect, so there are no recommendations for prophylaxis and treatment. The only suggestion we can offer is
that all patients who are being evaluated for potential IVIG
therapy need to be questioned about known risk factors for
stroke. The risk-to-benefit ratio of using IVIG in these
patients needs to be discussed with patients and family
members.59
Arterial and Venous Thrombotic Complications
Including Myocardial Infarction
One series and review of literature analyzing this complication was recently published in a dermatologic journal.62
This series demonstrates that IVIG-related thrombotic
arteriovenous complications are not uncommon in patients
with autoimmune disorders (6 [13%] of 46 patients developed IVIG-related thrombotic complications). Thrombotic complications frequently occurred during IVIG infusion (50%), although they were also observed within 1–8
days following IVIG infusion in other patients. Three of six
patients developed deep venous thrombosis or pulmonary
embolism, two developed myocardial infarction, and one
suffered a stroke. Although the outcome of the thrombotic complications was favorable in all their patients, the
authors’ literature review indicates a serious outcome with
a mortality rate of 20%–30%,62 with 15% of the patients
dying of IVIG-associated thrombosis.
In another large series of 279 IVIG-treated patients,63
5 (1.8%) developed acute myocardial infarction during or
shortly after (3–5 hours) infusion. These cases occurred
with the use of only one brand (Polygam).
Chapter 17
As with other complications of this therapy, there are no
specific recommendations except for reweighing the riskto-benefit ratio, close monitoring, infusion at a slow rate,
and (if possible) administering not-too-high doses after
good hydration in patients with underlying predisposing
factors. No consensus has been reached on the use of prophylactic antiplatelets or anticoagulants.
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Severe, Acute Complications of Dermatologic Therapies
175
serious dermatological diseases, this chapter deals with the
other side of the coin – namely, the adverse effects, consequences, and risks of our treatments.
This chapter identified five major drugs or drug groups
(biologics, MTX, CSA, retinoids, and IVIG) used in dermatology that are associated with an element of risk in causing
serious and sometimes fatal adverse reactions. Basic principles of diagnosing, monitoring, and treating these adverse
effects were presented.
Aseptic Meningitis
Aseptic meningitis is an inflammation of the meninges that
clinically presents with headache, nausea, vomiting, fever,
photophobia, painful eye movements, and nuchal rigidity.
Drug-induced aseptic meningitis (DIAS) is usually benign,
the clinical course is short lived, and there is spontaneous
resolution of the symptoms without sequelae within hours
to days after discontinuation of therapy. No deaths were
reported in association with this syndrome.64,65
The main challenge for the clinician is, however, the
diagnosis. The differential diagnosis of DIAS is broad and
includes infectious causes. Bacterial meningitis has symptoms that are similar, if not identical, to those of DIAS,
and these two entities cannot be distinguished on clinical
grounds. Bacterial culture of the CSF may help in the diagnosis. Treatment with third-generation cephalosporins has
been suggested in cases where the presence of bacterial
meningitis is a possibility.64 Viral aseptic meningitis is
another important consideration in terms of frequency,
although less critical in terms of prognosis and management. Finally, other noninfectious causes of aseptic meningitis should be considered, such as SLE aseptic meningitis,
as well as other drugs that can cause the syndrome. Intracranial bleeding, especially in patients with idiopathic thrombocytopenic purpura and bleeding disorders, must also be
considered. Computed tomographic scans can be used to
rule out hemorrhage.
CONCLUSIONS
Dermatologists have the good fortune to work on the most
accessible organ of the body. This gives them numerous
advantages and greatly facilitates not only the diagnosis
but also the treatment of the skin disease, because many
inflammatory and neoplastic conditions can be effectively
managed using a wide range of externally applied modalities. All this notwithstanding, many serious, widespread,
and life-threatening dermatoses often need to be treated
with potent systemic therapies. Because systemic drugs are
increasingly available, and are often essential and indispensable for the treatment of dermatological diseases, drug toxicity and adverse events are a significant problem. In view
of the continuing development of new and effective therapies, it is expected that their incidence will not decrease.
Whereas this book is mostly devoted to the treatment of
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Severe, Acute Complications of Dermatologic Therapies
177
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CHAPTER 18
Severe, Acute Allergic and Immunological
Reactions I: Urticaria, Angioedema,
Mastocytosis, and Anaphylaxis
Samuel H. Allen
BACKGROUND
Local wheals (synonyms: “nettle rash,” hives) and erythema
that resemble the effect of the common stinging nettle
(Urtica dioica) on the skin is known as urticaria. The edema
involves superficial skin to the mid-dermis. Pruritus is common.
Angioedema (synonyms: angioneurotic edema, Quinke’s
edema) produces a similar eruption but with larger edematous areas that affect both the dermal and subcutaneous
and/or submucosal tissues. Angioedema is usually painful
rather than itchy and is less well defined or normal in
color. Both types of reaction can be triggered by drug allergies, insect stings or bites, desensitisation injections, cold
temperature, other physical stimuli, or ingestion of certain
foods, particularly eggs, shellfish, nuts, or fruits.
Mastocytosis is caused by an abnormal conglomeration
of mast cells at a particular site. Degranulation, through
rubbing or contact, triggers release of excessive histamine,
resulting in localized swelling.
Anaphylaxis represents an extreme form of acute allergic reactions that is mediated by immunoglobulin E (IgE).
Anaphylaxis is an example of a type I hypersensitivity reaction (see Chapter 19). Although erythema, urticaria, and
angioedema may all occur, it is the systemic hypotension
and shock that determine the outcome. It is a clinical emergency characterized by profound shock that may rapidly
lead to cardiorespiratory arrest. A similar picture from nonallergic causes is called an “anaphylactoid reaction.”
URTICARIA
urticarias (Table 18.1). The trigger may not always be
identified, even when such reactions are recurrent. This
can be a frustration to the patient and the dermatologist
alike. Urticaria may accompany, or even be the first symptom of, severe viral infection including hepatitis, infectious
mononucleosis, and rubella. Similar lesions may precede,
or be associated with, vasculitis (urticarial vasculitis), pemphigoid, or dermatitis herpetiformis.
Dermatographism is a wheal-and-flare reaction seen
after scratching or stroking the skin firmly with a hard
object, and is caused by an exaggerated release of histamine.
Pressure urticaria is caused by sustained pressure from tight
clothing, hard seats, and stiff footwear and may present as
an immediate or late (4–6 hours, occasionally 24 hours)
reaction to the pressure stimulus. Cold urticaria varies in
severity and is induced by cold wind or bathing in cold
water. Bronchospasm and histamine-mediated shock occur
in extreme cases and may result in drowning. In its rare
familial form it appears in infancy. Abnormal serum proteins may be found.
Warm environments often exacerbate the physical
urticarias, but pure heat urticaria is rare. Solar urticaria
is likewise a rare condition in which ultraviolet rays from
sunlight cause an urticarial eruption. Aquagenic urticaria
is independent of temperature and occurs on skin contact
with water. Cholinergic urticaria appears to be caused by
an unusual sensitivity to acetylcholine and is characterized
by small, highly pruritic, discrete wheals surrounded by
a large penumbra of erythema that occur after exertion,
stress, or heat exposure. A skin challenge test using methacholine 1:5000 may reproduce the lesions in about one third
Urticaria (see Figure 18.1) may result from different stimuli on an immunologic or nonimmunologic basis. The
most common immunologic mechanisms are hypersensitivity mediated by IgE and activation of the complement
cascade.
The physical urticarias, which account for approximately 25% of cases, include dermatographism and the
pressure, cold, heat, solar, cholinergic, and aquagenic
page 178
TABLE 18.1: Physical Urticarias
Pressure
Cold
Heat
Solar
Cholinergic
Aquagenic
e.g., dermatographism
Chapter 18
●
Severe, Acute Allergic and Immunological Reactions I
179
URTICARIA
PHYSICAL
URTICARIA
NO
YES
PROVOKED BY
DIRECT CONTACT
WITH A
SUBSTANCE?
Simple or retarded
dermographism
rub with a blunt tip
If duration is longer than 6 weeks
CHRONIC IDIOPATHIC URTICARIA
NO
NO
OF GENETIC
ORIGIN?
NO
YES
Solar urticaria
photosensitivity test
Cholinergic urticaria
small papules
induced by heat,
physical effort, stress
Cold urticaria
test with ice cube
sheathed in plastic
Heat urticaria
test with test tube of
hot water
YES
Contact urticaria
rapid result patch test,
prick test, or scratch test
Hereditary
angioneurotic edema
investigate for
deficiency of C1
esterase inhibitor
Aquagenic urticaria
immersion test: hand in
water at ambient
temperature
Delayed pressure urticaria
test pressure with a
weight strapped on to
the body
Vibratory angioedema
occupational
e.g., pneumatic
hammer-drill
OF SYSTEMIC
ORIGIN?
Lesions persisting for
more than 24h, not very
itchy, accompanied by
joint pains, myalgias;
histopathological
appearance that of
vasculitis
NO
MEDICAMENTOUS
OR FOOD ALLERGY
YES
NO
INFECTIOUS
ORIGIN
YES
Investigate for:
SLE
Still disease
Macroglobulinemia
Blood disease
Hyperthyroidism
Urticarial vasculitis
Painstaking history
with regard to:
drugs
(especially
acetylsalicyclic acid)
food
(especially
preservatives and
colorings)
provocation tests
YES
Hepatitis A, B, or C
Infectious mononucleosis
Parasitosis
Focus of bacterial infection
Focus of mycotic infection
FIGURE 18.1: Algorithmic approach to urticaria. Adapted from Lachapelle JM, Tennstedt D, Marot L. In Atlas of Dermatology. SLE,
systemic lupus erythematosus.
of cases. A more reliable diagnostic method is to induce
the urticarial reaction through exercising the subject with
occlusive dressing to promote sweating.
Chronic urticaria and angioedema with symptoms lasting more than 6 weeks are more difficult to explain;
only rarely can a specific cause be found.1 Some patients
with chronic urticaria demonstrate autoantibodies directed
against mast-cell epitopes with histamine-releasing activity, but these are the exception. Occasionally, chronic
ingestion of an unsuspected drug or chemical is responsible (e.g., from antibiotics used in animal husbandry
that may be present in small quantities in meat for
human consumption, from the use of nonprescription
drugs, or from preservatives, dyes, or other food additives)
(Table 18.2).
Despite anecdotal reports of urticaria occurring with
lymphoma and systemic malignancy, no association was
found in a large epidemiological study by Lindelöf and
colleagues.2 In contrast, a higher frequency of autoimmune disease is found among patients with ordinary urticaria.3
TABLE 18.2: Nonphysical Urticarias
Food allergens
Fish, shellfish (lobster, shrimp, crab), eggs,
dairy products, chocolate, nuts (especially
peanuts), strawberries, pork, tomatoes,
apples, oranges, bananas, celery, beans
Food additives
Tartazine, food dyes, sodium benzoate,
MSG
Salicylates
Aspirin, mesalazine, sulfsalazine, NSAIDs
Other drugs
Penicillins, cephalosporins, blood products,
vaccines, insulin
Infection
Bacterial, viral, protozoal, helminthic
Systemic disorders Autoimmune and collagen-vascular
diseases, reticuloses, SLE
Contact urticaria
Meat, fish, vegetables, plants (common
stinging nettle, poison ivy, giant hogweed,
sumac), animals, insects, caterpillars
Papular urticaria
Site of insect bites, bee sting
Inhalants
House dust mite, animal dander, feathers,
grass, pollen
MSG, monosodium glutamate; NSAIDs, nonsteroidal antiinflammatory
drugs; SLE, systemic lupus erythematosus.
180 E MERGENCY D ERMATOLOGY
ANGIOEDEMA
A familial form of urticaria was described by Milton and
termed hereditary angioedema in 1876.4 It is transmitted
as an autosomal dominant trait and thus affects successive
generations. The term of angioneurotic edema was introduced a few years later, as it was believed that mental stress
could precipitate attacks.5 Hereditary angioedema is now
known to be associated with a deficiency in serum inhibitor
of the activated first component of complement.6
The genetic defect has been mapped to chromosome
11. More than 100 different mutations of the C1-inhibitor
gene have been described. In 85% of cases, the deficiency
is due to lack of C1 esterase inhibitor; in the remainder,
a malfunction to C1 inhibitor is the cause. A spontaneous
mutation is found in up to 25% of cases.7
Worldwide, the incidence of hereditary angioedema
varies between 1:10,000 and 1:150,000. Seventy-five percent of patients present before the age of 15 years.
In contrast to urticaria, angioedema affects both the
reticular dermis and subcutaneous tissues. Recent data suggest that histamine-releasing immunoglobulin G (IgG)
antibody directed against ε region of the constant fragment (Fc ), or anti-Fc ε antibodies are the cause of the disease, removal or suppression by immunomodulation being
followed by remission.8
Most patients with hereditary angioedema have a personal or family history of recurrent attacks of angioedema
or abdominal pain. An important exception to this is
where a spontaneous mutation has occurred. Attacks are
often precipitated by trauma including surgical procedures,
pregnancy, viral illness, emotional stress, and drugs such
as estrogen and angiotensin-converting enzyme (ACE)
inhibitors. The combination of ACE inhibitors and estrogens is contraindicated.
Cutaneous angioedema of the extremities is the first
presenting sign in 75% of patients. The edema tends to
be recurrent, is nonpitting in nature, and demonstrates
a rapidly expanding unifocal, indurated swelling that is
painful rather than pruritic. Urticaria is not part of the syndrome. The areas usually affected are the extremities, genitalia, and face. Twenty-five percent of patients also suffer
from gastrointestinal (GI) symptoms including abdominal
cramps, nausea, vomiting, colic, and (occasionally) signs of
obstruction.
Cutaneous signs of angioedema usually develop gradually over 12–36 hours and may last up to 5 days whereas the
GI symptoms usually subside with 24 hours. Conversely,
upper airway obstruction may develop rapidly within 20
minutes of onset resulting in an acute respiratory syndrome
that may prove fatal. Up to 40% of all undiagnosed patients
die as a result of upper airway obstruction.
MASTOCYTOSIS
Mastocytosis is a condition of unknown etiology characterized by an excessive accumulation of mast cells in various
body organs and tissues. Mastocytosis occurs in three
forms: 1) mastocytoma (a benign cutaneous tumor), 2)
urticaria pigmentosa that is characterized by multiple colored or brown macules or papules that urticate when stroked and may become vesicular or even bullous, and 3) systemic mastocytosis in which there are mast-cell infiltrates
in the skin, lymph nodes, liver, spleen, GI tract, and bones.
Patients with mastocytosis suffer from arthralgias, bone
pain, and anaphylactoid reactions. Other symptoms result
from overstimulation of H2 histamine receptors, leading to
peptic ulcer disease and chronic diarrhea.
ANAPHYLAXIS
Anaphylaxis is an acute systemic reaction that occurs in
a previously sensitized person who is reexposed to the
sensitizing antigen. The most common antigens are foreign serum, parenteral enzymes, blood products, -lactam
antibiotics, other drugs, and wasp and bee stings. Anaphylaxis may be aggravated or even induced by exercise.
It is an IgE-mediated reaction that occurs when antigen
(foreign protein, polysaccharide or hapten coupled with a
carrier protein) reaches the circulation. Leukotrienes, histamine, and other mediators are generated or released when
the antigen reacts with IgE on sensitized mast cells and
basophils. These mediators cause smooth muscle contraction responsible for wheeze and GI symptoms as well as
vascular dilatation that leads to circulatory collapse. Capillary leakage into the tissues causes urticaria and angioedema
and results in a further decrease in the plasma volume leading to shock. Fluid may leak into the alveoli and produce
pulmonary edema. Obstructive angioedema of the upper
airway may also occur. Finally, profound hypotension may
result in arrhythmia and cardiogenic shock.
Typically the patient feels uneasy for approximately 1–
15 minutes after exposure to the allergen. The patient
then becomes more agitated and flushed. He or she may
experience palpitations, paresthesias, pruritus, throbbing
in the ears, coughing, sneezing, and difficulty in breathing
due to laryngeal edema or bronchospasm. Urticaria and
angioedema may be evident. Nausea, vomiting, and abdominal pain and diarrhea are less common. Shock develops
within another 1–2 minutes, and the patient may become
incontinent, convulse, and lose consciousness.
CLINICAL AND LABORATORY AIDS REQUIRED
FOR DIAGNOSIS
Urticaria
Urticaria is a clinical diagnosis. In urticaria, pruritus (generally the first symptom) is followed shortly by the appearance
of wheals that may remain small (1–5 mm) or may enlarge.
The larger ones tend to clear in the center and may be
noticed first as large rings (>20 cm across) of erythema and
edema. Ordinarily, crops of hives come and go; a lesion may
Chapter 18
appear in one site for several hours, then disappear only to
reemerge at another site later. The changing morphology
of lesions that may evolve over minutes to hours may lead
to geographic or bizarre patterns.
The cause of acute urticaria is usually self-evident. Even
when it is not so obvious, a diagnostic investigation is seldom required because of the self-limiting nature of the
eruption.
In cases of chronic urticaria, a careful history, examination, and screening tests should be carried out to eliminate
possible underlying systemic lupus erythematosus, polycythemia rubra vera, vasculitis syndrome, or infection. A
few patients with intractable urticaria are hyperthyroid. A
serum-sickness–like prodrome with urticaria may be associated with acute hepatitis B. Quantitative immunoglobulins,
cryoglobulins, cryofibrinogens, and antinuclear antibodies
are often sought in cold urticaria but rarely found. Although
often suspected, controllable psychogenic factors are rarely
identified.
The histological changes may be very slight but usually there is edema, vascular and lymphatic dilatation, and
a variable perivascular cellular infiltrate of lymphocytes,
monocytes, polymorphs, and histiocytes. On electronmicroscopy, dermal mast cells show signs of degranulation.
Various vasoactive substances are thought to be involved
including histamine, kinins, leukotrienes, prostaglandins,
and complement.
Urticarial lesions lasting more than 24 hours raise the
possibility of this being a vasculitic disorder. Urticarial
lesions of vasculitic etiology are more fixed than in classical
urticaria. They last for 2–3 days and are frequently accompanied by joint pains and fever. Reduced serum complement levels with raised inflammatory markers are observed.
A skin biopsy is most useful in these circumstances as
urticarial vasculitis is an uncommon entity.
Angioedema
Angioedema represents a more diffuse swelling affecting
the loose subcutaneous and/or submucosal tissues. The
dorsum of the hands or feet, eyelids, lips, and genitalia are
the usual sites affected. Involvement of the mucous membranes may present as wheeze or stridor that may be mistaken for asthma. Edema of the upper airway is potentially
life-threatening.
The diagnosis of hereditary angioedema is made by
measuring complement C4 levels, which remain low, even
between attacks. This test carries 100% sensitivity and
100% negative predictive value in an untreated patient. A
low C1 inhibitor level will confirm the diagnosis. If the C1
inhibitor is unexpectedly normal, a C1 functional assay can
be performed.
Mastocytosis
In localized mastocytosis, the histamine content in tissue
is usually high, commensurate with the elevated mast cell
●
Severe, Acute Allergic and Immunological Reactions I
181
concentration. In systemic mastocytosis, urinary excretion
of histamine and its metabolites are high. Plasma histamine
and prostaglandin D2 may also be elevated.
Anaphylaxis
The diagnosis of anaphylaxis is usually self-evident when
there has been exposure to a known allergen. In the case of
unknown exposure, increased IgE and serum tryptase levels will strongly support the diagnosis. It is worth remembering, however, that anaphylaxis may be immediate or
delayed. Even in the case of a bee sting, anaphylaxis may
be delayed for up to 20 minutes due to the rate of absorption of the toxin from the embedded sting sac. Acute lifethreatening edema of the airway can occur more immediately when there is local swelling following a bee or wasp
sting to the pharynx, which may occur when the insect has
inadvertently fallen into a beer can or glass and is unknowingly drunk by the unsuspecting partygoer.
DIFFERENTIAL DIAGNOSIS
Differential diagnosis for urticaria and angioedema
includes persistent papular eruptions from insect bites such
as flea or gnat bites. These eruptions can usually be distinguished from the urticarias by their central punctum.
Contact urticaria may be caused by a host of substances
varying from chemicals to foods to medications, but it is
usually limited to areas exposed to the contactant. Streaked
urticarial lesions may be seen in acute allergic plant dermatitis (e.g., poison ivy, oak, or sumac). Phytophotodermatitis is caused by the exposure of skin to plant extracts
and sun and is common in hot climates (e.g., where lime
juice is used in cocktails). The possibility of protoporphyria should be considered in any sun-related pruritic
reaction.
The differential diagnosis for anaphylaxis includes all
causes of shock (e.g., acute internal hemorrhage, sepsis syndrome, cardiogenic shock) and the Waterhouse–
Friderichsen syndrome.
THERAPY
Urticaria
Acute urticaria is a self-limited condition that generally
subsides in 1–7 days. Treatment is chiefly palliative. If the
etiological trigger is known, it should be avoided. A specific
exclusion diet (e.g., salicylate and tartrazine-free diet) may
be helpful. If the cause is not apparent, all nonessential
drugs should be discontinued until the reaction has subsided.
If treatment is indicated, the initial management will include H1 antihistamines. Doses should be increased weekly
to tolerance. Antihistamines from different classes may
be systematically tried if initial choice is ineffective or
182 E MERGENCY D ERMATOLOGY
intolerable. Combinations of different antihistamines are
often effective.
Most symptoms can usually be relieved with diphenhydramine 50–100 mg every 4 hours, hydroxyzine 25–
100 twice a day, or cyproheptadine 4–8 mg every 4
hours. Hydroxyzine is the preferred drug for cholinergic
urticaria; anticholinergic drugs are ineffective at tolerable
doses.
Terfenadine (60 mg b.i.d.) is a nonsedating antihistamine that has been reported to be effective in chronic
idiopathic urticaria. Concomitant use with erythromycin
(and related macrolide antibiotics) or ketoconazole (and
related imidazole) leads to increases in the plasma levels
that may cause cardiac arrhythmias. It is not recommended
in lactating or pregnant women. Another nonsedating antihistamine, astemizole, has been reported to be effective
in the majority of patients with seasonal allergic rhinitis
and chronic idiopathic urticaria.9,10 The long half-life of
astemizole is a major disadvantage if skin-prick testing is
needed or if the patient becomes pregnant while on therapy. Another less sedating antihistamine approved for use
is loratadine in a dosage of 10 mg daily. It has a shorter
half-life than astemizole and is similar to the other antihistamines in its effectiveness. It appears not to interact with
imidazole antifungals or macrolide antibiotics.
Oral antihistamines with tranquilizing properties are
usually beneficial (e.g., hydroxyzine 25–50 mg b.i.d. or
cyproheptadine 4–8 mg q 4–8 h for adults; for children,
hydroxyzine 2 mg/kg/day divided q 6 h, and cyproheptadine 0.25–0.5 mg/kg/day divided q 6–8 h).
Doxepin (a tricyclic antidepressant) 25–50 mg twice
daily, or more commonly 25–75 mg at bedtime, may be the
most effective agent for some adult patients. It should be
used with caution because of its anticholinergic side effects
and promotion of cardiac arrhythmias.
Prednisone in a dose of 40 mg daily may be necessary in
more severe cases of urticaria and in cases of angioedema.11
It will usually suppress both acute and chronic forms of
urticaria; however, the use of systemic glucocorticoids is
rarely indicated because properly selected combinations of
agents with less toxicity are usually effective. Furthermore,
after steroids are withdrawn, the urticaria virtually always
returns if it had been chronic.
Other agents with some promise as adjuvant therapy
include calcium channel blockers (used for at least 4 weeks),
terbutaline 1.25–2.5 mg three times a day, and colchicine
0.6 mg twice a day.
Local treatment is rarely of benefit. Starch baths twice
daily or Aveeno baths, prepared by adding one cupful of
finely refined cornstarch or a packet of Aveeno to a comfortably warm bath, may alleviate symptoms in some patients.
Alternatively, one may use a lotion containing 0.5% camphor, 0.5% menthol, and 0.5% phenol topically or in addition to the bathing. Topical glucocorticoids should not be
used.
Hereditary Angioedema
Hereditary angioedema may present as a medical emergency that requires rapid therapeutic intervention. The
edema progresses until the complement components have
been consumed. Iatrogenic cases are not uncommon.
Acute attacks that threaten to produce airway obstruction should be treated promptly by establishing an airway.
Aminocaproic acid 8 g every 4 hours may succeed in terminating the attack. Epinephrine, an antihistamine, and a
glucocorticoid should be administered even though the evidence base is unproven. Parenteral pain relief, antiemetics,
and intravenous fluid replacement are recommended for
abdominal attacks.
Replacement therapy using C1 inhibitor is the only therapy that has been successfully used in a prospective doubleblind, placebo-controlled trial.12 Although not available in
the United States, it has been the treatment of choice in
Europe for more than 20 years.
A partially purified C1 inhibitor fraction of pooled
plasma has been shown to be safe and effective for prophylaxis (e.g., prior to a dental procedure or endoscopy).13
Alternatively, 2 units of fresh frozen plasma can be given.
Although a complement substrate in the plasma might provoke an attack, this has not been observed in symptom-free
patients.
Long-term management will have to take into account
both the frequency and severity of attacks as well as special circumstances such as pregnancy, surgical procedures,
and children. For long-term prophylaxis of hereditary
angioedema, androgens are effective. One of the impeded
androgens should be used. Treatment is commenced with
stanozolol 2 mg times a day or danazol 200 mg three times
a day. When control is achieved, the dosage should be
reduced as much as possible to minimize masculinizing side
effects in women and reduce the cost. These drugs are not
only effective but also have been shown to raise the low C1
inhibitor and C4 toward normal.
Mastocytosis
Cutaneous mastocytosis usually develops in childhood.
The solitary mastocytoma will usually involute spontaneously. Urticaria pigmentosa either clears completely or
is substantially improved by adolescence. These conditions rarely, if ever, progress to systemic mastocytosis.
Treatment with an H1 antihistamine is usually all that is
needed.
If systemic mastocytosis ensues, the symptoms should
be treated with an H1 or H2 antihistamine. Aspirin therapy
may be tried, but with caution as this may enhance production of leukotrienes. For GI symptom control, oral cromolyn sodium 200 mg four times a day (100 mg four times
a day for children 2–12 years old) should be given. There
is no effective treatment available to reduce the number of
tissue mast cells.
Chapter 18
Anaphylaxis
Severe reactions with generalized swelling, urticaria, angioedema, dizziness, sweating, pounding headache, stomach
cramps, chest tightness, and a sensation of choking or
impending doom may signify an impending anaphylaxis.
In cases of acute pharyngeal or laryngeal angioedema,
epinephrine 1:1000, 0.5 mL by subcutaneous injection
should be given immediately. Nebulized epinephrine 1:100
dilution and intravenous antihistamine (e.g., diphenhydramine 50–100 mg) will usually prevent airway obstruction. Urgent intubation or emergency tracheostomy may
be required, followed by 100% O2 therapy and resuscitation. (See Chapter 19. Allergy to bee sting as an example
of a type I allergic hypersensitivity [anaphylaxis] reaction.)
Confirmation that an allergic reaction has taken place
can be made by measuring the serum tryptase. Most deaths
will occur because of delays in accessing emergency treatment.
COURSE AND PROGNOSIS
Most episodes of acute urticaria and angioedema are acute
and self-limited and resolve spontaneously over a period
of 1–2 weeks. In about half the cases of chronic urticaria,
spontaneous remissions occur within 2 years. Control of
stress often helps to reduce the frequency and severity of
episodes. Alcohol, coffee, and tobacco should be avoided as
these may aggravate the symptoms. Certain drugs, such as
aspirin, may also exacerbate symptoms. When urticaria is
produced by aspirin, sensitivity to other nonsteroidal antiinflammatory drugs and to foods or drugs containing the
additive tartazine should be investigated.
Patients with chronic mastocytosis generally have a good
prognosis. The course of an anaphylactic reaction is unpredictable and is largely determined by the speed with which
the patient can access appropriate emergency services.
All patients with a history of anaphylaxis should carry
a preloaded epinephrine syringe (EpiPen; 300 g) for
●
Severe, Acute Allergic and Immunological Reactions I
183
emergencies. Any person with a history of allergy should
wear a MedicAlert bracelet at all times bearing the details
of this allergy.
REFERENCES
1. Greaves MW. Chronic urticaria. N Engl J Med. 1995;
332:1767.
2. Lindelöf B, Sigurgeirsson B, Wahlgren CF, Eklund G.
Chronic urticaria and cancer: an epidemiological study of
1155 patients. Br J Dermatol. 1990; 123:453–6.
3. O’Donnell BF, Swana GT, Kobza Black A. Organ and nonorgan specific autoimmunity in chronic urticaria. Br J Dermatol. 1995; 153 Suppl 45:42A.
4. Milton JL. On giant urticaria. Edinb Med J. 1876; 22:513–26.
5. Quinke H. Uber akutes umschriebenes Hautodem. Monatshefte Prakt Dermatol. 1882; 1:129–31.
6. Donaldson VH, Evans RR. A biochemical abnormality in
hereditary angioneurotic edema; absence of serum inhibitor
of C’1-esterase. Am J Med. 1963; 35:37–44.
7. Tosi M. Molecular genetics of C-inhibitor. Immunobiology.
1998; 199:358–65.
8. Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol.
2005; 53:373–88.
9. Breneman D, Bronsky EA, Bruce S, Kalivas JT, et al. Cetirizine and astemizole therapy for chronic idiopathic urticaria:
a double-blind, placebo-controlled, comparative trial. J Acad
Dermatol. 1995; 33:192–8.
10. Krausse HF. Therapeutic advances in the management of
allergic rhinitis and urticaria. Otolaryngol Head Neck Surg.
1994; 111:364.
11. Pollack CV Jr., Romano TJ. Outpatient management of acute
urticaria: the role of prednisone. Ann Emerg Med. 1995;
26:547.
12. Longhurst HJ. Emergency treatment of acute attacks in
hereditary angioedema due to C1 inhibitor deficiency: what
is the evidence? Int J Clin Pract. 2005; 59:594–9.
13. Gompels MM, Lock RJ, Abinun M, Bethune CA, et al.
C1 inhibitor deficiency: consensus document. Clin Exp
Immunol. 2005; 139:379–94.
CHAPTER 19
Severe, Acute Allergic and Immunological
Reactions II: Other Hypersensitivities and
Immune Defects, Including HIV
Samuel H. Allen
HYPERSENSITIVITY REACTIONS
A hypersensitivity reaction (HSR) is an uncommon, usually immune-mediated response to a drug or other substance. It is estimated that HSRs account for approximately 5%–10% of all drug-related adverse events.
Although severe drug hypersensitivity is rare, it is of concern because it can cause serious illness or death. There
are four basic types of immune-mediated hypersensitivity
(Table 19.1).
Type I – Immediate (Atopic or Anaphylactic)
Type I hypersensitivity is an allergic reaction provoked by
exposure to a specific type of antigen known as an allergen. Exposure may be by ingestion, inhalation, injection,
or direct contact. Type I reactions are characterized by
an exaggerated release of immunoglobulin E (IgE), which
binds to mast cells and basophils. Later exposure to the
same allergen results in cross-linking of bound IgE on the
sensitized cells. This cross-linking causes degranulation
and secretion of pharmacological mediators (such as histamine, leukotriene, and prostaglandin) that act on the surrounding tissues, causing vasodilatation and smooth muscle contraction. The reaction may be local or systemic, and
symptoms may vary from mild irritation to anaphylactic
shock, which is the result of an acute systemic reaction and
can be fatal.
Examples of type I reactions and their triggers include
allergic asthma (house dust mite), hay fever (grass pollen),
allergic rhinitis (animal dander), and nut and drug allergies.
Because it takes some time to produce IgE antibodies, type
I HSRs usually begin at least several days after starting a
new drug. If a person stops the drug and restarts it later,
the reaction can be immediate, because the immune system
is already primed to respond to it. Occasionally, HSRs can
occur for the first time several months (and sometime years)
after starting a drug.
Skin eruptions occur in approximately 90% of type I
HSRs. The most common manifestation is an itchy red
measles-like eruption that typically develops 1–4 weeks
after starting a new drug. A rash often appears first on the
trunk and then spreads outward. The mucous membranes
may be involved.
In Stevens–Johnson syndrome (SJS) and erythema multiforme major, patients develop blisters on the skin and
mucous membranes. Other manifestations may include
fever, aphthous ulcers, and injection of the eyes. Extensive skin loss may occur in toxic epidermal necrolysis. Sections of the skin may die and peel off, leaving raw areas
TABLE 19.1: Types of Hypersensitivity Reaction
Type
Alternative name
Associated disorders
Mediator(s)
I
II
Allergic
Cytotoxic, antibody
dependant
Atopy, anaphylaxis, asthma
Erythroblastosis fetalis,
Goodpasture syndrome,
autoimmune hemolytic anemia
IgE
IgM or IgG (complement)
III
Immune complex
disease
Serum sickness, Arthus
reaction, SLE
IgG (complement)
IV
Cell mediated
Contact dermatitis,
tuberculosis, chronic
transplant rejection
Cell mediated
page 184
Chapter 19
ALLERGY TO BEE STING AS AN EXAMPLE OF
A TYPE I ALLERGIC HYPERSENSITIVITY
(ANAPHYLAXIS) REACTION
Insects of the order Hymenoptera include wasps and bees.
Stinging is a defense mechanism designed to incapacitate
other insects. Bees differ from wasps in that their stinging
apparatus is inserted into the victim on stinging. Sting venom
comprises proteolytic enzymes, phospholipases, metalloproteinases, and toxins. Antigen 5 (or Ves g V) from yellow jacket
wasps (Vespula germanica) and phospholipase (Api m II)
from honeybees (Apis millifera) are the major allergyprovoking venom components. Sensitization to insect venom
can occur after a single sting. Although cross-reaction allergy
can occur, most people remain allergic to either wasp or bee,
but not both.
Pain, redness, and swelling normally occur at the site of
a sting. This is not an allergy, but rather a local toxic reaction to the venom. This reaction evolves over a period of a
few hours and settles within 1–2 days without any adverse
consequences. A more immediate and severe reaction can
occur, however, in an individual who has been sensitized by a
previous wasp or bee sting. If allergic, he or she may develop
a reaction that can vary from mild localized swelling to lifethreatening anaphylaxis. Typically there is localized redness
and swelling spanning two joints, intense itching, and pain.
More severe reactions cause generalized swelling, urticaria,
angioedema, dizziness, sweating, pounding headache,
stomach cramps, chest tightness, and a sensation of choking
and/or impending doom. Symptoms may develop up to 20
minutes after the sting. This represents the time between the
release of the sting and the effect of the venom components
on the victim following the insect attack.
If stung by a bee, the sting sac will continue to actively
pump venom if left in situ. Therefore, if the stinging apparatus is visible, it should be carefully extricated from the flesh
of the victim to prevent further toxin release. The sac should
be removed without squeezing. The honeybee (Apis spp.)
is unique in that it possesses a barbed stinging organ. The
female honeybee, however, carries the stinger and dies
shortly after discharging a sting.
that resemble burns. These reactions are not true allergic reactions but appear to involve the release of inflammatory cytokines in response to a superantigen such as in
toxic shock syndrome (toxic shock syndrome toxin 1 and/or
exfoliatin A or B).
Fever is a common feature of drug-induced hypersensitivity. Other manifestations include soft-tissue swelling,
enlarged lymph nodes, sore throat, cough, difficulty breathing, gastrointestinal (GI) symptoms, dizziness, muscle and
joint pain, blood cell abnormalities, blood vessel inflammation, and liver or kidney dysfunction.
●
Severe, Acute Allergic and Immunological Reactions II
185
TREATMENT OF WASP OR BEE STING
ALLERGIC REACTION
A double dose of oral antihistamine such as chlorpheniramine 8 mg should be administered in adults and older
children. In the case of a generalized reaction, one should
administer immediate intramuscular chlorpheniramine
10 mg, oral corticosteroid (prednisone 30 mg) and give a
-agonist inhaler or nebulizer.
In the case of shock or respiratory difficulties, 0.5 mL
of intramuscular epinephrine (1:1000) plus intramuscular
chlorpheniramine 10 mg and hydrocortisone 200 g should
be administered and arrangements made to transport the
patient to a suitable treatment facility.
All patients with a history of allergy should carry a
preloaded epinephrine syringe (EpiPen 300 g) for emergencies. Repeat injections should be administered every
5 minutes until a satisfactory response is achieved. For
children younger than 5 years, 0.1–0.3 mL of epinephrine
(1:1000) should be administered according to size and age,
and arrangements made to transport the child to an emergency department for further monitoring. Confirmation that
an allergic reaction has taken place can be made by measuring the serum tryptase.
A person known to be wasp or bee allergic should have a
MedicAlert bracelet carrying details of this allergy.
DESENSITIZATION
Venom desensitization immunotherapy is a useful means of
treatment for patients with severe generalized venom allergy
and is particularly useful for beekeepers, horticulturists, and
gardeners. Weekly injections are given during the initial treatment phase and then monthly for another 3 years. At the end
of the therapy the patient should be able to tolerate 100 g of
venom – equivalent to two bee stings – with no adverse reaction. This therapy should be carried out only in specialist clinics where resuscitation facilities are available because there
is a small risk of inducing an allergic reaction. Anti-wasp and
anti-bee venom vaccines are available, but these are wasp
and bee species-specific.
The most severe type of drug-induced allergic reaction
is anaphylaxis, which can occur within seconds or minutes
after restarting a drug to which the person has previously
been exposed. Symptoms include hives, swelling, constriction of the upper airway, falling blood pressure, rapid heartbeat, shock, and cardiovascular collapse.
Treatment depends on the severity of the reaction. Antihistamines and corticosteroids are usually indicated. In the
case of anaphylaxis, immediate epinephrine to maintain
blood pressure should be administered. In all situations,
the provocative agent should be avoided.
186 E MERGENCY D ERMATOLOGY
Type II – Antibody-Dependent
In type II hypersensitivity, the antibodies produced by the
immune response bind to antigens on the patient’s own
cell surfaces. The antigens recognized in this way may be
either intrinsic (self) or extrinsic (foreign) antigens. These
cells are recognized by macrophages and dendritic cells that
act as antigen-presenting cells, causing B cells to respond
by producing antibodies against the foreign protein. Examples of this type of reaction include autoimmune hemolytic
anemia, transfusion reactions, transplant rejection, Goodpasture syndrome, pemphigus, Graves’ disease, myasthenia
gravis, and rheumatic fever. Because the reaction is antibody mediated, the reaction will evolve over a period of
1–3 days.
Type III – Immune Complex
Type II hypersensitivity occurs when antigens and antibodies are present in roughly equal measure, causing extensive cross-linking. Large immune complexes that cannot be
cleared are deposited in tissue to induce an inflammatory
response. The reaction develops over days to weeks. Examples of this type of reaction include rheumatoid arthritis, serum sickness, systemic lupus erythematosus (SLE),
Arthus reaction, farmer’s lung, and polyarteritis nodosa.
Type IV – Cell-Mediated (Delayed-Type Hypersensitivity)
Type IV hypersensitivity is often called delayed type as the
reaction takes 2–3 days to develop. Unlike other types, it
is not antibody mediated but rather represents a type of
cell-mediated response.
Cytotoxic (CD8+) and helper (CD4+) T cells recognize
antigens in a complex with the major histocompatibility
complex molecules class I or II, respectively. The antigenpresenting cells are macrophages or dendritic cells that
secrete interleukin-12 (IL-12). This secretion stimulates
further CD4+ T-cell proliferation. These T cells secrete
IL-2 and interferon-␥ , inducing type I cytokines. Activated
CD8+ cells destroy target cells, and activated macrophages
transform into multinucleated giant cells. This type of reaction is seen in contact dermatitis (e.g., poison ivy), atopic
dermatitis, leprosy, and tuberculosis. The Mantoux reaction is an example of a delayed-type HSR.
IMMUNE DEFECTS
Deficiencies of the immune system may result in recurrent infections, autoimmunity, and susceptibility to malignancy. Although intrinsic congenital immunodeficiencies
are rare, the widespread use of corticosteroid and immunosuppressive therapies (as well as the spread of the human
immunodeficiency virus [HIV] pandemic) means that the
dermatologist is increasingly being called to assess problems relating to immunosuppression. In the context of an
TABLE 19.2: Congenital and Acquired Immunodeficiencies
Congenital
Neutophil deficiency
Congenital neutropenia
Cyclical neutropenia
Leukocyte adhesion defects
Hyper IgE syndrome
Shwachman syndrome
Chronic granulomatous disease
Storage diseases
Chediak–Higashi syndrome
Acquired
Drug-induced
myelosuppression
Hypersplenism
Autoimmune neutropenia
Corticosteroid therapy
Diabetes mellitus
Hypophosphatemia
Myeloid leukaemia
Influenza
Complement deficiency
C3, C1q, I, H deficiency
C5, 6, 7, 8, 9 deficiencies
Mannan-binding lectin deficiency
Antibody deficiency (B-cell defects)
X-linked
Myeloma
hypogammaglobulinemia
Common variable
immunodeficiency
Lymphoma
Specific IgA deficiency
Specific antibody deficiency
Splenectomy
Congenital rubella
T-cell deficiencies
DiGeorge anomaly
IL-2 deficiency
Signal transduction defect
Measles
Corticosteroids
Calcineurin inhibitors
(e.g., cyclosporine)
Combined T- and B-cell deficiencies
Severe combined
Protein–calorie
immunodeficiency
malnutrition
Wiskott–Aldrich syndrome
Immunodeficiency of
prematurity
Ataxia telangiectasia
Hyper IgM syndrome
Duncan syndrome
HIV/AIDS
immune defect, the patient is often systemically unwell and
the dermopathy may constitute an emergency.
Immunodeficiency may be congenital or acquired
(Table 19.2). Dysfunction may occur in either the quantitative (number of cells) or the qualitative (function of cells)
aspect. These aspects include deficiencies of
●
neutrophils (and monocytes/macrophages),
●
complement pathway,
●
B-cell defects (causing antibody deficiency),
●
T-cell defects (causing impaired cell-mediated immunity), or
●
combinations of any of the preceding aspects.
More than 100 different congenital immunodeficiencies
due to specific genetic defects have been described; most
Chapter 19
TABLE 19.3: Immune Defects and Associated Opportunistic
Infections
Neutrophil deficiency
Staphylococcus aureus
Coagulase-negative
staphylococcus
Escherichia coli
Pseudomonas aeruginosa
Bacteroides spp.
Candida spp. (systemic)
Absidia spp.
Klebsiella pneumoniae
Serratia marcescens
Aspergillus fumigatus
Mucor spp.
B-cell (antibody) deficiency
Campylobacter spp.
Mycoplasma spp.
Echovirus
Ureaplasma spp.
Complement deficiency
(lytic pathway C5–C9)
Meningococcus
Gonococcus (disseminated)
T-cell–mediated immunodeficiency
Listeria monocytogenes
Salmonella spp. (nontyphi)
Mycobacterium tuberculosis
Candida spp. (mucocutaneous)
Cryptococcus neoformans
Pneumocystis jiroveci
Herpes zoster
Cytomegalovirus
Legionella pneumophila
Nocardia spp.
Atypical mycobacteria spp.
Toxoplasma gondii
Histoplasma capsulatum
Herpes simplex
Measles virus
Epstein–Barr virus
are rare. They usually present in childhood, but some types
and the less severe forms may not become apparent until
adulthood. Much more common are acquired immunodeficiencies, which can result from malnutrition, splenectomy,
immunosuppressive therapy, drug side effects, and/or
infection. The most common infective cause is HIV, which
leads to acquired immune deficiency syndrome (AIDS).
Opportunistic infections occur when there is weakness
of host defense mechanisms regardless of the cause. The
nature of the infection may sometimes indicate the specific
type of immune defect (Table 19.3). Opportunistic infections usually present insidiously. An underlying immune
defect should be suspected in patients presenting with
recurrent infections, particularly with unusual organisms
or at unusual sites (Table 19.4).
TABLE 19.4: Warning Signs of Immune Deficiency
• 8 respiratory tract infections/year in a child, or
• >4 respiratory tract infections/year in an adult
• >1 infection requiring hospital admission or intravenous
antibiotics
• Infections with unusual organisms
• Infections at unusual sites
• Chronic infection unresponsive to usual treatment
• Early end-organ damage (e.g., bronchiectasis)
• Positive family history
●
Severe, Acute Allergic and Immunological Reactions II
187
Defects in Neutrophils
Defects of neutrophils result in a predisposition to bacterial infections that results in extracellular infection.
The risk of infection rises steeply once the neutrophil
count falls below 0.5 × 109 /L. The gut is normally colonized with potentially pathogenic bacteria that can readily lead to septicemia following immunosuppression from
whatever cause. The duration of neutropenia can be
reduced by use of granulocyte colony-stimulating factor or granulocyte–macrophage colony-stimulating factor.
Prompt antiinfective therapy for febrile episodes during
neutropenia is essential. Often, preemptive prophylaxis
is prescribed to commence approximately 1 week after
chemotherapy – the time to clinically significant neutropenia following immunosuppressive therapy. A particular and typically benign variant of neutropenia is cyclical
neutropenia, which produces cycles of neutropenia every
3–5 weeks.
Defects of neutrophil function include autosomal recessive congenital leukocyte adhesion defect, hyper-IgE syndrome, and Shwachman syndrome that may resemble cystic
fibrosis. Hyper-IgE syndrome produces recurrent frequent
staphylococcal boils and furuncles – hence its synonym, Job
syndrome – and is associated with elevated levels of IgE.
Unusual eczema-like skin eruptions and severe lung infections resulting in pneumatoceles may occur. Many patients
with autosomal dominant hyper-IgE syndrome fail to lose
their baby teeth and have two sets simultaneously.
Chronic granulomatous disease usually presents in early
or late childhood. Patients present with chronic suppurative
granulomas or abscesses affecting the skin, lymph nodes,
and sometimes the lung and liver, as well as osteomyelitis. Because macrophages are also affected, cell-mediated
opportunistic infections may also be seen, such as atypical mycobacteria, Nocardia, and salmonellae. Diagnosis is
established by the nitroblue tetrazolium test.
Complement Deficiency
Complement deficiencies are rare. They can be associated
with increased susceptibility to infection with Haemophilus
and pneumococcal infection, especially in early childhood
prior to development of a sufficiently wide specific antibody
repertoire.
There are two major patterns of infection associated
with complement deficiency: Deficiency of C3, C1q, or
factors I or H give rise to an increased susceptibility to capsulated bacteria, such as Haemophilus influenza, pneumococcus, meningococcus, and Group B streptococcus. These
patients may also develop SLE-like immune complex disorders. Conversely, deficiency of the lytic complement pathway, C5–9, causes susceptibility to disseminated neisserial infections, meningococcemia, and gonococcemia. C1
esterase inhibitor deficiency is not associated with infection but with hereditary angioedema (see Chapter 18).
188 E MERGENCY D ERMATOLOGY
B-Cell Defects (Antibody Deficiency)
Combined B- and T-Cell Defects
In X-linked hypogammaglobulinemia, B cells and plasma
cells are reduced resulting in a profound reduction in all
the immunoglobulin classes. T cells are normal. The specific gene defect is found on the X chromosome. X-linked
hypogammaglobulinemia typically presents with infections
such as meningitis and mycoplasmal infection after the first
3–6 months of life, when passively transferred maternal
antibody has largely been lost. Intravenous immunoglobulin (IVIg) replacement therapy is successful, and most
patients are able to treat themselves at home.
Common variable immunodeficiency is a late-onset
antibody deficiency that may present in childhood or adult
life. Immunoglobulin G (IgG) levels are especially low. It is
similar to X-linked hypogammaglobulinemia, but a particular feature is lymph-node hyperplasia that may express
itself as nodular lymphadenopathy and lymphoreticular
malignancy. The findings of reduced immunoglobulin levels with normal B-cell numbers indicate the diagnosis.
Regular immunoglobulin replacement therapy (IVIg) with
antimicrobials for opportunistic infection is the mainstay
of management.
Specific immunoglobulin A (IgA) deficiency is extremely
common, affecting 1 in 600 of the UK population. Most
cases are asymptomatic, but some patients have an associated celiac disease or other autoimmune disorder.
Hypogammaglobulinemia is seen in the immune paresis of patients with myeloma and chronic leukemia or
lymphoma. Splenectomy causes impaired defense against
capsulated bacteria, particularly pneumococcus. Hyposplenism associated with severe sickle cell disease is responsible for the increased risk of infection in such patients.
Pneumococcal, meningococcal, and Haemophilus influenzae
type B (Hib) vaccination before elective splenectomy and
the use of penicillin prophylaxis can largely eliminate the
risk of serious infection. Hypogammaglobulinemia can also
occur in congenital rubella.
The most severe immunodeficiencies are those that affect
both B- and T-cell responses. These immunodeficiencies
can stem from a variety of defective mechanisms but tend to
have rather similar clinical features, combining the opportunistic infections of cell-mediated immunodeficiency with
those of antibody deficiency.
Severe combined immunodeficiency (SCID) syndrome
usually presents in the first weeks of life. Failure to thrive,
absent lymphoid tissue, lymphopenia, and hypogammaglobulinemia with multiple severe infections are typical.
Immunoglobulin therapy is effective for the antibody deficiency, but the cell-mediated opportunistic infections are
the main determinants of outcome. Bone-marrow transplantation is the definitive approach and has had significant success, especially if carried out early in the disease
course. More recently, gene therapy and attempts to correct adenosine deaminase deficiency associated with SCID
have had some success.
Failure of class switching from immunoglobulin M
(IgM) to other classes of antibody leads to normal or high
levels of IgM associated with low IgG and IgA. T-cell function is impaired, leading to opportunistic infection with P.
jirovecii, Cryptosporidium (including sclerosing cholangitis),
herpes virus infections, candidosis, and cryptococcosis.
Wiskott–Aldrich syndrome is an X-linked, mainly cellmediated defect associated with falling immunoglobulins.
Clinical features may include eczema, thrombocytopenia,
autoimmune defects, and lymphoreticular malignancies.
Epstein–Barr virus (EBV)-associated immunodeficiency
(Duncan syndrome) results in polyclonal EBV-driven lymphoproliferation, combined immunodeficiency, aplastic
anemia, and lymphoid malignancy.
T-Cell Defects
DiGeorge syndrome (22q11 deletion syndrome) occurs
in 1 in 4000 live births. It is a defect of branchial arch
development leading to abnormal thymic growth. Associated features include dysmorphic facies, hypoparathyroidism, and cardiac defects. Patients present with features
of impaired T cells including mucocutaneous candidosis
and Pneumocystis carinii pneumonia (now renamed Pneumocystis jiroveci) (PcP), often with chronic diarrhea due to
a variety of pathogens. The absent thymus can be documented radiologically. CD3+ and CD4+ T-cell subsets are
reduced, and T-cell–proliferative responses are impaired.
Immunoglobulin production is usually normal. Management entails prompt treatment of opportunistic infections.
Thymic transplant and bone-marrow transplant have had
some success.
HIV AND AIDS
AIDS was first recognized in 1981.1 It is caused by human
immunodeficiency virus-1 (HIV-1). HIV-2 causes a similar
illness to HIV-1 but is less aggressive and restricted mainly
to western Africa.
In 2007, the World Health Organization estimated that
there were 33.2 million people living with HIV/AIDS.2
The cumulative death toll since the pandemic began is more
than 20 million. The vast majority of deaths have been in
sub-Saharan Africa, but Asia, which currently bears about
one fifth of the burden of disease, could surpass this.
Combination therapy, composed of three active drugs
(“triple cocktail”) from two or more different drug classes,
constitutes highly active antiretroviral therapy (HAART).
As of 2008, there were more than 25 different antiretroviral
drugs from 7 different drug classes (Table 19.5), offering
the HIV-infected patient the potential for lifelong suppression of viral replication, even if the prospect of achieving
eradication of the virus, either through a vaccine or potent
combination therapy, remains illusive. Although HAART
Chapter 19
●
Severe, Acute Allergic and Immunological Reactions II
CD4 count ~1000
TABLE 19.5: Antiretroviral Drug Classes
Viral load
Nucleoside reverse transcriptase
inhibitors (NRTI)
Nucleotide reverse transcriptase
inhibitor (NtRTI)
Non-nucleoside reverse transcriptase
inhibitors (NNRTI)
Protease inhibitors (PI)
Fusion inhibitors
Integrase inhibitors
CCR5 co-receptor inhibitors
a
b
c
CD4 count
Drug (abbreviation)
Zalcitabine (ddC)
Didanosine (ddI)
Lamivudine (3TC)
Zidovudine (AZT)
Stavudine (d4T)
Abacavir
Darunavir
Emitricitabine (FTC)
Tenofovir (TDF)
Viral load/CD4 count
Drug class
189
HIV
viral load
Emergence of strong
CD8 T-cell responses
Below a CD4 count
of 200 prophylaxis
against opportunist
infection becomes essential
Decline of CD8
T-cell responses
Continuous rapid
viral turnover in
lymphoid tissue
CD4 count
‘Set point’
0
6 months
Years
Time
Nevirapine
Delaviridinea
Efavirenz
Etravirine (TMC-125)
Indinavirb
Ritonavir
Nelfinavir
Lopinavirc
Atazanavirb
Fosamprenavirb
Saquinavirb
Amprenavira,b
Tipranavira,b
Enfuvirtide (T-20)
Raltegravir
Maraviroc
FIGURE 19.1: Natural history of human immunodeficiency
virus (HIV) and acquired immune deficiency syndrome (AIDS).
reaction in the presence of a negative or equivocal HIV
antibody test following recent exposure to HIV.
The principal dermatological manifestation, occurring
in up to 75% of cases of acute seroconversion, is a nonspecific rash. This usually appears as a maculopapular erythematous exanthem, notably of the face, palms, and soles
(Figure 19.2). Painful oral ulceration, genital ulceration,
Restricted use.
Coformulated with low-dose ritonavir.
Usually given with boosting low-dose ritonavir.
has resulted in great benefit to patients, novel side effects
to these drugs have emerged, many of which affect the skin.
Natural History of HIV and AIDS
Without treatment, a person with HIV may develop one or
more opportunistic infections and/or cancers. Death results
from these illnesses, which the HIV has made the body
more vulnerable to, and not directly from the HIV virus
itself (Figure 19.1).
HIV Seroconversion
HIV seroconversion illness develops in approximately 75%
of persons following acute infection with HIV. It occurs 2–
6 weeks after exposure and lasts a few days to several months
but usually less than a fortnight. The symptoms are nonspecific but may mimic a flu-like illness with headache. It can be
mistaken for infectious mononucleosis with lassitude, fever,
arthralgia, myalgia, and lymphadenopathy. Weight loss,
nausea, and diarrhea are common. Rarely, presentation may
be neurological (aseptic meningitis, Bell palsy, encephalitis,
myelitis, polyneuritis, or Guillain–Barré syndrome).3 Diagnosis is confirmed by a positive HIV polymerase chain
FIGURE 19.2: Rash of seroconversion illness.
190 E MERGENCY D ERMATOLOGY
TABLE 19.6: Cutaneous Manifestations of HIV Infection
Neoplasia
Infections
Other eruptions
Kaposi sarcoma
Non-Hodgkin lymphoma
Anal carcinoma
Herpes simplex (genital/oral/labial)
Herpes zoster (multidermatomal and disseminated)
Candidiasis (oral/vulvovaginal)
Tinea cruris/pedis
Tinea versicolor/rosea
Chancroid
Lymphogranuloma venereum
Syphilis
Cryptococcosis
Warts (oral/genital)
Dry skin and scalp
Ichthyosis, xeroderma
Seborrheic dermatitis
HIV-associated gingivitis
Papular pruritic eruption (Ofuji disease)
Fixed drug reactions
Black nail discoloration (zidovudine)
In-growing toenails (indinavir)
Hair changes
Fat redistribution syndrome
erythema multiforme, and SJS may occur. There is often
an associated hepatitis with transient derangement of liver
transaminases and mild anemia. Skin biopsy is nonspecific.
An acute decrease in the CD4+ count at seroconversion coincides with a surge in plasma HIV RNA levels to
more than 1 million copies/mL. The decrease in the CD4+
count may be sufficient to allow opportunistic infections to
occur. Because of the exceedingly high HIV viral load at
this time, the patient is highly infectious should he or she
engage in sexual activity. It is estimated that one quarter
of HIV transmission occurs during this time. Attempts to
eradicate HIV from the blood at this early stage to reduce
the risk of transmission as a public health problem have
been unsuccessful.
The severity of the seroconversion illness is related to
the subsequent speed of development of AIDS. Without
treatment, the median time to develop AIDS is approximately 8 years. This asymptomatic phase is called the
“latent period.” Many patients will be unaware of their HIV
status during this time and may unwittingly pass on their
infection.
B-cell lymphoma
Squamous cell carcinoma
Scabies
Bacillary angiomatosis
Molluscum contagiosum
Oral hairy leukoplakia
Pyomyositis
Histoplasmosis
Mycobacterial infections
Onychomycosis
Aphthous ulcers
Acne
Psoriasis
Hypersensitivity reactions
Hyperpigmentation
Seborrheic Dermatitis
This condition is probably the most common skin manifestation of HIV, occurring in up to 80% of all patients (Figure 19.3). It may be widespread and severe, and is often
worse in late-stage HIV disease. Red scaly patches typically affect the hair-bearing areas of the skin such as the
nasolabial folds, scalp, and flexures. Treatment is that of the
R
underlying condition using HAART. Topical Oilatum
(Steiffel, Miami, FL) and topical or systemic imidazoles
can be helpful.
Oral–Esophageal Candidiosis (Thrush)
Oral candidosis is a frequent manifestation that, in the
absence of prior antibiotics, steroids, or immunosuppressive therapy, should immediately alert the clinician to the
possibility of HIV infection. Severe disease may involve
the posterior pharynx and esophagus, leading to dysphagia
SPECIFIC SKIN CONDITIONS IN HIV INFECTION
Virtually all dermatological conditions are more common
and more severe in HIV infection. Unusually florid skin
infections, neoplasias, drug reactions, and other unusual
eruptions form the bulk of dermatological manifestations
(Table 19.6). Early HIV-associated diseases include xerosis
with pruritus, seborrheic dermatitis, and an itchy folliculitic
dermatitis that may be fungal (Malassezia furfur), staphylococcal, or eosinophilic in etiology.
FIGURE 19.3: Seborrheic dermatitis.
Chapter 19
and further weight loss. Less commonly, the patient may
present with erythematous candidosis, which appears as a
sore red smooth shiny tongue.
Candida albicans is normally sensitive to fluconazole
(50 mg daily). In cases of nonresponse, antifungal drug
sensitivity to imidazoles, caspofungin, and amphotericin
should be requested from the microbiology reference lab.
Endoscopy with biopsy should be performed to confirm
the diagnosis and exclude the main differential diagnosis
of cytomegalovirus (CMV) ulceration. Multiple copathologies with different types of pathogens are not uncommon
in late-stage HIV and AIDS.
●
Severe, Acute Allergic and Immunological Reactions II
191
affect multiple dermatomes and is often florid. Persistent,
recurrent, or disseminated varicella zoster disease may also
occur.
Diagnosis is confirmed by viral culture, biopsy for characteristic inclusion bodies, or electron microscopy. Treatment is with high-dose (10 mg/kg tds) IV acyclovir. Specialist help should be sought in the management of ophthalmic
shingles because of the risk of permanent loss of sight. The
response to treatment and the risks of postherpetic neuralgia appear to be similar to those in the HIV-negative
population.
Human Papillomavirus
Oral Hairy Leukoplakia
Oral hairy leukoplakia is seen as adherent white plaques on
the lateral margin of the tongue and is virtually pathognomonic of HIV infection. It is associated with EBV infection of the oral mucosa. It may be treated with acyclovir,
although this is rarely indicated. Oral hairy leukoplakia and
oral candidiosis in untreated patients predict progression
to profound immune deficiency and development of AIDS
within 1–2 years.
Human papillomavirus infection is frequent among HIVpositive gay men. The disease may be extensive and difficult to manage. Lesions on the hands and feet (especially
periungual) are also common and may attain considerable
size, requiring surgery. Lesions usually improve on commencement of HAART. Human papillomavirus vaccination reduces the risk of infection and oncogenic transformation.4
Cryptococcosis
Molluscum Contagiosum
Molluscum contagiosum is an epidermal poxvirus infection that occurs in late-stage HIV disease. It is found in
approximately 10% of AIDS patients. The lesions are usually 2- to 5-mm-diameter papules with a central umbilicus
and tend to develop on the face, neck, and genitalia. The
lesions usually disappear with treatment of the underlying
HIV. Liquid nitrogen cryotherapy, topical retinoids, and
cautery may be tried in cases of unsightly giant mollusca.
The main differential diagnosis is disseminated cryptococcosis.
Herpes Simplex Virus Infections
Herpes simplex virus infection should be considered in any
ulcerated or eroded lesion. These lesions can be painful,
especially around the mouth and genitals. Recurrent, extensive, and troublesome herpes infections may occur in latestage disease. Treatment is with high-dose acyclovir. Acyclovir resistance may develop, in which case cidofovir or
foscarnet could be used as alternatives. An important differential is syphilis, which is more common in HIV. Syphilitic
gumma produces painless lesions.
Cutaneous cryptococcosis is caused by Cryptococcus neoformans (the etiological agent of cryptococcal meningitis) and
occurs in very-late-stage disease (CD4+ <50 cells/mm3 ).
It looks similar to molluscum. Serum cryptococcal antigen
test is useful in the diagnosis. Treatment is with fluconazole.
Crusted Scabies
A severe variant of Sarcoptes scabiei infection producing
a hyperkeratotic eruption (crusted scabies) may occur in
advanced HIV. The infestation is often heavy, and patients
are highly infectious. Uniquely in HIV infection, the face
and neck can be affected. Paradoxically, the patient may
not complain of severe itch. Treatment is with permethrin
lotion. Ivermectin may also be of benefit, but the side effects
should be weighed.
Psoriasis
Psoriasis is associated with severe flares in HIV infection,
leading some to speculate on an infective etiology of this
inflammatory condition. Treatment is with standard therapies. Treatment of the HIV will often improve the psoriasis.
Varicella Zoster Virus
Shingles in an otherwise healthy person should act as an
indicator for inquiry about risk factors for HIV infection.
It can occur at any stage of the HIV natural history but
is more frequent with failing immunity. In patients with
a low CD4+ count (<100 cells/mm3 ), the eruption may
Bacillary Angiomatosis
Bacillary angiomatosis is more common in HIV-infected
individuals than are other bacterial infections such as
syphilis and infections due to Staphylococcus aureus (folliculitis, cellulitis, and abscesses).
192 E MERGENCY D ERMATOLOGY
Bacillary angiomatosis is due to the cat-scratch bacillus
Bartonella henselae. Lesions range from solitary superficial
red–purple lesions resembling Kaposi sarcoma to multiple
subcutaneous nodules or hyperpigmented plaques. Lesions
are painful and bleed readily. Disseminated infection leads
to fevers, lymphadenopathy, and hepatosplenomegaly.
Diagnosis is with Warthin–Starry silver staining for aggregates of intracellular bacilli.
Eosinophilic Folliculitis
Eosinophilic folliculitis, also known as pustular pruritic
eruption or Ofuji disease, is more common in persons of
dark skin types and increases in frequency with advancement of immunosuppression. It is associated with a raised
IgE and eosinophilia. The cause is not known. Itchy follicular papules and pustules affect the face, chest, and back.
Treatments are often unsatisfactory but include topical
steroids, phototherapy, and antihistamines.
Kaposi Sarcoma
Kaposi sarcoma is caused by human herpesvirus 8 (HHV8), which is transmitted primarily through saliva. It is more
common in men who have sex with men. The disease may
be indolent or fulminant. Rapid clinical deterioration usually ensues with visceral involvement. It usually presents
as painless purple macules, papules, nodules, and plaques
affecting the limbs, face, and oral mucosa (especially the
hard palate). The differential diagnosis includes bacillary
angiomatosis and pyogenic granuloma. Prognosis depends
on the CD4+ count. There is a wide range of therapies
depending on the extent of the disease. The widespread
use of HAART has resulted in a decline in the incidence of
the disease. Combination therapy itself can result in regression of mucocutaneous lesions and even visceral disease and
so is an important cornerstone of management.
ADVERSE DRUG REACTIONS
Adverse drug reactions are common in HIV and include
both acute (e.g., abacavir HSR) and chronic (e.g., fat
redistribution syndrome) reactions. Predictable reactions
include drug side effects that occur in most patients who
take a drug or combination of drugs. These are drug and
dose dependent and not dependent on host factors. Other
drug reactions previously thought to be idiosyncratic are
now known to be genetically determined.
Nevirapine rash is a common side effect that begins
within 2–4 weeks of starting this treatment. If severe, it
may result in SJS. Recently, the human leukocyte antigen
HLA-DRB1∗ 01 has been found to be linked to rash associated with this class of drug.5 Pharmacogenetic screening
is now part of routine clinical practice in HIV medicine
since the introduction of HLA compatibility testing prior
to initiation of abacavir.
Abacavir Hypersensitivity Reaction
Abacavir (Ziagen) is a nucleoside analogue reverse transcriptase inhibitor licensed for the treatment of HIV. It
is frequently used as a first-line drug because of its oncedaily formulation and favorable lipid (fat redistribution syndrome) profile. It is an active component of coformulations
Kivexa (with lamivudine) and TRIZIVIR (with lamivudine plus zidovudine). Abacavir HSR occurs in 5%–8%
of patients during the 6 weeks of therapy, with a median
onset of 11 days.6,7 It usually presents with fever (80%)
and rash (70%). Less common symptoms include nausea,
vomiting, pruritus, malaise, diarrhea, abdominal pain, and
fatigue. Numbness of the skin; puffiness of the throat, face,
and neck; swollen glands; conjunctivitis; mouth ulcers; and
low blood pressure may also occur.
Symptoms of the HSR to abacavir are nonspecific and
may mimic influenza, the key difference being the presence
of GI symptoms with abacavir. Symptoms worsen with continued use of the drug. Rapid reversal of symptoms occurs
on discontinuation of abacavir.
An abacavir HSR may be life threatening; therefore, all
patients prescribed this should be made familiar with the
symptoms and should know to notify their doctor immediately if they develop any of these. More severe and even fatal
reactions have been reported in patients rechallenged with
abacavir after stopping the drug. Subsequent rechallenge
with abacavir is therefore absolutely contraindicated.
Abacavir hypersensitivity is strongly associated with an
HLA-B∗ 5701 allele. Testing for the HLA B∗ 5701 haplotype reduced the incidence of HSRs to zero in a randomized trial of nearly 2000 patients.8 All patients should
therefore be screened for this allele prior to commencing
therapy.
The HLA B∗ 5701 allele appears to be more common
in white Caucasians and least common in black Africans
infected with HIV (and in whom dermititis is often more
difficult to distinguish). It is recommended that genetic
testing should be routine for people of all ethnicities to
reduce the instances of misdiagnosis of hypersensitivity in
which abacavir is inappropriately withdrawn from patients
who could have benefited from it.
Immune Restoration Inflammatory Syndrome
Immune restoration inflammatory syndrome (IRIS) is
an adverse consequence of the restoration of pathogenspecific immune responses in HIV-infected patients during
the initial months of HAART. The inflammatory syndrome
reflects the restoration of a previously impotent immune
system as it mounts an excessive response against organisms that were already present, but dormant, in the body.
Chapter 19
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Severe, Acute Allergic and Immunological Reactions II
193
therapy is generally avoided. There have been anecdotal
reports of successful management of reactions using pentoxifylline, thalidomide, and the asthma medication montelukast, but in most cases reactions resolve on their own
without any additional treatment.
REFERENCES
FIGURE 19.4: Suppurative mycobacterial adenopathy as an
immune restoration inflammatory syndrome reaction following
commencement of highly active antiretroviral therapy.
The immune restoration can have various manifestations, including lymph-node inflammation associated with
Mycobacterium avium-intracellulare complex (Figure 19.4);
eye inflammation (uveitis or vitritis) associated with CMV;
worsening of tuberculosis, cryptococcosis, or toxoplasmosis symptoms; and elevated liver enzymes associated with
hepatitis B or C co-infection.
The incidence of IRIS is greatest in patients with
advanced immune suppression (CD4+ count <100 cells/
mm3 ) at the start of therapy. Immune restoration reactions
are associated with larger viral load reductions (2.5 log or
greater) or CD4+ cell increases after starting HAART.
Starting an anti-HIV treatment with a combination that
included a ritonavir-boosted protease inhibitor was also
associated with an increased risk of IRIS.9
Because flare-ups indicate improvement of immune
function following antiretroviral therapy, antiretroviral
therapy is continued in all but the most serious cases.
Even then it is usually only stopped temporarily until the
patient’s condition has stabilized. Antiinflammatory medications may help decrease symptoms during the intense
inflammatory phase, but routine use of corticosteroid
1. Gottlieb MS, Schroff R, Schanker HM, et al. Pneumocystis carinii pneumonia and mucosal candidiasis in previously
healthy homosexual men: evidence of a new acquired cellular
immunodeficiency. N Engl J Med. 1981; 305:1425–31.
2. UNAIDS AIDS epidemic update, December 2007 [cited
March 2008]. Available from: www.unaids.org.
3. Bunker CB, Staughton RCD. HIV-associated disease: dermatology. In: Gazzard BG, editor. AIDS Care Handbook.
London: Mediscript, 2002.
4. Koutsky LA, Ault KA, Wheeler, CM, et al. A controlled trial
of a human papillomavirus type 16 vaccine. N Engl J Med
2002; 347:1645–1.
5. Vitezica ZG, Milpied B, Lonjou C, et al. HLA-DRB1∗ 01 associated with cutaneous hypersensitivity induced by nevirapine
and efavirenz. AIDS 2008; 22:540–1.
6. Hetherigton S, McGuirk S, Powell G, et al. Hypersensitivity
reactions during therapy with nucleoside reverse transcriptase
inhibitor abacavir. Clin Ther 2001; 23:1603–14.
7. Hermandez JE, Cutrell A, Edwards M, et al. Clinical risk factors for hypersensitivity reactions to abacavir: restrospective
analysis of over 8,000 subjects receiving abacavir in 34 clinical trials. In: Program and abstracts of the 43rd Interscience
Conference on Antimicrobial Agents and Chemotherapy,
Chicago, September 14–17, 2003. Washington DC: American Society for Microbiology, 2003:339. Abstract.
8. Mallal S, Phillips E, Carosi G, et al. HLA-B∗ 5701 screeening
for hypersensitivity to abacavir. N Engl J Med 2008; 358:568–
79.
9. Manabe YC, Campbell JD, Sydnor E, Moore RD. Immune
reconstitution inflammatory syndrome: risk factors and treatment implications. J Acquir Immune Defic Syndr 2007;
46:456–62.
CHAPTER 20
Graft Versus Host Disease
Jasna Lipozenčić
Ronni Wolf
THE SKIN is a major target organ for both acute and
chronic graft versus host disease (GVHD) after stem cell
transplantation (SCT). Although SCT is a life-saving measure and the treatment of choice for many patients with
various hematologic malignancies, a high incidence of complications and a transplantation-associated mortality of
approximately 30% are to be expected. GVHD is the major
cause of morbidity and mortality at any time following
SCT. The acute form occurs during the first 100 days after
transplantation in up to 50% of graft recipients, whereas
chronic GVHD develops in approximately 30%–50%, usually within 100–500 days following allogenic SCT. Target
organs in GVHD can be all of those with lymphoid cells
as well as epithelial structures, especially the skin, liver,
gastrointestinal (GI) tract, lung, eyes, and neuromuscular
system. Early diagnosis of GVHD can be difficult because
drug reactions, viral infections, and cutaneous reactions to
radiation therapy may have similar clinical and histological similarities. Histological findings of GVHD correlate
poorly with clinical severity of the disease and have a limited role in predicting disease stage and progression.1–4 The
skin manifestations, histopathologic features, prophylaxis,
and therapy of acute and chronic GVHD are presented in
this chapter.
PATHOPHYSIOLOGY OF GVHD
GVHD is the result of a complex interaction of associative inflammation, endotoxicity, and activation of alloreactive cells. Cytotoxic donor T lymphocytes are mediators
and effectors in GVHD. Proinflammatory cytokines in the
cells of the donor and the recipient play an important role
in the pathogenesis of GVHD. In acute GVHD, there are
increased serum concentrations of tumor necrosis factor-α
(TNF-α), interferon-γ (IFN-γ), interleukin 1 (IL-1), IL2, and IL-6, but they are not specific for GVHD because
bacterial infections show similar findings. The only correlation has been found between elevated IL-2 receptor (IL2R) and severe GVHD.5–7 Prophylactic administration of
monoclonal anti–TNF-α antibodies in a patient with histocompatibility leukocyte antigen (HLA)-identical SCT in
twins significantly alleviated acute GVHD.8
GVHD is in direct correlation with HLA incompatibility between donor and recipient.9 Even in HLA-identical
related SCT without prophylactic immunosuppression,
GVHD occurs in 30%–50% of cases and has a severe course
in 10%–20% of cases because of so-called HLA minor antigens.10 HLA incompatibility between donors and patients
increases the incidence of GVHD. The age of patients as
well as difference in sex between donor and recipient are
also risk factors, such as when there are two different HLA
antigens and Y-chromosome–associated minor antigens.4
In HLA-identical SCT, the incidence of GVHD is less than
25% in patients younger than 30 years with acute GVHD,
but this number rises to 80% in patients older than 50
years.11,12 The incidence of chronic GVHD is also higher
in adults than in children.4
HLA incompatibility, age, and gender are not the only
factors responsible for GVHD.13–15 A three-phase model
may explain the pathophysiology of GVHD. Phase I is
“toxic” and lasts for approximately 60 days, whereas phase II
begins with “lichenoid” symptoms before the 30th day and
lasts until approximately the 100th day. Phase III starts near
the 80th day and is characterized by “sclerodermiform”
symptoms and cell infiltrate. There is interaction between
different cell populations in both donor and recipient as
well as between mediators of inflammation, and the result is
cell death (apoptosis) in target organs of GVHD. Chronic
GVHD often develops from acute GVHD through costimulation of cytokine production, and end-cell apoptosis through endotoxins is intensified. In this phase, there
is hypersensitivity of macrophages through Th1-cytokine
(INF-γ) stimulation. In acute GVHD, there is activation
of Th1 cytokines with the production of proinflammatory
mediators (TNF-α, IL-1), accompanied by organ-specific
destruction and Th1 activation.
Risk factors for GVHD are genetic polymorphism in
the promoter region of inflammatory (TNF-α) and antiinflammatory (IL-10) cytokines. In chronic GVHD, there
is the added risk factor of a former acute GVHD and the
subsequent activation of Th2 cells and cytokine production.
The chronicity of GVHD is due to alloreactive T cells
having increased the production of IL-4 or IFN-γ, which
induces collagen synthesis through fibroblasts.4
page 194
Chapter 20
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Graft Versus Host Disease
195
ACUTE GVHD
Acute GVHD begins 2–6 weeks after transplantation
(median 3 weeks). In one study, GVHD took place after
allogenic SCT in 35% of patients with HLA-identical
donors, and the disease course was severe in 10%–20%
of these cases (erythroderma, toxic epidermolysis). Acute
GVHD is manifested on skin, liver, and the GI tract, as well
as the lymphatic system, bone marrow, and the mucosa of
the mouth and respiratory system. Development of “hyperacute” GVHD has been described as occurring 7–14 days
after SCT.11,12
Skin Manifestations of Acute GVHD
The skin is the target organ of acute GVHD in more
than 90% of cases. Early manifestations of acute GVHD
include generalized pruritus, dysesthesia, painful palms of
the hands and soles of the feet, or edema and erythema
of the ears.13 A maculopapular eruption first appears on
the face, palms, and soles, followed by presentation on the
shoulders and abdomen and then the whole body. These
eruptions cannot be distinguished from a drug eruption or
viral exanthema, either clinically or histologically. Exanthemas are variable and can be purpuric, follicular, morbilliform, or scarlatiniform. Perifollicular papular reactions
indicate progression in a severe course, being characteristic of GVHD.4
Erythema on the palms, soles, and ears is typical in
GVHD (Figure 20.1). Exanthemas with progression to
erythroderma and blisters with a positive Nikolsky phenomenon are signs of a severe course. The most severe cases
are those with bullous GVHD that include toxic epidermal
skin and mucosal necrolysis and septicemia. Toxic epidermal necrolysis (TEN) has been reported in 6% of patients
with a very high mortality. In this phase of GVHD, it is
not easy to distinguish the epidermal necrolysis of SCT
from that of drug-induced TEN. Hyperacute GVHD with
TEN has been reported to begin 8 days after bone-marrow
transplant.14
Mucosal reactions present as xerostomia, symptomatic
of salivary gland dysfunction and pain upon eating as well
as mucosal hypersensitivity. Mucosal reactions found in the
mouth in acute GVHD can be fine papular white lesions,
whitish lichenoid-reticular signs, or desquamative erosions.
In the progressive stage of acute GVHD, there are fingernail changes with periungual erythemas, hyperkeratosis,
onycholysis, pigmentations, and hemorrhagia of the nail
plates.
Extracutaneous Manifestations
The liver and the GI tract can be target organs after
allogenic SCT. GI manifestations are present in 30%–
50% of cases of acute GVHD.15 They appear early or
shortly after the skin manifestations and include diarrhea,
FIGURE 20.1: Graft versus host disease, acute stage. There is
erythema on the face and palms. (Photo courtesy of Ivan Dobrić,
MD, PhD, Zagreb, Croatia.)
vomiting, anorexia, malabsorption, abdominal pain, ileus,
and colon hematuria, all of which are signs of a severe
course. Liver disorders (bilirubin, alcal phosphatase, γglytamyltranspeptidase) with hepatomegaly are the second
most prevalent manifestations after those of the skin, and
are found in 40%–60% of cases.15
Clinical Stages of Acute GVHD
Acute GVHD severity has been graded by the pattern of
organ involvement and clinical performance status, using
a system introduced more than 30 years ago:16 clinical
stage and percentage of skin lesions, GI disorders, volume of diarrhea (mL/day), and value of bilirubin.4,6,16 For
example, stage I is characterized by a maculopapular exanthema (<25% body size), bilirubin 2–3 mg/dL, and diarrhea of 500–100 mL/day, whereas stage IV is characterized
196 E MERGENCY D ERMATOLOGY
by bullous manifestations with TEN in the skin, bilirubin
>15 mL/dL, and pain or ileus.4,6,16,17 In acute GVHD, the
“grade” survival is correlated with GVHD severity in grade
(specifically, >90% survival in grade I, ∼60% in grades II
and III, and 0% in grade IV).
The International Bone Marrow Transplant Registry
has adopted a new severity index for grading acute GVHD,
based on objective parameters of target organs.17 It has
been proposed that the Severity Index enhances design and
interpretation of clinical trials in the current era of allogeneic blood and bone-marrow transplantation.17
Histological Changes of Acute GVHD
Prophylaxis depends upon the degree of severity of acute
GVHD and on histomorphologic changes resulting from
GVHD. The dynamism of GVHD makes the histologic
picture unstable, and it characteristically changes during
the course of illness due to its being influenced by many
other factors. Histological findings of the skin in early acute
GVHD show focal basal cell degeneration of the epidermis and sometimes sparse perivascular lymphocytic infiltration in the upper dermis. In the late acute phase, there is a
hypersensitivity reaction and activation of endothelial cells
as well as penetration of T cells into the papillary dermis.
The clinical signs include cytotoxic folliculitis and “satellite
necrosis” because of the presence of T cells in the papillary
dermis, lymphocytes in the epidermis, and hair follicles as
well as necrosis of keratinocytes/apoptosis or necrosis.4
Histopathologic changes in acute GVHD have been
described as grade I (vacuolization of basal cells of inflamed
lymphocyte infiltrate in the upper dermis or epidermis),
grade II (dyskeratosis of some keratinocytes, exocytosis of
lymphocytes around necrotic keratinocytes in the epidermis [“satellite phenomenon”]), grade III (the beginning of
late signs in the basal membrane zone with sparse necrosis in the epidermis), and grade IV (complete depletion of
necrotic epidermis) (Figure 20.2).4
These histopathologic changes are not specific to
GVHD, and similar ones can be found in viral exanthems,
in drug eruptions, and post-chemotherapy. This is the reason for the need for optimal timing for skin biopsies: 24–48
hours after exanthema, before administering GVHD therapy, repeated biopsies in the early phase of acute GVHD,
with paraffin block serial slices for focal GVHD with mostly
follicular involvement.15
FIGURE 20.2: Graft versus host disease, acute stage, stage II.
Histological feature: rare subepidermal infiltrate of lymphocytes
(with rare lymphocytes in lower epidermis), hydrops degeneration of basal layer of epidermis, and “satellite” cell necrosis.
Hematoxylin and eosin, ×240. (Photo courtesy of Ivan Dobrić,
MD, PhD, Zagreb, Croatia.)
repeated, that biopsies are taken, and that microbiological
findings are available. Increased values of liver enzymes or
GI disorders can appear concomitantly with acute GVHD.
Another cause for consideration are the side effects of
immunosuppressive therapy.
Physicians need to recognize atypical early skin involvement in acute GVHD in patients after SCT so that they can
promptly initiate appropriate treatment.18 There is a suggestion of an association between acquired ichthyosis with
GVHD.19 Epidermodysplasia verruciformis in the setting
of GVHD after SCT has also been described.20
Differential Diagnosis
The clinical manifestations of viral exanthema and drug
eruption are similar to dermal manifestations in the initial phase of GVHD. Bullous changes take place after total
beam radiotherapy, accompanied by palmoplantar pain and
stomatitis, some weeks later. Thus, it is imperative that
the diagnosis is clear-cut, that clinical examinations are
Prognosis of Acute GVHD
The morbidity and mortality rates that determine prognosis in progressive acute GVHD are high after SCT.
Whereas prognosis is good in cases of isolated skin GVHD
or GVHD grade II when response to the first course of
therapy is positive, it is grave in patients with refractory
Chapter 20
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Graft Versus Host Disease
197
or severe GVHD. Even patients with GVHD grades II–IV
have a low mortality rate if they react to initial therapy with
complete remission. Fewer than 50% of patients with acute
grades II–IV GVHD have long-term survival, so early diagnosis and therapy are essential. The most prevalent causes
of death are infections, bleeding, and suppression of liver
function.
CHRONIC GVHD
Chronic GVHD (100–500 days after SCT) is a multisystem
disease, and between 30% and 50% of allogeneic transplantation patients develop it. The major risk factor for chronic
GVHD is acute GVHD. Chronic GVHD can be either
subclinical or clinical and either limited or extensive. Skin
changes are local in 20% of cases and generalized in 80%.
They can be progressive (32%) following acute GVHD as
well as “de novo” (30%). Chronic GVHD can appear after
ultraviolet radiation, trauma, or herpes zoster.4
Skin Manifestation of Chronic GVHD
Skin is the most frequently targeted organ in chronic
GVHD.4,13,15 The initial changes that take place, together
with other early manifestations of chronic GVHD, include
persistent face erythema with marked pigmentation, mouth
dryness, and sensitivity to spicy food that can be associated
with oral pain. Because skin changes can appear rapidly
after sun exposure, sunscreens are vital for these patients.
One fifth of them have a localized skin form of GVHD
and rarely exhibit liver symptoms. The dermal expression
is mostly lichen ruber planus (LRP), lichen sclerosus et
atrophicus, or skin lesions linear to or along Blaschko lines;
circumscript scleroderma is rare (3%). Generalized forms
seen in disseminated GVHD are erythema, desquamation,
telangiectasia, and pigmentation disorder. There are two
chronic disseminated GVHD forms: lichenoid and sclerodermiform. The former is similar to LRP and characterized
by livid-brown papules on the extremities (Figure 20.3).
They are often present periorbitally, on the ears, hands, and
soles, and lichenoid papular lesions are sometimes localized
at the hair follicles. Generalized skin lesions and erythroderma are rare. Postinflammatory hyperpigmentation may
appear after regression of the lesions, whereas hypopigmentation is uncommon. Pityriasis rosacea-like lesions
in GVHD with rapid regression have been described as
well.4
In addition to LRP, mucosal mouth lesions in chronic
GVHD include Wickham striae, erosions, ulcerations or
leukoplakia, painful erosions, and xerophthalmia similar to
that found in sicca syndrome. Nail disturbances are seen in
approximately 40% of patients, and they range from onycholysis, pterygium, and atrophy to total nail loss.
Sweat glands often show a disturbance of function until
dehydration. Other changes include pigment loss in hair,
FIGURE 20.3: Graft versus host disease, chronic stage,
lichenoid form. Papulous exanthema on the trunk. (Photo courtesy of Ivan Dobrić, MD, PhD, Zagreb, Croatia.)
cicatricial alopecia, poikiloderma with alopecia in sclerodermiform form, as well as vitiligo.
Sclerodermiform GVHD is a severe sequela of chronic
GVHD that often occurs before LRP GVHD (Figure 20.4). It is a type of sclerosis of the dermis with localized
morphea and generalized skin lesions that include contractures and ulcers with possible superinfections. This form
is associated with HLA-A1-B1 and B2. Fasciitis is rare in
chronic GVHD, as are eosinophilic fasciitis and cellulitis.4
Extracutaneous manifestations in chronic GVHD represent severe multisystem disease with involvement of the
liver (30%), GI tract (diarrhea ∼30%), lung (dyspnea,
bronchitis), eyes (conjunctivitis, keratitis), and the neuromuscular system. Glomerulonephritis and arthritis are
uncommon.
Clinical Stages of Chronic GVHD
Chronic GVHD can start subclinically (∼30%) or display
clinical symptoms (70%) that are either localized (20%)
198 E MERGENCY D ERMATOLOGY
FIGURE 20.4: Graft versus host disease, chronic stage, scleroderma form. Induration and hyperpigmentation of the skin.
(Photo courtesy of Ivan Dobrić, MD, PhD, Zagreb, Croatia.)
or generalized (80%).4 The traditional clinical grading
system11,12 is divided into three categories: subclinical
grade I without evidence of GVHD but with positive histological findings; clinical grade II with limited disorders
and localized skin lesion and liver dysfunction; and clinical
grade III with extensive skin lesions, liver dysfunction, and
hair loss accompanied by histological evidence of aggressive hepatitis, necrotic lesions, and cirrhosis in addition to
other organ involvement, such as the eyes, oral mucosa,
colon, and lung.4,11,12
Histological Changes in Chronic GVHD
As in acute GVHD, there are four histological forms:4 1)
acanthosis, parakeratosis, hyperkeratosis, and hypergranulosis of the epidermis; 2) lichenoid GVHD with lichenoid
infiltrate and melanophages, eosinophils, and plasma cells
in the papillary dermis (Figure 20.5); 3) sclerodermiform
GVHD with homogenous and swollen bundles of collagen
and loss of appendages (Figure 20.6); and 4) atrophy of the
epidermis (late phase). The lupus band test is positive in
86% of biopsies in chronic GVHD. There are no specific
FIGURE 20.5: Graft versus host disease, chronic stage
lichenoid form. Histological feature: hypergranulosis and rare
subepidermal bordered infiltrate of lymphocytes. Hematoxylin
and eosin, ×200. (Photo courtesy of Ivan Dobrić, MD, PhD,
Zagreb, Croatia.)
histologic parameters to differentiate between acute and
chronic GVHD.
Differential Diagnosis
Differential diagnosis of chronic GVHD includes circumscribed and systemic scleroderma, lichenoid drug eruption,
lupus erythematosus, pityriasis rosea, eosinophil fasciitis,
Sjögren syndrome, rheumatoid arthritis, and primary biliary cirrhosis.
Prognosis of Chronic GVHD
Prognosis is more favorable, if the disease is limited to skin
or liver involvement. In cases of more extensive disease in
which multiple organs are affected and there is inadequate
response to therapy, 80% of the patients will die. The prognosis of sclerodermiform GVHD is grave. Morbidity and
mortality are highest in patients whose disease process had
Chapter 20
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Graft Versus Host Disease
199
antilymphocyte or antithymocyte serum, as in vivo T-cell
reducers, is used as well. Basic prophylaxis can decrease the
incidence of acute GVHD but not of chronic GVHD. The
therapeutic regimen for corticosteroid-resistant cases consists of cyclophosphamide, antithymocyte globulin, antilymphocyte globulin, pentostatin or monoclonal antibody
against T lymphocytes or against immunosystem mediators (IL-2R, TNF-α).4 The addition of other immunosuppressive therapeutic agents in GVHD comprises a risk for
infections (fungal, viral) as well as associated Epstein–Barr
virus lymphomas. Supportive therapy is fundamental for
acute and chronic GVHD infections.4
Chronic GVHD
FIGURE 20.6: Graft versus host disease, chronic stage, scleroderma form. Histological feature: acellular dermis with swollen
bundles of collagen and loss of structure in the interfascicular
space and subepidermal melanophages. (Photo courtesy of Ivan
Dobrić, MD, PhD, Zagreb, Croatia.)
begun with acute GVHD and lowest in patients who had
not undergone acute GVHD previously. The most prevalent causes of death are bacterial and viral infections.
PROPHYLAXIS AND THERAPY FOR GVHD
The most important factor in primary prophylaxis is choice
of donors and histocompatibility. Drug prophylaxis is also
essential.
Acute GVHD
Basic prophylaxis begins on the day of transplantation.
It is initially intravenous and is followed by 6 months of
oral cyclosporine A (CSA) in combination with methotrexate (MTX) or systemic corticosteroids instead of MTX.
Tacrolimus is currently preferred over cyclosporine and
some studies favor mycophenolate mofetil over MTX.4 In
vitro physical separation of immunocompetent T cells or
Skin lesions are the first manifestations in 90% of GVHD
cases, but all target organs must be evaluated before therapy is administered. CSA and corticosteroids comprise the
initial therapy. When an alternative therapy is needed due
to resistance, mycophenolate mofetil with tacrolimus is one
option, having shown a good effect in 50% of patients with
drug-resistant chronic GVHD. In isolated skin GVHD,
photochemotherapy with 8-methoxypsoralen is effective
as is D-penicillamine and azathioprine as well as highdose thalidomide. Acitretin and clofazimine can be given
for sclerodermiform GVHD resistant to etretinate. Extracorporal photopheresis is also effective and has fewer side
effects. Ultraviolet B phototherapy is considered adjuvant
therapy in chronic GVHD.4 Causal therapy is not yet
available. Known side effects of therapy associated with
immunosuppression involve the kidney and lead to liver
and bone-marrow impairment as well as to tumors. The
use of sunscreens is an important supplement to medication. Therapy for GVHD patients should be in the hands
of hematologists and dermatologists.
MANAGEMENT OF GVHD
The influence of nonmyeloablative and ablative conditioning regimens on the occurrence of acute and
chronic GVHD was recently evaluated in 137 patients.21
Myeloablative regimens included intravenous bisulfan/
cyclophosphamide (n = 45) and fludarabine/melphalan
(n = 29). The nonmyeloablative group (n = 63) received
fludarabine/idarubicin/cytarabine, cisplatin/fludarabine/
idarubicin, and fludarabine/cyclophosphamide. The actuarial rate of grades II–IV acute GVHD was significantly
higher in patients receiving ablative regimens (36%)
compared with the nonmyeloablative group (12%). The
cumulative incidence of chronic GVHD was higher in the
ablative group (40%) compared with the nonmyeloablative
group (14%).21 The time of onset of GVHD and survival
rate were analyzed in 395 patients with hematologic
malignancies who underwent a nonmyeloablative regimen of 2 Gy total-body irradiation with or without
200 E MERGENCY D ERMATOLOGY
fludarabine followed by postgrafting immunosuppression
with mycophenolate mofetil and CSA. The cumulative
incidences of grades II–IV acute GVHD and extensive
chronic GVHD were 45% and 47%, respectively. Highdose corticosteroid treatment for acute or chronic GVHD
was started at a median of 79 days and 30 days after transplantation, respectively.22 When the donors were related,
the cumulative incidence of nonrelapse mortality among
patients with GVHD was 55% at 4 years when prednisone
was started before day 50. The authors concluded that
patients with early-onset GVHD after nonmyeloablative
SCT from HLA-identical related donors might benefit
from intensified primary immunosuppressive treatment.22
The decision to treat immediately for GVHD without performing a skin biopsy provided the best patient outcomes.23
When the prevalence of GVHD was 50% or higher (typical
for allogeneic SCT), the best outcomes were obtained with
treatment for GVHD and no skin biopsy. In populations
with a prevalence of GVHD of 30% or less, obtaining a
skin biopsy specimen to guide treatment was predicted
to provide the best patient outcome.23 The findings of a
recent report showed that a better therapeutic approach
would be to reduce the extent of immunosuppression and
allow the patient’s immune system the opportunity to reject
the allograft donor T cells. The patients who responded
to withdrawal of immunosuppression had a later onset of
symptoms and a lower level of donor CD3+ T cells at the
start of treatment.24 Other investigators suggested that
the patients with “composite” skin GVHD may benefit
from an earlier, more aggressive immunosuppressive
interventional strategy.25 Imatinib showed a major impact
on chronic myeloid leukemia treatment strategies. Indeed,
GVHD involving the skin, liver, and digestive tract has
been described in the syngeneic transplant setting, either
with or without administration of prophylactic CSA:
Complete remission was achieved with imatinib.26
CONCLUSIONS
GVHD is a devastating complication following SCT, and
the prevention of GVHD should be the highest priority.
Management of these patients should be multidisciplinary
and involve hematologists and dermatologists. There are
no known preventative measures for the causes of GVHD
nor means of avoiding the side effects of immunosuppression that are often present in affected patients. Management
is determined according to the stage of GVHD, and early
diagnosis is of the essence.
ACKNOWLEDGMENT
Professor Ivan Dobrić, MD, PhD, Chief of the Dermatohistopathological Laboratory of the University
Department of Dermatology and Venereology, School of
Medicine and University Hospital Center, Zagreb, Croatia,
provided the original figures of GVHD from his private
collection.
REFERENCES
1. Kohler S, Hendrickson MR, Chao NJ, Smoller BR. Value of
skin biopsies in assessing prognosis and progression of acute
graft-versus-host disease. Am J Surg Pathol. 1997; 21:988–96.
2. Zhou Y, Barnett MJ, Rivers JK. Clinical significance of skin
biopsies in the diagnosis and management of graft-vs-host
disease in early postallogeneic bone marrow transplantation.
Arch Dermatol. 2000; 136:717–21.
3. Vargas-Dı́ez E, Fernández-Herrera J, Marin A, et al. Analysis of risk factors for acute cutaneous graft-versus-host disease after allogeneic stem cell transplantation. Br J Dermatol.
2003; 148:1129–34.
4. Karrer S. Cutaneous graft-versus-host disease. Hautarzt.
2003; 54:465–80; quiz 481–2.
5. Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J
Med. 1991; 324:667–74.
6. Thomas ED, Storb R, Clift RA, et al. Bone-marrow transplantation. N Engl J Med. 1975; 292:895–902.
7. Grimm J, Zeller W, Zander AR. Soluble interleukin-2 receptor serum levels after allogeneic bone marrow transplantations as a marker for GvHD. Bone Marrow Transplant. 1998;
21:29–32.
8. Holler E, Kolb HJ, Eissner G, Wilmanns W. Cytokines in
GvH and GvL. Bone Marrow Transplant. 1998; 22:S3–S6.
9. Klingebiel T, Schlegel PG. GVHD: overview on pathophysiology, incidence, clinical and biological features. Bone Marrow Transplant. 1998; 21:S45–S49.
10. Goulmy E, Schipper R, Pool J, et al. Mismatches of minor
histocompatibility antigens between HLA-identical donors
and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med. 1996;
334:281–5.
11. Sullivan KM. Graft-versus-host disease. In: Thomas ED,
Blume KG, Jorman SJ, editors. Hematopoietic cell transplantation. 2nd ed. Malden (MA): Blackwell Science Inc.; 1999.
pp. 515–36.
12. Sullivan KM, Deeg HJ, Sanders J, et al. Hyperacute graftversus-host disease in patients not given immunosuppression
after allogeneic bone marrow transplantation. Blood. 1986;
67:1172–5.
13. Volc-Platzer B. Graft-versus-host disease. Hautarzt. 1992;
43:669–77.
14. Takeda H, Mitsuhashi Y, Kondo S, et al. Toxic epidermal
necrolysis possibly linked to hyperacute graft-versus-host disease. J Dermatol. 1997; 24:635–41.
15. Heymer B. Clinical and diagnostic pathology of graft-versushost disease. Berlin: Springer; 2002.
16. Glucksberg H, Storb R, Ferer A, et al. Clinical manifestations
of graft-versus-host disease in human recipients of marrow
from HLA-matched sibling donors. Transplantation. 1974;
18:295–304.
17. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR
severity index for grading acute graft-versus-host disease:
retrospective comparison with Glucksberg grade. Br J
Haematol. 1997; 97:855–64.
Chapter 20
18. Kuskonmaz B, Güçer S, Boztepe G, et al. Atypical skin graftvs-host disease following bone marrow transplantation in an
infant. Pediatr Transplant. 2007; 11:214–16.
19. Huang J, Pol-Rodriguez M, Silvers D, Garzon MC. Acquired
ichthyosis as a manifestation of acute cutaneous graft-versushost disease. Pediatr Dermatol. 2007; 24:49–52.
20. Kunishige JH, Hymes SR, Madkan V, et al. Epidermodysplasia verruciformis in the setting of graft-versus-host disease. J
Am Acad Dermatol. 2007; 57:S78–S80.
21. Couriel DR, Saliba RM, Giralt S, et al. Acute and chronic
graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant. 2004; 10:178–85.
22. Mielcarek M, Burroughs L, Leisenring W, et al. Prognostic
relevance of ‘early-onset’ graft-versus-host disease following
non-myeloablative haematopoietic cell transplantation. Br J
Haematol. 2005; 129:381–91.
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23. Firoz BF, Lee SJ, Nghiem P, Qureshi AA. Role of skin
biopsy to confirm suspected acute graft-vs-host disease:
results of decision analysis. Arch Dermatol. 2006; 142:175–
82.
24. Chinnakotla S, Smith DM, Domiati-Saad R, et al. Acute graftversus-host disease after liver transplantation: role of withdrawal of immunosuppression in therapeutic management.
Liver Transpl. 2007; 13:157–61.
25. Bridge AT, Nelson RP, Schwartz JE, et al. Histological evaluation of acute mucocutaneous graft-versus-host disease in
nonmyeloablative hematologic stem cell transplants with an
observation predicting an increased risk of progression to
chronic graft-versus-host disease. Am J Dermatopathol. 2007;
29:1–6.
26. Pelosini M, Galimberti S, Benedetti E, et al. Skin and stomach
graft versus host disease after syngeneic BMT in CML: a case
report. Leuk Res. 2007; 31:1603–4.
CHAPTER 21
Erythroderma/Exfoliative Dermatitis
Virendra N. Sehgal
Govind Srivastava
AN EXTREME STATE of skin irritation resulting in
extensive erythema and/or scaling of the body in several
skin disorders may ultimately culminate in erythroderma/
exfoliative dermatitis. Largely, it is a secondary process;
therefore, determining its cause is needed to facilitate precise management.1 Its clinical pattern is fascinating and
has been the subject of detailed studies: Its changing scenario in various age groups,2–4 its presentation postoperatively, and its occurrence in human immunodeficiency
virus (HIV)-positive individuals are vivid indicators. Several factors may be responsible for the causation of this
extensive skin disorder. A detailed outline of a patient’s
history to elicit possible triggering events, namely, infection, drug ingestion, topical application of medicaments,
and sun/ultraviolet light exposure, among other factors. It is
also challenging to manage the condition, because the intricate process puts an extensive strain on an already compromised body system.1,2,5,6 In addition, the original dermatosis may be masked by extensive erythema/scaling, thus making it difficult to obtain a clear-cut diagnosis. Its intriguing
clinical expression in neonates/infants and children poses
a serious emergent challenge for its life-threatening overture.7,8
surveys from India and The Netherlands, the annual incidence was recorded as variable at 35–0.9 per 100,000 skin
patients.1,13 A study based on an analysis of 138 consecutive erythroderma patients from South Africa found that
75% were black, 22.5% Indian, and 2.5% white.6 A large
number of patients were HIV positive, where a drug reaction was the most common cause, and men were affected 2–
3 times more frequently.
The incidence as a function of age is usually variable, and
any age group may be affected; however, affected (excluding hereditary disorders/atopic dermatitis) patients are usually older than 45 years,1 with an average age of onset of
55 years. Erythroderma is a rather uncommon situation in
the pediatric age group. A sample of 80 patients with erythroderma contained only 7 of the pediatric age group, of
which only 3 belonged to 0–3 years and the other 4 to 4–
13 years, equating to an incidence of 8.8%.1,14,15 Male-tofemale ratio was approximately equal, whereas age at onset
varied according to its etiology. In a significant study comprising neonatal and infantile (up to 1 year) erythroderma,
the composition was 30% in an immunodeficiency state,
24% in ichthyosis, 18% in Netherton syndrome, 20% had
papulosquamous/eczematous dermatoses, and a further 8%
were idiopathic.16
DEFINITION
Erythroderma and exfoliative dermatitis are largely
synonymous; however, erythroderma is the preferred
term1,9,10 and is currently in vogue. The former is characterized by extensive and pronounced erythema, coupled
with perceptible scaling, whereas the latter is conspicuous
by the presence of widespread erythema and marked scaling. Accordingly, 90% or more skin-surface involvement is
considered as a salient prerequisite to make a clinical diagnosis of exfoliative dermatitis.1,11 Some disorders in infants
may initially be localized and then eventually develop into
extensive erythema.12
INCIDENCE
It is hard to obtain a precise incidence for erythroderma/exfoliative dermatitis, as most reports are retrospective and do not address the issue of overall incidence. In
ETIOLOGY
Erythroderma/generalized exfoliative dermatitis possesses
a wide spectrum of etiology, in both the pediatric and adult
population (Tables 21.1 and 21.2a, b).
Erythroderma/exfoliative dermatitis may embrace or
be caused by certain preexisting dermatosis, drug-induced
malignancy, and miscellaneous/idiopathic disorders.1,12
Preexisting Dermatoses
Several dermatologic disorders or their therapy can result
in exfoliative dermatitis (Tables 21.1 and 21.2a). This is
the single most common cause of adult/pediatric exfoliative dermatitis in the majority of studies.1,4,13,17–20 Psoriasis
is the most common cause of exfoliative dermatitis among
adults.1,13 The causative disorders can be masked due
to generalized erythema and/or scaling and have to be
page 202
Chapter 21
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Erythroderma/Exfoliative Dermatitis
203
TABLE 21.1: Erythroderma/Exfoliative Dermatitis in Children –
Etiology
TABLE 21.2a: Dermatoses Frequently Resulting in Exfoliative
Dermatitis in Adults
Cause(s)
Disease(s)/Syndrome(s)
Common
Uncommon
Immunologic
disorders
Omenn syndrome
Graft versus host disease
Cutaneous T-cell lymphoma
Hypogammaglobulinemia
DiGeorge syndrome
Psoriasis
Airborne contact dermatitis
Seborrheic dermatitis
Atopic dermatitis
Staphylococcal scalded
skin syndrome
Phytophotodermatitis
Photosensitive dermatitis
Pityriasis rubra pilaris
Pemphigus foliaceus
Stasis dermatitis
Ichthyosiform erythroderma
Candidiosis
Dermatophytosis
Mastocytosis
Lichen planus
Reiter syndrome
Toxic epidermal necrolysis
Diffuse/erythrodermic mastocytosis
Sarcoidosis
Pemphigoid
Lupus erythematosus
Crusted (Norwegian) scabies
Metabolic/nutrition Kwashiorkor
disorders
Renal failure
Acrodermatitis enteropathica
Cystic fibrosis dermatitis
Leiner disease
Infections
Amino acid disorders
Staphylococcal scalded skin syndrome
Scarlet fever
Neonatal candidiasis
Toxic shock syndrome
Toxicities/drug
reactions
Boric acid toxicity
Drug-induced erythroderma/exfoliative
dermatitis
Part component
of various
syndrome(s)
Netherton syndrome
Sjögren–Larsson syndrome
Keratitis–ichthyosis–deafness syndrome
Ectodermal dysplasias
Neutral lipid storage disease with ichthyosis
Conradi–Hünermann syndrome
Trichothiodystrophy
Cutaneous
disorders
Atopic dermatitis
Psoriasis vulgaris
Ichthyosis–harlequin, lamellar, bullous
Diffuse cutaneous mastocytosis
Toxic epidermal necrolysis
Pityriasis rubra pilaris
Seborrheic dermatitis
Crusted scabies
Data adapted from Sehgal VN, Srivastava G, Sardana K. Erythroderma/
exfoliative dermatitis – a synopsis. Int J Dermatol. 2004; 43:39–47.
carefully looked.21,22 In young children, the dermatoses
form the main cause of erythroderma.
Drugs
Topical and systemic medications are notorious for precipitating erythroderma/exfoliative dermatitis. An apparent increase in the drug-induced instances may be directly
proportional to the introduction of new drugs.1,14,23–27
Apart from the well-known allopathic medicines, homeopathic, Unani, Ayurvedic, herbal, and common home
remedies have been incriminated.1,15 Many drug eruptions that commonly present as morbilliform, lichenoid,
or urticarial forms may often progress to extensive erythema and exfoliation. The inventory of drugs causing
erythroderma/exfoliative dermatitis is increasing; however,
the most common are shown in Table 21.2b. Drug-induced
erythroderma due to dapsone/antileprosy drug hypersen-
Data adapted from Sehgal VN, Srivastava G, Sardana K. Erythroderma/
exfoliative dermatitis – a synopsis. Int J Dermatol. 2004; 43:39–47.
sitivity may often mimic cutaneous T-cell lymphoma in
terms of both clinical features and histopathology. Fortunately, it resolves after withdrawal of the offending drug(s)
and the administration of supportive therapy.
Malignancies
One of the clinical expressions of reticuloendothelial neoplasms and internal blood vessel malignancies
may be erythroderma. The latter invariably affect older
individuals, and erythema/exfoliative dermatitis is considered to be a salient cutaneous marker of internal
malignancy. Lymphomas in general and T-cell lymphoma
(comprising mycosis fungoides and Sezary syndrome
TABLE 21.2b: Common Drugs Causing Exfoliative Dermatitis
in Adults
Acetaminophen
Actinomycin-D
Allopurinol
Arsenic
Barbiturates
Captopril
Chloroquine diphosphate
Chlorpromazine
Cimetidine
Dapsone
Gold
Hydantoin sodium
Interferon
Isoniazid/isonicotinic hydrazide
Isotretinoin
Lithium
Mercurials
Minocycline
Nitrofurantoin
Omeprazole
Para-amino salicylic acid
Penicillin
Phenothiazine
Phenytoin
Quinidine
Rifampicin
Streptomycin
Sulfadiazine
Sulfonylurea
Tetracycline
Thalidomide
Tolbutamide
Vancomycin
Data adapted from Sehgal VN, Srivastava G, Sardana K. Erythroderma/
exfoliative dermatitis – a synopsis. Int J Dermatol. 2004; 43:39–47.
204 E MERGENCY D ERMATOLOGY
[its leukemia variant, in particular]) are often reported to
present as exfoliative dermatitis. In adults they constitute
more than 25%–40% of cases of malignancy-related erythrodermas.4,13,14,28–31 Exfoliative dermatitis may precede,
accompany, or follow T-cell lymphomas, and its appearance may be identical to that of benign erythroderma. An
immunophenotypic study with the use of advanced antibody panels may be required to distinguish it from the
benign form.32 Reticular cell sarcoma, acute and chronic
leukemia, and malignant histiocytosis are a few other implicated conditions. Carcinoma of the colon, lung, prostate,
thyroid, fallopian tubes, larynx, and esophagus have also
been alleged to cause the condition. An insidious, debilitating, progressive course, absence of a history of a previous skin disorder, and recalcitrant nature may warrant
an exploration of the possibility of an underlying malignancy.1,15,33–35
Miscellaneous/Idiopathic Disorders
Hepatitis, irradiation, acquired immune deficiency syndrome (AIDS), graft versus host disease (GVHD), Ofuji
papuloerythroderma, Omenn syndrome, and several cutaneous disorders can also cause the condition from infancy
to old age.1,15,36–38 Other cutaneous disorders causing
erythroderma are discussed in the “Clinical Features/
Connotation” section. Despite the best endeavors, a small
proportion of patients remain in whom no clear-cut etiology can be defined; their disorders are classified as idiopathic. A sustained effort during the course of follow-up
may lead to the precise definition of the etiology.1,15
PATHOGENESIS
The pathogenesis of the erythroderma/exfoliative dermatitis appears complex. It is surmised that the condition
develops secondary to an intricate interaction of cytokines
and cellular adhesion molecules; interleukin 1, 2, and 8;
intercellular adhesion molecule 1; and the tumor necrotic
factor.39 These interactions result in a dramatic increase
in the epidermal turnover rate, accelerated mitotic rate,
and an increased absolute number of the germinative skin
cells. The time required for cells to mature and travel
through the epidermis is decreased and is manifested as an
increased loss of epidermal material, together with a significant loss of protein and folate.40 In contrast, the exfoliation of normal epidermis is much less and contains very
little important viable material, such as nucleic acids, soluble proteins, or amino acids. Abel and colleagues41 studied
the immunophenotypic characteristics of benign (psoriasis,
dermatitis, drug induced) and malignant (Sezary syndrome,
mycosis fungoides) forms of erythroderma, and found
them to be similar. In immunohistochemical studies,42 the
dermal infiltrate in patients with Sezary syndrome mainly
showed a T-helper-2 cytokine profile, whereas benign reac-
tive erythroderma showed a T-helper-1 cytokine profile,
indicating that, although clinically similar, they have different underlying pathogenic mechanisms. In addition to
these basic alterations, all earlier mentioned disorders have
their own specific pathogenesis.
CLINICAL PRESENTATION/CONNOTATION
Exfoliative dermatitis starts as patch(es) of erythema
accompanied by pruritus. The patch(es) enlarge and coalesce to form extensive areas of erythema, which eventually
spread to cover all or most of the skin surface. Exfoliative dermatitis is also associated with profuse scaling, which
has its onset 2–6 days after erythema with individual variations. The acute form is heralded by the formation of large
scales, whereas the chronic form is recognized by small
scales. The skin is conspicuously bright red, dry, scaly, hot,
and indurated. Mild to severe pruritus is usually present. In
addition, the nails become thick, lusterless, dry, brittle, and
show ridging of the nail plate. Periorbital skin inflammation
and edema cause ectropion and epiphora. Lymphadenopathy, hepatosplenomegaly, edema of the feet/ankles, and
gynecomastia may also be observed. The basal metabolic
rate is increased, and a catabolic state causes significant
weight loss over time. At times, patients can slip into
an irreversible hypothermia or hyperthermia. The former
may result in ventricular bradycardia and hypotension. An
increased peripheral blood flow may result in high-output
cardiac failure. All body systems may be affected by these
manifestations. The general picture is modified according
to the nature of the underlying disorder.1,15
Cutaneous Disorder
Atopic Dermatitis. This condition is a well-conceived clinical cutaneous expression of atopy. It is a pruritic, eczematous dermatosis, the clinical manifestations of which chronically fluctuate with remissions and relapses. (Figure 21.1)
FIGURE 21.1: Atopic dermatitis.
Chapter 21
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Erythroderma/Exfoliative Dermatitis
205
harlequin ichthyosis are born with generalized thick hyperkeratotic covering, which may prove fatal following acute
respiratory distress. Bullous (epidermolytic hyperkeratosis) ichthyosis initially may present with widespread areas
of denuded skin. Gradually, blistering diminishes and is
replaced with ichthyosiform erythroderma with overt clinical features.8,46
Diffuse Cutaneous Mastocytosis. This condition is a wellappreciated rare entity in which the entire skin is heavily
infiltrated with mast cells. Trivial injury, trauma, and pressure may cause extensive urtication and bullae formation.
Unlike the adult-onset variety, cutaneous mastocytosis of
infancy and childhood may regress spontaneously.47
FIGURE 21.2: Erythroderma/exfoliative dermatitis: psoriatic
erythroderma.
Most individuals with atopic dermatitis have an atopic
diathesis identified through personal or family history of
asthma, allergic rhinitis, and/or conjunctivitis and atopic
dermatitis and/or predisposition to overproduction of
immunoglobulin E (IgE) antibodies. Infants and children are most commonly affected. Erythema, exudation,
papules, vesiculopapules, scales, and crust are its salient
acute lesions. It may transform itself into erythroderma.
Despite being widespread, the child is apparently well and
thriving. Sparing of axilla and groins distinguishes it clinically from seborrheic dermatitis in typical cases.1,15,43,44
Psoriasis. Psoriasis is the most common underlying disorder, and its features may be present until the whole body
develops exfoliative dermatitis. In a few cases, generalized
pustular psoriasis may also be present. There may be a
history of preceding plaque(s); treatment with tar, potent
steroids, or psoralen plus UVA (PUVA) therapy; intermittent infections; or emotional stress.1,15
Congenital erythrodermic psoriasis is extremely uncommon, which is also true in infancy; however, its incidence
is directly proportional to the increase in age. The clinical features of psoriasis are similar to those observed in
adults with psoriatic erythroderma (Figure 21.2).1,45 The
prognosis of the condition is poor in infants and young
children.8,16
Ichthyosis. Several syndromes with ichthyosis as an important component may be responsible for erythroderma in
infants and children. Harlequin fetus, bullous ichthyosis,
lamellar ichthyosis, and congenital ichthyosiform erythroderma (CIE) are its other clinical variants and are
required to be taken cognizance of. A collodian membrane
encasement is an essential part of both CIE and lamellar
ichthyosis. In CIE, it is replaced with exfoliative erythroderma, whereas in lamellar ichthyosis it is followed by
generalized ichthyosis with plate-like scales. Infants with
Toxic Epidermal Necrolysis. This is a fascinating clinical
expression wherein there is widespread blistering of the skin
and/or mucous membrane. There is an extensive sloughing
of the epidermis and dermis, and underneath the slough is
“naked” and is attended by enormous exudation. There is
a considerable loss of proteins and electrolytes. There is impaired thermoregulation and altered immunologic function; hence, patients are infection prone. This reaction pattern is mediated through the breakdown products or toxins
of the microorganism, antibiotic medication administered
to treat infective disorders, and/ or polysorbate toxicity.
The condition is most frequently encountered in adults,
but occasionally has been reported in infants.48–50
Pityriasis Rubra Pilaris. Erythroderma following pityriasis rubra pilaris (PRP) is fairly diagnostic, as it usually
starts in childhood or adulthood51,52 and the lesions occupy
the hair follicle in the form of papules and/or plaques
with “islands of sparing.” Reddish follicular papules and/or
plaques with thick, dry scales comprise its cardinal clinical expression (Figure 21.3). Invariably, it has an acute
onset and is usually accompanied by pruritus. It is inherited as an autosomal dominant trait with variable expression and reduced penetrance. The familial form of PRP
typically begins in early childhood with a gradual onset,
and most of the familial cases are of type V (atypical juvenile type). The remainder of the familial cases belong to
either type III (classic juvenile) or type IV (circumscribed
juvenile).49–54
Seborrheic Dermatitis. This condition is a fairly common
cause of erythroderma in children, less so in adults, and
presents as erythematous moist, scaly lesions that occupy
the seborrheic sites, namely scalp, axilla, neck, napkin,
retroauricular area, and front and back of the chest. The
scales are large, greasy, and yellow. It is amenable to various treatments.4,12
Crusted Scabies. Crusted or hyperkeratotic scabies is usually nonpruritic owing to impairment of the sensory nerves.
206 E MERGENCY D ERMATOLOGY
confirmation by western blot is mandatory to establish the
diagnosis of HIV. The condition is amenable to specific
topical and oral treatment.38,55
Immunologic Disorders
Omenn Syndrome/Familial Reticuloendotheliosis. This
condition has infrequently been diagnosed in the recent
past; nonetheless, the demonstration of abnormal histiocytic appearing cells in the skin, lymph nodes, spleen,
and liver are significant. Erythroderma, failure to thrive,
pronounced lymphadenopathy, and recurrent infections
are the salient clinical features. Marked leukocytosis, eosinophilia, anemia, hypogammaglobulinemia, and
depressed T-cell immunity are its other supplements. T
lymphocytes CD4 5RO+ may be demonstrated at the
molecular level,16 and a skin biopsy may confirm the diagnosis16,18 and help in differentiating it from Netherton syndrome and GVHD although it is mostly fatal. Cyclosporin
and bone-marrow transplantation can be effective therapies.12,56–58
HypoGammaglobulinemia. An infant who is apparently
normal at birth but who subsequently develops fever, diarrhea, and rapidly progressive generalized exfoliative dermatitis (erythroderma) may have hypogammaglobulinemia. Monthly replenishment by intravenous infusion of
gamma globulin alleviates fever and erythema.59
GVHD. This condition is known to occur in infants who,
unknowingly, are transfused with nonirradiated blood or
have received small amount of maternal blood by placenta
in utero. Usually these infants have primary immunodeficiency. Its clinical presentation is a nonspecific morbilliform eruption, which gradually progresses to erythroderma
with epidermal sloughing.12,60
FIGURE 21.3: Erythroderma/exfoliative dermatitis: developing
in (juvenile) pityriasis rubra pilaris.
It is characterized by sand-like, thick, tan crusts that flake
off revealing underlining normal skin. The lesions are usually generalized. Fissures may be a constant source of fatal
septic events. Crusted lesions are frequently encountered
in immunocompromised HIV/AIDS and are a potential
source of perpetuating the disease in the form of epidemics.
The diagnosis is confirmed through the demonstration
of Sarcoptes scabiei. A first- and second-generation screening test (enzyme-linked immunosorbent assay) followed by
Cutaneous T-cell Lymphoma. Cutaneous T-cell lymphoma (CTCL) is a rare entity in children and is likely
to be overlooked; however, in particular cases its features
are lymphadenopathy, splenomegaly, and lymphocytosis.
Sezary-like notched cells can be identified in the peripheral blood smear. In contrast to Omenn syndrome, the
immunoglobulin G levels are elevated. Its histopathology
is pathognomonic.12,60
DiGeorge Syndrome. This condition is an uncommon
cause of erythroderma and is characterized by maculopapular/eczematous lesions that may progress to cover the whole
of the skin surface. In severe combined immunodeficiency,
the affected child often develops localized/widespread
eczematous or seborrheic dermatitis.61
Chapter 21
Metabolic/Nutritional Disorders
Kwashiorkor Cryoglobulins. This is a common form
of routine malnutrition in both underdeveloped and
developing countries. It may present with generalized erythema, edema, and increased skin fragility. Excessive protein loss may result in renal and/or hepatic failure in older
children.12
Acrodermatitis Enteropathica. This condition is a wellrecognized clinical entity in infants and children. The initial lesions are vesiculobullous, crusted, or psoriasiform in
mostly perioral and perianal locations. It is usually accompanied by diarrhea, photophobia, and irritability. In addition to low serum zinc levels, serum alkaline phosphatase
levels are also reduced, as this enzyme is zinc dependent.
A similar condition may be observed in children with
AIDS.12,62
Cystic Fibrosis Dermatitis. Initial presentation of this disease is quite different and is characterized by the development of severe, rapidly progressive, and unresponsive
psoriasiform lesions. Pulmonary and gastrointestinal components complicate the condition later. The skin lesions
may resolve following administration of pancreatic
enzymes and nutritional supplements.63
Leiner Disease. This condition is composed of a group of
disorders with similar presentations characterized by erythroderma, diarrhea, and failure to thrive. Ever since its first
description, several innovations have been made, including
that by Glover and colleagues,59 who proved that some of
the affected individuals with Leiner phenotype may have an
associated immunodeficiency. Where the infant is apparently normal at birth and dermatitis and diarrhea make an
early appearance, then the latter is severe and chronic. The
dermatitis is associated with progressive erythema and erosions, which may ultimately become generalized. The condition does not respond to topical/oral medication. Adequate nutritional support along with hyperalimentation and
individualized treatment may be helpful.12,59,64
Amino-Acid Disorders. Several reports have demonstrated
the deficiency of various amino acids and their association
with erythroderma. Maple syrup urine disease is an interesting example. Its treatment includes restriction of essential amino acids; otherwise, the severity of the dermatitis
worsens with increased control on amino-acid intake.65
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Erythroderma/Exfoliative Dermatitis
207
is generalized rapidly and progresses to sloughing and
erosions. Histopathology examination often will distinguish it from toxic epidermal necrolysis. Occasionally,
widespread staphylococcal pustulation resembling generalized candidiasis may develop in a healthy child; however,
culture is usually positive for Staphylococcus. Accordingly,
response to a relevant antimicrobial is ensured.12,66
Scarlet Fever. This condition forms an important differential diagnosis of rubella, toxic shock syndrome, severe
staphylococcal infection, drug eruptions, mononucleosis,
and exanthem subitum. The erythroderma is transient
and successfully resolves following administration of penicillin/erythromycin.
Congenital Neonatal Candidosis. The initial lesions are in
the form of a maculopapular eruption. Congenital candidosis gradually supervenes with the appearance of classical pustules, especially over the palms and soles. It spreads
rapidly and often involves the umbilicus. The diagnosis is
easy: either through the demonstration of mycelia/conidia
in 10% potassium hydroxide mount or on Gram stain followed by positive culture of Candida spp. Sometimes systemic antifungals cause rapid resolution of the disease, and
in the neonatal form of generalized cutaneous candidiasis
the lesions start in the oral cavity or napkins area.12,67
Toxic Shock Syndrome. The clinical features of this condition include fever, hypertension, and diffuse macular
blanching erythroderma, followed by desquamation of the
palms and soles. Dysfunction of various organs or systems
may be life threatening. Surgical wound infection of the
skin, subcutaneous and/or soft tissue, and also of bone may
be predisposing factor(s).12,49
TOXICITY AND DRUG REACTIONS
Boric Acid Toxicity
Maculopapular lesions progressing to erythema, edema,
and desquamation are the salient clinical features of this
condition, and the Nikolsky sign may be positive. Other
features include alopecia, vomiting, diarrhea, fever, and
irritability caused by inadvertent absorption of boric acid
powder from the diaper area, where boric acid has been
used as a dusting powder.68
Drug Induced
Infections
Staphylococcal Scalded Skin Syndrome. Unlike other erythrodermas in children, staphylococcal scalded skin syndrome (SSSS) onset is acute and accompanied by fever, systemic toxicity, and a positive Nikolsky sign. The erythema
Drug-induced erythroderma in children is commonly
observed with sulfonamide, isoniazid, streptomycin, nonsteroidal antiinflammatory drugs, and antiepileptic drugs;
however, cases have also been recorded with Ayurvedic,
Unani, homeopathic, and indigenous medications (Table
21.2b). A history of drugs for certain dermatoses/systemic
208 E MERGENCY D ERMATOLOGY
disorders may be elicited prior to the onset of exfoliative
dermatitis. Erythema is acute in onset and progresses to
generalized exfoliation, which may resolve over the course
of 2–6 weeks.1 Topical preparations have caused generalization of the existing dermatoses in a proportion of cases.
If the incriminating drug(s) is withdrawn and symptomatic
treatment instituted, the prognosis is excellent.49
Neutral Lipid Storage Disease with Ichthyosis
(Dorfman–Chanarin Syndrome)
This condition resembles CIE. Demonstration of lipid vacuoles in the skin and elsewhere in the body supports its diagnosis. It may also have features such as cataract, myopathy,
sensory-neural deafness, and growth retardation.12,72
Conradi–Hünermann Syndrome
VARIOUS SYNDROMES
Trichothiodystrophy (Tay Syndrome)
The affected newborn may have collodion membrane and
erythroderma with other features, including brittle, sparse
hair, variable ichthyosis, and central nervous system manifestations. Erythroderma resolves itself during infancy.12,69
This condition affects infants and is characterized by the
presence of bands of ichthyosiform erythroderma along the
lines of Blaschko. The bands resolve in due course, leaving behind follicular atrophoderma. Radiography shows an
asymptomatic, focal, enchondral calcific strippling.12,73
HEMODYNAMIC/METABOLIC DISTURBANCES
Netherton Syndrome
Infants and children affected with this disorder show a generalized exfoliative erythroderma. Trichorrhexis invaginata
(bamboo hair) and atopy are its other features. The disease may be confused with generalized atopic dermatitis. A
genetic linkage has been established to the SPINK-5 gene
locus on chromosome 5q32 encoding the serum protease
inhibitor LEKTI. This information may be useful in prenatal testing in any subsequent pregnancy of the mother of
the affected child.70
The disease may cause an enormous aberration of body
metabolism. The increased skin blood flow may cause
hypothermia and profound heat loss. Compensatory hypermetabolism and an increased basal metabolic rate without any primary increase in thyroid activity may ensue.
Excessive protein loss through scaling and leaking through
skin, hemodilution due to the increased plasma column,
and hypermetabolism may contribute to hyperalbuminemia and severe edema. High-output cardiac failure may
occur at any time.1,2,74
HISTOPATHOLOGY
Sjögren–Larsson Syndrome
Coincident with erythroderma occurring during infancy,
the affected child has scaling, spasticity, and mental retardation. The diagnosis is made on the basis of enzyme
assays on leukocytes, fibroblasts, or skin biopsy, which may
reveal a deficiency of enzyme fatty alcohol oxidoreductase.69
Keratitis–Ichthyosis–Deafness
Keratitis–ichthyosis–deafness syndrome is a rare disorder
in which the infant usually has diffusely thickened erythematous skin, which peels off in the course of the first week
of life. Subsequently, atypical prominent follicular keratosis
is identified over the head and extremities. In the following
years or decades, keratoconjunctivitis with noticeable vascularization (pannus), along with neurosensory deafness,
occurs.71
Ectodermal Dysplasias
Erythroderma is rather an uncommon feature of the disease, and other pathognomonic features help in the diagnosis of this disorder.12
The histopathology of exfoliative dermatitis often reveals a
nonspecific picture, consisting of orthokeratosis (hyperkeratosis, parakeratosis), acanthosis, and a chronic perivascular
inflammatory infiltrate with or without eosinophilia. The
clinicopathologic correlation in erythroderma is difficult,
because the specific features of the dermatosis are masked
by the nonspecific features of erythroderma.10 In a study
on Sezary syndrome, the diagnosis was established by the
clonal population of T cells in the blood, despite a lack of
diagnostic features on biopsy.75 Others clinicians76 advocated that the submission of multiple simultaneous biopsies from the affected skin enhanced the accuracy of the
histopathologic diagnosis, and the cause could be identified in up to one half of cases. The stage of the disease
can modify the histopathologic picture; in the acute stage,
spongiosis and parakeratosis are prominent, whereas in the
chronic stage acanthosis and elongated rete ridges are seen.
Despite the uniformity of the clinical expression of erythroderma, diagnostic histopathologic features of the underlying disease are retained in the majority of patients.77 Skin
biopsies from characteristic clinical lesions may often confirm the diagnosis of psoriasis, PRP, ichthyosiform erythroderma, or pemphigus foliaceus.1,48,78 Drug-induced
exfoliative dermatitis may often reveal a lichenoid interface dermatosis histopathology.79 In erythroderma due to
Chapter 21
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Erythroderma/Exfoliative Dermatitis
209
TABLE 21.3: Histological Clues to the Diagnosis of Erythroderma
Disease
Histologic clues
Psoriasis
Parakeratosis, Munro microabscess, suprapapillary plate thinning, squirting papillae, regular
acanthosis
Cutaneous T-cell lymphoma
(CTCL)/Sezary
Exocytosis of mononuclear cells, epidermotropism, Pautrier microabscesses
Drug reaction
Vascular change, necrotic keratinocytes
Actinic reticuloid
Hyperkeratosis, acanthosis, superficial and deep mixed dermal infiltrate with some atypical
mononuclear cells
Pityriasis rubra pilaris
Alternating orthokeratosis and parakeratosis (vertically and horizontally) with or without keratotic
plugging
Sarcoidosis
Dermal noncasketing epithelioid “naked” cell granulomas; occasional, giant cells surrounded by
sparse lymphocytes
Contact dermatitis
Spongiosis, eosinophils within dermal infiltrate
Lymphoproliferative diseases
Interstitial pattern of atypical cells between collagen bundles
Scabies
Perivascular and interstitial infiltrates with eosinophils, scabetic mite/scybala/fecal pellets in
stratum corneum
Dermatophytosis
Focal parakeratosis, hyphae in stratum corneum
Pemphigus
Supra basal intraepidermal cleavage, acantholytic keratinocytes, (acantholytic cells), direct
immunofluorescence depicting IgG-bound cell surface, circulating antibodies
Pemphigoid
Subepidermal bulla with eosinophils
Acute graft versus host disease
Vacuolar change, satellite cell necrosis
Atopic dermatitis
Spongiosis, eosinophils within dermal infiltrate
Seborrheic dermatitis
Parakeratosis with neutrophils at lips of follicular ostia
Dermatomyositis/Subcutaneous
lupus erythematosis
Vacuolar change, colloid bodies increased dermal mucin
Idiopathic subacute
Parakeratosis, spongiosis, epidermal hyperplasia, papillary dermal edema, superficial
perivascular lymphohistiocytic infiltrate
Idiopathic chronic
Compact hyperkeratosis, psoriasiform hyperplasia, little spongiosis, papillary dermal thickening
Data adapted from Sehgal VN, Srivastava G, Sardana K. Erythroderma/exfoliative dermatitis – a synopsis. Int J Dermatol. 2004; 43:39–47.
lymphoma, the infiltrate may gradually become polymorphic until it acquires specific diagnostic features. This
makes repeated skin biopsies, additional investigations of
lymphocytes in peripheral blood, and sustained followup in dubious situations mandatory to permit the correct
diagnosis.76 Microscopic clues to the diagnosis of erythroderma, if reviewed systematically, can reveal the underlying
diagnosis (Table 21.3).
Additional tests to increase the diagnostic specificity include immunophenotyping and direct immunofluorescence.75
INVESTIGATIONS/DIAGNOSIS
Mild anemia, leukocytosis, increased erythrocyte sedimentation rate, hypoalbuminemia, hyperglobulinemia, and
hyperuricemia are frequent findings.4,10,14,75 Increased IgE
may be observed in erythroderma when caused by atopic
dermatitis and drug reactions, although it has also been
reported in other settings.75 A decreased CD4+ T-cell
count was observed in patients with erythroderma in the
absence of HIV disease, as a consequence of sequestration
of the lymphocytes in the skin.81 Circulating Sezary cells
at greater than 20% are indicative of Sezary syndrome,
but at less than 10% are nonspecific findings in erythroderma. Immunophenotyping, flow cytometry, and, in particular, B-cell and T-cell gene rearrangement analysis may
be helpful in confirming the diagnosis of lymphoma when
it is strongly suspected.3 Actinic retinoid is differentiated
from Sezary syndrome by the increased CD8+ T cells in
the latter and the nuclear contour index of peripheral blood
lymphocytes.75 A detailed guide to investigations is given
in Table 21.4.
A detailed history of the sequence of events leading
to the development of erythroderma/exfoliative dermatitis is a prerequisite in all patients. Often the clues obtained
may help in the diagnosis and appropriate management. A
thorough clinical examination is required to diagnose the
etiology of exfoliative dermatitis and to allow appropriate
urgent symptomatic treatment. An astute practitioner will
210 E MERGENCY D ERMATOLOGY
TABLE 21.4: Investigations/Laboratory Tests – Basic
Investigations
• Weight, temperature, pulse, respiratory rate charting
• Fluid intake/output charting
• Complete hemogram, total and differential leukocyte
counts, absolute platelet count, erythrocyte sedimentation
rate
• Liver and kidney function tests, including serum electrolytes
• Histopathology
• Schedule urine macroscopy and microscopy
• Electrocardiogram (ECG) and chest radiograph
Disease-specific investigations:
• Skin scrapings/KOH (Norwegian scabies/Extensive tinea
corporis)
• Patch test (after recovery, for suspected allergic contact
dermatitis, photoallergic contact dermatitis, airborne contact
dermatitis)
• Serum immunoglobulin E (atopic dermatitis)
• Serum and urine protein electrophoresis (multiple
myeloma)
• Angiotensin-converting enzyme levels, serum calcium
(sarcoidosis)
• Cultures may show bacterial overgrowth or the herpes
simplex virus
• CD4+ T-cell count/CD8+ T cells
• Human immunodeficiency virus 1 and 2 testing, including
western blot test, to exclude acquired immunodeficiency
syndrome
• Immunology-antinuclear antibody, rheumatoid factor,
anti-DNA
• Fine-needle aspiration cytology lymph nodes, bone-marrow
examination (lymphoma/leukemia)
• Direct immunofluorescence (Pemphigus foliaceous,
lichen planus, lupus erythematosus, graft versus host
disease)
• Immunophenotyping, flow cytometry, and particularly, B-cell
and T-cell gene rearrangement analysis – if lymphoma is
strongly suspected
• Workup for occult malignancy, if suspected: chest radiograph,
computed tomography scan and ECG, ultrasonography
abdomen, stool for occult blood, mammography,
sigmoidoscopy, prostate examination, cervical smear, as
indicated
Data adapted from Sehgal VN, Srivastava G, Sardana K. Erythroderma/
exfoliative dermatitis – a synopsis. Int J Dermatol. 2004; 43:39–47.
be able to identify the nature of the underlying dermatosis
and proceed to confirm his or her suspicions. Histopathology is paramount and is rewarding in more than 50% of
cases if a diligent effort is made. Fine needle aspiration
cytology may be vital to distinguish between dermatopathic
and malignant lymphadenopathy. In a recent development.
Heteroduplex analysis of T-cell receptor gamma gene rearrangement can be used as an important diagnostic tool in
skin biopsies to classify the underlying etiology of erythroderma.82 T-cell clonality analysis may be useful for the
diagnoses of cutaneous T-cell lymphoma in patients with
erythroderma.83
MANAGEMENT
All cases should be considered as a dermatologic emergency
and should preferably be hospitalized for treatment. Serious general medical problems may occur in due course if
not appropriately treated. The initial management of all
types of erythroderma is the same regardless of the etiology. The principle of management is to maintain skin moisture, avoid scratching, avoid precipitating factors, apply
topical steroids, and treat the underlying cause and complications.1,15,49,75 The patient requires a regulated environmental temperature, avoiding cooling and overheating.
Together with general management, all unnecessary medication should be avoided. Cutaneous applications should
be soothing and mild due to the already inflamed skin.
Mild topical steroids/emollients after lukewarm washing
can act as an antipruritic. Antihistamines (H1 receptor) can
be administered to enhance the effect.
After the acute irritated state of the skin has improved,
further treatment can be undertaken according to the etiology. Antimicrobials can be added to control secondary
infections. Any hemodynamic or metabolic aberrations
must be addressed appropriately. Each case requires regular
monitoring of protein, electrolyte balance, circulatory status, and body temperature. Blood urea, serum electrolyte,
and fluid balance should be monitored.
Erythroderma commonly resists therapy until the
underlying disease is treated (e.g., phototherapy, systemic
medications in psoriasis). The outcome is unpredictable
in idiopathic erythroderma, and the course is marked by
multiple exacerbations; prolonged glucocorticoid therapy
is often needed. Appropriate inpatient/outpatient medications are influenced by the underlying etiology of erythroderma. For example, prednisone may be contraindicated
in exfoliative dermatitis secondary to psoriasis, whereas
retinoids are an excellent choice for this disease. Systemic
steroids may be helpful in some cases, but should be avoided
in suspected cases of psoriasis and SSSS.84 Low-dose
methotrexate or cyclosporin can be safely administered in
erythrodermic psoriasis.1,49 Carbamazepine is effective in
the treatment of psoriatic erythroderma;85 however, the
same drug has caused exfoliative dermatitis/erythroderma
in a few studies.86 Similarly, methotrexate therapy for psoriasis has been reported to cause exfoliative dermatitis.87
The ideal treatment for erythrodermic cutaneous lymphoma is still elusive. Various modalities, such as systemic
steroids, PUVA, total-body electron-beam irradiation, topical nitrogen mustard, systemic chemotherapy, and extracorporeal plasmapheresis, have been tried with variable results.88 A proposed plan of treatment is given in Table 21.5.
Evaluation of infants and children suffering from erythroderma/exfoliative dermatitis is paramount. It not only
assists in forming the precise treatment strategy, but also
alleviates the anxiety of the child’s carer who will be confronted with a dilemma. It is, therefore, imperative to arrive
Chapter 21
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Erythroderma/Exfoliative Dermatitis
211
TABLE 21.5: Treatment of Erythroderma
General
Specific (topical)
-Inpatient care required
-Topical steroids (Triamcinolone -Sedative antihistamine H1
receptor (Hydroxyzine
acetonide cream 0.025%–
hydrochloride 25–50 mg orally
1.0%) under wet dressing
every 4–6 h)/any other
-Adequate bed rest and
sedation
-Monitor fluid intake/electrolyte
balance/temperature regulation -Apply tap water wet dressings
2–3 hourly; gradually reduce
-High protein diet/nutritional
frequency, followed by
support
emollients application
-Discontinue all unnecessary
medications
-Daily tepid bath may be
soothing.
Specific (systemic)
Disease specific
Psoriasis – Methotrexate,
retinoids, phototherapy
Atopic dermatitis – Systemic
steroids, antibiotics, antivirals
-Institute systemic antibiotics
Pityriasis rubra pilaris –
(to cover secondary infection by Retinoids, methotrexate,
Staphylococcus aureus)
systemic steroids
Toxic epidermal necrolysis –
Intravenous immunoglobulins
-Systemic steroids (used with
caution) – atopic dermatitis,
seborrheic dermatitis; avoid in
psoriasis and infections; taper
down
Lymphoma – Extracorporeal
phototherapy, PUVA,
alkylating-agents
Scabies – Permethrin 5%,
Ivermectin 200 µg/kg
PUVA, psoralen plus UVA.
Data adapted from Sehgal VN, Srivastava G, Sardana K. Erythroderma/exfoliative dermatitis – a synopsis. Int J Dermatol. 2004; 43:39–47.
at a probable diagnosis based on the salient clinical features
vide supra and relevant investigations. The differential diagnosis of erythroderma/exfoliative dermatitis in infants and
children is intricate, bizarre, and extensive. Common causes
of the disease should be considered in the first instance,
and it is worthwhile to recapitulate atopic dermatitis, seborrheic dermatitis, toxicity/drug reactions, and infections
as the most common causes of erythroderma.1,2,49,75
The basic management of erythroderma is supportive
therapy and correction of the hematologic, biochemical,
and metabolic imbalances. A regulated environmental temperature gives symptomatic relief to the affected patient.
Liberal uses of emollients are useful in soothing the irritated skin. Low-potency topical corticosteroids are useful in only a few patients and may be ineffective or even
harmful in other patients. The authors and other skeptics
do have severe reservations.1,49 The unfolding of underlying pathology may prove useful in defining an appropriate
treatment.74 Thus, a judicious individualized approach is
required when treating erythroderma/exfoliative dermatitis in the pediatric age group.
Newer drugs such as rituximab,89 tacrolimus,90 infliximab,91 and so forth can be tried after weighing the pros
and cons and individual merits.
COMPLICATIONS AND PROGNOSIS
Exfoliative dermatitis is a complex disorder involving many
factors, but the net outcome depends on the underlying disease. The disease course is rapid, if it results from
drug allergy, lymphoma, leukemia, contact allergens, or
SSSS.1,3,75 The disease course is gradual if it results from
the generalized spread of a primary skin disease (e.g.,
psoriasis or atopic dermatitis).49,84 Drug-induced cases of
exfoliative dermatitis recover completely if initial medical management is promptly undertaken.75 Despite skilled
efforts, exfoliative dermatitis can sometimes prove fatal,
especially in elderly patients. Secondary infection, dehydration, electrolyte imbalance, temperature dysregulation,
and high-output cardiac failure are potential complications
in all cases.
Postinflammatory hypopigmentation or hyperpigmentation may occur, especially in individuals with dark skin.
Generalized vitiligo or pyogenic granuloma has also been
recorded after exfoliative dermatitis.88,92 Nevi and keloid
formation are rare benign sequelae, as are alopecia and nail
dystrophies.8 In initial documented studies, the recorded
death rate varied from 18% to 64%;1,14,49,75 however, the
mortality has been reduced due to advances in more rapid
diagnosis and improved therapeutic regimens.
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50. Sehgal VN, Srivastava G. A toxic epidermal necrolysis (TEN)
Lyell’s syndrome. J Dermatol Treat. 2005; 16:278–86
51. Sehgal VN, Srivastava G. Juvenile and adult (juvenile) pityriasis rubra pilaris. Int J Dermatol. 2006; 45:438–46.
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53. Gelmetti C, Schiuma AA, Cerri D, et al. Pityriasis rubra pilaris
in childhood: a long-term study of 29 cases. Pediatr Dermatol.
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●
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CHAPTER 22
Acute, Severe Bullous Dermatoses
Snejina Vassileva
A VARIETY OF SKIN diseases may present with the
appearance of blisters (Table 22.1). The skin reacts with the
formation of vesicles or larger bullae to a number of external
physical, chemical, and biological insults. Adverse reactions
to systemic or topically applied drugs occupy an important
place in the differential diagnosis of blistering eruptions.
Bullous lesions can also occur as a manifestation of systemic diseases, as is the case of the bullae seen in diabetic
patients. Atypical blistering forms of several inflammatory
dermatoses exist, such as bullous lichen planus, bullous
morphea, or bullous mycosis fungoides. In all these cases,
blistering lesions are infrequent and temporary, in contrast to a group of chronic cutaneous disorders referred to
as “bullous dermatoses,” where vesiculobullous lesions are
the main and characteristic clinical feature. Some bullous
dermatoses are due to genetically determined loss of basic
structural elements in the skin that maintain the cohesion
between the keratinocytes in the epidermis, or between the
epidermal layer and the dermis within the basement membrane zone (BMZ). The majority of bullous dermatoses,
however, are acquired organ-specific autoimmune diseases
in which the autoantibodies target structural proteins in the
skin. These disorders constitute one of the major sources
of morbidity and mortality in dermatology.
Acquired autoimmune bullous dermatoses are a heterogeneous group of uncommon but often debilitating diseases
including pemphigus, bullous, and cicatricial pemphigoid
(CP) and related entities, linear immunoglobulin A (IgA)
disease (LAD), epidermolysis bullosa acquisita (EBA), and
dermatitis herpetiformis (DH). Their histological classification is based on the level of the skin at which the cleft
occurs and the mechanisms of blistering process. Intraepidermal acantholytic blisters, characteristic of pemphigus,
result from autoantibody binding to desmosomal proteins
leading to functionally impaired desmosomes and acantholysis. In the pemphigoid group of diseases, the autoantibodies are directed against different components of the
dermal–epidermal junction, which results in subepidermal
blistering. Several diagnostically relevant clinical signs and
symptoms can be derived from the level of the cleft formation. Intraepidermal blisters, for instance, tend to be
more flaccid and fragile and therefore rupture easily due to
their thinner roof. In contrast, subepidermal blisters have a
thick, “tense” roof and can remain intact even when firmly
compressed.
Autoimmune bullous dermatoses are often misdiagnosed, and sometimes the delay in their diagnosis and
institution of appropriate treatment can result in death.1
Usually, in routine dermatologic practice, a careful clinical
evaluation is sufficient to differentiate the transitory blisters of bacterial, viral, or parasitic origin, or those seen
in the dermatitis/eczema group, or to orient the clinical
diagnosis toward a possible immunobullous disease. Several clinical features, such as age of onset, family history,
history of exposure to hazardous factors, known underlying systemic or other dermatologic diseases may provide
clues as to the etiology of a blistering eruption.2 A further
step in the clinical recognition of bullous diseases takes into
consideration the lesion morphology, distribution, evolution, and presence of characteristic clinical signs, such as the
Nikolsky sign (i.e., lateral pressure in the vicinity of a blistering lesion produces detachment of the epidermis). The
diagnosis of autoimmune bullous diseases, however, strictly
relies on histological and immunologic criteria, the latter
being provided by the results of the application of specialized immunohistology techniques.3,4 Histological examination of a biopsy specimen from an early intact vesicle
would discriminate among intraepidermal and subepidermal blister formation and the underlying histopathology
patterns, but the direct and indirect immunofluorescence
(DIF and IIF, respectively) techniques are essential in the
diagnosis of immunobullous diseases. DIF reveals the type
and location of the immunoreactants (immunoglobulins,
complement components, fibrin, properdin) deposited in
vivo in a patient’s skin.5 It is performed on biopsy specimens from normal-appearing skin immediately adjacent
to a bullous lesion (perilesional skin). DIF on the patient’s
skin that has been separated through lamina lucida through
incubation in a 1.0 M solution of NaCl allows further discrimination between the various subepidermal blistering
diseases characterized by immune deposits in the lamina
lucida or in the deeper layers of the BMZ. IIF is used
for detecting circulating autoantibodies in the body fluids
(blood, serum, blister fluid). Immunoelectron microscopy
is a method combining the advantages of immunohistochemistry techniques and the resolution power of electron
page 215
216 E MERGENCY D ERMATOLOGY
TABLE 22.1: Causes of Blistering
Physical/Chemical
Friction
Pressure ulcers (decubitus ulcers)
Suction (vacuum) blisters
Thermal injury (burn, freezing)
Ultraviolet light irradiation
Carbon monoxide poisoning
Fracture blisters
Infectious
Impetigo contagiosa
Bullous impetigo/Staphylococcal scalded skin syndrome
Bullous erysipelas
Syphilis (pemphigus neonatorum)
Herpes simplex
Varicella-Zoster
Coxsackie (Hand–foot–mouth disease)
Dyshidrosiform tinea/Pompholyx
Parasitic
Scabies
Insect bites
Allergic/Immunologic
Contact dermatitis
Dyshidrosiform eczema/Pompholyx
Fixed drug eruption
Erythema exsudativum multiforme
Blistering drug eruptions
Stevens–Johnson syndrome/Toxic epidermal necrolysis
Coma-induced blisters
Bullous amyloidosis
Bullous lichen planus
Bullous morphea
Bullous allergic vasculitis
Bullous mastocytosis
Bullous pyoderma gangrenosum
Bullous mycosis fungoides
Leukemic bullae
Grover disease (transient acantholytic dermatosis)
Metabolic diseases
Porphyria (cutanea tarda, erythropoietic)
Pseudoporphyria (can be also drug induced)
Chronic renal failure (hemodialysis)
Bullosis diabeticorum
Pellagra
Autoimmune
Pemphigus
Pemphigoid
Linear immunoglobulin A disease
Epidermolysis bullosa acquisita
Bullous systemic lupus erythematosus
Dermatitis herpetiformis
Genetic/Hereditary
Hailey–Hailey disease
Darier disease
Epidermolysis bullosa hereditaria
Congenital bullous erythroderma
Kindler syndrome
Incontinentia pigmenti
Hydroa vacciniforme
microscopy that is used to identify the different ultrastructural binding sites of immunoglobulins and complement
within the dermal–epidermal junction in the subepidermal
blistering diseases.6 Immunoblotting and immunoprecipitation are used to identify the antigen or antigens precipitated by the autoantibodies circulating in a patient’s
serum.7 Enzyme-linked immunosorbent assay (ELISA) is
used as a sensitive method for the detection of autoantibodies to the immunodominant epitopes in pemphigoid and
pemphigus.
For several decades, a variety of both local and systemic
therapies has become available that can be used to treat
these diseases. Although the mortality from autoimmune
bullous diseases has decreased significantly during the past
several decades, they still represent one cause of morbidity
in dermatology, and the common causes of death are often
due to the complications of the therapeutic agents used.
Suppression of autoantibody production and tissue binding is a main route in treating patients with autoimmune
bullous dermatoses.
PEMPHIGUS
Pemphigus is a group of rare, life-threatening autoimmune
blistering diseases characterized by widespread blistering
and erosions of the skin and mucous membranes. It is mediated by pathogenic autoantibodies against desmosomal
cadherins desmoglein 1 and desmoglein 3.8 Because desmosomes constitute the main adhesion structure of the epidermis, binding of autoantibodies to their target antigens
leads to loss of cell–cell adhesion between keratinocytes
and intraepithelial blister formation, called acantholysis.
Three major variants of pemphigus are currently recognized: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus (PNP). These variants differ considerably in their clinical, histological, and immunological
features and prognosis. Pemphigus vulgaris, also known
as “deep” pemphigus, is characterized by blister formation
above the basal-cell layer and is associated with antibodies
against desmoglein 3, which is located in the lower portions
of the epidermis and is found in both the skin and mucous
membranes. In contrast, pemphigus foliaceus or “superficial” pemphigus is characterized by subcorneal acantholysis
and antibodies against desmoglein 1, which is expressed in
the upper epidermal layers and is found only in the skin.
Pemphigus vulgaris affects both the skin and mucous membranes, mainly the oral mucosa, whereas in pemphigus foliaceus the lesions are confined to the skin. Several subtypes
of both forms of pemphigus exist.
Before the advent of corticosteroids in the 1950s, pemphigus had been a deadly disease with mortality rates up
to 90%–100% of affected patients within 2 years of onset.9
The introduction of corticosteroids and immunosuppressive drugs has dramatically transformed what was almost
invariably a fatal illness into one the mortality of which is
Chapter 22
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Acute, Severe Bullous Dermatoses 217
FIGURE 22.1: Painful erosions on the lip mucosa in a patient
with pemphigus vulgaris.
FIGURE 22.2: Erosive lesions of lid margins and conjunctiva in
a patient with mucocutaneous pemphigus vulgaris.
now less than 10%.10 Despite the advances in management
and improved prognosis, pemphigus is still regarded as a
chronic debilitating condition in which the patient’s life is
mainly endangered by the complications and side effects of
the long-term treatment and not by the disease itself.
Pemphigus vulgaris is the most common and one of
the most severe forms of pemphigus that still carries a
grave prognosis. Although people from all races can be
affected, pemphigus vulgaris is more prevalent in some
ethnic groups (Ashkenazi Jewish, Japanese), and in some
regions such as the Mediterranean and Balkan countries.11
Individuals with certain human leukocyte antigen (HLA)
allotypes are predisposed to the disease, although the susceptibility gene differs depending on ethnic origin;12 thus,
HLA-DRB1∗ 0402 is associated with the disease in Ashkenazi Jews and DRB1∗ 1401/04 and DQB1∗ 0503 in nonJewish patients of European or Asian descent. Pemphigus
vulgaris most often affects middle-aged adults, the mean
age of onset being between the age of 40 and 60 years.
In the majority of cases, the disease starts from the oral
mucosa and nasopharynx and in 50%–60% of patients may
remain localized to these sites for months. Flaccid blisters
that easily rupture by leaving painful erosions are characteristic of the mucosal variant of pemphigus vulgaris
(Figure 22.1). The erosions show little or no tendency to
heal, which results in decreased food intake and progressive
loss of weight. There is usually a characteristic foetor ex ore.
Other mucous membranes such as the conjunctiva (Figure 22.2), esophagus, and genital and anal mucosa may be
involved.
Within various periods of time, cutaneous involvement
develops in addition to the mucosal disease. The skin
lesions are characterized by flaccid, peripherally extending bullae, arising on unchanged skin. The flexural areas,
trunk, face, and scalp are most often affected (Figure 22.3).
If left untreated, the disease shows a progressive course
with appearance of new bullous lesions and involvement of
larger areas of skin. Individuals younger than 18 years can
be rarely affected (pemphigus juvenilis, childhood pemphigus, adolescent pemphigus).13 In the pediatric population,
the disease has a similar course to that in adults.
Histopathologically, pemphigus vulgaris is characterized by acantholytic intraepidermal blister formation above
the basal layer of keratinocytes (Figure 22.4). The immunologic hallmark of pemphigus vulgaris is the demonstration
of in vivo bound and circulating immunoglobulin G (IgG)
autoantibodies against the cell surface of keratinocytes.
DIF reveals deposits of IgG on the epithelial cell surface throughout the epidermis, a diagnostic staining pattern found in practically all patients with active disease
(Figure 22.5). The deposits are found in the perilesional
and clinically normal skin and mucosa, but the best results
are obtained from biopsy specimens from perilesional skin.
FIGURE 22.3: Pemphigus vulgaris: few flaccid blisters on normal skin and large peripherally extending erosions.
218 E MERGENCY D ERMATOLOGY
FIGURE 22.6: Indirect immunofluorescence with pemphigus
serum on human esophagus substrate: binding of immunoglobulin G antibodies on the epithelial cell surface (network epidermal fluorescence).
FIGURE 22.4: Acantholysis with suprabasilar clefts in pemphigus vulgaris. Few acantholytic cells floating in the blister cavity.
The presence of circulating autoantibodies can be detected
and measured using various serologic assays including IIF,
immunoblotting, and ELISA. IIF reveals serum IgG antibodies, which produce the characteristic epithelial cell surface fluorescence pattern on monkey esophagus (or human
esophagus) as a substrate (Figure 22.6). Their titers correlate with the activity of the disease. Immunoblot analysis
can detect autoantibody profiles that have been defined to
be specific for each clinical phenotype of pemphigus.14,15
Patients with mucosal involvement, with no or limited
skin blisters (mucosal dominant phenotype of pemphigus
vulgaris) demonstrate autoantibody binding to a 130 kd
FIGURE 22.5: Direct immunofluorescence on perilesional skin
in pemphigus: intercellular fluorescence pattern with immunoglobulin G throughout the epidermis.
protein (desmoglein 3), whereas patients with mucocutaneous involvement have autoantibodies that react with
desmoglein 3 but also with desmoglein 1 (160 kd protein)
(Figure 22.7). Patients with dominant skin disease have
higher desmoglein 1 antibody titers than those with oraldominant pemphigus vulgaris.16 Therefore, the presence of
desmoglein 1 antibodies in pemphigus vulgaris is predictive of a potentially more severe phenotype with extensive
skin involvement.17 A standardized ELISA is commercially
available to measure autoantibody titers to both desmoglein
1 and 3.
Pemphigus vegetans is a rare clinical form of pemphigus
vulgaris (1%–2% of patients) affecting the intertriginous
areas, where hypertrophic, papillomatous, or verrucous
vegetating lesions are present. Two types of pemphigus
vegetans are distinguished: 1) the Neumann type, in which
long-lasting (refractory) erosions in the folds are transformed into vegetating lesions (Figure 22.8); and 2) the
Hallopeau type, characterized by the appearance of pustules, rapidly followed by formation of verrucous vegetating
plaques with peripheral pustules resembling Figure 22.9.18
Pemphigus foliaceus is a rare variant of pemphigus characterized by subcorneal epidermal blisters and pathogenic
IgG anti-desmoglein 1 autoantibodies.19 Clinically, pemphigus foliaceus manifests with transient cutaneous superficial blisters that are fragile to the point that often only scaly,
crusted erosions with erythema are found on physical examination (Figure 22.10). Lesions are typically in a seborrheic
distribution – the central face, head, neck, and upper torso.
Most often the disease remains localized for several years,
but may progress to erythroderma (Figure 22.11). The fact
that the mucous membranes are not affected is an important clinical feature that differentiates pemphigus foliaceus
from pemphigus vulgaris. The absence of mucosal lesions in
Chapter 22
1
2
3
4
5
●
Acute, Severe Bullous Dermatoses 219
6
FIGURE 22.7: Immunoblot analysis of pemphigus sera on epidermal extracts. Lanes 1 and 2: control sera from patients
with pemphigus foliaceus and pemphigus vulgaris, respectively.
Lanes 5 and 6: the antibodies bind to both the 160 kd and 130 kd
antigens.
pemphigus foliaceus is explained by the compensatory presence of desmoglein 3 in the squamous mucosal epithelia.20
DIF is similar to that in pemphigus vulgaris, but a stronger
staining has been described in the upper epidermal portion. Circulating antiepithelial cell surface IgG antibodies
are best detected by IIF using guinea pig lip substrate. By
immunoblotting and ELISA, the antibodies in pemphigus
foliaceus specifically bind to desmoglein 1.
An endemic subtype of pemphigus foliaceus, known as
fogo selvagem (from the Portuguese “wild fire”), exists
in certain regions of Brazil and other countries of South
America.21 Endemic pemphigus foliaceus differs from the
nonendemic form of the disease in its geographic distribution, high familial incidence, and younger age of onset;22
a higher incidence of severe generalized exfoliative forms
is related to a greater morbidity and mortality in fogo selvagem. An endemic form of pemphigus foliaceus has also
been recently described in Colombia23 and Tunisia.24 The
endemic nature of the condition is thought to be precipitated by an immune response to an environmental antigen(s), currently not yet identified.
FIGURE 22.8: Neumann type of pemphigus vegetans: vegetations arise at the places of persisting erosions.
Pemphigus erythematosus, also referred to as pemphigus seborrhoicus, or Senear–Usher syndrome, is a rare
subtype of pemphigus foliaceus that combines clinical and
immunopathologic features of pemphigus and cutaneous
systemic lupus erythematosus (SLE) (Figure 22.12). Usually the scalp, face, upper portions of the chest, and back
are involved. The lesions of the face may show the typical
butterfly distribution characteristic of SLE. In addition to
the intercellular epidermal staining pattern, DIF in pemphigus erythematosus shows a band of immunoreactants at
the dermal–epidermal junction.
PNP is the most severe variant of the disease, occurring
in association with malignancies, mainly of B-cell lymphoproliferative origin. It was defined in 1990 on clinical, histological, and immunologic criteria.25 The autoantibody
response in PNP is directed against an antigen complex
composed of desmogleins 1 and 3, as well as to desmosomal proteins of the plakin family, including desmoplakins
I and II, envoplakin, periplakin, the 230 kd antigen of bullous pemphigoid (BP), and a yet not fully identified 170kda antigen.26,27,28 Clinical symptoms of PNP combine
features of pemphigus, erythema multiforme, or Stevens–
Johnson syndrome, BP, and lichen planus. Severe involvement of multiple mucous membranes is a major clinical
220 E MERGENCY D ERMATOLOGY
FIGURE 22.11: Pemphigus foliaceus: exfoliative erythroderma.
FIGURE 22.9: Hallopeau type of pemphigus vegetans: a solitary vegetating plaque resembling pyoderma vegetans.
FIGURE 22.10: Nonendemic pemphigus foliaceus: scaly, erythematous plaques with few crusted erosions at the periphery,
located in the seborrheic zones.
FIGURE 22.12: Pemphigus erythematosus: superficial crusted
erosions with erythema and scaling on sun-exposed skin.
Chapter 22
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Acute, Severe Bullous Dermatoses 221
FIGURE 22.14: Palmoplantar blistering and targetoid lesions
are suggestive of paraneoplastic pemphigus.
FIGURE 22.13: Paraneoplastic pemphigus: prominent involvement of the ocular, nasal, and oral mucosa, extending on the
lips.
feature (Figure 22.13). Cutaneous lesions are polymorphic
and may consist of flaccid but also tense blisters, morbilliform exanthema, lichenoid or psoriasiform changes,
as well as palmoplantar target lesions (Figure 22.14).29
DIF reveals deposits of immunoreactants in the intercellular (pemphigus-like) and/or linear BMZ (pemphigoidlike) pattern. By IIF, PNP antibodies react with the simple,
columnar, and transitional epithelial tissue substrates (rat
bladder substrate) in addition to the stratified squamous
epithelium.30
Approximately 80% of reported cases with PNP are
linked to non-Hodgkin’s lymphoma, CLL, and Castleman disease, and less commonly Waldenström macroglobulinemia, T-cell lymphoma, thymoma, Hodgkin’s disease,
retroperitoneal sarcoma, reticulum cell sarcoma, roundcell liposarcoma, and inflammatory fibrosarcoma have been
described.31,32 Isolated reports on association with solid
cancers exist.33 The mortality rate in PNP is estimated
to be more than 90%. Death is usually secondary to sepsis, gastrointestinal (GI) bleeding, multiple organ failure,
or respiratory failure. Respiratory failure with features
of bronchiolitis obliterans occurs in approximately 30%
of patients.34 Recently, the term “paraneoplastic autoimmune multiorgan syndrome” was introduced to encompass the aggregate of signs and symptoms associated with
the distinct morbid process affecting the skin, mucosa,
and lungs in a heterogeneous group of patients with
PNP.35
Drug-induced pemphigus, first recognized half a century ago, is attributed mainly to molecules that contain
a thiol (–SH) group, such as D-penicillamine, captopril,
and thiopronine, or a disulfide bond that readily releases
SH groups, such as penicillin and cephalosporins.36 It
has been demonstrated that these drugs possess powerful acantholytic qualities in vitro.37 Other drugs known to
induce pemphigus contain an active amide group in their
molecule.38 In some cases, the disease disappears when the
drug is withdrawn (drug-induced pemphigus), but it usually
continues even after removal of the initiating agent (drugtriggered pemphigus). Some cases of pemphigus have been
described after occupational contact with pesticides, which
led to the description of “contact pemphigus” as a variant of
environmentally induced disease.39,40 Besides, pemphigus
has been reported in association with several other autoimmune diseases, including SLE, myasthenia gravis, rheumatoid arthritis, and BP.
Systemic corticosteroids are the mainstay of treatment
for pemphigus. Several corticosteroid regimens have been
proposed in the literature, and there has been a debate on
whether rapid institution of treatment and higher initial
steroid dose are related to more favorable outcome. Usually prednisolone is administered at a dose of 40–60 mg
daily in mild disease, and 60–100 mg daily in more severe
cases, with or without other immunosuppressive agents,
and is continued until there is cessation of appearance of
new blistering lesions and healing of the majority of erosions.41 The dosage is then reduced by one half until all of
the lesions have cleared, followed by tapering to a minimum
effective maintenance dosage. Because the disease has a
222 E MERGENCY D ERMATOLOGY
chronic course, patients receiving long-term corticosteroid
therapy frequently have serious side effects. Alternative or
adjuvant therapies for patients who do not respond to or
who experience complications from corticosteroids include
immunosuppressive agents such as cyclophosphamide, azathioprine, cyclosporine, methotrexate, and mycophenolate mofetil, and immunomodulatory drugs and procedures such as dapsone, gold salts, and plasmapheresis.42
Administration of high-dose intravenous immunoglobulins
(2 g/kg/month) has been successfully employed in cases of
pemphigus unresponsive to conventional immunosuppressive treatment.43 Recently, a single cycle of rituximab, a
monoclonal antibody directed against the CD20 antigen of
B lymphocytes, has been demonstrated to effectively control severe pemphigus, but the potential long-term risks of
this treatment need to be further assessed.44
Even with the use of corticosteroids and other immunosuppressive agents, there is still significant morbidity and
mortality associated with pemphigus. A common cause of
death is infection secondary to the immunosuppression
required to treat the disease. Most deaths occur within the
first few years of the disease. Unfortunately, many of the
drugs used to treat this disease have serious side effects,
and patients must be monitored closely for infection, renal
and liver function abnormalities, electrolyte disturbances,
hypertension, diabetes, anemia, and GI bleeding.45
AUTOIMMUNE SUBEPIDERMAL BULLOUS
DERMATOSES
Autoimmune subepidermal blistering dermatoses include
the pemphigoid group of diseases, LAD, EBA, and DH.
With the exception of DH, all these disorders are characterized by circulating and tissue-bound autoantibodies against various components of the dermo-epidermal
anchoring complex.46 Anchoring complexes are specialized focal attachment sites within the cutaneous BMZ that
play a crucial role in dermo-epidermal adhesion. Antibody
binding to various proteins within this complex results
in dermo-epidermal separation and tense blister formation. The dermo-epidermal anchoring complex consists
of hemidesmosomes of the basal keratinocytes, anchoring filaments of the basement membrane, and anchoring
fibrils of the papillary dermis. Structural proteins within
this complex, described as autoantigens in various autoimmune bullous dermatoses, include BP antigen 180 (BP,
pemphigoid gestationis, mucous membrane pemphigoid,
LAD), BP230 (BP), ␣64 integrin (mucous membrane
pemphigoid), laminin 5 and 6 (mucous membrane pemphigoid), and type VII collagen (EBA and bullous SLE).
Recent advances in the molecular characterization of BMZ
components have led to a better understanding of the interaction between these molecules as well as the autoimmune
response against these proteins.
PEMPHIGOID GROUP
The pemphigoid group of autoimmune bullous dermatoses
is characterized by the production of autoantibodies targeting adhesion molecules that are part of the hemidesmosomes at the dermal–epidermal junction. Their immunohistological hallmark is the formation of subepidermal
blister and deposits of immunoreactants, usually IgG and
complement, along the BMZ. The pemphigoid group
of bullous dermatoses comprises BP, mucous membrane (cicatricial) pemphigoid, pemphigoid gestationis,
and lichen planus pemphigoides. Other recently identified
rare forms of pemphigoid include p200 pemphigoid, p105
pemphigoid, and antilaminin 5 pemphigoid.
BP
BP is a subepidermal autoimmune bullous disease typically
affecting elderly individuals older than 60 years. In 1953,47
BP was first described as a separate disease from pemphigus
vulgaris, and later studies in 196748 revealed the presence
of in vivo bound and circulating autoantibodies directed
against the BMZ of stratified epithelia. Two hemidesmosomal proteins, the BP antigen 230 (BP230), also termed
BP antigen 1 (BPAG1) and the BP antigen 180 (BP180),
also termed BP antigen 2 (BPAG2) or type XVII collagen,
have been identified as the targets of the autoantibodies
in BP.49,50 A passive-transfer mouse model of BP strongly
suggests that antibodies directed against the BP180 protein
are of primary pathogenic importance in the development
of the disease (Liu et al, 1993).
BP is believed to be the most common autoimmune
blistering disease in Western European countries, with an
estimated incidence of 6–7 cases per 1 million population
per year in France51 and Germany52 and even higher in
the United Kingdom.53 The disease appears to be rarer in
the Far East.54 Historically, BP has been thought to be of
better prognosis than pemphigus.55 Over the past decade,
however, several large European studies demonstrated that,
even with treatment, patients with BP have a prognosis as
grim as a diagnosis of end-stage heart disease, with more
than 40% of patients dying within 12 months.56–58 Much
of the mortality may be related to the age and the general
condition of patients. In a retrospective study from Scotland, 48% of patients with BP died within 2 years of diagnosis, particularly from respiratory diseases.59 Treatment
with corticosteroids and other immunosuppressive agents
may also play a role. It has been suggested that patients
with circulating antibodies to BPAG2 tend to have a poorer
prognosis due to a more severe disease requiring higher
doses of systemic steroids.60,61
Clinically, BP is characterized by a polymorphic eruption consisting of large, tense blisters on erythematous or
normal-appearing skin, urticaria-like patches and plaques,
Chapter 22
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Acute, Severe Bullous Dermatoses 223
FIGURE 22.15: Bullous pemphigoid in an elderly man: tense
blisters on inflammatory background, involving the flexural surfaces and lateral trunk.
and eczematous plaques. Usually, the eruption is intensely
pruritic. There might be a prodromal period of generalized pruritus that lasts for months without any skin
manifestations.62 The eruption is usually widespread, with
a predilection for the flexural surfaces of the arms and
legs, lower abdomen, and the lateral aspects of the trunk
(Figure 22.15). Localized forms also occur. In rare occasions, BP may affect mucosal surfaces such as the mouth,
but scarring is not observed. Rarely, BP may occur in
children.63
BP has been described in association with carcinoma
at various sites, as well as with sarcoma, melanoma, and
lymphoproliferative disorders; however, case–control studies did not confirm the significance of this association,
which seems to be most likely related to the old age of
the patients.64 Thus, unless abnormalities are found on
physical examination, exhaustive investigations to rule out
malignant disease are not recommended. Association of
BP with a variety of other autoimmune disorders (such
as rheumatoid arthritis, Hashimoto thyroiditis, dermatomyositis, SLE, and autoimmune thrombocytopenia) was,
but evidence for such an increased incidence was not,
revealed by large controlled studies regarding such a relationship.65 In some cases BP has been thought to be induced
by physical injury (burn, radiotherapy, ultraviolet irradiation)66 or by systemic or topical medications.67
The diagnosis of BP relies on the histology findings of
subepidermal blistering accompanied by eosinophilic infiltration in the superficial dermis, and on the results of IF
testing. Linear IgG and C3 deposition at the BMZ are
observed on DIF of perilesional skin (Figure 22.16). IIF
reveals circulating IgG anti-BMZ antibodies in patients’
serum that react with the epidermal side of 1.0 M NaCl split
skin as a substrate (Figure 22.17). Autoantibodies against
the NC16A domain of BP180 are identified by ELISA.
FIGURE 22.16: Bullous pemphigoid: direct immunofluorescence on perilesional skin showing linear C3 at the basement
membrane zone.
Treatment of BP consists of corticosteroids, administered at lower doses (0.5–0.75 mg/kg/day) than those
used to treat pemphigus, alone or in combination with
steroid-sparing agents such as azathioprine, mycophenolate mofetil, or tetracycline. These drugs are usually started
simultaneously, followed by a gradual tapering of the prednisone and continuation of the steroid-sparing agent until
clinical remission is achieved. Methotrexate may be used
in patients with severe disease who are unable to tolerate
prednisone. Plasma exchange therapy may be considered
in refractory cases. Because most morbidity and mortality are secondary to treatment, there is now a tendency to
treat patients with less aggressive regimens. In mild cases,
potent topical corticosteroids may be sufficient. The disease is self-limited, and approximately one half of treated
cases will remit within 6 years.68
Mucous Membrane (Cicatricial) Pemphigoid
Mucous membrane pemphigoid, previously known as
CP, is a rare but well-defined variant of pemphigoid,
224 E MERGENCY D ERMATOLOGY
FIGURE 22.17: Bullous pemphigoid: indirect immunofluorescence on salt-split skin substrate reveals binding of antibodies
to the roof of the blister.
characterized by erosive, scarring subepidermal blistering
lesions of mucosal surfaces, particularly of the oral mucosa
and ocular membranes, and less often, the skin. Depending on the mucosal surface that is mainly affected, patients
with mucous membrane pemphigoid may first present to
the ophthalmologist, dermatologist, dentist, gastroenterologist, gynecologist, otolaryngologist, or to the primary
care physician. The oral mucosa is almost always affected,
followed by other mucosae (eye, nose, pharynx, larynx,
esophagus, genitalia, anus) and rarely the skin. Desquamative gingivitis is the most common oral manifestation
(Figure 22.18), but nonhealing ulcers on buccal mucosa and
soft and hard palates are not rare. Bullae quickly rupture,
leaving slowly healing erosions, followed by scarring and
adhesions between the various structures of the oral cavity
involved. Laryngeal involvement may lead to a sore throat,
FIGURE 22.19: Ocular cicatricial pemphigoid: conjunctival erosions on the lower lid with multiple synechiae.
hoarseness, and possible loss of speech. Supraglottic stenosis secondary to erosions, scarring, and edema may necessitate a tracheostomy as the airway is further compromised.
Esophageal erosions and scarring can lead to the formation
of strictures, with dysphagia, odynophagia, and weight loss.
Ocular CP is characterized by progressive subconjunctival
cicatrization that leads to decreased vision, photosensitivity, scarring, and fibrosis that can eventually cause blindness
(Figure 22.19). The course of the disease is usually slow but
progressive and may be punctuated by periods of explosive
inflammatory activity. There is a 2:1 preponderance for
women; the average age of onset of CP is reported to be 65
years, but this does not take into account the observation
that most cases of CP are relatively advanced at the time of
diagnosis.69
A less frequently encountered variant of CP, referred to
as Brunsting–Perry benign pemphigoid, is characterized by
vesiculobullous lesions and scarring confined to the head
and neck areas.70
Pemphigoid Gestationis
FIGURE 22.18: Bleeding erosions on the gingival and lip
mucosa in cicatricial pemphigoid.
Pemphigoid gestationis, previously known as “herpes gestationis,” is a pregnancy-specific autoimmune subepidermal blistering dermatosis that usually develops in the second or third trimester and clinically presents with severely
pruritic urticarial lesions that progress to large tense bullae (Figure 22.20). The estimated incidence of the disease
ranges between 1 in 10,000 and 1 in 50,000 pregnancies,71
with only 14% of the cases developing postpartum.72
Pemphigoid gestationis is characterized by linear deposition of C3 along the BMZ on DIF and by the presence of
circulating IgG autoantibodies directed toward the transmembrane 180 kd protein BPAG2. Epitope mapping of
the antigen showed that pemphigoid gestationis and BP
autoantibodies bind to a common antigenic site within
Chapter 22
FIGURE 22.20: Tense blisters with clear fluid over the inner
aspect of the forearms in a patient with pemphigoid gestationis.
the noncollagenous domain (NC16A) of BPAG2.73 The
exact pathogenesis of pemphigoid gestationis is still largely
unknown, but it has been postulated that the disease is primarily related to an allogeneic reaction against the fetoplacental unit, triggered by an aberrant expression of major
histocompatibility complex class II molecules in the placenta. The result is an autoimmune response directed
against the chorioamniotic cells but cross-reacting with
BPAG2 in the skin. Hormonal factors have also been implicated in the pathogenesis of the disease as flares have been
reported with menses or use of oral contraceptives.
LAD
LAD is an autoimmune subepidermal blistering disease
defined by the presence of linear deposits of IgA at the
dermal–epidermal junction. It was first recognized as a
separate entity from DH in 1979,74 based on the finding
of in vivo bound IgA anti-BMZ antibodies and the lack
of an associated gluten-sensitive enteropathy. Currently,
there is compelling evidence that the IgA autoantibodies
in LAD are directed against heterogeneous antigen targets in the BMZ and ultrastructurally localize to the lamina
lucida, anchoring fibrils, or the lamina densa.75 The major
●
Acute, Severe Bullous Dermatoses 225
LAD antigens identified by immunoblot analysis in dermal and/or epidermal tissue extract include BP180 (and its
breakdown products, the 97 kd and 120 kd antigens) and
BP230, a 285 kd antigen, and collagen VII.76–79
LAD can occur at any age, but there are two peaks
of onset: in adults between 40 and 60 years old, and in
children of preschool age. Although the childhood variant
has been formerly considered as a distinct entity termed
“chronic bullous disease of childhood,” both forms of LAD
have identical immunopathologic features and are currently
regarded as one and the same disease process. The estimated incidence of LAD in studies from Western Europe
varies from 0.22 to 0.5 per million.80–82 It has been reported
to be more common in women than in men.83
Although in the majority cases LAD is “idiopathic,”
there have been a number of triggering factors reported,
including trauma, ultraviolet exposure, infections, and
a wide range of drugs, such as vancomycin, penicillin,
antiepileptics, captopril, diclofenac, and sulfonamides.84
Drug-induced LAD tends to resolve after discontinuation of the offending drug and is associated with a
lower morbidity;85 however, some more severe cases mimicking erythema multiforme, Stevens–Johnson syndrome,
and toxic epidermal necrolysis have been described.86–88
Other important systemic associations of LAD include
autoimmune diseases, such as inflammatory bowel disease,
SLE, dermatomyositis, rheumatoid arthritis, and acquired
hemophilia. Besides, a relationship between LAD and lymphoid but also nonlymphoid malignant diseases has been
reported, including Hodgkin disease, non-Hodgkin’s lymphoma, chronic lymphatic leukemia, multiple myeloma,
and plasmocytoma, but also visceral malignant tumors such
as bladder, breast, esophageal, uterine, ovarian, thyroid,
and renal cell carcinoma.89
The clinical features of LAD can be heterogeneous. The
cutaneous eruption is characterized by large, tense bullae,
which may arise on normal skin or on erythematous bases,
and urticarial plaques. Arciform or annular blister arrangement at the periphery of the lesions that show a tendency
to heal in the center is a characteristic feature of LAD,
described as the “cluster of jewels” sign (Figure 22.21).
Lesions are usually generalized, with some tendency to
grouping but, in contrast to DH, no symmetry is present.
Common areas of involvement include the lower trunk
and limbs, especially the inner thighs and pelvic regions;
the latter distribution is more typical for childhood LAD.
Pruritus may be severe or entirely absent. Mucous membrane involvement is frequent, reported in 60%–80% of
patients;90 rarely mucosal involvement can be the sole clinical manifestation.
The diagnosis of LAD is based on the histology, which
invariably shows a subepidermal blister with a superficial
dermal infiltrate of neutrophils, and on the DIF finding of
linear IgA along the BMZ. The IIF of patient’s serum can
be either negative or detect low levels of IgA anti-BMZ
226 E MERGENCY D ERMATOLOGY
FIGURE 22.21: Adult linear immunoglobulin A dermatoses:
annular lesions with tense blisters at the periphery (“cluster of
jewels” sign).
FIGURE 22.22: Classical epidermolysis bullosa acquisita: atrophy and milia are observed at the sites of healing mechanobullous lesions.
antibodies that would react with the epidermal, dermal, or
both sides of the blister when tested on saline-separated
skin as a substrate.
The aim of treatment in LAD is to suppress disease activity with the minimum treatment possible. In the majority
of cases there is spontaneous remission between 3 and 6
years after disease onset; therefore, it is important not to
overtreat the disease. Dapsone is the empiric therapy of
choice in managing LAD; occasionally, low-dose oral corticosteroids are needed as an adjuvant. There are reports
of successful treatment of LAD with macrolide antibiotics.91 Immunosuppressive agents such as mycophenolate
mofetil and cyclosporine have been used with a variable
success. Successful use of IVIG therapy has been reported
in patients with progressive LAD that was unresponsive
to dapsone, systemic corticosteroids, and systemic antibiotics.92
tary dystrophic epidermolysis bullosa and characterized by
spontaneous or trauma-induced blisters that heal with scars
and milia. In addition to this “classical” mechanobullous
form, however, several inflammatory subtypes of EBA were
described that can be clinically indistinguishable from BP
or CP,97–100 and LAD, and can, therefore, remain underdiagnosed. EBA is a chronic disease that is difficult to treat
and for which there is no cure.101 It is associated with significant morbidity resulting from involvement of various
skin and mucosal surfaces.
The exact incidence and prevalence of EBA is unknown,
but it seems to be a rare disease. The results from few available studies showed an incidence of 0.22 cases per million
people per year in Germany,102 0.26 per million per year in
France, 0.23 per million per year in Kuwait,103 to a slightly
higher incidence of 0.5 per million per year in Singapore.104
It appears that EBA is slightly more common in women and
in blacks.105 The mean age of onset is in persons in their
40s; the disease occurs infrequently in elderly persons and
even less often in children.
The clinical features of EBA are heterogeneous. The
“classical” form presents as a noninflammatory mechanobullous disease with acral distribution. Due to the extreme
mechanical fragility of the skin, blisters occur under minor
trauma over the back of the hands, knuckles, elbows, knees,
sacral area, and feet. Healing occurs with scarring and milia
formation (Figure 22.22).
Approximately one half of patients with EBA present
with widespread inflammatory vesiculobullous eruption
mimicking BP. There is often prominent involvement of
the trunk and flexural skin (Figure 22.23). In contrast to
classical EBA, skin fragility is not prominent and scarring
and milia formation may be minimal or absent. In some
cases, overlapping between both the classical and the BPlike forms may exist, or can be seen in evolution.
EBA
EBA is an acquired autoimmune bullous dermatosis characterized by subepidermal blisters, and tissue-bound and
circulating antibodies directed against sublamina densa of
the epithelial basement membranes.93 The patient’s antibodies recognize type VII collagen, which is the major
component of anchoring fibrils, the structures that connect lamina densa of the BMZ to the papillary dermis.94
It was first described by Elliott95 more than 100 years ago
as an acquired form of epidermolysis bullosa, with clinical
features highly reminiscent of the inherited forms of dystrophic epidermolysis bullosa, in which a hereditary defect
in the gene encoding for type VII collagen results in paucity
of anchoring fibrils and skin fragility. In 1971, Roenick
and colleagues96 established the first diagnostic criteria for
EBA as an adult-onset disease closely resembling heredi-
Chapter 22
●
Acute, Severe Bullous Dermatoses 227
FIGURE 22.23: Inflammatory epidermolysis bullosa acquisita:
widespread blistering eruption involving the trunk.
FIGURE 22.24: Epidermolysis bullosa acquisita: indirect
immunofluorescence on salt-split skin substrate reveals
binding of antibodies to the floor of the blister.
Another group of patients with EBA may have predominant involvement of the mucous membranes that
can result in irreversible complications similar to those
seen in CP, including blindness and esophageal strictures.
Tracheal involvement and upper airway obstruction requiring tracheotomy have been described.106 EBA has been
reported in association with a number of other systemic
diseases, including SLE, inflammatory bowel disease,
amyloidosis, multiple myeloma, autoimmune thyroiditis, diabetes mellitus, acquired hemophilia, and multiple
endocrinopathy syndromes.107 The most frequent association is with inflammatory bowel disease. A recent study
showed that sera from patients with Crohn disease reacted
by immunoblot analysis with type VII collagen, which exists
in both the skin and the gut.108 In addition, paraneoplastic cases of EBA in association with lymphoproliferative
malignancies have been reported.109
DIF of perilesional skin reveals linear deposits of IgG
and more rarely, C3 at the BMZ. On IIF, in the serum
of 10%–30% of patients, circulating IgG anti-BMZ antibodies are present that bind to the dermal side of a saltsplit skin substrate (Figure 22.24). In patients who lack
serum anti-BMZ antibodies, DIF on salt-split skin sections
is helpful to discriminate EBA from BP by demonstrating deposits of immunoreactants at the dermal side of the
blister.110 Using direct immunoelectron microscopy, the
IgG and/or C3 deposits were found to localize to the sublamina densa region of dermal–epidermal junction.111 By
immunoblotting (or immunoprecipitation), EBA autoantibodies bind to 290 kd and 145 kd proteins, which represents the full-length ␣ chain of type VII collagen or
its amino-terminal globular NC1 domain, respectively.94
A sensitive ELISA for the detection of autoantibodies
to type VII collagen using recombinant protein is also
available.112
Treatment for EBA is challenging and is often unsatisfactory. Mild cases follow a chronic time course, whereas
aggressive disease is often difficult to control and is associated with a significant mortality rate. Systemic corticosteroids, used as standard treatment for EBA, often
in combination with cyclophosphamide, azathioprine, or
methotrexate, may be ineffective in some cases. Some therapeutic success has been reported with colchicine, dapsone, photopheresis, infliximab, or high-dose intravenous
immunoglobulin.113
DERMATITIS HERPETIFORMIS
Dermatitis herpetiformis (DH), also known as Duhring
disease, is an uncommon subepidermal blistering disease
characterized by an intensely pruritic cutaneous eruption,
typical IF findings, and association with a gluten-sensitive
enteropathy. Since its initial description in 1884 by Louis
Duhring,114 DH has been confounded for decades with
BP under the term Duhring–Brocq disease. Through the
1960s to 1970s, however, several clinical and IF features,
typical for DH and not found in other immunobullous diseases, were identified that led to the current concept of DH
as a distinct immunobullous disorder, strongly related to
celiac disease (CD) in the spectrum of the gluten-sensitive
disorders.115–117 DH and CD have a common immunogenetic background, sharing a strong association with certain major histocompatibility complex antigens, such as
HLA-B8, HLA-DR3, and HLA-DQw2. First-degree relatives of patients with DH frequently develop CD. Immunohistologically, DH is characterized by granular deposits
of IgA and complement C3 in the papillary dermis of
uninvolved skin.118 Recently, it has been found that epidermal and tissue transglutaminases, cytosolic enzymes
involved in cell envelope formation during keratinocyte
228 E MERGENCY D ERMATOLOGY
FIGURE 22.25: Dermatitis herpetiformis: symmetric pruritic
polymorph eruption on the buttocks.
differentiation, are the major autoantigens recognized in
the skin lesions of DH and targeted by the circulating
IgA antibodies to endomysium (intermyofibril substance
of smooth muscle) found in the serum of patients with DH
and CD.119,120
Clinically, DH presents with an intensely itchy cutaneous eruption involving symmetrically the extensor surfaces, including elbows, knees, shoulders, sacrum, and
buttocks. The eruption is polymorphic and consists of
urticarial plaques, erythematous papules, and vesicles, often
grouped in a herpetiform pattern (Figure 22.25). As the
vesicles are heavily excoriated, only small erosions, crusting, and postinflammatory pigment changes can be seen in
evolution. The scalp and face are often affected. Mucosal
surfaces are usually spared, although oral lesions have been
frequently described earlier, probably due to confusion of
the disease with pemphigoid or LAD. The onset of DH
is usually in the second or third decade, but may occur at
any age. A diet overloaded with gluten or iodides (seafood)
can often precipitate a flare of the eruption. The eruption
runs a chronic course, with flares and remissions, especially
if unrecognized or left untreated. Patients from both genders may be affected, but there seems to be a slightly higher
male preponderance.
DH and CD show an uneven geographic distribution,
with higher incidence rates in Europe or in populations
with European descent. In Sweden and Finland, the incidence is between 0.86 and 1.45 in 100,000 per year. In
Anglo-Saxon and Scandinavian populations, the prevalence
is between 10 and 39 per 100,000.121 In contrast, DH is
extremely rare in Orientals and is uncommon in Asians
and Afro-Caribbeans.122 Morbidity in DH is mainly related
to the intense pruritus, scratching, discomfort, and insomnia, as well as to the risk of superimposed bacterial or viral
infections. Systemic complications include complications
of the associated gluten-sensitive enteropathy, which is now
accepted to be present in practically all patients with DH,
despite the fact that most of them may have only subclinical GI disease. Symptoms related to the gluten-sensitive
enteropathy are milder than those seen in patients with CD
without skin findings but may include malnutrition, weight
loss, abdominal pain, dyspepsia (they can even mimic peptic ulcer disease), and perforation. Deficiency states (such
as folate deficiency, iron deficiency anemia, and B12 deficiency), neurologic disturbances, bone disease, infertility,
chronic fatigue, and premature dental loss may all be seen.
Patients with DH, similarly to those with CD, have
a higher incidence of associated autoimmune disorders,
including thyroid disorders, atrophic gastritis, type I diabetes, pernicious anemia, Addison disease, vitiligo, and various connective tissue disorders.4 Besides, patients with
DH, like patients with CD, are at an increased risk for developing GI lymphoma of T-cell lineage, usually described
as enteropathy-associated T-cell lymphomas.4,123 Therefore, when DH is diagnosed, examinations for possible
signs and symptoms of such associations is necessary.124
The diagnosis of DH is based on clinical, histologic,
and IF criteria. Histologic examination of an early vesicle
FIGURE 22.26: Dermatitis herpetiformis: direct immunofluorescence on perilesional skin showing granular immunoglobulin A
deposits at the dermal–epidermal junction, more intense in the
tips of the dermal papillae.
Chapter 22
lesion shows subepidermal blister formation with collections of neutrophils forming microabscesses in the dermal
papillae. DIF of perilesional uninvolved skin shows granular deposition of IgA and complement C3 along the BMZ,
mostly confined to the tips of the dermal papillae (Figure 22.26). IIF of patients’ sera shows IgA-antiendomysial
antibodies on monkey esophagus as a substrate; however, no anti-BMZ antibodies are present in DH. Serum
antibodies to tissue transglutaminase are detected using
ELISA.
The treatment of DH is aimed to combat both the skin
and GI symptoms. The most common medications used
to treat DH are dapsone and sulfapyridine. Administration
of dapsone with a starting dose of 50–100 mg daily is usually followed by a dramatic response, with disappearance
of the pruritus within 24 hours; this rapid response helps
to confirm the diagnosis. Common side effects of dapsone
therapy that should be carefully monitored include hemolysis, methemoglobinemia, and agranulocytosis; dapsone
is contraindicated in patients with glucose-6-phosphate
dehydrogenase deficiency. In patients who do not tolerate dapsone, the cutaneous eruption can be alternatively
controlled by sulfapyridine 0.5–2.0 g daily (to a maximum
dose of 4.0 g daily) or with sulphamethoxypyridazine 0.5–
1.0 g daily; however, sulfonamides do not influence the
GI changes. Similar to the treatment of CD, treatment of
DH should always include a gluten-free diet for a lifetime,
which may result in remission of both the skin lesions and
the bowel disease. The results of a retrospective study of
487 patients with DH showed a protective role for a strict
gluten-free diet against development of lymphoma in DH
patients.125
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100. Caux F, Kirtschig G, Lemarchand-Venencie F, et al. IgAepidermolysis bullosa acquisita in a child resulting in blindness. Br J Dermatol. 1997; 137:270–5.
101. Woodley DT, Chen M, O’Toole E, Chan L. Epidermolysis bullosa acquisita. In: Kanitakis J, Vassileva S, Woodley
D, editors. Diagnostic immunohistochemistry of the skin.
London: Chapman & Hall; 1998. pp. 114–22.
102. Zillikens D, Wever S, Roth A, et al. Incidence of autoimmune subepidermal blistering dermatoses in a region of central Germany. Arch Dermatol. 1995; 131:957–8.
232 E MERGENCY D ERMATOLOGY
103. Nanda A, Dvorak R, Al-Saeed K, et al. Spectrum of autoimmune bullous diseases in Kuwait. Int J Dermatol. 2004;
43:876–81.
104. Wong SN, Chua SH. Spectrum of subepidermal immunobullous disorders seen at the National Skin Centre Singapore:
a 2-year review. Br J Dermatol. 2002; 147:476–80.
105. Gammon WR. Epidermolysis bullosa acquisita. Semin Dermatol. 1988; 7:218–24.
106. Wieme N, Lambert J, Moerman M, et al. Epidermolysis bullosa acquisita with combined features of bullous pemphigoid
and cicatricial pemphigoid. Dermatology. 1999; 198:310–
13.
107. Hallel-Halevy D, Nadelman C, Chen M, Woodley DT. Epidermolysis bullosa acquisita update and review. Clin Dermatol. 2001; 19:712–18.
108. Chen M, O’Toole EA, Sanghavi J, et al. The epidermolysis bullosa acquisita antigen (type VII collagen) is present
in human colon and patients with Crohn’s disease have
autoantibodies to type VII collagen. J Invest Dermatol. 2002;
118:1059–64.
109. Radfar L, Fatahzadeh M, Shahamat Y, Sirois D. Paraneoplastic epidermolysis bullosa acquisita associated with
multiple myeloma. Spec Care Dentist. 2006; 26:159–
63.
110. Gammon WR, Kowalewski C, Chorzelski TP, et al. Direct
immunofluorescence studies of sodium chloride-separated
skin in the differential diagnosis of bullous pemphigoid and
epidermolysis bullosa acquisita. J Am Acad Dermatol. 1990;
22:664–70.
111. Yaoita H, Briggaman RA, Lawley TJ, et al. Epidermolysis
bullosa acquisita: ultrastructural and immunological studies.
J Invest Dermatol. 1981; 76:288–92.
112. Chen M, Chan LS, Cai X, et al. Development of an ELISA
for rapid detection of anti-type VII collagen autoantibodies
in epidermolysis bullosa acquisita. J Invest Dermatol. 1997;
108:68–72.
113. Chen M, Hallel-Halevy D, Nadelman C, et al. Epidermolysis bullosa acquisita. In: Hertl M, editor. Autoimmune
diseases of the skin, pathogenesis, diagnosis, management.
Vienna: Springer-Verlag; 2001. pp. 99–122.
114. Jordon RE, Chorzelski TP, Beutner EH. Clinical significance of autoantibodies in bullous pemphigoid. In: Beutner EH, Chorzelski TP, Beutner EH, editors. Autosensitization in pemphigus and bullous pemphigoid. Springfield
IL: Charles C. Thomas; 1970. pp. 91–9.
115. Nicolas MEO, Krause PK, Gibson LE, Murray JA. Dermatitis herpetiformis. Int J Dermatol. 2003; 42:588–600.
116. Rose C, Zillikens D. Dermatitis herpetiformis Duhring. In:
Hertl M, editor. Autoimmune diseases of the skin, pathogenesis, diagnosis, management. Vienna: Springer-Verlag;
2001. pp. 85–98.
117. Alonso-Llamazares J, Gibson LE, Rogers III RS. Clinical,
pathologic, and immunopathologic features of dermatitis
herpetiformis: review of the Mayo Clinic experience. Int J
Dermatol. 2007; 46:910–19.
118. Van Der Meer JB. Granular deposits of immunoglobulins
in the skin of patients with dermatitis herpetiformis. An
immunofluorescent study. Br J Dermatol. 1969; 81:493–503.
119. Dieterich W, Laag E, Bruckner-Tuderman L, et al. Antibodies to tissue transglutaminase as serologic markers in
patients with dermatitis herpetiformis. J Invest Dermatol.
1999; 113:133–6.
120. Sardy M, Karpati S, Peterfy F, et al. Comparison of a tissue
transglutaminase ELISA with the endomysium antibody test
in the diagnosis of gluten-sensitive enteropathy. Z Gastroenterol. 2000; 38:357–64.
121. Cotell S, Robinson ND, Chan LS. Autoimmune blistering
skin diseases. Am J Emerg Med. 2000; 18:288–99.
122. Banfield CC, Allen J, Wojnarowska F. Dermatitis herpetiformis and linear IgA disease. In: Kanitakis J, Vassileva S,
Woodley D, editors. Diagnostic immunohistochemistry of
the skin. London: Chapman & Hall; 1998. pp. 105–13.
123. Sigurgeirsson B, Agnarsson BA, Lindelof B. Risk of lymphoma in patients with dermatitis herpetiformis. Br Med J.
1994; 308:13–15.
124. Reunala T, Collin P. Diseases associated with dermatitis herpetiformis. Br J Dermatol. 1997; 136:315–18.
125. Lewis HM, Renaula TL, Garioch JJ, et al. Protective effect
of gluten-free diet against development of lymphoma in dermatitis herpetiformis. Br J Dermatol. 1996; 135:363–7.
CHAPTER 23
Emergency Management of Purpura and
Vasculitis, Including Purpura Fulminans
Lucio Andreassi
Roberta Bilenchi
PURPURIC LESIONS are the clinical expression of the
passage of erythrocytes from the vascular compartment to
the extravascular one, generally following damage related
to permeabilization of the walls of small vessels. At times,
they are the only clinical feature, at other times the sign
of a more complex morbid process and the expression of a
serious condition, as in the systemic vasculitides.
The clinical spectra of vasculitides are broad, with a variety of conditions ranging from mainly cutaneous involvement with a relatively benign course, such as leukocytoclastic vasculitis, to situations in which the cutaneous
involvement is less evident but an integral part of a process that could progress to a critical situation requiring
emergency treatment. Acute pulmonary insufficiency or
renal blockage, as an expression of a systemic vasculitis,
is relatively frequent in intensive care units.1,2 Central
and peripheral nervous system involvement, cardiac failure,
and intestinal ischemia, as complications or first presenting
signs of systemic vasculitides, are clinical conditions commonly encountered in current practice.3–5 Purpura fulminans (PF), often associated with disseminated intravascular coagulation (DIC), is a dramatic condition that must
be identified correctly and differentiated from purpura
simplex.6
Purpuras and vasculitides are medical emergencies that
require rapid diagnosis, identification of the causal factors, and initiation of a treatment, which is often aggressive but must be carried out as early as possible.7 Particularly important in this regard are some situations
occurring in Henoch–Schönlein purpura (HSP), Wegener
granulomatosis (WG), Churg–Strauss syndrome (CSS),
polyarteritis nodosa (PAN), microscopic polyangiitis
(MPA), Kawasaki disease (KD), and PF (Table 23.1).
Dermatologists may encounter situations involving the
evolution or complications of pathologies with initial cutaneous involvement or be called to assist with the diagnosis and management of emergency patients; therefore,
knowledge of the disease entities included in the group
of purpuras and vasculitides, particularly of the conditions
that could progress to emergency situations, must be an
integral part of the dermatologist’s training. The aim of
this chapter is to call attention to purpuras and vasculitides
that can present as or evolve into emergency situations and
to the procedures for managing these patients.
CLINICAL PRESENTATION
AND PATHOGENESIS
HSP is an immunoglobulin A (IgA)-mediated leukocytoclastic vasculitis characterized by antiseptic lesions with
perivascular infiltrates, fibrinoid necrosis, and vascular
occlusion caused by platelet thrombi. The disease occurs
mainly in children, sometimes following an upper respiratory tract infection, and has an acute onset distinguished
by cutaneous manifestations on the buttocks and extensor
surfaces of the extremities and by general symptoms such as
discomfort, headache, fever, polyarthralgia, and abdominal
TABLE 23.1: Purpuras and Vasculitides Potentially Evolving
into Emergency Situations
Disease
Possible conditions requiring
emergency treatment
Henoch–Schönlein
purpura
Abdominal and renal
complications
Wegener granulomatosis
Pulmonary and renal involvement
Churg–Strauss syndrome
Hemoptysis and respiratory
failure, myocardial infarction,
myocarditis, renal failure
Polyarteritis nodosa
Renal insufficiency,
cardiomyopathy, gastrointestinal
bleeding, bowel perforation
Microscopic polyangiitis
Deterioration of renal function and
respiratory failure
Kawasaki disease
Cardiac involvement in the acute
stage; development of coronary
artery aneurysms later in the
course
Purpura fulminans
Disseminated intravascular
coagulation
page 233
234 E MERGENCY D ERMATOLOGY
pain. In most cases, HSP resolves without leaving any negative traces, but in some cases kidney involvement can
progress to renal insufficiency.8
The cutaneous involvement begins with a symmetric
macular erythematous rash on the lower extremity, which
rapidly evolves into purpura. Initially, the eruption may
be limited to the malleolar skin but usually extends to the
dorsal surface of the legs, buttocks, and ulnar side of the
upper extremities. Within 12–24 hours, the macules turn
into palpable dark red purpuric lesions, sometimes merging
into vast ecchymosis-like patches. In children younger than
2 years, the cutaneous involvement may be dominated by
marked edema on the scalp, periorbital region, hands, and
feet. The intensity of the edema, attributed to the intestinal
loss of proteins, is related to the severity of the vasculitis.
Palpable purpura occurs in all cases of HSP and is almost
always the first presenting sign, whereas articular involvement and possible renal and abdominal involvement appear
later.9
In the criteria recently proposed by the European
League against Rheumatism (EULAR) for the classification of childhood vasculitides, a prerequisite for the diagnosis of HPS is palpable purpura associated with another
clinicopathological feature, such as diffuse abdominal pain,
tissue deposits of IgA, arthritis or arthralgia, renal involvement shown by hematuria, or proteinuria.10 The cutaneous
manifestations are crucial for an early preliminary diagnosis, which must then be confirmed.
WG is a multisystemic disease characterized by necrotizing granulomas of the respiratory apparatus, disseminated vasculitis, and glomerulonephritis. Both sexes can be
affected, usually in middle age, although there are occasional cases of children and people older than 70 years.
The etiology is unknown, although numerous studies support an autoimmune origin.11,12
An autoimmune etiology of WG is suggested by the
almost constant presence of granular pattern antineutrophil
cytoplasmic antibodies (c-ANCA), the levels of which are
correlated with the severity of the disease and are predictive
of relapses. The frequent finding of IgA and IgE, the possible association with human leukocyte antigen (HLA) HLAB8 and HLA-DR2, and the efficacy of immunosuppressive therapy are further elements supporting an autoimmune origin.13 Protease 3 (PR-3), an enzyme stored in
the azurophilic granules of neutrophils and monocytes,
seems to be the main target of c-ANCA. Another enzyme,
a myeloperoxidase (MPO) contained in the azurophilic
granules, could play a role because it is activated by perinuclear pattern antineutrophil cytoplasmic antibodies (pANCA), found in a small number of patients.14 In vitro
studies have shown that ANCA are able to activate leukocyte degranulation and the release of toxic radicals and lysosomal enzymes responsible for a cytokine-mediated inflammatory process.15 In vivo studies have not provided direct
evidence of the responsibility of ANCA in the pathogenesis
of WG.16 The role of an infectious agent has been hypoth-
esized on the basis of the good results of sulfamethoxazoletrimethoprim treatment of early signs of the disease.17 The
histopathological features seen in recent lesions confirm the
hypothesis of an immune-mediated pathogenesis because
they document an involvement of neutrophils and endothelial cells as possible targets and promoters of the inflammation. Indeed, we know that endothelial damage and neutrophil activation can produce mediators of inflammation
that lead to the recruitment of monocytes and T cells able
to increase the endothelial damage.
Clinically, the disease begins with the classic triad of respiratory tract involvement, systemic vasculitis of the small
vessels, and focal glomerulonephritis, although the clinical pattern is not always complete. Upper respiratory tract
involvement occurs in more than 70% of patients, with
manifestations in the nasal mucosa, which is affected by
an inflammatory process with hemorrhage, necrosis, and
ulceration that can even lead to destruction of the septal
cartilage and deformation of the nasal profile. Lower respiratory tract involvement occurs in approximately 50%
of cases, with pulmonary, nodular, and cavity lesions, a
frequent cause of hemoptysis. Nephropathy in the initial
phases occurs in approximately 20% of patients, with a
rapid increase later in the course. The joints, eye, and
nervous system can be compromised to variable degrees
according to the progression of the disease.
The clinical picture is rarely dominated by cutaneous
lesions, the initial frequency of which is relatively low
but can rise to more than 50% in the advanced phases
of the disease. The first and most typical signs are papulonecrotic lesions located mainly on the elbows, knees, and
buttocks, sometimes preceded by an erythematous, edematous, or vesicular inflammatory phase. Subcutaneous nodules and ulcerative lesions with the appearance of pyoderma
gangrenosum can be found at the onset and in the later
phases. Purpuric manifestations involving extensive skin
areas, associated or not with erythematous and vesicular
lesions, are observed more frequently in the late phases
of WG but can sometimes be present at onset and are an
important sign for diagnostic purposes.18
The diagnosis of WG generally follows histopathological examination of a tissue fragment taken from the nasal
mucosa and is generally based on the demonstration of
granulomatosis and vasculitis. The detection of ANCA and
the identification of their pattern (i.e., cytoplasmic or perinuclear) are useful diagnostic complements and can contribute to a more complete classification, which naturally
requires instrumental and functional examinations of the
respiratory apparatus and kidneys.
CSS is a severe necrotizing vasculitis of the small vessels usually associated with asthma and eosinophilia, which
is why it is also called allergic granuloma.19 The onset
of the syndrome is often ambiguous, with the appearance of mainly asthmatic or rhinitic respiratory symptoms
that can precede the visceral, neurological, and cutaneous
involvement by some years. Classically, there are three
Chapter 23
●
Emergency Management of Purpura and Vasculitis, Including Purpura Fulminans
phases: the initial one characterized by allergic rhinitis,
nasal polyposis, sinusitis, and asthma; the intermediate one
with recurrent episodes of pneumonia and gastroenteritis
associated with circulating eosinophilia; and the final one in
which respiratory involvement prevails. In the final phase,
there may also be digestive apparatus involvement with the
appearance of hematic diarrhea, urinary apparatus involvement with hematuria, articular involvement with arthralgia,
and heart and peripheral nervous system involvement. The
latency between the appearance of the first symptoms and
the advanced phase is 3 years on average. Death is generally
due to a granulomatous infiltration of the heart or vasculitis
of the coronary arteries.20
Cutaneous involvement in CSS occurs in approximately
70% of cases and is often late and polymorphic, with purpuric maculopapular lesions on the extremities, mainly the
acral parts. More rarely, there are cutaneous and subcutaneous nodules on the head and extremities. The cutaneous
lesions do not differ from those found in other forms of
vasculitis and are characterized by purpuric manifestations,
nodules, and polymorphic-like erythematous patches, with
possible progression to necrosis.21,22
Histologically, there is a leukocytoclastic vasculitis in
the initial phase, followed by the formation of a palisading
granuloma around the foci of collagen degeneration, with
the presence of nuclear dust.23 The granuloma presents
basophilic or eosinophilic staining, according to the predominance of neutrophils or eosinophils in the infiltrate.
The process can involve both small vessels of the dermis
and larger vessels of the subcutis, although the finding of
vasculitis is not constant. At times, it is possible to observe
deposits of C3 and fibrin in the vessel wall.24
CSS falls into the group of ANCA-vasculitides including WG and microscopic angiitis, often with poorly defined
borders between the different entities.25,26 ANCA, circulating antibodies directed against antigenic constituents of
the cytoplasm of polymorphonuclear neutrophils, seem to
play an important role in the pathogenesis of the disease.
In vitro studies have shown that various types of antigenic stimuli (such as drugs, viruses, and bacteria) increase
the serum levels of tumor necrosis factor-␣ (TNF-␣) and
interleukin-1, with activation of polymorphonuclear neutrophils and transfer of PR-3 from the intracytoplasmic
azurophilic granules to the cell membrane. The interaction of PR-3 with circulating ANCA causes the subsequent
degranulation of polymorphonuclear neutrophils and tissue damage. Recent studies suggest that ANCA are more
involved in the vasculitic manifestations, such as glomerulonephritis, whereas the eosinophilic infiltration and the
associated cytotoxicity could be responsible for the cardiomyopathy. If confirmed, these results would support
an individual stratification in accordance with the clinical
pattern.27
PAN is a multisystemic vasculopathy of medium and
small arteries (and sometimes arterioles), mainly involving
the skin, kidneys, nerves, and gastrointestinal (GI) tract. It
235
can develop after a phase characterized by aspecific symptoms, such as discomfort, fever, weight loss, and muscular
and/or articular pain. Cutaneous involvement is frequent
with purpuric lesions, livedo reticularis, nodules, ulcers,
and gangrene.
The most frequent cutaneous signs are painful nodules
of variable size and number, located mainly on the lower
extremities, particularly the legs. The nodules are usually
the first cutaneous sign; they appear after a more or less
long benign course and develop with multiple flares leaving a pigmentary or livedoid residue with characteristic
reticular pattern. The livedo reticularis is more evident
in some areas, such as the legs, feet, buttocks, and shoulder blades, and can persist as the only evidence of vascular
damage.28
The pathogenetic mechanisms leading to the vascular
damage are probably heterogeneous and involve the intervention of immune complexes, ANCA, adhesion molecules,
cytokines, and antibodies against endothelial cells. The
immune complexes are the result of previous infections
and act via the activation of complement able to attract
neutrophils. ANCA play an important role in inducing
endothelial damage but are not always present in PAN. Various adhesion molecules (lymphocyte function-associated
antigen 1, intercellular adhesion molecule 1, endothelial
cell leukocyte adhesion molecule 1) are able to favor contact between neutrophils and endothelial cells and to initiate the cascade of events leading to vasculitis.
In approximately 10% of subjects with PAN, there
is a contemporaneous hepatitis B virus (HBV ) infection. In these patients, circulating immune complexes,
formed by HBV antigens and relative antibodies, could
play an important role in the pathogenesis of the vasculitic
lesions.29,30
MPA is a systemic necrotizing vasculitis frequently associated with glomerulonephritis and pulmonary involvement. Considered the microscopic form of PAN, it
acquired clinical autonomy in 1994 after the consensus conference aimed at redefining the classification of small-vessel
vasculitides.31 Involvement of the small vessels, including
arterioles, capillaries, and venules, is absent in PAN but is
typical of MPA. In pathogenetic terms, MPA, along with
WG and CSS, belongs to the group of small-vessel vasculitides linked to the role of ANCA. Anti-MPO p-ANCA
antibodies, present in MPA and absent in PAN, help to differentiate the two disease entities.32 The absence of granulomas and the lack of upper respiratory tract involvement
help to distinguish MPA from WG, although the distinction is not always easy.33
MPA generally has a rapid and progressive course, and a
timely diagnosis can be important for effective treatment. In
this regard, the finding of cutaneous signs may be useful for
the purposes of the histological examination. They present
as erythematous or purpuric macules, mainly located on the
extremities and are observed in more than 50% of cases.34
The cutaneous histopathology of MPA is characterized
236 E MERGENCY D ERMATOLOGY
FIGURE 23.1: Purpura fulminans and disseminated intravascular coagulation in a 71-year-old man suffering from leg ulcers
and diabetes. Note the multiple hemorrhagic bullae.
by a necrotizing vasculitis with a moderate neutrophilic
infiltrate affecting the papillary and middle dermis and
the subcutaneous tissue. The detection and titration of
ANCA could be useful for diagnostic and prognostic
purposes.35
KD, a vasculitic syndrome of unknown origin described
in 1967, is characterized by an eruption associated with
fever of relatively brief duration. Initially thought to be a
benign self-resolving process, it was later related to a series
of deaths from myocardial infarction due to thrombotic
occlusion of aneurismatic coronary arteries. Exceptional in
adolescents and adults, KD is typically a childhood disease
with a higher incidence in Asian populations, particularly
in Japan and China.36
The etiology of KD is unknown, although the idea of an
infectious origin is attractive. This origin is suggested by
the self-resolving course, lack of relapses, fever, exanthema,
and adenopathy, all typical of an infectious disease. Direct
attempts to isolate an infectious agent have proven negative.
It is possible that KD is the result of an immune response
induced by different microbial agents. This hypothesis is
supported by the frequent isolation of infectious microorganisms in individual cases and the similarities to other syndromes caused by multiple agents, such as aseptic meningitis.37
The inflammatory infiltrate found in KD, characteristic of a vasculitis, can involve blood vessels throughout
the organism. In autopsies, aneurysms have been found
in arteries in many regions (e.g., the celiac, mesenteric,
femoral, iliac, and renal arteries).38
The diagnosis is based on fever persisting for at least
5 days and alterations of the extremities, characterized in
the acute phase by palmoplantar edema and in the subacute phase by desquamation of the fingertips, hands, and
feet. Other typical signs are polymorphic exanthema, bilat-
eral hyperemic conjunctivitis without secretion, redness of
the lips and oral cavity, fissuration of the lips, strawberry
tongue, and hyperemia of the pharynx and oral cavity. A
usually unilateral laterocervical lymphadenopathy is also
frequently observed.39
Cardiovascular symptoms may be evident as early as the
acute phase of KD, and they are the main cause of long-term
morbidity and mortality. In this phase, the pericardium,
myocardium, endocardium, valves, and coronary arteries
can be involved. Cardiac function shows anomalies such as
tachycardia and myocardial contractile deficit, a cause of
insufficiency and shock.40
Coronary artery aneurysms develop in 15%–25% of
untreated persons and can lead to myocardial infarction,
sudden death, or ischemic cardiac disease.41,42 Various
point systems are available to identify children at high risk
of coronary arteriopathy.43
PF, a disease generally associated with sepsis, is found
most frequently in children. The clinical pattern is often
dominated by shock with hypotension and hypovolemia,
clinically distinguished by a weak and frequent pulse, anxiety, pallor, cold sweating, and cyanotic lips. The cutaneous
lesions consist of purpuric patches that rapidly evolve into
peripheral hemorrhagic necrosis, sometimes preceded by
bulla formation. PF is almost always associated with or progresses to DIC, an expression of thrombocytopenia with
increased production of thrombin and fibrinolysis (Figures 23.1 and 23.2).
The lesions in PF are generally considered the result
of a Schwartzman-like reaction. The Schwartzman phenomenon occurs when a dose of endotoxin is intravenously
(IV) injected into animals previously inoculated subcutaneously with a small dose of the same endotoxin. The
reaction occurs within a few hours at the site of the first
inoculation and is characterized by an inflammatory event
FIGURE 23.2: Cellulitis with signs simulating purpura fulminans in a 56-year-old woman. The clinical presentation was dominated by the appearance of purpuric patches, hemorrhagic bullae, and fever.
Chapter 23
●
Emergency Management of Purpura and Vasculitis, Including Purpura Fulminans
that rapidly progresses to necrosis. The Schwartzman phenomenon cannot be explained by an immune mechanism
and is probably due to a toxic effect. In PF (at least in the
forms associated with sepsis), the vascular lesions are considered the result of a necrotizing inflammatory process
caused by infectious agents. Meningococcus is the most
frequent cause of PF, but other infectious agents have been
recorded, such as Pneumococcus and Staphylococcus.44,45 A
malignant tumor, a possible triggering factor in PF, has
been found in a significant number of cases.46
In PF lesions, there is extensive coagulation in the small
vessels, with fibrin thrombi and a modest inflammatory
component. This feature differentiates PF from other vasculitides such as HSP, characterized by an accentuated
inflammatory component.47
PF is associated with marked hematic alterations, particularly low concentrations of fibrinogen, coagulation factors, and platelets, due to consumption of platelets and
extended prothrombin and partial thromboplastin times.
Fibrinogen-degradation products tend to increase, and the
concentrations of proteins C and S and antithrombin III
(AT III) tend to decrease. DIC often develops under these
conditions; it is the consequence of anomalous thrombin
activation leading to the conversion of fibrinogen to fibrin,
as well as of the activation and consumption of platelets.
These coagulation alterations are believed to be related
to systemic anomalies, particularly activation of protein
C, which are congenital or induced by pathological conditions.48
MANAGEMENT AND TREATMENT
The treatment of patients affected by purpuras and vasculitides, in critical or emergency conditions, is based on
general reanimation techniques and case-specific measures.
Useful general procedures are those aimed at improving the hemodynamic and hydroelectrolytic imbalance and
correcting eventual coagulation anomalies, which could
require specific drugs in addition to substantial plasma
and/or whole-blood infusions.
Systemic vasculitides associated with circulating ANCA
are characterized by frequent renal parenchyma involvement, represented by a necrotizing glomerulonephritis,
which translates into acute renal insufficiency. The presence in the blood of autoantibodies with an important role
in the pathogenesis of the lesions has prompted the use of
plasmapheresis, on the assumption that rapid removal of
the autoantibodies and, at the same time, coagulation factors and mediators of inflammation could strongly affect
the progression of the disease (Table 23.2).49,50
Corticosteroids are the most important category of
immunosuppressor drugs used in the treatment of systemic
vasculitides. They can be useful in all forms of vasculitides but are the first-line agents in several forms, such as
WG, CSS, and PAN. Corticosteroids can be used alone
237
TABLE 23.2: Drugs and Procedures Used in the Treatment of
Emergencies Related to Purpuras and Vasculitides
Drugs and
procedures
Indications
Plasmapheresis
ANCA-associated systemic vasculitides
Corticosteroids
All vasculitides; first-line treatment in
WG, CSS, PAN
Cyclophosphamide
Associated with corticosteroids in WG,
CSS, PAN
Azathioprine and
methotrexate
Used as maintenance therapy in patients
with WG, CSS, PAN
Intravenous
immunoglobulins
First-line treatment in Kawasaki disease;
potential alternative treatment for
ANCA-associated systemic vasculitides
Infliximab
Able to induce clinical remission in acute
or active ANCA-associated vasculitides
Rituximab
Active in refractory or relapsed
ANCA-associated WG
ANCA, antineutrophil cytoplasmic antibodies; WG, Wegener
granulomatosis; CSS, Churg–Strauss syndrome; PAN, polyarteritis
nodosa.
in the less severe forms but are usually combined with
cyclophosphamide in the severe forms. Other immunosuppressors, such as azathioprine and methotrexate, are
used as maintenance therapy in the remission phases of the
disease.51
The appearance of IV immunoglobulins (IVIg) has further expanded the therapeutic arsenal for systemic vasculitides. At high doses, IVIg can interfere with the immune
system at various levels, being indicated in various pathologies based on inflammation–immune mechanisms. IVIg
have proven particularly useful for KD, but their use (alone
or associated with corticosteroids or other immunosuppressor) has also proven successful in the ANCA-associated
vasculitides.52
New prospects in the treatment of systemic vasculitides
have recently been provided by the introduction of biological drugs, particularly infliximab, etanercept, and rituximab. In association with conventional therapy, infliximab,
an anti-TNF chimeric monoclonal antibody, has been able
to induce clinical remission in various systemic vasculitides,53 whereas the efficacy of etanercept has been modest.
Rituximab, a genetically chimeric murine–human CD20
antigen expressed on the surface of B lymphocytes, is more
promising as it has proven effective against refractory or
relapsed ANCA-associated WG.54
HSP
The management and therapy of HSP patients must take
into account various factors such as age, possible renal
involvement, and the presence of complications such as
nervous system involvement. HSP is generally a benign
238 E MERGENCY D ERMATOLOGY
disease with a good prognosis, characterized in more than
80% of patients by a single episode lasting a few weeks,
with relapses in 10%–20% of cases and chronic forms,
particularly renal insufficiency, in 5% of cases. For this
reason, the usefulness of always adopting a systemic therapy has been placed in doubt, particularly treatment with
steroids, because placebo-controlled prospective studies
have shown their limited efficacy.55 Prophylactic steroid
therapy is unable to prevent renal and gastrointestinal (GI)
complications but is indicated in the treatment of abdominal pain, subcutaneous edema, and nephritis.56 Prednisone,
at 1 mg/kg/day for 2 weeks followed by a lower dose for
another 2 weeks, has been shown to improve the GI and
articular involvement and to reduce the severity of renal
involvement. Other immunosuppressors (e.g., azathioprine, cyclophosphamide, cyclosporin, and mycophenolate
mofetil) can be combined with steroids, although their use
is controversial in view of the low efficacy recorded in
clinical trials.57 Similar conclusions have been made about
other drugs, such as IVIg, vitamin E, and other antioxidants.58 Plasmapheresis deserves separate mention because
it has proven effective in delaying the progression of renal
damage.59
Etanercept, a soluble TNF receptor fusion protein, is not
very effective, inducing long-lasting remissions in only
a minority of the treated patients,63 whereas infliximab,
a chimeric monoclonal antibody against TNF, seems to
merit further investigation.64 The results obtained with rituximab, a chimeric monoclonal antibody against CD20, are
more interesting because it causes depletion of B cells in the
blood within 6–12 months. By this mechanism, rituximab
seems to recreate the tolerance to ANCA antigens, at least
in some WG patients.65
WG can also be treated with other drugs, including
leflunomide, mycophenolate mofetil, and deoxyspergualin.
Leflunomide inhibits de novo synthesis of pyrimidine, necessary for the function of activated T lymphocytes. Its use
in WG can control relapses in a high number of subjects.66 Mycophenolate mofetil is an inhibitor of inosine
monophosphate dehydrogenase, an essential enzyme for
purine synthesis and thus for the proliferation and function of lymphocytes. Its use in the maintenance of remission in subjects treated with corticosteroids and cyclophosphamide has not proven very effective, and it requires
further evaluation.67 Deoxyspergualin, of unclear mechanism of action, has proven effective in WG patients unresponsive to conventional therapies.68
WG
The use of conventional immunosuppressors has led to significant improvement of the course and prognosis of WG,
although there are still serious limitations due to possible
cytotoxic side effects and frequent relapses after the suspension of treatment. Many doubts remain about the use of
biological therapies, whereas there is great hope concerning the possible development of drugs that will interfere
with specific targets with an important role in maintaining
the autoimmune response (e.g., ANCA).60,61
The standard treatment of WG involves the combination of cyclophosphamide and corticosteroids until remission and then maintenance therapy with azathioprine or
methotrexate. Complete remission or marked improvement compatible with a normal social life is recorded in
90% of cases, although relapses are frequent (50%) and the
drugs have high toxicity. Replacing cyclophosphamide with
methotrexate after remission is achieved may be advantageous in view of its low toxicity, and it could be used as
the first-line agent in association with corticosteroids.62 All
the previously mentioned drugs induce immunosuppression with the consequent risk of opportunistic infection,
above all Pneumocystis jiroveci pneumonia, although this
can be prevented by sulfamethoxazole–trimethoprim treatment, especially during remission. This drug has also been
used satisfactorily to reduce relapses, above all in patients
with limited, not very aggressive forms.
WG has also been the subject of trials to assess the
efficacy of biological drugs, especially by means of antiTNF-␣ agents, likely involved in the pathogenesis of WG.
CSS
Corticosteroids are the first-line agents in the treatment of
CSS. They can be used according to the standard procedures, but some authors suggest high IV doses, especially
in emergency situations. The response is usually dramatic:
The eosinophilia is normalized, the asthma regresses, and
the muscle enzyme levels return to normal. After the result
has been obtained, the steroids can be gradually tapered to
a minimal dose able to control the disease. If the corticosteroids are not sufficient to control the disease, it may be
necessary to combine cyclophosphamide (the use of which
is always advisable) and steroids in life-threatening cases.
Methotrexate could also be helpful to control CSS and can
be associated with steroids.69
In severe cases, particularly when steroids and
cyclophosphamide do not induce remission, anti-TNF
agents such as infliximab and etanercept can be used,
although they could increase the risk of infections. In
this regard, prophylactic treatment with sulfamethoxazole–
trimethoprim may be appropriate. An alternative could
be the use of recombinant interferon-␣ (IFN-␣).70 More
recently, encouraging results have been obtained with rituximab, but the data must be confirmed by larger trials.71,72
IV gammaglobulins could be a valid alternative in
patients unresponsive to conventional treatment, especially
those presenting with myocardiopathy and neuropathy.
The mechanism of action of this therapy is still unclear and
requires further investigation, but this does not diminish
the practical efficacy of the treatment.73
Chapter 23
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Emergency Management of Purpura and Vasculitis, Including Purpura Fulminans
PAN
First, the systemic forms must be distinguished from the
limited forms and the idiopathic forms from the HBVrelated forms. That said, the treatment of PAN depends on
the severity of the clinical features, quantified by the degree
of involvement of the affected organs. In particular, it is necessary to assess the extent of proteinuria and creatininemia,
the severity of eventual cardiomyopathy and GI signs, and
the nervous system involvement. In general, corticosteroids
associated with cyclophosphamide represent the standard
treatment of PAN, whereas antiviral agents and plasmapheresis are necessary in HBV-related cases.74,75
In patients with a relatively benign prognosis, corticosteroids alone may be sufficient. Prednisone, commonly
used in the treatment of PAN, must be administered until
regression of the symptoms, generally after approximately
1 month. The dose can then be tapered to a level able to
control the disease, after which the minimal dose must be
maintained for 9–12 months.
Cyclophosphamide is generally associated when the disease is refractory to treatment with steroids alone, during
relapses, and generally in all severe cases. Pulsed IV administration is the most common procedure, but oral administration can be used when it is unsuccessful. The association of cyclophosphamide with steroids for more than 1
year should be avoided.
In HBV-related cases, plasmapheresis is considered the
treatment of choice, because it can remove the viral components, including circulating immune complexes. Antiviral agents, such as IFN-␣2b and lamivudine, are obviously
important in such cases, possibly in combination. Naturally, corticosteroids are always indicated in PAN.76,77 On
exceptional occasions, HBV-related PAN may show a fulminant onset, requiring treatment with prednisone combined with pulsed IV cyclophosphamide and lamivudine.78
MPA
As in other forms of vasculitis, the initial treatment of
MPA consists of the induction of remission with prednisone
and cyclophosphamide. The initial dose of prednisone is
1 mg/kg/day for 1 month or at least until significant
improvement is observed. This dose is followed by a weekly
decrease to the maintenance dose, which can be continued for long periods, possibly on alternate days. The initial cyclophosphamide dose is 1.5–2 mg/kg/day, but higher
doses may be required (possibly IV) in emergency situations (e.g., in capillaritis with pulmonary hemorrhage).79
After remission, it is necessary to establish a maintenance
regimen, continuing the prednisone and replacing the
cyclophosphamide with azathioprine or methotrexate, both
at relatively low doses. Alternative drugs to be combined
with prednisone in the maintenance phase are methotrexate, cyclosporin, and mycophenolate mofetil.80 Pneumocys-
239
tis carinii and Pneumocystis jiroveci infections are prevented
by sulfamethoxazole–trimethoprim administered 3 times a
week.
KD
The treatment of acute KD is aimed at reducing inflammation in the walls of the coronary arteries and preventing
thrombosis, whereas long-term therapy in individuals with
coronary aneurysms is aimed at preventing ischemia and
myocardial infarction. The acute phase procedures, often
carried out in emergency conditions, are based on the earliest possible administration of aspirin and IVIg.81
Although aspirin is an important antiinflammatory and
has antiplatelet aggregation activity, its use alone does not
seem to reduce the frequency of coronary alterations. During the acute phase of KD, it is administered at 80–100
mg/kg/day in association with IVIg, which potentiates the
antiinflammatory effect. Aspirin is administered at high
doses until fever subsides, generally after 2–3 days, and is
then used at 3–5 mg/kg/day for antiplatelet aggregation
until the patient is free of the risk of coronary alterations.82
The mechanism of action of IVIg is still unknown, but
administration leads to rapid lowering of the fever and resolution of the clinical signs of KD in most patients. The
prevalence of coronary disease drops from 20%–25% in
children treated with aspirin alone to 2%–4% in those
treated with IVIg and aspirin in the first 10 days of the
disease. IVIg treatment is also indicated in patients diagnosed after the 10th day of the disease if the fever persists, because the antiinflammatory effect could be helpful.83 Occasionally, some patients may not respond to the
initial IVIg infusion or show only a partial response. These
subjects are usually treated with an additional IVIg infusion, but its efficacy must still be demonstrated.84
The use of corticosteroids in acute KD is controversial
and still under investigation. According to recent studies,
IV administration of methylprednisolone as an adjuvant
of conventional therapy with IVIg and aspirin seems to
improve the prognosis.85 Another drug used in the acute
phase of KD is pentoxifylline, which is well tolerated, practically without toxicity, and perhaps able to further reduce
the risk of coronary aneurysms.86 Other drugs have been
used along with corticosteroids in patients unresponsive to
conventional treatment, including cytotoxic agents such as
cyclophosphamide and anti-TNF-␣ monoclonal antibodies. Among these, infliximab is particularly promising, but
its use requires additional evaluation.87
PF
PF patients often present in a critical condition and must
be treated in an intensive care unit, where appropriate procedures to deal with shock can be carried out. Such procedures, particularly treatment of hypovolemia by infusions
240 E MERGENCY D ERMATOLOGY
TABLE 23.3: Anticoagulant Substances Used in the Treatment
of PF
Drugs
Indications
Heparin
Mainly as a bolus followed by an
infusion; low-molecular-weight heparins
in the prophylaxis of relapse
Protein C
First line in PF due to protein C
deficiency; adjuvant hemostatic support
in PF-associated meningococcemia
Antithrombin III
May be reduced in PF, and its
replacement has been shown to
normalize levels and reverse
disseminated intravascular coagulation
Tissue plasminogen
activator
To be used for PF unresponsive to
conventional treatment
Epoprostenol
Has been used to treat PF from sepsis
in infants and neonates
Dextran
May be used in PF patients who fail to
respond to plasma and heparin therapy
PF, purpura fulminans.
of plasma and physiological solution, correction of the acid–
base imbalance, and assisted ventilation, combined with
appropriate antibiotic therapy, have considerably reduced
the mortality due to PF. The efficacy of the treatment, both
quoad vitam and to prevent or limit the possible necrotic
evolution of acral lesions, largely depends on the precocity
of treatment. The role of dermatologists can be decisive in
this regard because they can identify PF and its possible
infectious origin on the basis of the first presenting symptoms. The problem is to distinguish a PF from a vasculitis
with cutaneous involvement, and this is not always easy to
do. Acral involvement, hemorrhagic bullae, a tendency to
necrosis, and hypovolemic shock are all suggestive of PF.88
Some laboratory tests can be helpful for diagnostic and
therapeutic purposes. The blood levels of prothrombin
fragments 1 and 2, the D-dimer test, the AT III level, fibrinand fibrinogen-degradation products, the platelet count,
the prothrombin time, and the levels of other coagulation
factors can all provide useful indications.89
The availability of tests to investigate more thoroughly
the coagulation system has led to the isolation and synthesis
of new drugs that affect the coagulation process at various
levels. These drugs have been added to the traditional therapeutic arsenal and deserve a brief discussion regarding PF
treatment (Table 23.3).
Although one of the oldest anticoagulant drugs, heparin can still play a role in the treatment of PF.90 It must
be administered as early as possible, even though there are
some reservations, because it can cause thrombocytopenia
and bleeding and there are no validated dosage schedules
to use in all cases. Administration as a bolus followed by
slow infusion seems to be the most reliable procedure,91
but there are reports of relapses due to too early suspension.92 The introduction of low-molecular-weight heparins
is interesting in this regard, but further investigation is
required.93
Protein C, an important physiological anticoagulant factor, is a vitamin K–dependent protease activated by thrombin. Its activated form, along with protein S (which acts as
a cofactor), degrades factor Va to factor VIIIa.94 Its blood
level is a useful reference to determine the quantity and
timing of administration.95 The clinical course is the most
important parameter for the establishment of when protein
C infusion will be useful and if it can be suspended. Protein
C is the first-line agent in cases of neonatal PF associated
with homozygote protein C deficiency.96 It is administered
by continuous or intermittent IV infusion until normalization and stabilization of the coagulation parameters.97
AT III is a glycoprotein produced by the liver with
a powerful inhibitory effect on the cascade of reactions
involved in coagulation. Although its name indicates activity against thrombin, it interferes with virtually all the
enzymes of coagulation and is particularly active when
administered with heparin, with which it forms an anticoagulation complex. It is indicated for the prevention and
treatment of thromboembolic processes due to AT III deficiency, of which two forms are known: those due to an
absolute lack of the factor (type I) and those due to an
inadequately functioning AT III (type II).98
Absolute or functional AT III deficiencies, such as those
occurring during a surgical intervention, pregnancy, childbirth, sepsis, polytrauma, and/or other pathological conditions associated with acute consumption coagulopathy and
which can lead to DIC, are elective conditions for the use of
AT III, although the efficacy of this treatment has recently
been placed in serious doubt.99 AT III can be diminished
during PF, and the restoration of normal levels by infusion
could help to improve the clinical course.100
Plasminogen activators, essential to convert plasminogen to plasmin and to initiate fibrinolysis, include urokinase, streptokinase, and various substances of tissue and
vascular origin, particularly tissue plasminogen activator
(t-PA), a human enzyme now obtained with the recombinant DNA technique (rt-PA). rt-PA, currently used in
the treatment of myocardial infarction and ischemic stroke,
has recently been applied successfully in the treatment of
peripheral thromboses caused by physical agents101 and in
the treatment of PF.102 rt-PA is able to activate fibrinolysis without unpleasant hemodynamic consequences. It is
administered by infusion at 0.25–0.5 mg/kg/h, and treatment can be prolonged if necessary.103 The possible risk
of bleeding has raised some doubts about the use of rt-PA
in PF, and it has been suggested that it be adopted only in
forms unresponsive to conventional treatment.104
Epoprostenol is generally used to inhibit platelet aggregation during renal dialysis, especially when there is a high
risk of hemorrhagic problems following heparin use. It is
Chapter 23
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Emergency Management of Purpura and Vasculitis, Including Purpura Fulminans
also used to treat primary pulmonary hypertension refractory to other treatments, generally together with other
anticoagulants. Because its half-life is only approximately 3
minutes, it must be administered by continuous IV infusion.
Because it is a potent vasodilator, its side effects include hot
flashes, headache, and hypotension. In PF from sepsis, it
has been used in children and neonates at 5–20 ng/kg/min
without significant collateral effects.105,106
Dextrans are glucose polymers of variable molecular
weight used as plasma substitutes and as antithrombotics
because they are able to reduce platelet aggregation. The
rheological effect produced by these molecules is due to
their ability to adhere to the endothelial surface (reducing the reactivity between the cell and vessel surfaces),
to hemodilution, to reduction of cell aggregation, and to
increased platelet rigidity with consequent reduced adhesive ability and aggregation. These activities are translated
into improved flow in the microcirculation and increased
oxygen transport. Dextran with a molecular weight of 40
has been used in PF as an adjuvant of other treatments,
particularly heparin therapy.107
The management of PF patients must be based on general reanimation procedures and identification of the causal
factor, particularly recognition of an infectious agent and
administration of an appropriate antibiotic. In meningococcal sepsis, the most frequent event (especially in children), the first-line antibiotic is penicillin; however, in
cases in which the nature of the sepsis is unclear, a thirdgeneration cephalosporin, such as cefotaxime, can be used
from the beginning. Subsequent strategies are aimed at correcting and restoring the altered coagulation mechanisms.
In this context, the use of the drugs reported in Table 23.3
must be weighed and based on the clinical and laboratory
findings in the individual cases.
CONCLUSIONS
Systemic vasculitides can frequently evolve into emergency conditions and sometimes present a critical situation
from their onset. The latter occurs most frequently in PF,
whereas progress to a critical situation is observed in HSP,
WG, CSS, PAN, MPA, and KD. The management of such
patients may require the dermatologist because the correct
interpretation of cutaneous lesions, an integral part of the
clinical pattern, can provide substantial help in identifying
the nature and phase of the disease. Dermatological assistance may be essential in the treatment of lesions largely
involving the skin.
The clinical features in an emergency situation requiring
treatment in an intensive care unit mainly include abdominal and renal complications in HSP; pulmonary and renal
involvement in WG; hemoptysis, respiratory and renal
failure, myocarditis, and myocardial infarction in CSS;
renal insufficiency, cardiomyopathy, and GI bleeding and
perforation in PAN; deterioration of renal function and
241
respiratory failure in MPA; and cardiac involvement in
the acute phase and subsequent development of coronary
aneurysms in KD. The emergency situation can be particularly serious in PF, a disease that frequently evolves into
DIC, a dramatic condition often culminating in death.
When present, dermatological signs can be decisive in
arriving at the correct diagnosis and treatment. Purpuric
lesions mainly situated on the lower extremities, associated
with polyarthralgia and abdominal pains, are almost always
sufficient for a diagnosis of HSP. Acral inflammatory
manifestations, sometimes associated with polymorphic
exanthema and laterocervical lymphadenopathy in a child
with persistent high fever, reliably indicate a diagnosis of
KD; however, it can be more difficult to interpret cutaneous
lesions in conditions suspected to be WG, CSS, PAN, or
MPA. The histological examination and other hematochemical data can provide other useful information for a
diagnosis. PF deserves special consideration because it can
assume different clinical signs as a result of a meningococcal infection, especially in children, or as the evolution of a
vascular pathology in adults. In both situations, necrotizing
purpuric lesions are decisive for an accurate diagnosis.
The management and treatment of emergencies caused
by systemic vasculitides must be carried out in an intensive
care unit, where the patient can benefit from procedures
aimed at improving the pulmonary ventilation and cardiocirculatory conditions and normalizing the hemodynamic
and hydroelectrolytic imbalance. In this context, infusions
of plasma (or its substitutes) and of whole blood may be
useful. Regarding the use of specific drugs, corticosteroids
are the first-line agents in WG, CSS, and PAN, diseases
in which the association of cyclophosphamide can complete the emergency procedure. IVIg are fundamental in
KD, where they can drastically reduce the onset of cardiological complications. Other drugs, such as azathioprine,
methotrexate, and the most recent biological drugs, are
more suitable for the prevention of relapses. The correction of coagulation alterations, fundamental in PF, requires
much attention because it must be carried out with drugs
such as heparin, protein C, AT III, and plasminogen activators, the use of which demands accurate monitoring of
laboratory parameters and, above all, proven clinical experience.
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CHAPTER 24
Emergency Management of Connective
Tissue Disorders and Their Complications
Kristen Biggers
Noah Scheinfeld
COLLAGEN VASCULAR diseases are complex multiorgan states of pathologic dysfunction. The collagen vascular diseases that most commonly result in emergency
situations include systemic lupus erythematosus (SLE),
dermatomyositis (DM), and scleroderma. This chapter will
review emergency management of connective tissue disorders and their complications. In particular, the clinical and
laboratory aids required for diagnosis, therapy, and prognosis will be reviewed. Because we assume that the reader
has a basic understanding of the diseases, the chapter does
not review them.
SLE
SLE is a complex state of systemic dysregulation that can
affect any organ system (see Figure 24.1). The noted writer
Flannery O’Connor died at the age of 39, after surgery led
to a reactivation and intensification of lupus that resulted
in fatal kidney failure. As lupus can be a systemic disease,
the most serious emergency management pertaining to it
includes cardiovascular, pulmonary, hematologic, neurological, renal, and gastrointestinal (GI) dysfunctions.1 The
prevalence of SLE for 15- to 44-year-old white women has
been estimated to be between 18.3 and 40 cases per 100,000
and twice that for 15- to 44-year-old black women.2 The
American College of Rheumatology has established a standard for the diagnosis of SLE, based on the patient having 4
of 11 criteria, including positive titers for various antibodies
(Table 24.1).3
SLE, oxidized lipid levels (such as oxidized low-density
lipoprotein and proinflammatory high-density lipoprotein) are increased, adhesion molecules are upregulated,
and cytokines (such as monocyte chemotactic protein-1,
tumor necrosis factor-␣, interferon-␥ , interleukin-1, and
interleukin-12) are upregulated. These oxidized lipids deposit in the walls of coronary vessels. Autoantibodies bind
to the oxidized lipids, forming immune complexes, which
provide a basis for the development of atherosclerosis.
The most common cardiac pathology in SLE patients
is pericarditis with a reported prevalence of 60%. Valvular, myocardial, and coronary vessel lesions can also be
manifested in SLE patients.4 Atherosclerotic cardiovascular disease is common and is related to increased antiphospholipid antibodies.4 Patients with lupus nephritis are at
an increased risk for developing hypertension.4 Antiphospholipid syndrome can result in ventricular dysfunction,
intracardiac thrombi, myxomas, and pulmonary hypertension. The coronary arteries are not immune from the effects
of vasculitis associated with lupus.
Diagnosis
Laboratory testing and imaging studies are utilized in the
diagnosis of lupus-related cardiac disease, as in other cardiac diseases. Elevated lipid or C-reactive protein levels
can be seen in patients with cardiac abnormalities associated with SLE. Mild pericarditis, valvular lesions, and
TABLE 24.1: Antibodies Associated
with Systemic Lupus Erythematosus
CARDIOVASCULAR DYSFUNCTION AND SLE
Background
There are manifold intersections of cardiovascular dysfunction and SLE. In patients with long-standing lupus, the
most common causes of death are due to cardiovascular
events.
The basis for cardiovascular disease in patients with
lupus is complex and seems to involve a combination of
inflammatory and immune mechanisms. In patients with
page 245
Antinuclear antibody (ANA)
Anti-double-stranded DNA (anti-dsDNA)
Anti-Smith (anti-Sm) antibody
Anti-anionic phospholipids antibodies
Mostly anti-cardiolipin (aCL)
Anti-2 glycoprotein 1 antibodies
Anti-C1Q antibodies
Anti-Ro (SSa) antibody
Anti-La (SSb) antibody
246 E MERGENCY D ERMATOLOGY
FIGURE 24.1: Classic malar and facial erythema of systemic
lupus erythematosus.
myocardial dysfunctions can be detected with echocardiography, a technique that is both sensitive and specific.
Therapy
Patients with SLE and cardiovascular disease are approached similarly as non-SLE patients with heart disease.
Lifestyle changes are recommended, including dietary and
exercise counseling. Risk factors, such as increased lipid levels, are targeted for reduction. Because patients with SLE
are predisposed to clotting, it has been suggested that they
should be placed on more aggressive anticoagulant therapy.
All patients with SLE should take aspirin prophylactically,
and more potent anticoagulants should be added to the
treatment regimen as needed.
Course and Prognosis
Cardiovascular events in patients with SLE are less severe
due to advances in therapy.
PULMONARY DYSFUNCTION AND SLE
Background
SLE is associated with respiratory pathology in all anatomic
locations, including the pleura, pulmonary parenchyma,
airways, vessels, and respiratory muscles. These disease
processes can occur in one area of the respiratory system
or in multiple places simultaneously. Pulmonary symptoms
can wax and wane, further increasing the morbidity and
mortality associated with lupus.
In SLE, the most common respiratory complaints are
attributed to pleural disease, a pathology that affects up
to 35% of patients.5,6 As in cardiovascular disease, lupus
autoantibodies form immune complexes that are deposited
in the pleura, resulting in injury. Other pulmonary disorders associated with SLE patients include acute lupus pneumonitis, alveolar hemorrhage pleural disease, pneumonia,
diffusion impairments, diffuse alveolar hemorrhage, acute
lupus pneumonitis, thrombosis, and pulmonary hypertension.4,7 Sudden-onset dyspnea and fever are characteristic of acute lupus pneumonitis and alveolar hemorrhage, which also results in hypoxemia and a chest
x-ray demonstrating patchy alveolar infiltrates.7,8 Patients
affected by diffuse alveolar hemorrhage (1%–5% of patients
with SLE)9,10 have a 50%–90% risk of death attributed
to the acute decrease in hemoglobin levels.4,7,11,12 SLE
therapy, including glucocorticoids or immunomodulatory agents, increases a patient’s risk for developing
pneumonia.13,14
Pulmonary physiology is adversely affected in patients
with SLE.15 In a study comparing the lung function of
70 nonsmoking, non-lupus patients with 70 age-matched,
nonsmoking SLE patients showed normal lung function
in 83% of subjects in the control group and only 33%
in SLE patients.15 Diffusion capacity of carbon monoxide in the lung (DLCO) is the most common adversely
affected pulmonary function test and can be decreased even
in the absence of a concomitant restrictive lung disease.15,16
As in vessels throughout the body, antiphospholipid antibodies can be deposited in the pulmonary vessels, causing
thrombosis17,18 that results in fatal pulmonary hypertension, unresponsive to therapy.
Diagnosis
Imaging studies, including computed tomography (CT)
and magnetic resonance imaging (MRI), are useful in developing a diagnosis of lung disease in patients with SLE.19,20
Additional diagnostic information can be gained from pulmonary function tests and lung biopsy.
Therapy
Corticosteroids are the mainstays of treatment for SLE
patients with pulmonary disease. Cyclophosphamide (500–
1000 mg/m2 intravenously [IV] every 4 weeks) can be used
in resistant cases. This therapy has been reported to be
especially effective in treating interstitial lung disease.21,22
Steroid-sparing agents such as azathioprine and methotrexate are useful in some situations.3 Extremely resistant cases
may benefit from plasmapheresis or IV immunoglobulin
(IVIg). Recently, rituximab has been shown to increase the
Chapter 24
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Emergency Management of Connective Tissue Disorders and Their Complications
247
effectiveness of traditional therapy when used as an adjunct
in patients who are unresponsive to traditional therapy
alone.
phenomenon and livedo reticularis are associated with
an increased risk of neuropsychiatric manifestations in
patients with SLE.27
Course and Prognosis
Diagnosis
The course of SLE associated with neuropsychiatric conditions can be extended and complex. The prognosis of SLE
associated with neuropsychiatric conditions is not good and
is a negative prognostic indicator for the morbidity and
mortality associated with SLE.
In patients with SLE-associated neuropsychiatric disorders, a spinal tap can be performed and may show increased
cell counts, increased protein levels, and increased
immunoglobulins in the cerebrospinal fluid.28 Less invasive diagnostic techniques can be utilized to detect cranial bleeds, thrombosis, vasculitis, and inflammation, and
include CT, MRI, and transcranial Doppler monitoring.28
HEMATOLOGIC DYSFUNCTION AND SLE
Background
Therapy
Vasculitis and thrombosis are common manifestations of
SLE. In addition to making antiphospholipid antibodies,
patients with lupus can make antiplatelet antibodies that
precipitate thrombocytopenia.4
In patients with SLE, neuropsychiatric complications are
controlled by treating the underlying pathology, as in
the other organ systems mentioned previously.4 IVIg and
plasmapheresis are often used sooner in neuropsychiatric
conditions associated with SLE than when other organ
systems are affected due to the severe complications that
can result if insufficiently treated.4
Diagnosis
The antiphospholipids produced in patients with SLE
include anticardiolipin antibodies, lupus anticoagulants,
and anti-2 glycoprotein-1–specific antibodies.23,24 Lupus
anticoagulant levels can be assessed via blood titers.23,24 If a
patient is suspected of having a thrombus, imaging studies
can be performed to confirm.
Course and Prognosis
Patients with SLE associated with neuropsychiatric conditions resistant to IVIg and/or plasmapheresis therapy
can be emergently administered pulsed high dose intravenous methylprednisolone to bring the disease rapidly
under control.29,30
Therapy
Hematologic dysfunction in lupus is treated symptomatically with immunosuppressives for vasculitis and anticoagulants for thrombosis. Nonsteroidal therapy includes azathioprine and methotrexate.3 Thrombocytopenia caused
by anti-deoxyribonucleic acid (anti-DNA) antibodies can
be treated with IVIg.25
Course and Prognosis
Increased risk of thrombotic events is especially dangerous
in pregnant women and can be fatal for both the mother
and the fetus.
NEUROLOGICAL DYSFUNCTION AND SLE
RENAL DYSFUNCTION AND SLE
Background
The most common systemic complication of SLE is
renal disease,1,31–33 the manifestations of which include
focal proliferative, diffuse proliferative, or membranous
glomerulonephritis.34 Anti-DNA antibodies form complexes with double-stranded DNA polynucleotide antigens
that deposit in the small vessels of the kidney, which is the
major cause of lupus nephritis. Type III sensitivity reactions, during which antibodies bind with fixed antigens to
form a complex, may also play a role in lupus nephritis.
It has also been hypothesized that sensitized T cells may
contribute to renal pathology in lupus patients.
Background
Rarely, SLE is associated with neuropsychiatric conditions
including organic brain syndrome, seizures, cerebrovascular accidents, strokes, psychosis, peripheral neuropathy,
and achorea.4 Even less common neuropsychiatric manifestations are aseptic meningitis, pseudotumor cerebri,
Guillain–Barré syndrome, athetosis, and cerebral venous
sinus thrombosis.4 Many neurologic disorders in SLE
are related to the deposition of antiphospholipid and
anti-ribonucleoprotein (anti-RNP) antibodies.26 Raynaud
Diagnosis
The presence of proteinuria (>0.5 g/d) or cellular casts is
required to diagnose renal involvement in patients with
SLE, as defined by the American College of Rheumatology.34 Lupus nephritis and renal dysfunction can be
further complicated by the presence of antiphospholipid
antibodies, low complement (C3) levels, thrombocytopenia, anemia, or hypertension, and death may result.35
Immune complexes composed of DNA double-stranded
248 E MERGENCY D ERMATOLOGY
polynucleotide antigens and anti-DNA antibodies may be
found in patients with lupus nephritis and may be elevated.
In addition to serum testing, a renal biopsy may be performed to diagnose focal proliferative, diffuse proliferative,
or membranous glomerulonephritis.34
Therapy
As in most patients with lupus, corticosteroids are the mainstay of treatment for patients with lupus nephritis with
the addition of mycophenolate mofetil (MMF) and azathioprine to the therapeutic regimen.36–38 IV cyclophosphamide (0.5 g/m2 ) may be necessary for refractory renal
disease or in patients with diffuse proliferative lupus nephritis. When this treatment is selected, cyclophosphamide
is infused monthly for 6 months, and then every several
months for a full year following remission.39
TABLE 24.2: Maternal Antibodies
Anti-Ro(SS-A)
Anti-La(SS-B)
U1-RNP
GI perforations. In cases of perforation or bowel ischemia,
the affected area should be surgically resected as the first
step in treatment.
Course and Prognosis
Lupus patients with acute GI symptoms can rapidly
progress to life threatening status without immediate intervention.
NEONATAL LUPUS ERYTHEMATOSUS
Course and Prognosis
In patients who meet the criteria for SLE-associated renal
disease, their survival is largely determined by their creatinine levels.1,31–33 Patients with SLE-associated renal disease may suffer from end-stage renal disease and require
dialysis.
GI DYSFUNCTION AND SLE
Background
GI dysfunction is common in patients with SLE, and over
a lifetime affects 60%–70% of those patients. The liver is
particularly susceptible in patients with lupus and antiphospholipid syndrome. Portal hypertension, cirrhosis, biliary
cirrhosis, autoimmune hepatitis, Budd–Chiari syndrome,
hepatic infarct, and hepatic-veno-occlusive disease are all
possible associated conditions. Other GI manifestations
include vasculitis throughout the GI tract, oral ulcers, dysphagia, intestinal infarction or bleeding, splenic infarction,
and acute pancreatitis. Corticosteroids used to treat SLE
can have adverse effects on the GI tract by causing spontaneous hemorrhage.
Background
Women with lupus have several autoantibodies (Table
24.2) that are capable of crossing the placenta. A pregnant
woman with lupus can pass these antibodies on to her fetus,
resulting in neonatal lupus erythematosus (NLE). After
delivery, the infant can present with dermatologic signs
similar to those in adults with SLE. Pathology specific
to infants with NLE include characteristic dermatologic
manifestations (raccoon eyes) and congenital heart block.21
Diagnosis
M-mode fetal echocardiograms and Doppler ultrasounds
performed between 18 and 24 weeks gestation can be useful in detecting atrioventricular (AV) heart block or atrial
arrhythmia in a fetus with NLE. If a heart block is detected,
these studies can also determine the degree of the block (1st,
2nd, or 3rd) as well as any valvular (especially tricuspid)
regurgitation or other congenital anatomic cardiac anomalies.
Pregnant women with lupus should receive fetal
echocardiograms throughout their pregnancies to facilitate
the early identification of heart block.
Diagnosis
Lupus patients can present with abdominal pain, anorexia,
hemorrhage, nausea, and vomiting. Clinical testing may
yield little as far as symptom etiology.
Therapy
Patients with chronic symptoms can be treated with corticosteroids or anticoagulants. Those with an acute presentation should be assessed quickly, as emergent surgery is usually the treatment of choice. Exploratory surgery is often
required in patients with suspected peritoneal collections or
Therapy
When a first- or second-degree AV block has been identified in a fetus with NLE, corticosteroids can be administered to the mother in an attempt to eliminate the heart
block. The reversal of third-degree heart block with corticosteroids is highly unlikely.
Course and Prognosis
Unfortunately, completely unremarkable echocardiograms
can change in 1 week to an echocardiogram demonstrating
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Emergency Management of Connective Tissue Disorders and Their Complications
249
TABLE 24.3: Dermatomyositis Antibodies43
Antibodies associated
with dermatomyositis
Antibodies overlapping with other
collagen vascular diseases
Antisynthetase
Anti–Mi-2
Anti-SRP
Anti-Ku
Anti–PM-Scl
Anti–U1 RNP
Anti-Ro
Data adapted from (43).
GI TRACT AND DM
FIGURE 24.2: Gottron sign of dermatomyositis: reddish
plaques on the joints and on the fingers.
cardiomyopathy or third-degree AV block without warning. Only 80% of infants with NLE-related first-degree
heart block survive the first year. Of those children who do
survive, the majority of them will need a pacemaker.
DM
DM is an inflammatory myopathy, the nature of which is
idiopathic. The manifestations of this disease include progressive symmetrical proximal muscle weakness and dermatologic manifestations (e.g., Gottron papules, heliotrope
eruption) (see Figure 24.2).40 Additional organ systems
affected in systemic DM are the GI tract, lungs, and blood
vessels.41,42 The systemic manifestations are responsible
for emergent situations in patients with DM.42 Ricky Bell,
a football player, who was a standout running back for
the University of Southern California Trojans, and played
for Tampa Bay and San Diego in the National Football
League, died from heart failure caused by DM.
To be diagnosed with DM, a person must present
with at least 3 of the following clinical criteria: 1) muscle
weakness; 2) muscle biopsy pathology; 3) elevated creatine
kinase, aldolase, lactate dehydrogenase, aspartate aminotransferase, or alanine aminotransferase, all of which point
to muscle involvement; 4) a triad of electromyographic
abnormalities; or 5) skin eruption.43 In all manifestations
of the disease, creatine kinase levels may be used to track
the progression of or the response to treatment of DM.43
Specific serum antibody levels can be drawn to aid in the
diagnosis of DM (Table 24.3).
Muscle involvement may be tracked using electromyography, ultrasonography, or MRI.44 Additionally, a muscle biopsy can be performed to assess muscle involvement
and will show immune-mediated necrosis and regenerating
fibers. On skin biopsy, mucin in the background of interface
dermatitis is commonly seen histologically.45
Background
DM can affect much of the GI tract, especially the esophagus and intestines. Esophageal disease is common in
patients with DM (15%–50%) and most often stems from
problems associated with weakness of the cricopharyngeal
striated muscles or dysfunction of the lower esophagus.46
Of all patients with DM, approximately 30% of them will
die from complications associated with aspiration pneumonia.46 Less frequently (and especially in young patients with
DM), ulceration, perforation, or hemorrhage may occur in
the GI tract as a result of vasculopathy in that area.47
Diagnosis
DM can cause inflammation in the GI tract, leading to
patients presenting with reflux esophagitis, abdominal pain,
and cycles of constipation alternating with diarrhea.48 A
traditional GI workup, including CT, MRI, colonoscopy,
and barium studies are used, as in other GI diseases, to
assess the severity of disease.49
Treatment
Surgical intervention and immunosuppressives are the
standard of care for treating GI disease in DM. IVIg may
be successful in treating resistant esophageal disease that
might otherwise be life threatening.50–52
Course and Prognosis
The pharyngeal muscle weakness in patients with DM
causes loss of control of foods and can result in aspiration.
Due to the aspiration risk, these patients may be placed on
a feeding tube.53 Patients with esophageal muscle weakness
do not respond well to therapy; therefore, they have a poor
prognosis.46,53
PULMONARY SYSTEM AND DM
Background
Pulmonary disease is a fairly common occurrence in
patients with DM (15%–30%), and in 50% of these patients
250 E MERGENCY D ERMATOLOGY
TABLE 24.4: Antisynthetase
Antibodies
Anti-Jo
Anti–Pl-7
Anti–Pl-12
Anti-O
Anti-EJ
Anti-KS
it is the first presenting sign of the disease.49 The majority
of DM patients presenting with respiratory disease (60%)
have an insidious onset. Others (25% of patients) have an
acute onset of signs, and 15% of patients have an infraclinical onset that presents as an incidental finding on exam.
Patients with amyopathic DM can have fatal pulmonary
diseases or pulmonary complications.54
Pulmonary inflammation is the leading pathology in
lung diseases in patients with DM.49 Respiratory muscle
weakness leads to hypoventilation and esophageal muscle
weakness leads to aspiration, both of which result in inflammatory processes.49 Additionally, the treatment for DM
itself, usually immunosuppressive therapies, can leave the
patient susceptible to opportunistic infections or hypersensitivity pneumonitis.49
Pulmonary diseases associated with DM include pulmonary hypertension,48 pneumothorax, pneumomediastinum, interstitial lung disease, and subcutaneous emphysema.55
Diffuse alveolar damage, respiratory bronchiolitis, bronchiolitis obliterans, and pneumonia (desquamative interstitial and nonspecific interstitial) are all interstitial
pulmonary diseases caused by fibrosing alveolitis in
DM.54
hand.56 Additionally, patients with pulmonary fibrosis may
express the myositis antibody, anti-Se.43
Therapy
As in patients with other forms of DM, corticosteroids
remain the treatment of choice for patients suffering from
pulmonary disease.57 High-dose IV corticosteroids can be
administered in severe cases with acute onset. If corticosteroids fail to alleviate symptoms, methotrexate can be
added to the regimen or administered alone as a secondline agent.58 Azathioprine, cyclophosphamide, chlorambucil, cyclosporine, MMF, or chlorambucil can be used as
third-line treatments.58 Interstitial pulmonary disease in
DM responds well to cyclosporin A therapy.59–61 IVIg and
rituximab may be used in resistant cases.50–52
Pulmonary function tests and CT scans should be
repeated regularly to assess treatment effectiveness and progression of disease.
Course and Prognosis
Unfortunately, for patients with pulmonary symptoms in
the context of DM, their prognosis is poor.49 Pulmonary
fibrosis results in interstitial lung disease and pulmonary
hypertension, both of which are often fatal. The chronic
respiratory insufficiency resulting from interstitial lung disease is fatal in 30%–66% of patients.48
CARDIOVASCULAR DISEASE AND DM
Background
Although cardiac disease is rarely a complication of DM,
when it presents, it is usually fatal.48 Inflammatory myositis
can result in cardiac dysfunction as can vasoconstriction
from vasculitis.62
Diagnosis
Patients with DM and associated pulmonary disease may
present with the symptoms of exertional dyspnea and nonproductive cough, as well as the clinical sign of bibasilar
fine crackling rales.54 Because pulmonary physiology can
be affected, further studies should include pulmonary function testing, which demonstrate decreased DLCO and a
restrictive pattern.54 A high-resolution CT scan should be
performed with the pulmonary function tests as part of the
initial workup.
Antisynthetase antibodies (Table 24.4) can be seen in
DM patients with pulmonary disease.43 Patients with an
acute onset of interstitial pulmonary fibrosis and dramatic
polymyositis that is resistant to therapy should be considered for antisynthetase syndrome.55,56 This often fatal syndrome can be seen in patients with DM and antisynthetase
antibodies who also suffer from fever, interstitial pulmonary
fibrosis, Raynaud phenomenon, arthritis, and mechanic’s
Diagnosis
When a patient with DM presents with cardiac symptoms, the same tests should be performed as would be on
any patient presenting with cardiac symptoms. These standard cardiac tests should reveal the location and degree
of involvement of heart muscle. Cardiac disease is more
common in patients who produce the antibody to signal
recognition particle (anti-SRP antibody).43 Additional testing could include blood-vessel biopsies. A biopsy of a vessel
affected by DM should demonstrate scarring in the vessel
wall, with or without associated fibrosis.
Treatment and Prognosis
For those patients who suffer from DM-associated cardiac disease, few treatment options are available, and those
Chapter 24
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Emergency Management of Connective Tissue Disorders and Their Complications
251
PULMONARY DISEASE AND SCLERODERMA
Background
Pulmonary fibrosis, a normal manifestation of scleroderma,
results in interstitial fibrosis of the lungs. Vasculidities
resultant from SS and interstitial fibrosis can both lead to
the development of pulmonary hypertension, as seen in
5%–50% of patients with scleroderma.65,66
Diagnosis
Patients present with dyspnea on exertion as their initial
manifestation of pulmonary hypertension. Clinically, pulmonary hypertension is tested, while the patient is exercising and is defined as an increase in mean pulmonary arterial
pressure to greater than 25 mm Hg.65
Therapy
FIGURE 24.3: Scleroderma of the hand demonstrating sclerodactyly.
that are available are usually unable to alleviate disease.
Having pulmonary and cardiac symptoms simultaneously
greatly increases a patient’s risk of fatality.48 Neurological symptoms can appear in children with DM due to
inflammatory changes in the blood vessels.47 These
vasculitis-associated conditions include stroke, hemiparesis, seizures, and pseudoseizures.47
SCLERODERMA (SYSTEMIC SCLEROSIS)
Scleroderma, by definition, is a systemic disease and can
have adverse affects on the GI, renal, and pulmonary systems. The respiratory system is most commonly the location for pathology that can be emergently life threatening
in patients with systemic sclerosis (SS).63,64 In fact, Paul
Klee (the noted Swiss artist who had scleroderma) died of
scleroderma-related pulmonary fibrosis that led to respiratory failure. It can affect the skin and lead to hardening
of the skin, nail fold changes, calcinosis, and sclerodactyly
(Figure 24.3).
Early stages of scleroderma-related pulmonary hypertension are treated as is hypertension in most disease
states, with vasodilators. While the vascular damage is
still reversible, calcium channel blockers and prostanoids
(prostaglandin E1 and iloprost) are the treatments of choice
and have been shown to be effective early in the disease process.66–68 With progression of pulmonary hypertension, patients with scleroderma may benefit from IV
epoprostenol, a prostanoid analog.69 A newer, more stable
compound, treprostinil, is administered subcutaneously65
and is more effective than epoprostenol at relieving
pulmonary symptoms and decreasing arterial pressure
and vascular resistance.70 Bosentan, an oral endothelin
antagonist, and sildenafil, an oral cyclic guanosine 3 ,
5 -monophosphate phosphodiesterase type five (cGMP
PDE5) inhibitor, have been effective in relieving the symptoms of pulmonary hypertension in patients with scleroderma.71,72 A significant relief of symptoms and adverse
effects associated with pulmonary hypertension has been
observed when a combination therapy including bosentan, iloprost, and sildenafil is administered to scleroderma
patients.
For pulmonary fibrosis, immunosuppressives are the
treatment of choice. In cases of severe pulmonary fibrosis,
100 mg/d doses of cyclophosphamide have been shown to
improve both forced vital capacity and overall survival.73–75
Some investigators believe, however, that corticosteroids
have no positive effect on lung function.74
Course and Prognosis
In patients with scleroderma-related pulmonary disease,
their initial symptom of dyspnea on exertion increases
in severity. Such patients usually end up suffering
from right-sided heart failure, which further increases
symptoms.65
252 E MERGENCY D ERMATOLOGY
RENAL DISEASE AND SCLERODERMA
Background
The most common systemic manifestation in scleroderma, occurring in 25% of patients, involves the renal
system.42 Renal crisis is more prevalent in scleroderma
patients whose symptoms include the presence of antiribonucleic acid (RNA) polymerase III antibody in the
serum, rapidly progressive skin thickening,76 pericardial
effusion, arrhythmias, and anemia.77 Additionally, the
treatment for SS, corticosteroids, especially cyclosporine,
can precipitate renal crisis.77 Renal crisis presents within
the first 4 years of diagnosis of scleroderma in the majority of patients (75%), rarely occurring in patients suffering
from SS for many years.78
Patients with SS develop narrowed arteries and arterioles.77 This phenomenon greatly impacts upon the kidneys
and can result in renal crisis.77 A positive-feedback loop
occurs that significantly restricts the blood flow to the kidneys. Initially, collagen deposits in arteriole walls, decreasing their diameter and limiting blood flow to the kidneys.
The juxtaglomerular apparatus recognizes the postglomerular decrease in blood pressure and releases renin.77
This release of renin activates the renin–angiotensin system, resulting in increased secretion of angiotensin II.
Angiotensin II causes vasoconstriction of the afferent and
efferent arterioles in the kidney. This vasoconstriction further limits blood flow, leading to ischemia and renal crisis.77
some patients may require dialysis. In general, renal crisis is viewed as an indicator of poor prognosis in patients
with SS.
MIXED CONNECTIVE TISSUE DISEASE
Background
Patients with symptoms that overlap those of SLE, SS, and
DM are classified as having a mixed connective tissue disease.
Diagnosis
The presence of anti-uridine-rich RNA-small nuclear
ribonucleoprotein (snRNP) antibodies is required to diagnose a patient with mixed connective tissue disease. As
would be expected, pulmonary disorders in patients with
mixed connective tissue disease resemble those seen in
patients with lupus, DM, and scleroderma. These disorders
include interstitial fibrosis (20%–65%), pleural effusion
(50%), pulmonary hypertension (10%–45%), and pleurisy
(20%). Other less common pulmonary features of MCTD
include pulmonary vasculitis, thromboembolism, aspiration pneumonia, miscellaneous infections, hemorrhage,
obstructive airway disease, respiratory failure (hypoventilatory), and diaphragm muscle weakness.
Treatment
Diagnosis
There are recognized diagnostic criteria for renal crisis in patients with scleroderma. Patients usually present
with a dramatic spike in arterial blood pressure with concomitant symptoms of headaches, visual disturbances, and
seizures, and signs of thrombocytopenia, microangiopathic
hemolytic anemia, accelerated oliguric renal failure, pericardial effusion, and congestive heart failure.76 The diagnostic criteria for hypertensive scleroderma renal crisis are
elevated serum creatinine, proteinuria, hematuria, thrombocytopenia, and hemolysis.76 The majority of patients
(90%) present with hypertension,76 and nearly all of them
have elevated renin plasma levels.77
As in patients with DM, corticosteroids are the gold standard for treatment of pulmonary symptoms in patients with
mixed connective tissue disease.
Course and Prognosis
The prognosis for patients with pulmonary hypertension in
the setting of mixed connective tissue disease is similar to
those with pulmonary hypertension associated with other
collagen vascular disorders: grim. Despite aggressive treatment, usually symptomatic relief is briefly attained before
the disease contributes to the patient’s mortality.
CONCLUSIONS
Therapy
The only effective treatment for people in renal crisis is
an angiotensin-converting enzyme (ACE) inhibitor to help
dampen the effects of the increased plasma renin levels.78
Course and Prognosis
Although ACE inhibitors have been shown to decrease
mortality and morbidity associated with renal crisis,79
Because collagen vascular diseases are widely systemic,
effecting many organ systems, their successful treatment
is as complex as the diseases themselves. Most important
to treatment success is early recognition and proper diagnosis. Early therapy may prevent possible life-threatening
emergencies in the future. Because many patients may
initially present with dermatologic manifestations, it is
important for the physician to look beyond the patient’s
primary complaint to the possible outcomes of systemic
manifestations.
Chapter 24
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Emergency Management of Connective Tissue Disorders and Their Complications
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Emergency Management of Connective Tissue Disorders and Their Complications
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CHAPTER 25
Skin Signs of Systemic Infections
Jana Kazandjieva
Georgeta Bocheva
Nikolai Tsankov
MANY SYSTEMIC infections have cutaneous presentations that sometimes are unspecific. These cutaneous signs
and symptoms may be helpful in making the proper diagnosis, prescribing the appropriate therapy, and assisting in
prevention. Some clinical manifestations of systemic infections highlight the possible infectious etiology for unusual
cutaneous lesions.
Bacterial systemic infections may be more common in
remote areas of the world; these same bacterial diseases
also may be seen, however, in travelers or immigrants
from these areas. Some of these infections, such as plague
and melioidosis, are potential biological weapons used for
bioterrorism.
MELIOIDOSIS
Melioidosis is a highly invasive and resistant infection
caused by the gram-negative bacterium Burkholderia pseudomallei, which is synonymous with the old nomenclature
Pseudomonas pseudomallei.
The first reported cases of P. pseudomallei were initially
known as Whitmore disease. In 1911, a British pathologist,
Captain Alfred Whitmore, described a case of pneumonia
in a young boy in Burma, where P. pseudomallei was isolated as the causative agent.1 The term “melioidosis” was
subsequently used in 1921. It is derived from the Greek
word “melis” meaning “a distemper of donkeys,” because
it resembles glanders, which causes mainly pulmonary disease in asses.2 This infection is endemic in Southeast Asia
and North and Central Australia, and peaks during the
monsoon seasons.3 The disease in those regions often
causes septicemia and death. Melioidosis also occurs sporadically in temperate countries and is mostly imported by
travelers.4
Melioidosis contributes from 20% to 40% of deaths
due to community-acquired septicemia in Northeast Thailand, especially in rice farmers.5 In Singapore, the disease
is uncommon, even though a significant percentage of the
population has been exposed to B. pseudomallei.6 The overall
mortality rate remains near 45%, despite antibiotic therapy.
Before the antibiotic era, 95% of patients died.2
B. pseudomallei is distributed in soil and surface water;
thus, infection can be spread via inoculation though cutaneous abrasions. Inhalation or ingestion of contaminated
bacilli materials is less frequent. Melioidosis is strongly
associated with diabetes mellitus (50% of Asian patients),
and is 4 times more common in men than in women.
Clinical Features
Clinical manifestations develop after an incubation period,
which varies from a few days to several months or years.
Patients develop high fever and rigors, as well as occasional
confusion, stupor, jaundice, and diarrhea. The clinical spectrum includes five possible forms of presentations: acute
fulminant septicemia (fatal within days); subclinical form;7
subacute and chronic presentations (more likely associated
with skin involvement); and relapsing–remitting course of
the disease (requiring prolonged antibiotic treatment).8
The disease can be localized or disseminated with multiorgan involvement. Any organ can be involved in melioidosis with rapid development of small abscesses, which tend
to coalesce to form larger abscesses, especially in lungs
(50% of the cases), skin and subcutaneous tissues, bones
and joints, liver, spleen, kidney, and brain.
Most commonly, melioidosis presents as an acute pulmonary infection, causing fulminant necrotizing pneumonia, septicemia, and death, or as an indolent cavitary disease,
and mild bronchitis.2 Severe melioidosis is usually seen in
immunocompromised patients (with diabetes mellitus or
renal failure).5 Metastatic infection can remain latent for
years. Common laboratory findings include anemia, neutrophil leukocytosis, coagulopathy, and renal and hepatic
abnormalities.9
Cutaneous Manifestations
Very rarely, melioidosis can be demonstrated as a subacute form with cutaneous manifestations only.10–12 Skin
involvement, seen in 10%–20% of the patients with
melioidosis, varies greatly. Patients often receive pustules
and cutaneous abscesses, associated with lymphangitis,
page 256
Chapter 25
cellulitis, or regional lymphadenitis.9,13,14 Draining sinuses
from lymph nodes or bone may develop. Abscesses may
ulcerate15 and sometimes can form ecthyma gangrenosum–
like lesions, or even progress to necrotizing fasciitis.9,16
The most common cutaneous manifestation in children
is acute suppurative parotitis. Severe urticaria has been
described in one case of pulmonary melioidosis.17 There
are also some case reports of melioidosis, associated
with cutaneous polyarteritis nodosa and porphyria cutanea
tarda.18,19 In acute septicemia, patients may develop nonspecific flushing, cyanosis, and a pustular eruption.20
●
Skin Signs of Systemic Infections
257
Because of the variety of skin presentations many infectious
diseases must be considered: fungal infections, tuberculosis,
and atypical mycobacterial infections. Cat scratch disease,
tularemia, and lymphogranuloma venereum have similar
clinical and histological presentations. Staphylococcal and
streptococcal infections should be also considered.
belonging to the Enterobacteriaceae family. The infection occurs most often during traveling to endemic regions
(with 18 times greater risk compared with the other) such
as: the Indian subcontinent, Southeast and Far-East Asia,
the Middle East, Africa, and Central and South America.28
Small endemics can occur sporadically as the result of food
handlers who are carriers of S. typhi. Worldwide typhoid
fever remains a health threat. Reported cases now are
fewer than 500 per year.29 The case-fatality rate is reduced
to 2% by using the appropriate antibiotics and improvements in supporative care; nevertheless, in some developing
countries, the case-fatality rate is higher – approximately
30%.30
S. typhi affects only humans during ingestion of food or
water contaminated with the feces of patients with active
diseases, or people who are asymptomatic carriers. The
incubation period ranges from 5 to 21 days.31 The severity
of disease is in parallel with the amount of bacteria ingested.
The illness is usually characterized by nonspecific manifestations.
Treatment
Clinical Features
The treatment of melioidosis includes intensive care, draining of abscesses, and antibiotic therapy. Usually B. pseudomallei antibiogram shows resistance to aminoglycosides,
polymyxins, fluoroquinolones, and many -lactams (the
older generation penicillins and cephalosporins); nevertheless, the bacillus is highly susceptible to amoxicillin/
clavulanic acid, tetracyclines, and chloramphenicol. The
treatment of melioidosis requires multiple antibiotics combination. Resistance to a single antibiotic may occur during
the treatment. A course of antibiotics is recommended for
at least 2 months, but may require prolonged antibiotic
therapy to prevent complications, including osteomyelitis,
sepsis, and (rarely) rupture of mycotic aneurysm.21
The localized cutaneous form of melioidosis can be
successfully treated with combinations of amoxicillin/
clavulanic acid (60 mg/kg/day orally three times daily)
and tetracycline (40 mg/kg/day orally three times daily)
or trimethoprim/sulfamethoxazole. Systemic involvement
requires an extra use of intravenous (IV) ceftazidime (120
mg/kg/day twice daily) for 2–4 weeks, plus the oral combination described above for the subclinical forms of melioidosis.15
Typhoid fever classically presents with prolonged fever,
headache, paradoxical bradycardia, and gastrointestinal
symptoms, including abdominal pain,32 and a rosecolored eruption. Many extraintestinal manifestations of
S. typhi infection, such as osteomyelitis, intraabdominal
abscess, urinary tract infection, and meningitis, have been
described.33 Fever, which is seen in 98%–100% of patients,
is the most common finding. The classic relative bradycardia (Faget sign) and the presence of rose spots34 are the
clues to the diagnosis. Laboratory findings in this infection are also nonspecific – thrombocytopenia, proteinuria,
elevated transaminases, and relative leukopenia.35
Initially, patients present with diarrhea and abdominal
pain. Other associated signs, less commonly found, are
a nonproductive cough, constipation, meningismus, deafness, confusion, and weight loss. Asymptomatic hepatitis
is common. Severe kidney and liver failure with marked
jaundice has also been described. Pancreatitis can occur in
typhoid fever, ranging from enzyme abnormalities to pancreatic abscesses requiring surgery.36
Early diagnosis and treatment of typhoid fever allows
prevention of the complications and spread of the infection. Complications may occur involving any organ and
system. Splenic abscess represents nearly 30% of complicated Salmonella abdominal infection of untreated typhoid
fever.32,37 Other complications are intestinal hemorrhage
and perforation. Perforation classically occurs in Peyer
patches of the terminal ileum. Other less common complications include toxic myocarditis, hepatitis, cholecystitis,
polymyositis, mild bronchitis, and toxic confusional state.35
Typhoid fever may affect the kidneys, leading to nephrotic
syndrome.29,36
Differential Diagnosis
TYPHOID FEVER
Salmonella infections in humans include gastroenteritis,
typhoid fever, bacteremia, and localized infection. Localized infection is a complication commonly affecting bones
and joints, although subcutaneous, splenic,22 breast, and
intraperitoneal abscesses23–27 have been described.
Typhoid fever is a systemic febrile disease caused
by Salmonella typhi, a flagellated, gram-negative bacillus
258 E MERGENCY D ERMATOLOGY
A chronic carrier state may occur in up to 3% of treated
patients. Patients with cholelithiasis are at greater risk for
persistence of S. typhi.
third-generation cephalosporins (e.g., IV ceftriaxone 2 g/d
for 5 days, especially for patients with cholelithiasis) are
also effective for treatment of typhoid fever.
LEPTOSPIROSIS
Cutaneous Manifestations
In 30%–50% of patients,35 so-called rose spots are
described as a cutaneous classical manifestation. The spots
are caused by bacterial embolization, and bacterial cultures
taken from the rose spots may be positive. Lesions are characterized as pink blanching papules, 2–4 mm in diameter, localized mainly on the mid-trunk, developing often
between the 7th and 12th day of infection.
Subcutaneous abscesses may rarely occur as a localized
skin and soft-tissue complication due to S. typhi bacteremia.
Salmonella bacteremia increases among the patients with
acquired immune deficiency syndrome (AIDS), in whom
these abscesses are found.38 Abscess formation in most
described cases are secondary and usually do not ulcerate.
Most reported cases of subcutaneous abscesses were due to
Salmonella species other than S. typhi.37,38 A unique case of
cutaneous ulceration occurred as a clinical manifestation
of S. typhi infection in a nonimmunocompromised patient
with complete absence of systemic signs.39
Another possible skin presentation is pustular dermatitis. Purpura or skin petechiae are rare, and are described
mainly in the setting of Salmonella endocarditis.33 A patient
with cutaneous leukocytoclastic vasculitis associated with
abdominal lesions developed during typhoid fever but without endocarditis was reported.37
Differential Diagnosis
The differential diagnosis of typhoid fever includes other
systemic febrile illnesses: brucellosis, tularemia, leptospirosis, tuberculosis, rickettsial disease, viral hepatitis, mononucleosis, AIDS, and cytomegalovirus infection.35 Additional
infections to consider include malaria, dengue fever, and
schistosomiasis. Noninfectious etiologies, such as lymphoma, leukemia, or adverse drug reaction, can also cause
prolonged fever.
Treatment
Antimicrobial therapy is necessary. Worldwide, chloramphenicol was the most commonly used antibiotic for
typhoid fever. Unfortunately, resistance to chloramphenicol is increasing, especially in Southeast Asia. Amoxicillin
and trimethoprim/sulfamethoxazole are also efficacious in
the treatment of acute infection and the carrier state, but a
high incidence of resistance is reported, too.
Fluoroquinolones (e.g., oral ciprofloxacin 500 mg twice
daily for 10 days) are currently the drugs of choice for
typhoid fever.40 They have the lowest incidence of both
relapse and development of a chronic carrier state. The
Leptospirosis is a spirochetal infection caused by
pathogenic Leptospira species. The spirochetes have hooked
ends, and because of that Stimson named them Spirochaeta
interrogans for their resemblance to a question mark.41
Within the species of Leptospira interrogans, 200 serovars
are recognized.
Leptospirosis is presumed to be the most widespread
zoonosis in the world,42 with many wild and domestic animal reservoirs. Leptospirosis causes clinical illness in both
humans and animals. Human infection is typically due to
exposure to infected animal urine, by direct contact or indirect exposure through water or soil.43 The usual portal
of entry is damaged skin or the conjunctiva. Inhalation of
water or aerosols may result in infection of the respiratory
tract.44 Rarely, infection may follow animal bites.45,46
The incidence of infection is significantly higher in
tropical countries because of warm and humid conditions,
allowing the much longer survival of leptospires.47,48 The
disease is seasonal, with peaks (in the summer) in temperate regions and (in rainy seasons) in areas with warm climates. Cases of leptospirosis also follow floods and hurricanes.49,50 Within the United States, the highest incidence
was found in Hawaii.51 Leptospirosis is highly endemic in
Malaysia52,53 and Nicaragua.54–57
Some occupational groups have a significant risk for leptospirosis. The infection was recognized early on in sewer
workers (first reported in the 1930s),58–61 then in fish workers (86% of all cases in northeast Scotland) and coal miners.62 More recently, fish farmers have been shown to be at
higher risk,63 particularly for infection with L. icterohaemorrhagiae,64 because of the high mortality rate associated
with the L. icterohaemorrhagiae serogroup.
Clinical Features
The spectrum of human leptospirosis is extremely wide,
ranging from subclinical infection to a severe multiorgan
infection with high mortality rate. Leptospirosis mainly
affects liver and kidney. The classical syndrome of Weil
disease represents only the most severe presentation. This
syndrome, demonstrated by icteric leptospirosis with renal
failure, was first reported by Adolf Weil in Heidelberg.65
In humans, severe leptospirosis is frequently caused by
serovars of the L. icterohaemorrhagiae serogroup. Thus, in
Europe, serovars L. icterohaemorrhagiae and L. copenhageni,
carried by rats, are usually responsible for leptospiral infection.
The clinical manifestation of leptospirosis is biphasic,
with an acute or septicemic phase lasting about a week,
Chapter 25
followed by the immune phase, characterized by antibody
production and excretion of leptospires in the urine.66,67
Most of the complications of leptospirosis are associated
with tissue invasion of leptospires during the immune phase
of the infection.
The majority of cases are subclinical and mild. A smaller
proportion of anicteric leptospirosis is presented as a febrile
illness, with chills, severe headache (with retro-orbital pain
and photophobia), myalgia, abdominal pain, conjunctival
suffusion, and (rarely) a skin eruption. In addition, aseptic
meningitis may be found in 25% of all cases. Some anicteric
form of the disease challenged this view and demonstrated
severe anicteric leptospirosis.68 The mortality is almost nil
in anicteric form, but 2.4% of the anicteric patients in a
Chinese outbreak received massive pulmonary hemorrhage
and death.69
The icteric form of the disease affects between 5%
and 10% of all patients with leptospirosis.70 Icteric leptospirosis is more severe, often rapidly progressive, with
a high mortality rate, and ranges between 5% and 15%.
The jaundice occurring in leptospirosis is not associated
with hepatocellular necrosis. Serum bilirubin, transaminase, and alkaline phosphatase level elevations are usually
minor.
Leptospirosis is a common cause of acute renal failure (ARF), which occurs in 16%–40% of cases.71–73 Serum
amylase level is often significantly increased in association
with ARF,74,75 but clinical signs of pancreatitis are rare.
Thrombocytopenia occurs in more than 50% of cases, is
usually associated with multiorgan involvement, and is a
predictor for ARF development.76,77 Thrombocytopenia
in leptospirosis is transient and does not result from disseminated intravascular coagulation.78,79
Pulmonary involvement can be the major manifestation
of leptospirosis in some cases.80–82 The severity of respiratory disease is unrelated to the presence of jaundice.83
Pulmonary signs and symptoms may present with cough,
dyspnea, hemoptysis (from mild to severe), and adult respiratory distress syndrome. Intraalveolar hemorrhage may
be found, even in the absence of pulmonary symptoms, and
may be severe, causing death.84–86 Radiographic abnormalities are most commonly noted in the first week of the disease, presented by alveolar infiltrates.
Cutaneous and Mucosal Manifestations
The skin eruption in the anicteric form of leptospirosis
is often transient, lasting less than 24 hours. Petechial,
ecchymotic, or purpuric skin lesions may occur in leptospirosis. Conjunctival suffusion is seen in the majority
of patients and in the presence of scleral icterus is thought
to be pathognomonic for Weil disease.87 Bacterial causes of
erythema nodosum, in particular leptospirosis, also should
be considered.88 A rare complication of leptospirosis may
be Kawasaki syndrome.89,90
●
Skin Signs of Systemic Infections
259
Recently, a case of anicteric leptospirosis, presenting
with respiratory insufficiency and acquired ichthyosis, was
described.91 The sudden appearance of ichthyosis, especially in adults, has been considered a marker of systemic
disease. Acquired ichthyosis may be associated with malignant disease and autoimmune disorders, as well as systemic infections (like the association of leptospirosis and
ichthyosis mentioned earlier in this chapter).
Differential Diagnosis
The multiorgan involvement of leptospirosis may be confused with other tropical infections – malaria, dengue,
enteric fever, typhoid fever, and melioidosis. Influenza
should be considered in mild anicteric cases.
Treatment
Treatment of leptospirosis varies depending on the duration and severity of the symptoms. Patients with mild,
flu-like symptoms are treated only symptomatically. The
management of icteric leptospirosis requires admission and
treatment of the patients in an intensive care unit. Patients
with ARF need dialysis. Cardiac monitoring is also necessary during the first few days.
Recently, the antimicrobial susceptibility of 13 Leptospira isolates (from Egypt, Thailand, Nicaragua, and
Hawaii) to 13 antimicrobial agents has been studied. Leptospires were susceptible to penicillin G, cefotaxime, ceftriaxone, and fluoroquinolones (moxifloxacin, ciprofloxacin,
and levofloxacin). Tetracyclines had the highest MIC90s
(minimum inhibitory concentration required to inhibit the
growth of 90% of organisms). 92 Leptospiral infection can
be successfully treated by penicillin G or doxycycline. IV
penicillin should be given at a dosage of 8 million units/day
for 7–10 days.93,94 A treatment regimen of oral doxycycline is 100 mg twice daily; for short-term prophylaxis –
doxycycline 200 mg once weekly.95
PLAGUE
The plague is a synonym of an old and forgotten infection, often used today with a totally different meaning –
as a curse, trouble, harassment, and so forth. Globally, the
World Health Organization reports 1000–3000 cases of
plague naturally occurring worldwide every year. In 2006, a
total of 13 human plague cases were reported in the United
States. This is the largest number of cases reported in a single year in the United States since 1994.96
The discovery of Yersinia pestis is fascinating. The
microbe causing the disease was invisible and unknown
until 1894, when Alexandre Yersin described it. Yersin was
sent to Hong Kong to conduct research on a bubonic plague
epidemic that was sweeping through China. Yersin arrived
in Hong Kong on June 15, 1894. Seven days later, while
260 E MERGENCY D ERMATOLOGY
Rodents or human
carry Y. pestis
in their blood.
Human or rodent
is infected.
Flea drinks rodent’s
blood.
Flea regurgitates
blood into the bitten
area.
Y. pestis multiply in
flea’s gut.
Flea bites
human or
rodent.
FIGURE 25.1: Usual path of plague transmission.
working in a small bacteriological research laboratory set
up for him, he isolated the plague bacillus.
The Japanese bacteriologist Shibasaburo Kitasato
(1852–1931) had arrived a shortly before Yersin in Hong
Kong. Within a few days, he also found a bacillus and
announced it to the world via telegraph. Kitasato published
his findings in Japanese and English at the same time that
Yersin published his discovery in French. People in various
parts of the world credited one or the other with the discovery, depending on which journals they had read. Yersin
named the organism Pasteurella pestis after his teacher
Pasteur, but since 1970, the bacillus has been known as
Yersinia pestis.
Plague is an infectious disease of animals and humans
caused by the bacterium Y. pestis. Y. pestis is a non–sporeforming, gram-negative coccobacillus measuring 1.5 ×
0.75 µm. The genome of Y. pestis has been sequenced,
including the three virulence plasmids, pPst, pLcr, and
pFra.97 Y. pestis belongs to the group of bacilli with low
resistance to environmental factors. Sunlight, high temperatures, and desiccation have a destructive effect, and ordiR
and preparations connary disinfectants such as Lysol
taining chlorine kill it in 1–10 minutes. Y. pestis circulates
particularly in rodents in the natural foci of infection found
on all continents except Australia. Plague is spread from
one rodent to another by flea ectoparasites and to humans
either by the bite of infected fleas or when handling infected
hosts (Figure 25.1). At least 30 types of fleas and more
than 200 species of mammals in 73 genera serve as reservoirs.98
The plague has had three pandemic waves.99 The first
certain plague pandemic, known as Justinian’s plague, was
recorded in the 6th century CE. The epidemic spread over
Asia, Africa, and Europe and claimed nearly 100,000,000
victims.
The second plague pandemic is the well-known “Black
Death” of the 14th century. It caused 50 million deaths, half
of them in Asia and Africa and the other half in Europe,
where a quarter of the population succumbed. The third
plague pandemic began in Canton and Hong Kong in 1894.
It was carried by rats aboard the swifter steamships and
spread rapidly throughout the world. Plague entered 77
ports on five continents. The last great outbreak of plague
occurred in the early 1900s in India, killing more than 20
million people.
There is a well-known classification of the clinical presentation of plague. Three types of plague are differentiated: bubonic, pneumonic, and septicemic.
Bubonic Plague
The classic form of infection is the bubonic plague (Greek
boubon = groin). It is transmitted only by a flea bite and is
not spread from person to person. The incubation period
varies from 1 to 8 days.
Clinical Features. The illness begins with fever, chills, and
pain in the area of the lymph nodes.
Cutaneous Manifestations. The characteristic sign is the
painful, swollen, and warm to the touch lymph node – a
“bubo” – which occurs in the groin, axilla, and/or cervical
region. Bubo location is primarily a function of the region
of the body in which an infected flea inoculates the plague
bacillus. Buboes are usually 1–10 cm in diameter and may
suppurate and rupture. Nausea, vomiting, and/or diarrhea
are common as systemic manifestations of the infection.
This form may progress to secondary pneumonic plague
or secondary septicemic plague. Bubonic plague has a
1%–15% death rate in treated cases and a 40%–60% death
rate if left untreated.
Differential Diagnosis. A wide differential diagnosis could
be made with cat scratch disease, ulceroglandular tularemia,
staphylococcal or streptococcal adenitis, mycobacterial
infection, lymphogranuloma venereum, chancroid, primary genital herpes, and even a strangulated inguinal
hernia.
Chapter 25
Pneumonic Plague
Pneumonic plague is the deadliest form. It is caused by
inhaling the bacteria and transmitting it. The transmission
requires close contact with an infected person. The incubation period is up to 6 days.
Clinical Features. The pneumonic plague begins with fulminant fever, malaise, myalgias, headache, and gastrointestinal symptoms. The death rate for pneumonic plague is
100% if not treated within the first 24 hours of infection.
Cutaneous Manifestations. Patients in the terminal stages
often develop large ecchymoses on the back – “the Black
Death.”
Differential Diagnosis. The differential diagnosis is made
with any case of severe gram-negative pneumonia,
community-acquired pneumonia (bacterial, Mycoplasma,
Legionella, Chlamydia), viral pneumonia (influenza, respiratory syncytial virus, cytomegalovirus, hantavirus), Q
fever, inhalational anthrax, tularemia, or ricin poisoning.
Recently, an outbreak of pneumonic plague in a remote diamond mine in the Democratic Republic of the Congo has
been registered. The multidisciplinary team of epidemiologists, physicians, and logisticians from Médecins Sans
Frontières confirmed 136 cases of pneumonic plague, 57
of them fatal.100
Septicemic Plague
Septicemic plague is caused by flea bites or is a result of
bubonic or pneumonic plague. It is not spread from person
to person, and occurs when plague bacteria multiply in the
blood. In this form, lymph nodes usually do not enlarge. It
is not contagious and has a 40% death rate in treated cases
and 100% in untreated cases.
Clinical Features. The clinical picture includes acute
fever, chills, prostration, abdominal pain, nausea, vomiting, and internal bleeding.
Cutaneous Manifestations. Purpuric skin lesions and gangrene of the distal digits (acral necrosis) are common. Rosecolored purpuric lesions give rise to the nursery rhyme
“Ring around the rosy.”101
In all forms, skin lesions may occur at the site of flea
bite (papules, vesicles, pustules), and petechiae and ecchymoses may occur during hematogenous spread. Ecthyma
gangrenosum has been reported in several patients as a rare
skin sign.102
Differential Diagnosis. Differential diagnosis should be
made with gram-negative sepsis, meningococcemia, rickettsiosis, malaria, and appendicitis.
●
Skin Signs of Systemic Infections
261
There are no widely available, rapid diagnostic tests
for plague. Blood, bubo aspirates, and sputum should be
stained with Giemsa stain. Smears typically show the bacillus to have a bipolar or “safety pin” appearance. Y. pestis is
slow growing in cultures of blood, bubo aspirate, sputum,
and skin lesions. Direct fluorescent antibody testing for Y.
pestis capsular (F1) antigen may be helpful. Several serologic
tests are also available (passive hemagglutination, enzymelinked immunosorbent assay). A single titer of more than
1:10 is positive for plague if the patient has not been vaccinated previously. With paired sera 4–6 weeks apart, a
fourfold increase in titer is considered confirmatory.
Treatment for Plague
The patients have to be isolated. The preferred treatment is
streptomycin (1 g intramuscularly [IM], 12 h) or gentamicin
(5 mg/kg IM or IV once daily, or 2 mg/kg loading dose
followed by 1.7 mg/kg IM or IV). Alternative therapeutic
regimens are courses with doxycycline (100 mg every 12
h or 200 mg once per day), ciprofloxacin (400 mg every
12 h), or chloramphenicol (25 mg/kg every 6 h, max 4 g/d).
The treatment’s duration is 10 days. In pregnant women,
gentamicin is the preferred choice.
As prevention, close physical contact is restricted to
proximity of no less than 2 m to a person who is symptomatic with plague. All health care personnel must take
precautions – wear goggles, gloves, gowns, and possibly
masks. In endemic areas, personal protective measures
such as use of insecticides and insect repellents are recommended for reducing the incidence of infection.103
Commercial plague vaccine dates back to 1896. At that
time killed bacteria were first used by Greer Laboratories
in its production. Nowadays, no vaccines are currently in
production.
Plague may be rare today, but doctors should be educated about the characteristic clinical signs of this infection. First because the bacillus is easily aerosolized and
second because the symptoms are not likely to arouse
suspicion until an epidemic is evident. Its potential usage
as a bioweapon should not be overlooked.104
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Nicaragua, 1995. J Infect Dis. 1998; 178:1457–63.
58. Alston JM. Leptospiral jaundice among sewer-workers.
Lancet. 1935; i:806–9.
59. Failey NH. Weil’s disease among sewer workers in London.
BMJ. 1934; 2:10–14.
60. Johnson DW, Brown HE, Derrick EH. Weil’s disease in Brisbane. Med J Aust. 1937; 1:811–18.
61. Stuart RD. Weil’s disease in Glasgow sewer workers. BMJ.
1939; i:324–6.
62. Waitkins SA. Leptospirosis as an occupational disease. Br J
Ind Med. 1986; 43:721–5.
63. Robertson MH, Clarke IR, Coghlan JD, Gill ON. Leptospirosis in trout farmers. Lancet. 1981; ii:626–7.
64. Gill ON, Coghlan JD, Calder IM. The risk of leptospirosis
in United Kingdom fish farm workers. J Hyg. 1985; 94:81–6.
65. Weil A. Ueber eine eigentümliche, mit Milztumor, Icterus
und Nephritis einhergehende akute Infektionskrankheit.
Dtsche Arch Klin Med. 1886; 39:209–32.
66. Kelley PW. Leptospirosis. In Gorbach SL, Bartlett JG, Blacklow NR, editors. Infectious diseases. 2nd ed. Philadelphia:
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67. Turner LH. Leptospirosis I. Trans R Soc Trop Med Hyg.
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68. Thomas JH, Stephens DP. Leptospirosis: an unusual presentation. Crit Care Resusc. 2006; 8:186.
69. Wang C, John L, Chang T, et al. Studies on anicteric leptospirosis. I. Clinical manifestations and antibiotic therapy.
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70. Heath CW, Alexander AD, Galton MM. Leptospirosis in the
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71. dos Santos VM, dos Santos JA, Sugai TA, dos Santos LA.
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72. Abdulkader RCRM. Acute renal failure in leptospirosis. Renal
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73. Winearls CG, Chan L, Coghlan JD et al. Acute renal failure
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74. Edwards CN, Everard COR. Hyperamylasemia and pancreatitis in leptospirosis. Am J Gastroenterol. 1991; 86:
1665–8.
●
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263
75. O’Brien MM, Vincent JM, Person DA, Cook BA. Leptospirosis and acute pancreatitis: a report of ten cases. Pediatr Infect
Dis J. 1998, 17:436–8.
76. Turgut M, Sunbul M, Bayirli D, et al. Thrombocytopenia
complicating the clinical course of leptospiral infection. J Int
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77. Edwards CN, Nicholson GD, Everard CO. Thrombocytopenia in leptospirosis. Am J Trop Med Hyg. 1982; 31:
827–9.
78. Edwards CN, Nicholson GD, Hassel TA, et al. Thrombocytopenia in leptospirosis: the absence of evidence for disseminated intravascular coagulation. Am J Trop Med Hyg. 1986;
35:352–4.
79. Nicodemo AC, Duarte MI, Alves VA, et al. Lung lesions
in human leptospirosis: microscopic, immunohistochemical,
and ultrastructural features related to thrombocytopenia. Am
J Trop Hyg. 1997; 56:181–7.
80. Teglia OF, Battagliotti C, Villavicencio R, et al. Leptospiral
pneumonia. Chest. 1995; 108:874–5.
81. O’Neil KM, Leland S, Richman Lazarus AA. Pulmonary manifestations of leptospirosis. Rev Infect Dis. 1991; 13:705–
9.
82. Martinez MA, Damia AD, Villanueva RM, et al. Pulmonary
involvement in leptospirosis. Eur J Clin Microbiol Infect Dis.
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83. Hill MK, Sanders CV. Leptospiral pneumonia. Semin Respir
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Intensive Care Med. 1987; 13:214.
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86. Alani FSS, Mahoney MP, Ormerod LP, et al. Leptospirosis presenting as atypical pneumonia, respiratory failure and
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87. Van Thiel PH. The leptospirosis. Universitaire Pers: Leiden;
The Netherlands. 1948.
88. Derham RLJ. Leptospirosis as a cause of erythema nodosum.
BMJ. 1976; 2:403–4.
89. Humphry T, Sanders S, Stadius M. Leptospirosis mimicking
MLNS. J Pediatr. 1977; 91:853–4.
90. Wong ML, Kaplan S, Dunkle LM, et al. Leptospirosis: a
childhood disease. J Pediatr. 1977; 90:532–7.
91. Othman N, Intan HI, Yip CW, et al. Severe leptospirosis
with unusual manifestation. J Trop Pediatr. 2007; 53:55–
8.
92. Ressner RA, Griffith ME, Beckius ML, et al. Antimicrobial
susceptibilities of geographically diverse clinical human isolates of Leptospira. Antimicrob Agents Chemother. 2008;
52:2740–4.
93. Edwards CN, Nicholson GD, Hassell TA, et al. Penicillin
therapy in icteric leptospirosis. Am J Trop Med Hyg. 1988;
39:388–90.
94. Kadurina M, Bocheva G, Tonev S. Penicillin and semisynthetic penicillins in dermatology. Clin Dermatol. 2003;
21:12–23.
95. McClain JBL, Ballou WR, Harrison SM, Steinweg DL.
Doxycycline therapy for leptospirosis. Ann Intern Med. 1984;
100:696–8.
264 E MERGENCY D ERMATOLOGY
96. Human plague–four states, 2006. MMWR Morb Mortal
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99. Tsankov N. Plague, epidemiology, clinics and therapy. XV
EADV Congress, Rhodes, October 4–8, 2006.
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101. Mee C. How a mysterious disease laid low Europe’s masses.
Smithsonian. 1990; 20:66–79.
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plague in Arizona: a spectrum including ecthyma gangrenosum due to plague and plague in pregnancy. Western J Med.
1985; 142:641–6.
103. Lazarus AA, Decker CF. Plague. Respir Care Clin N Am.
2004; 10(1):83–98.
104. Branda JA, Ruoff K. Bioterrorism. Clinical recognition
and primary management. Am J Clin Pathol. 2002; 117
Suppl:S116–23.
CHAPTER 26
Skin Signs of Systemic Neoplastic
Diseases and Paraneoplastic
Cutaneous Syndromes
Kyrill Pramatarov
THE SKIN MAY reflect many visceral diseases, malignancies included. Sometimes, the skin may even give a
clue to the underlying neoplasm. The French dermatologist Delacrétaz has definded the term “paraneoplasia:”
Cutaneous paraneoplastic syndromes are nonmetastatic manifestations on the skin as a result
of the existence of a malignant visceral tumor
and/or disease of the lymphoma group, especially leukaemias. The close relation between the
dermatosis and tumor is confirmed by the phenomenon of disappearance or not at all influenced skin disease, if the malignant tumor is
eliminated by operation, irradiation or cytostatics. The recurrence of the skin changes (dermatosis) indicates a relapse of the tumor or
metastases.1
Metastases to skin are more specific signs of internal cancer.
Sister Mary Joseph nodule (Figure 26.1) may be considered
more as metastases from an intraabdominal malignancy.
Clinically, Sister Mary Joseph nodule is an indurate nodule
or plaque. The surface of the nodule is sometimes ulcerated
with exudation of purulent or mucosal discharge. Occasionally, the lesions form a tumor. Sister Mary Joseph nodules
are signs of an advanced intraabdominal malignancy. They
appear as a sign of previously diagnosed neoplasia. The
primary malignancy is localized in the gastrointestinal or
genital tract, mainly as gastric adenocarcinoma, but also
adenocarcinoma of the ovary, colon, pancreas, prostate, or
liver.5
DERMATOSES HIGHLY ASSOCIATED WITH
MALIGNANCY
The paraneoplastic signs or syndromes may precede,
appear parallel to, or follow the appearance of the internal malignancy. There are many classifications of the paraneoplastic signs and syndromes, utilizing a variety of criteria: Some of them are based on the morphology of skin
changes, others are based on the frequency of the association of dermatosis/visceral malignancy. The paraneoplastic
signs and syndromes may be divided into two groups: indirect associations and direct associations with parallel evolutions corresponding to the paraneoplastic syndrome.2 The
pathogenesis of the development of paraneoplasias include:
●
peptides, mediators, and hormones released from the
tumor;
●
immunological defense reactions induced by the tumor
antigens and appearing after cross-reaction with the
structures of the skin;
●
deposits of immunocomplexes of tumor antigens and
antibodies;3 and
●
various cytokines and possibly growth factors.4
Acanthosis Nigricans Maligna
Besides malignant acanthosis nigricans, there is a benign form that may develop under various circumstances –
endocrinopathy and drug-induced forms. It may also be
clinical presentation of congenital conditions.
FIGURE 26.1: Sister Mary Joseph nodule.
page 265
266 E MERGENCY D ERMATOLOGY
FIGURE 26.2: Bazex syndrome (Photo courtesy of V. Benea,
MD).
In the malignant form, some epidermal growth factors produced by the tumor cells are responsible for the
clinical appearance. Clinically, malignant acanthosis nigricans is characterized by brown verrucous plaques. They
are located symmetrically on the back of the neck, groin,
and axillae. Similar lesions, but mostly darkly pigmented
papules, appear on the lips, eyelids, nipples, and the
anogenital area.
There is an extreme form that is always a clinical sign
of an internal malignancy. Brown thickening of the skin
over the dorsa of fingers or the palms may occur also. Oral
lesions may be present, as well. Malignant acanthosis nigricans is associated with adenocarcinoma of the gastrointestinal tract, cancer of the lung, gynecological tumors, and
lymphomas.6,7
Bazex Syndrome
Bazex syndrome (acrokeratosis paraneoplastica) is usually associated with carcinoma of the upper digestive
tract, including neoplasms of the lower lip, tongue,
tonsils, esophagus, and pharyngolaryngeal region (Figure 26.2).The upper part of the respiratory tract (the
upper third of the lung, especially) also may be involved
with malignancy in this syndrome. Other tumors have
been reported also: cancer of the prostate, bladder, and
lower part of the leg, and some hematologic malignancies.
The skin lesions appear in several phases. Initially, they
may resemble dermatitis, psoriasis, or lupus erythematosus. They begin with erythema and scaling and appear on
the fingers and toes. Rarely vesicles, bullae, and crusts are
present. The lesions are not itchy or painful. The nails are
hypertrophic with onycholysis. Sometimes, paronychia is
present. Similar changes appear on the nose and conchae
of the ears. In the later stages of the disease, the skin of
the body is also involved. Pityriasiform scaling appears on
the surfaces of the hands and feet. This scaling and a livid
erythema appear on the skin of the arms, legs, and trunk,
FIGURE 26.3: Erythema gyratum repens.
and (in severe cases) an erythroderma may be present. The
skin changes may even become hyperkeratotic on the skin
of the hands and feet.8,9
Erythema Gyratum Repens
Erythema gyratum repens is a paraneoplastic syndrome of
unknown etiology. The lesions of this syndrome consist of
erythematous concentric rings that form the classic woodgrain appearance (Figure 26.3). They may be flat or raised.
The skin changes are localized on the trunk, arms, and
thighs and proximal aspects of the extremities. The feet,
hands, and face are usually not affected. The rings spread
outward in a serpiginous pattern. The lesions are itchy, and
the pruritus may be severe.10
The pathogenesis is still obscure. Immunological pathogenesis of erythema gyratum repens is possible because
granular deposits of immunoglobulin G and C3 have
been detected at the basement membrane zone of both
involved and uninvolved skin.11 In 82% of erythema gyratum repens patients, there is internal malignancy of the
lung, breast, stomach, and/or esophagus. Regression of the
skin legions usually occurs with treatment of the underlying
cancer. Other diseases such as tuberculosis, CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, and sclerodactyly
also have been reported in association with erythema gyratum repens.12
Muir–Torre Syndrome
Muir–Torre syndrome is a rare autosomal dominant disorder. The skin lesions of Muir–Torre syndrome consist of
sebaceous epithelioma, adenoma, or carcinoma and multiple keratoacanthomas. The skin changes may precede the
appearance of the internal malignancies, but more often
they occur later. The internal malignancies are multiple.
They are less aggressive, and metastases rarely occur. The
tumors are mostly colorectal cancers. In 50% of patients,
Chapter 26
●
Skin Signs of Systemic Neoplastic Diseases and Paraneoplastic Cutaneous Syndromes
tumors of the genitourinary tract, breast, and/or upper gastrointestinal tract are detected.13,14
The Sign of Leser–Trelat
The sign of Leser–Trelat presents with numerous seborrheic keratoses, known as seborrheic warts or verrucae
senilis. They are common in elderly people, but the sign of
Leser–Trelat must be considered as a paraneoplastic sign, if
there is a sudden increase in the number or size of previous
existing keratoses and if their appearance is associated with
an internal malignancy.15 The lesions are itchy. Association of the sign of Leser–Trelat with malignant acanthosis
nigricans is quite possible, and this association supports the
hypothesis of the paraneoplastic nature of the sign. There
are no histological differences between common seborrheic
keratosis and those with malignancy.
The pathogenesis of the sign is unclear. Probably, a
tumor-secreted growth factor plays a role in its appearance. In most patients with the sign of Leser–Trelat, adenocarcinoma of the stomach is detected. The reported cases
with the sign of Leser–Trelat had malignancy of the breast,
colon, and/or rectum; less frequently, they had cancer of
the duodenum, esophagus, pancreas, ovary, uterus, cervix,
prostate, and/or gallbladder. The associated malignant diseases have an aggressive course; thus, the sign of Leser–
Trelat is a poor prognostic sign. Association of the sign
of Leser–Trelat has been reported with many hematologic
disorders, such as mycosis fungoides, lymphoma, leukemia,
and melanoma.16
Necrolytic Migratory Erythema (Glucagonoma
Syndrome)
Necrolytic migratory erythema (glucagonoma syndrome)
is strongly associated with the glucagon-secreting pancreatic islet cell tumor. Skin changes are erythematous, scaly,
and then crusted. Blisters can appear after pustular evolution due to bacterial or mycotic superinfection. The lesions
are often confluent and painful. The skin changes are localized on sites of friction and pressure, such as feet and legs,
but also on buttocks, groins, and the pubic area. Additionally, mucocutaneous lesions such as atrophic glossitis,
cheilitis, stomatitis, balanoposthitis, or vulvovaginitis can
appear. Because the condition is associated with pancreatic
tumors, high blood sugar levels are expected. The erythrocyte sedimentation rate is high. The amounts of free amino
acids and of free fatty acids are low.17
Sweet Syndrome
Sweet syndrome (acute febrile neutrophilic dermatosis) can
occur without other pathologic processes, but most commonly it might be associated with malignancy. In 85% of
cases, malignancy-associated Sweet syndrome is a marker
of hematologic neoplasm. The hematologic malignancies
267
include acute myeloid leukemia, Hodgkin disease, nonHodgkin lymphoma, myelodysplastic syndrome, myeloproliferative disease, and chronic myelogenous leukemia.18
The idiopathic form presents with tender plaques or
nodules located on the face, hands, and/or upper extremities. The skin is erythematous and livid. The diameter of
the lesions varies. Fever accompanies the skin changes, and
neutrophilia is detected. The condition responds promptly
to corticosteroids. There is a difference in the skin signs
between the idiopathic form and malignancy-related ones.
The latter are more severe, vesicular, bullous, or ulcerative. Other dermatoses can appear in the malignancyrelated variant, such as pyoderma gangrenosum, erythema
nodosum, or erythema multiforme. In the paraneoplastic form, the mucous membranes can be affected as well.
The extracutaneous involvement is more frequent: musculoskeletal signs and symptoms, involvement of the eyes, and
glomerulonephritis. In the paraneoplastic variant, there is
absence of neutrophilia, which is common in the idiopathic
form.19
Other Genodermatoses
Besides Muir-Torre syndrome, there are several autosomal dominant tumor-associated genodermatoses. These
include Gardner syndrome, Peutz–Jeghers syndrome, and
Cowden syndrome. In Gardner syndrome, multiple epidermoid cysts, fibromas, and primary osteoma of the skin
(which are associated with cancer of the colon) are present.
In Peutz–Jeghers syndrome, multiple perioral and mucosal
lentigines are observed. The skin changes are present
beginning in early childhood, but later the patients develop
tumor of the testis, ovaries, pancreas, and/or gastrointestinal tract. In Cowden syndrome, multiple trichilemmomas, trichoepitheliomas, hemangiomas, and oral and acral
papules appear in association with breast and thyroid cancer
or tumors of the gastrointestinal tract.3
Paraneoplastic Pemphigus
Paraneoplastic pemphigus is a mucocutaneous blistering
disease associated with malignancy and caused by Hodgkin
disease, non-Hodgkin lymphoma, chronic lymphocytic
leukemia, and/or Castleman disease, as well as Waldenstrom macroglobulinemia, T-cell lymphoma, thymoma,
retroperitoneal sarcoma, and/or reticulum cell sarcoma.
Reports on association with solid cancers are isolated.20,21
DERMATOLOGY DISORDERS THAT MAY BE
ASSOCIATED WITH MALIGNANCY
Pyoderma Gangrenosum
Pyoderma gangrenosum begins as a papule or pustule that
later develops into an erythematous nodule. These nodules
form an ulcer with irregular borders. The lesions have a
268 E MERGENCY D ERMATOLOGY
TABLE 26.1: Dermatologic Diseases and Disorders in Associations of Malignancy
Skin disorder
Related malignancy
References
Porphyria cutanea tarda
Amyloidosis
Ichthyosis acquisita
Granuloma annulare
Sarcoidosis
Hepatocellular carcinoma
Multiple myeloma
Multiple myeloma, non-Hodgkin lymphoma, Hodgkin disease
Non-Hodgkin lymphoma, Hodgkin disease, solid tumors
Solid tumors of cervix, liver, lung, uterus, testicles, melanoma;
leukemias, lymphomas, myeloma
Federman et al.30
Zappasodi et al.19
Zappasodi et al.19
Cohen31
Cohen31
Papuloerythroderma of Ofuji
T-cell lymphomas, hepatocellular carcinoma
Bullous pemphigoid
Relapsing polychondritis
Non-Hodgkin lymphoma
Adenocarcinoma of bladder, breast, bronchus, colon, lung,
pancreas, prostate, rectum, vocal cords; leukemias,
lymphomas, myeloma
Schepers et al.32
Nishijima33
Zappasodi et al.19
Cohen31
Systemic lupus erythematosus
Solid tumors of breast, cervix, ovary, brain, colon, biliary tract,
kidney, pancreas, stomach, rectum, thymus, urinary bladder;
leukemias, lymphomas, myeloma, nonmelanoma skin cancer
Cohen31
Erythromelalgia
Subcorneal pustular dermatosis
Dermatitis herpetiformis
Linear immunoglobulin A dermatosis
Erythroderma and exfoliative dermatitis
Pityriasis lichenoides et varioliformis acuta
Eosinophilic fasciitis
Scleroderma
Pityriasis lichenoides chronica
Myeloproliferative disease
Multiple myeloma, non-Hodgkin lymphoma
Non-Hodgkin lymphoma
Multiple myeloma, non-Hodgkin lymphoma
Hodgkin disease, non-Hodgkin lymphoma
Mycosis fungoides
T-cell malignant neoplasm
Ovarian cancer
Oncocytoma renis
Zappasodi et al.19
Zappasodi et al.19
Zappasodi et al.19
Zappasodi et al.19
Zappasodi et al.19
Kempf et al.34
Chan et al.35
Vottery et al.36
Lazarov et al.37
necrotic base, and hemorrhagic exudates may be present.
The lesions are painful and have a predilection for lower
extremity involvement. The sign of pathergy is present, and
lesions develop after minor trauma.19
Pyoderma gangrenosum is associated in approximately
50% of patients with such systemic diseases as ulcerative colitis, Crohn disease, and inflammatory arthritis.22
In 7% of cases, hematologic malignancies, most commonly
leukemias and multiple myeloma, are detected.19 When the
condition is associated with hematologic disorders, bullae
may also be seen on the face.23
Clubbing
Digital clubbing is associated with a disabling lung disease, mostly pulmonary emphysema, but also with chronic
bronchitis, hepatic cirrhosis, and inflammatory intestinal
diseases. It is characterized by an increase in the diameter
of the distal phalanges and alterations to the fingernails.
The disorder is classified into five phases. It begins with
an increase and fluctuation of the ungual bed and, in the
last phase, increase of the extremity with thickening of the
distal phalange and longitudinal striations are observed.26
Digital clubbing is associated with bronchogenic cancer,
and in this paraneoplastic form the bones are not usually
changed.27
Dermatomyositis
Dermatomyositis is an inflammatory myopathy with characteristic skin manifestations. The diagnostic criteria of
dermatomyositis include symmetrical proximal muscle
weakness, inflammatory myopathy, elevation of serum levels of muscle enzymes, electromyographic evidence of
myopathy, and typical cutaneous findings of dermatomyositis. The prevalence of malignancy in dermatomyositis ranges from 3% to 60%.24 Dermatomyositis may
precede, occur concurrently with, or develop after the
malignancy. The most expected tumors associated with
dermatomyositis are cancers of the ovary, stomach, lung,
and/or breast.25
Tripe Palms
Tripe palms present with brown thickening of the skin of
the palms, resembling pig intestine; hence, the name. The
epidermal ridges are broadened, and the sulci are deep.
These changes are associated with internal malignancy and
usually appear with acanthosis nigricans.28
Hypertrichosis Lanuginose
This paraneoplastic sign occurs in women, mostly. The
face is affected mainly. Less frequently, hypertrichosis is
Chapter 26
●
Skin Signs of Systemic Neoplastic Diseases and Paraneoplastic Cutaneous Syndromes
observed on the neck, trunk, arms, and legs. It must be differentiated from hirsutism and hypertrichosis, which occur
because of androgens produced by some endocrinologic
disorders. Hypertrichosis lanuginose appears with cancer
of the lung and/or colon.3
The vasculitides, which are a heterogenous group of diseases, are associated with cancer in approximately 5% of
the patients. Most commonly, patients with paraneoplastic vasculitis have such hematologic malignancies as hairy
cell leukemia and lymphomas. Vasculitis reported in association with hematologic malignancies includes leukocytoclastic vasculitis and polyarteritis nodosa.19,29
OTHER DERMATOLOGIC DISEASES ASSOCIATED
WITH MALIGNANCIES
Numerous additional dermatologic diseases and disorders have been reported in associations of malignancy
(Table 26.1).
Additionally, dermographism and pruritus must be considered as common paraneoplastic signs without any particular associations with malignancies.
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30. Federman D, Brescia G, Horne M, et al. Cutaneous manifestation of malignancy. Postgrad Med Online. 2004; 115:1–
13.
31. Cohen P. Granuloma annulare, relapsing polychondritis,
sarcoidosis, and systemic lupus erythematosus: conditions
whose dermatologic manifestation may occur as hematologic
malignancy – associated mucocutaneous paraneoplastic syndromes. Int J Dermatol. 2006; 45:70–80.
32. Schepers C, Malvehy J, Azon-Masoliver A, et al. Papuloerythroderma of Ofuji: a report of 2 cases including the first
European case associated with visceral carcinoma. Dermatology. 1996; 193:131–5.
270 E MERGENCY D ERMATOLOGY
33. Nishijima S. Papuloerythroderma associated with hepatocellular carcinoma. Br J Dermatol. 1998; 139:1115–
16.
34. Kempf W, Kutzner H, Kettelhack N, et al. Paraneoplastic
pityriasis lichenoides in cutaneous lymphoma: case report and
review of the literature on paraneoplastic reactions of the skin
in lymphoma and leukemia. Br J Dermatol. 2005; 152:1327–
31.
35. Chan LS, Hanson CA, Cooper KD. Eosinophilic fasciitis as a
paraneoplastic syndrome. Arch Dermatol. 1991; 127:862–5.
36. Vottery R, Biswas G, Deshmukh C, et al. Scleroderma and
dermographism in a case of carcinoma ovary. Indian J Dermatol Venereol Leprol. 2005; 71:429–30.
37. Lazarov A, Lalkin A, Cordoba M, et al. Paraneoplastic pityriasis lichenoides chronica. J Eur Acad Dermatol Venereol.
1999; 12:189–90.
CHAPTER 27
Burn Injury
Samuel H. Allen
ACUTE INJURY caused by burns produces some of the
most horrendous and harrowing deformities encountered
by persons working in the emergency and health care services. These injuries have a high mortality and, should
the patients survive, they will carry with them the lifelong
scars – physical, psychological, and emotional.
Worldwide, injury caused by fire is a major cause of morbidity, especially in sub-Saharan Africa where open fires are
used to heat food and water. Sadly, most of these injuries
occur in toddlers.
In the developed world, house fires and industrial accidents are the major culprits causing burn injury. In the
United States alone, more than 500,000 people are seen
in emergency departments each year as a result of burn
injury; more than 50,000 are admitted to hospital, and
more than 5000 deaths per year are attributed to the burn
injury.
Approximately 50% of household and domestic burn
injuries result from hot-water scalding and fires that occur
in the kitchen. Most are managed outside hospital practice.
Highest rates of burn-related injury and death are observed
in children younger than 5 years and elderly persons older
than 75 years.1 Since the introduction of gas-fired central
heating and the tightening of health and safety laws, the
incidence of these events has become less commonplace.
Heat energy is transmitted through radiation, conduction, and convection. Thermal injury usually occurs as a
result of fire, but chemicals, electricity, and radiation can
also cause burn injury. It is the direct effect of the flames’
heat that causes the greatest harm. When the skin’s integument is destroyed the essential function of the skin is lost,
leading to profound fluid loss as well as inflammation and
pain. To compound the injury, the burn is often associated with other injuries arising from the accident such
as shock, smoke and debris inhalation, and blunt trauma.
Superheated air may cause direct thermal injury leading
to upper airway edema and obstruction of the respiratory
tract. More than 50% of fire-related deaths are the result
of smoke inhalation.
local inflammatory changes. Large injury is associated
with systemic shock and organ hypoperfusion that is compounded by the pathological fluid loss. After resuscitation, the patient attains a hypermetabolic state associated
with gluconeogenesis, insulin resistance, and increased protein catabolism. Late complications can arise from tissue
edema and swelling, which in turn may lead to compartment syndrome, superimposed infection, and contractures.
Wound infection is often associated with multidrugresistant organisms as a result of prior use of broadspectrum antibiotics. Psychological sequelae are common
and include posttraumatic stress disorder, depression, and
body image disorder.
CLINICAL AND LABORATORY AIDS REQUIRED
FOR DIAGNOSIS
In most cases of burn injury the diagnosis and etiology
are self-evident. Even so, it is important to try to establish
the time of the injury as this will have implications in the
management and anticipation of complications. What may
be less clear is the extent – and depth – of the injury.
Extent of Burn
A rapid and usefully accurate estimate of the body surface
area of the injury can be calculated using the Rule of Nines
(Figure 27.1).2
Calculation of body surface area differs in children. For
children younger than 1 year, the head surface area represents approximately 18% of total surface area and the legs
14%. Therefore, for children older than 1 year, one should
add 0.5% to the leg area and subtract 1% from the head
surface area for each additional year until adult values are
attained. Alternatively, the Lund and Browder3 chart can
be used to estimate body surface area in children. For a
wide age range, the area of the palm plus palmer aspect of
the digits represents 1% of the total body area.
Depth of Burn
PATHOPHYSIOLOGY
A burn is caused by the coagulative destruction of the
skin and mucous membranes, leading to blistering and
Accurate assessment of the burn depth is important in making decisions about dressings and timing of surgery. The
depth may not always be clear from the initial assessment.
page 271
272 E MERGENCY D ERMATOLOGY
Superficial Partial-Thickness Burns. These burns affect
the superficial dermis (papillary layer) and epidermis. The
lesion has a red or mottled appearance with associated
swelling and blister formation. Scalding typically causes
this type of lesion. The skin often has a weeping or wet
appearance and may be hypersensitive, even to air. Exposure of the superficial nerves makes these injuries extremely
painful. Healing is usually complete within 2 weeks depending on the density of skin adnexae. Thin hairless skin (e.g.,
inner arm and eyelids) will heal more slowly than thick or
hairy skin (e.g., scalp or face) because it contains fewer hair
follicles or sweat glands that contain the regenerating keratinocytes.
FIGURE 27.1: Rule of Nines.2
Depth of burn was previously classified as first-, second-,
or third-degree burn but is now more accurately described
as an epidermal, superficial, or deep partial-thickness or
full-thickness burn (Figure 27.2).
Epidermal Burns. By definition, these burns affect only the
epidermis. The lesion is typified by sunburn. Erythema and
pain are present. Blistering is unusual in this type of injury.
The skin adnexae that contain regenerating keratinocytes
within the sweat glands and hair follicles are preserved, so
the lesion normally heals within a week without scarring.
Supportive therapy is all that is required. Regular analgesia
and intravenous fluids may be required if there is extensive
injury and/or signs of heat stroke.
ep
cial De ial
erfi
t
r
p
a
u
p ness
S
k
tial
par ness thic
k
thic
Full ess
kn
thic
n
r
u
b
Deep Partial-Thickness Burns. Damage to the deep dermis, which is the reticular layer containing the superficial
parts of the hair follicles and sweat and sebaceous glands,
is often the most difficult to assess and treat. Initial lesions
may appear superficial, even with blanching on pressure,
but on reexamination 48 hours later show fixed capillary
staining. Fewer skin adnexae – hence islands of regeneration – are present at this depth, so healing is slower. The
exposed dermis is pale white–yellow and insensate because
sensory nerves in the dermis are destroyed. Blistering is
common, and there is no capillary refill. Lesions heal with
scarring. If injuries are extensive or in functional or cosmetically sensitive areas they are better excised to a viable
depth and then skin-grafted for best functional recovery.
Healing takes between 3 and 8 weeks.
Full-Thickness Burns. In full-thickness burns, all regenerative tissues are destroyed such that healing may only
naturally occur from the edges of the wound. Consequently, healing usually results in considerable contraction.
The skin may vary in appearance between appearing dark,
charred, and leathery to appearing translucent, mottled, or
waxy white. Occasionally, the injury may be missed, being
mistaken for unburnt skin. All full-thickness burn injuries
should be excised and grafted unless they are small (<1 cm
in diameter) or in an area that would not compromise function. Analgesia to pinprick signifies a deep dermal or fullthickness injury.
The clinical features of epidermal, partial-, and fullthickness burns are shown in Table 27.1. A so-called fourthdegree burn exhibits destruction of the subcutaneous fat,
muscle, and sometimes bone. Such injury requires major
reconstruction and often amputation.
THERAPY
FIGURE 27.2: Classification of injury according to depth of
burn.
The chances of surviving a complex major burn injury are
better now than ever before. Patients should be managed
on a specialized burn unit or center with experience in
managing these types of injury. This management usually
Chapter 27
●
Burn Injury
273
TABLE 27.1: Clinical Features of Epidermal, Partial-, and Full-Thickness Burns
Depth
Color
Blisters
Capillary refill
Sensation
Epidermal
Superficial partial thickness
Deep partial thickness
Full thickness
Pink or red
Pink or red
Red or pale
White
No
+/−
+/−
No
Present
Present
no
no
Sore
Painful
+/−
No
involves a multidisciplinary effort involving the surgical
team, specialist nursing, microbiology, dieticians, physiotherapy, and psychology. It is important that the wound is
reviewed regularly until healing is ensured. Factors such as
the local or systemic inflammatory response, wound infection, dehydration, cooling, and nutritional support will
influence the outcome.
Immediate Management: Airway, Breathing,
and Circulation
Initial management of the burned patient requires an
urgent assessment of the airway, breathing, and circulation (ABC) of the injured person, an assessment of his or
her level of consciousness, and rapid fluid replacement.
All clothing should be removed unless adherent to the
burn victim’s flesh (in which case it should be cooled and
soaked with water for formal debridement later). Jewelry
such as rings and wristwatches should be removed to prevent later complications arising from edema of the extremities. Recent burn injury should be actively cooled with
copious amounts of tepid water for up to 20 minutes. Extra
caution should be taken in children as their greater surface
area-to-weight ratio may lead to hypothermia. The patient
should be nursed in a bed with warm, dry, clean linens
to prevent hypothermia. Any blisters should be left intact.
Antiseptic creams should not be applied.4
Inhalation injury should be suspected if there is burn
to the face, neck, and/or lips; hoarseness; or evidence of
carbon particles (produced by combustion) at the mouth or
in the sputum. Inhalation injury is more likely if the victim
is found in an enclosed space or if the injury occurred as a
result of an explosion.
Smoke inhalation usually consists of carbon monoxide (CO) and/or cyanide poisoning combined with a
severe chemical pneumonitis. Modern building construction materials yield significant amounts of cyanide. A carboxyhemoglobin level greater than 10% in a burn victim
would be indicative of inhalation smoke injury.
Anoxia is the first complication to consider. Causes
are laryngeal obstruction, pulmonary edema, contracted
burned skin encircling the chest, carboxyhemoglobin, anemia, and shock. The airway above the glottis is particularly susceptible to obstruction from heat-induced edema.
Inhalation injury may be subtle and often does not appear
in the first 24 hours, mandating that patients be observed
and have blood gases monitored for at least 24 hours prior
to discharge.
Acute inhalation injury requires transfer to a specialist
unit for endotracheal intubation and mechanical ventilation.
Management on the Burn Unit
Fluid Replacement. A flow sheet outlining the patient’s
management should be commenced and kept with the
patient on arrival on the burn unit. Baseline determination for the major burn patient is shown in Table 27.2.
Ideally, the patient should be weighed on admission to
the unit, and a full survey of the extent of other injuries
should be taken. This will often involve a radiological
survey.
The burn represents a large fistula leaking water, electrolytes, and protein. The rate of daily water loss through
the breached skin averages 0.30 mL/cm2 burned area. If
not done already, large-caliber intravenous lines must be
established. Any adult with more than 20% burns (i.e.,
two whole upper limbs or one whole leg) or a child with
more than 10% burns (i.e., one whole upper limb, excluding erythema) will require circulatory volume support. A
burn patient will require 2–4 mL of Ringer’s lactate or colloid solution per kilogram body weight per percent partialor full-thickness body surface burns in the first 24 hours. In
children, plasma equal to the child’s plasma volume should
be given for every 15% of skin burned. The intravenous
fluid rate is adjusted to give one half of the estimated fluid
TABLE 27.2: Baseline Determination for the Major Burn Patient
• Blood: complete blood count, blood type and cross-match,
carboxyhemoglobin, serum glucose, electrolytes
• Pregnancy test in women of child-bearing age
• Arterial blood gases
• X-ray: chest x-ray, other x-rays as indicated by injuries
• Time of injury
• Patient’s weight
• Estimate of burn injury: extent (% body surface area) and
depth of injury
• Comorbidities and medication
274 E MERGENCY D ERMATOLOGY
volume replacement within the first 8 hours after the burn
injury and the remainder in the subsequent 16 hours. Fluid
requirement calculations for infusion rates are based on
time from injury, not from the time fluid resuscitation is
initiated. The amount of fluid given should be adjusted
according to the individual patient’s response to maintain a
urinary output of 0.5–1 mL/kg/h (adult) or 1–1.5 mL/kg/h
(in children). The goal is to maintain vital organ function
while avoiding the complications of inadequate or excessive
fluid infusion that can lead to increased tissue edema.
Blood pressure may be difficult to obtain and may
be unreliable. Arterial line blood-pressure monitoring is
therefore preferable in the intensive care or burn unit setting with cardiac monitoring for signs of dysrhythmia.
Electrolyte, acid–base, and fluid balance will need to be
meticulously monitored with hourly urine output for which
the patient will require urinary catheterization. If there are
signs of nausea, vomiting, or abdominal distension, or if
burn involves more than 20% of the total body surface area,
nasogastric tube insertion will be required. Blood transfusion is rarely needed.
CO Poisoning. The diagnosis of CO poisoning should be
assumed in any injured person found in a smoke-filled environment. Patients with CO levels less than 20% usually
have no physical symptoms. Higher CO levels can cause
headache, nausea, confusion, coma, and/or death.
CO dissociates very slowly from hemoglobin, but this
can be increased by breathing high-flow oxygen via a nonrebreathing mask. Arterial blood gas determinations should
be obtained at baseline, but arterial pO2 does not reliably
predict CO poisoning. Therefore, 100% oxygen should be
administered after baseline carboxyhemoglobin levels have
been taken.
Severely burned patients may be agitated or anxious
from hypoxemia or hypovolemia rather than from pain.
The patient may then respond better to oxygen or increased
fluid administration rather than to narcotic analgesics or
sedatives that may mask other signs of hypoxemia or hypovolemia. Narcotics, analgesics, and sedatives should be
administered in small, frequent doses by the intravenous
route only.
Hyperbaric oxygen therapy has been used in the treatment of major burn injury. To be effective, hyperbaric
oxygen therapy must be started within 24 hours of the
burn (and preferably sooner). It is particularly useful in
cases of concomitant smoke inhalation and CO or cyanide
poisoning.
Airway Management. Stridor is an indication for immediate endotracheal intubation. Circumferential burn to the
neck can lead to swelling of the tissues around the airway
and will usually require intubation. If oxygen and humidification are not adequate, positive-pressure ventilation may
be needed.
Elevation of the head and chest by 20–30 degrees
reduces neck and chest wall edema. Chest wall escharotomy (burn incised into subcutaneous fat) may be required
in the case of a full-thickness burn of the torso, leading to
restriction of the chest wall motion. Local anesthesia is not
required because the skin is rendered insensate.
Nutritional Support. The average sodium loss is 0.03
mmol/cm2 , and the protein loss is similar to dilute plasma,
about 30 g/L. Extensively burned patients will require
approximately one-and-a-half times the calories and 2–3
times the protein needed in health. Feeding may be commenced via the nasogastric tube within 24 hours after the
burn injury. If oral feeding is not possible, potassium should
be administered by mouth or intravenously to prevent
ileus.
Wound Management
Superficial Partial-Thickness Burns. A moist, infectionfree environment facilitates the process of reepithelialization. In the case of a superficial partial-thickness injury,
an antimicrobial cream plus an occlusive dressing should
be applied. Hypafix applied directly to superficial wounds
can be useful to preserve mobility and allow washing of the
affected part with the dressing intact. It should be soaked
in oil (such as olive oil) for an hour before removal and
changed at least twice weekly until the wound has healed.
Alternatively, tulle gras or a silicone dressing such as Mepitel can be applied, with or without a silver sulfadiazine
cream or Acticoat and gauze.5
The wound should be cleaned, dressed, and reviewed
on alternate days to optimize healing. Antimicrobial cream
should be applied using the aseptic method with sterile
gloves to avoid inoculation of potentially pathogenic organisms into the wound. Facial burns heal well and may be
left exposed. Any burn that has not healed within 2 weeks
should be referred for reassessment.
Deep Partial-Thickness Burns. These injuries are the
most difficult to treat and assess. Some deep partialthickness injuries will heal if the wound environment is
optimized to encourage endogenous healing. Other injuries
will require excision and grafting.
Delay in reepithelialization beyond 3 weeks is associated with hypertrophic scarring. Therefore, all injuries that
show no sign of healing by 10 days should be referred to
a specialist burn unit for consideration of grafting. Either
the depth has been assessed incorrectly or the wound environment has become compromised.
A number of bioengineered skin substitutes have been
designed to promote healing. TransCyte, for example, contains nonviable allogenic fibroblasts that produce cytokines
that have been shown to improve healing in vitro. In a systematic review, such agents were at least as safe as biological
Chapter 27
skin replacements or topical agents.6 Bioengineered skin
substitutes, however, tend to be expensive and need to be
applied by trained staff in theatre.
Surgery
With major burns, the goal of therapy is geared toward
preservation of life and limb. Wounds that are obviously
deep at presentation must be referred early before tissue
necrosis triggers multiple organ failure or leads to sepsis.
In such cases, more superficial burns may be treated with
dressings until healing occurs or fresh donor sites become
available.
The best time for surgery is within 5 days of injury to
minimize blood loss. The burn eschar is shaved tangentially
or excised to deep fascia. The aim is to remove the nonviable
burnt skin while leaving a bed of viable tissue to allow for
regranulation.
The ideal covering is split-skin autograft from unburnt
areas. Thickness is usually tailored to the depth of the
excision for good cosmesis. Donor sites are often harvested adjacent to the injury to optimize the color match.
Unmeshed sheet graft is preferred for the best cosmetic
result and is used for the hands and face.
Where donor sites are sparse, or the wound bed is likely
to bleed profusely, the graft is perforated with a mesher to
allow expansion. Although this improves graft “take” where
the wound is bleeding after tangential excision, the mesh
pattern is permanent and unsightly.
Rotation of the donor site may be used where unburnt
split-skin donor sites are in short supply, or else the excised
wound is covered with a temporary cover until donor
sites have regenerated for reharvest. Examples of temporary cover include cadaveric allograft from an unrelated
donor, xenograft (pigskin is most commonly used), cultured
epithelial autograft, or a number of synthetic products.
Cultured epithelial autografts permit greater use of
available donor sites. Cultured cells can be applied as sheets
(available after 3 weeks) or in suspension (available within
1 week). The development of synthetic products (such as
Integra dermal regeneration template) has enabled surgeons to shave extremely large burns and still achieve physiological closure with potentially lower mortality than was
previously possible. These products can be used in combination with mesh graft to improve the final cosmetic
result.
Role of Antimicrobials
Unless soiled at the time of injury, an acute burn injury
is usually sterile because the heat from the initial burn is
sufficient to kill most skin bacteria. Antibiotics, therefore,
should not be routinely commenced following a burn injury
but should be reserved for the treatment of secondary infection.
●
Burn Injury
275
TABLE 27.3: Criteria for Referral to a Burns Center
• Deep burns involving:
• 10% or more of the total body surface area in adults, or
• 5% or more of the total body surface area in children
• Burns to the face, eyes, ears, hands, feet, genitalia, perineum,
inner joint surfaces
• Inhalation injury
• Significant chemical and electrical burns, including lightning
injury
• Burn injury with any of the following:
• Major preexisting illness such as diabetes that could
complicate management and recovery
• Suspected child abuse and neglect
• Concomitant injury
Wounds should be swabbed regularly for bacterial
growth and culture sensitivities. The choice of antimicrobials, if indicated, should be based on these results,
along with the results of screening swabs, for example, for
methicillin-resistant Staphylococcus aureus (MRSA).
Tetanus toxoid should be administered. Human antitetanus immunoglobulin should be considered if treatment
has been delayed or the wound is heavily contaminated with
soil or feces.
COURSE AND PROGNOSIS
A rough calculation of the survival probability can be made
using the formula:
100 – (age in years + area of burn, as a percentage)
For example, a 25-year-old man with a 30% burn can
expect a 45% [100 – (25 + 30)] survival.
Optimum treatment of the wound reduces morbidity
and reduces mortality. It also shortens the time to healing
and return to normal function and thus reduces the need
for plastic surgery.
CRITERIA FOR REFERRAL TO A BURN UNIT
Although not all the patients in the categories in Table 27.3
will require transfer to a specialized burn unit, consultation
with the appropriate center should take place at presentation to plan further management and anticipate possible
complications.
Full-thickness injuries have no regenerative elements
left. Unless they are very small, they will take weeks to heal
and undergo severe contraction. They should be referred
for surgery as early as possible.
COMPLICATIONS
The number and complexity of complications will depend
on the premorbid state of the patient as well as the extent
and type(s) of injury.
276 E MERGENCY D ERMATOLOGY
Compartment Syndrome
Raised intracompartmental pressure due to progressive
tissue damage and inflammation can impede compartmental blood flow leading to ischemia and anoxic necrosis. Fasciotomy and nerve decompression (requiring clinical vigilance and close liaison with the surgical team)
should be undertaken prior to the onset of irreversible
damage.
Infection
Unless there is debris in the wound, the thermal energy
from the burn will kill the commensal flora of the skin. The
routine use of broad-spectrum antibiotics on admission is
therefore not recommended, unless the wound involves
areas with a high bacterial load, such as the perineum or
feet, or where the wound has been soiled.
Exposed devitalized flesh provides a warm, moist culture medium, and a sterile wound can quickly become colonized when the skin has lost its integument. Even so, it will
normally take approximately 5 days for an infection or significant colonization to become established in a previously
sterile site.
If a wound infection is suspected or the patient develops
any signs of sepsis (raised temperature, raised C-reactive
protein, raised white cell or neutrophil count), then wound
swabs and blood cultures should be taken before embarking on “blind” antimicrobial therapy. The choice of antibiotics will depend on the unit guidelines based on the
local endemic resistance pattern and cost. Close liaison
with the microbiologist is essential to avoid inappropriate
prescribing.
The emergence of multiresistant organisms (including
resistant Pseudomonas spp., Acinetobacter baumannii, MRSA,
and vancomycin-resistant Enterococcus) within burn units
has become an increasing problem. The overall attributable
mortality rate for these organisms is high, and once established, eradication from the burn unit can be difficult
because of their ubiquitous nature and ability to survive
for prolonged periods on inanimate surfaces.
Thromboembolic Disease
Burn injury, coupled with fluid loss and a prolonged period
of rest in a warm environment, will increase plasma fluid
viscosity. Prophylaxis with a low-molecular-weight heparin is recommended but can be delayed until after initial
debridement and shave excision procedures. The clinical
team should be mindful of late thromboembolic complications such as deep vein thrombosis or pulmonary embolus.
D-dimers will be of limited use in the context of a recuperating burn patient, and diagnosis will rely on Doppler
ultrasound or venogram. Treatment will be as for a general
surgical patient with a target international normalized ratio
of 2.5, range 2–3.
OTHER TYPES OF BURN INJURY
Chemical Burns
Chemical burns may result from exposure to acids, alkalis,
and petroleum products. Alkali burns tend to be deeper and
more serious than acid burns.
Management involves washing the burn with copious
amounts of running water for at least 20–30 minutes (longer
for alkali burns). Certain chemicals will produce toxic products with only a small amount of water, so it is important
to use a copious amount of water to dilute the effects of
the chemical. If the toxic chemical is in powder form then
the powder should be brushed away before irrigation with
water.
Ocular chemical injury requires continuous irrigation
for at least 8 hours in the case of alkali burns.
Electrical Burns
Electrical burns account for approximately 3% of burn
patients attending specialized centers. These burns are
arbitrarily classified as high- or low-tension injuries
depending on the voltage, with high-tension burns resulting from shocks of greater than 1000 volts. Most electrical burns, however, are the result of low-tension domestic appliances. Other sources of current are overhead
high-voltage power lines and rail electrification, including the “third rail.” These overhead power lines pose a
threat not only to workers but also to sports enthusiasts
involved in pursuits such as fly-fishing, kite-flying, hanggliding, and parachuting.7,8 Removal of bodies from overhead cables will require electrical isolation at the point of
recovery.
Electric shock will cause reflex muscle contraction.
Thus, when navigating his or her way out of a smoke-filled
room, a firefighter will have been trained to feel the way
with the back of a hand rather than the palm, so that if an
exposed live wire is encountered the shock will produce a
repulsion of the limb rather than a grasp reflex.
The severity of electrical burn injury is related to the
voltage, duration of contact, and thickness and wetness of
the skin.
Electrical burns are often more serious than they appear
on the surface. Any organ between the entry and exit point
can be injured. High-voltage contact results in significant
rhabdomyolysis with myoglobinuria and subsequent risk of
renal failure. Death may occur as a result of cardiac stunning.
The histology of a skin injury shows a distinctive vertical elongation of the nuclei of the cells of the basal layer.
Chapter 27
The superficial epidermal cells may show similar changes.
Dermal–epidermal separation may be present with elongated degenerated cytoplasmic processes from the basal
cells protruding into this space.
Lightning Strike
Approximately 100 deaths occur every year from a lightning
strike in the United States. Millions of volts are conducted
through a channel of approximately 1-cm diameter in less
than a few milliseconds. Although 90% of victims survive
the lightning strike, up to 70% will suffer late organic or
psychological effects.
The classical dermatological injury is an arborescent or
feather-like lesion known as a Lichtenberg figure (Figure
27.2). Small burns at the site of metal objects held in the
hands or pockets may also be evident.9
Therapy is directed toward management of the extracutaneous complications that include respiratory arrest, gastric dilatation, ileus, cerebral edema, rupture of the tympanic membrane, and fractures.
●
Burn Injury
277
REFERENCES
1. Rajpura A. The epidemiology of burns and smoke inhalation
in secondary care: a population-based study covering Lancashire and South Cumbria. Burns. 2002; 28:121–30.
2. Wallace AB. The exposure treatment of burns. Lancet. 1951;
i:501–4.
3. Lund CC, Browder NC. The estimation of the areas of burns.
Surg Gynaecol Obst. 1944; 79:352–8.
4. Hettiaratchy S, Papini R. Initial management of a major burn:
I – overview. BMJ. 2004; 328:1555–7.
5. Papini R. Management of burn injuries of various depths.
BMJ. 2004; 329:158–60.
6. Pham C, Greenwood J, Cleland H, et al. Bioengineered skin
substitutes for the management of burns: a systematic review.
Burns. 2007; 33:946–57.
7. Chi L, Ning YD, Jun QF, et al. Electrical injuries from
graphite fishing rods. Burns. 1996; 22:638–40.
8. Campbell DC, Nano T, Pegg SP. Pattern of burn injury on
hang-glider pilots. Burns 1996; 22:328–40.
9. Cherington M, McDonough G, Olson S, et al. Lichtenberg
figures and lightning: case reports and review of the literature.
Cutis. 2007; 80:141–3.
CHAPTER 28
Emergency Dermatoses of the Anorectal
Regions
Yalçin Tüzün
Sadiye Keskin
ALTHOUGH THERE ARE some dermatological disorders that may affect the quality of life, the life-threatening
dermatoses of the anorectal region are infrequently seen.
When observed, bacterial infections would be the most
serious, often being life threatening. For this reason, making the correct diagnosis and providing appropriate care
is significant. Some of these disorders may be treated only
with surgical treatment.
Emergency dermatoses in the anorectal region are listed
in Table 28.1.
STAPHYLOCOCCAL CELLULITIS
The anorectal region can be susceptible to infection with
Staphylococcus aureus. The high temperature, pressure, friction, and humidity of this area encourage colonization by
staphylococci. Severe involvement with furunculosis and
abscesses suggests an overlap with hidradenitis suppurativa. Cellulitis and abscess formation can complicate cysts,
sinuses, and fistulas.1
Anorectal infections in patients with malignant disease
are serious and potentially life threatening. Although some
cases of anorectal cellulitis may respond to antimicrobials
alone, necrotizing fasciitis and Fournier gangrene have a
high risk. Swelling and fluctuation signifying abscess formation may develop. It is difficult to decide on the timing of
surgery. Perianal infiltration, ulceration, or abscess occurs
in 5% of hematological malignancies and may rarely be the
presenting feature.1
STREPTOCOCCAL DERMATITIS/PERIANAL
CELLULITIS
This syndrome is mostly seen in children between the ages
of 1 and 8. Boys are affected more frequently than girls.
Group A  hemolytic streptococci is the main cause (rarely
S. aureus).2 An association with acute guttate psoriasis has
also been reported.2
The child presents with pruritus, painful defecation, anal
soreness and redness, and satellite pustules of the buttocks.
Examination of the anus shows marked, sharply demarcated
erythema and causes discomfort. Rarely, proctocolitis may
be seen. Generally, systemic penicillin or topical mupirocin
is used in the treatment of this disease. If the disease is clinically less acute, erythromycin may be selected, depending
on resistance patterns.1
PERIANAL ABSCESS
Perianal and anorectal abscesses usually are seen with
painful swelling and suppuration. They are commonly
complicated by anal fistula. The usual cause of a perianal abscess is infection of the anal glands, but sometimes trauma or chronic illnesses (such as diabetes mellitus, Crohn disease, hidradenitis suppurativa, and rectal
carcinoma) predispose to its development.1
ECTHYMA GANGRENOSUM
Ecthyma gangrenosum is a cutaneous manifestation of
Pseudomonas aeruginosa in immunocompromised patients,
such as those with leukemia, severe burns, pancytopenia
or neutropenia, functional neutrophilic defect, terminal
carcinoma, or some other severe chronic disease. Healthy
infants may develop lesions in the perineal area after antibiotic therapy in conjunction with maceration of the diaper
area. Ecthyma gangrenosum usually develops because of
P. aeruginosa in the presence of bacteremia.
The clinical features are tender vesicles or pustules surrounded by narrow pink to violaceous halos. The lesions
become hemorrhagic and violaceous and rupture to become
round ulcers with necrotic black centers. The affected sites
are usually the buttocks and extremities, but sometimes
lesions can be seen in the anorectal region. The diagnosis
is usually made by the presence of the classic vesicle. The
contents of the vesicles will show gram-negative bacilli on
Gram stain, and cultures will be positive for P. aeruginosa.
Treatment is the immediate institution of intravenous
anti-Pseudomonas medications. Prognosis is poor if there is
a delay in diagnosis and institution of appropriate therapy
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279
TABLE 28.1: Urgent Dermatoses in the Anorectal
Region
Staphylococcal cellulitis
Streptococcal dermatitis/perianal cellulitis
Perianal abscess
Ecthyma gangrenosum
Necrotizing infections
and if the neutropenia has not been resolved by the end of
the course of antibiotics.3
NECROTIZING INFECTIONS (GANGRENOUS
CELLULITIS, INFECTIOUS GANGRENE, CREPITANT
SOFT-TISSUE WOUNDS)
These infections are characteristically rapidly developing,
progressive, and accompanied by such constitutional symptoms as severe pain and tenderness, with changes in the skin
that progress to bulla formation and frank necrosis. The
process can be found in the superficial or deep fascia with
secondary changes in the overlying soft tissues. Palpation
of the lesions may reveal tenderness or gas in the area of
involvement.4
There are a number of overlapping severe gangrenous
and necrotizing diseases that may affect the anorectal
and perineal region. They can be recognized and treated
with appropriate therapy immediately as they are lifethreatening diseases. Classification of necrotizing infections is shown in Table 28.2.
NECROTIZING FASCIITIS
Necrotizing fasciitis is a life-threatening infection that is
characterized by necrosis of subcutaneous tissue and fascia.
Necrotizing fasciitis can be divided into two groups: type
1 necrotizing fasciitis and type 2 necrotizing fasciitis.
Type 1 necrotizing fasciitis is more common in the
anorectal region. This infection is generally caused by a
TABLE 28.2: Classification of Necrotizing Infections
1. Necrotizing fasciitis
• Streptococcal gangrene (Type 2 necrotizing fasciitis)
• Type 1 necrotizing fasciitis
• Synergistic necrotizing cellulitis
• Fournier gangrene
2. Clostridial soft-tissue infections
• Anaerobic cellulitis
• Anaerobic myonecrosis
• Spontaneous, nontraumatic anaerobic myonecrosis
3. Meleney progressive bacterial synergistic gangrene
4. Gangrenous cellulitis in the immunosuppressed patient
5. Localized areas of skin necrosis complicating conventional
cellulitis
Data adapted from (4).
FIGURE 28.1: Scar tissue after necrotizing fasciitis (Photo
courtesy of Lawrence Charles Parish, MD, Philadelphia, PA).
mix of facultative and anaerobic microbes, often found in
the subcutaneous tissues following surgery, bowel perforation secondary to neoplasm or diverticulitis, trauma, or
parenteral drug abuse. It often occurs in patients with diabetes mellitus or malnutrition.4
Type 1 necrotizing fasciitis most commonly occurs on
an extremity, abdominal wall, and (rarely) perineum. Clinically, it is difficult to distinguish from streptococcal gangrene, but the initial pace of the illness may be slower
than that of type 2 necrotizing fasciitis. The involved area
may be painful at first and then evolve with objective findings, such as swelling, erythema, warmth, and tenderness.
Within several days, the skin color becomes purple, bullae develop, and frank cutaneous gangrene is seen. At this
stage the involved area is no longer tender due to destruction of superficial nerves in the subcutaneous tissues (Figure 28.1). Crepitation is often present, especially in patients
with diabetes mellitus or if there are gas-forming anaerobes
present.4
Type 2 necrotizing fasciitis or streptococcal gangrene
is more common in the other regions of the body compared to the anorectal region. In this infection, group
A  hemolytic streptococci alone are isolated in approximately 20% of patients. In perineal cases, there are almost
always mixed infections. The major mechanisms of tissue destruction include deformation of erythrocytes and
endothelial cell damage leading to thrombus formation,
hemorrhage, and tissue necrosis. The combination of kinin
activation, coagulation, and fibrinolysis leads to a disseminated intravascular coagulation–like picture. The many
streptococcal enzymes such as hyaluronidase, streptolysins,
and streptokinases also play a major role.5
280 E MERGENCY D ERMATOLOGY
The infection usually develops after minor trauma or
surgery. Initially, a small region of cellulitis is present,
but it expands rapidly, becoming dusky with bulla and a
necrotic scar. Crepitation may be present, especially in
mixed infections. The patient is ill with fever and extensive pain. There may be possible changes in mental status.
The pain decreases as the disease progresses because the
neurons are destroyed.5
In the histopathologic examination of necrotizing fasciitis, there is massive destruction of the soft tissue and fascia
with thromboses and liquefaction. The muscle may be secondarily damaged.
The most important therapeutic approach is extensive
surgical debridement. A complete removal of necrotic tissue is required; incision and drainage only or local debridement is not effective. For systemic therapy, penicillin G, 30
million units daily for at least 10–14 days, is combined with
clindamycin 600 mg three times daily for 1–2 days because
of anaerobe infections. Intravenous immunoglobulin is also
recommended, as well as organ-specific supportive measures.5
FIGURE 28.2: Fournier gangrene (Photo courtesy of Lawrence
Charles Parish, MD, Philadelphia, PA).
Fournier Gangrene
Fournier gangrene is a localized variant of necrotizing fasciitis that is seen in the genitalia and perineum. Necrotizing gangrene of the genitalia and perineum is a fulminate,
life-threatening infection. In 1883, Fournier described this
condition in five patients. Since then, approximately 500
cases have been published. Infections may be idiopathic
or secondary to local trauma or surgery and are usually polymicrobial. The organisms isolated include gramnegative bacilli, gram-positive cocci, and anaerobes.6
Fournier gangrene is 2 or 3 times more frequent in
men than in women, and the average age of patients is
38–44 years. It is rare in children; cases after neonatal circumcision, however, have been observed. In men, infection typically affects the scrotum, occasionally invades the
penis, and less frequently spreads to the perineum and
abdomen. The muscles and testes are usually spared. In
women, infection tends to involve both the vulva and the
perineum.6
The true incidence of the infection is uncertain,
although it seems to be higher in Asia and Africa. It is also
more common in immunocompromised hosts, with diabetes mellitus, cancer, vascular disease, or neutropenia, as
well as in human immunodeficiency virus–positive patients,
alcoholics, and transplant recipients. In several series, 20%–
40% of patients were diabetic and 35% were alcoholics.6
The onset of Fournier gangrene can be insidious, with a
discrete area of edema, erythema, and necrosis on the scrotum, progressing to advancing skin necrosis rapidly over 1–
2 days. Pain, swelling, and crepitation in the scrotum, perineum, or suprapubic region may be marked. Foul-smelling
drainage occurs, indicating a contribution from anaerobes.
Purplish discoloration of the scrotum and perineum, an
initial “red flag,” progresses to frank gangrene. The infection tends to be superficial, limited to skin and subcutaneous tissue and extending to the base of scrotum, but it
may spread to the penis, perineum, and abdominal wall
along fascial planes (Figure 28.2).2,6
Histologically, Fournier gangrene is characterized by
obliterative endarteritis and thrombosis of the subcutaneous vessels, fascial necrosis, and leukocyte infiltration.
Although necrotizing gangrene of the genitalia and perineum is a clinical diagnosis, a biopsy showing necrosis,
abscess formation, and vascular thrombosis is useful to confirm the disease and to obtain culture samples. Ultrasound
imaging may reveal gas or testicular involvement and may
help to identify Clostridium as the causal organism.6
Mortality rates of 25%–75% have been reported. Lower
mortality rates of 0%–40% have been reported by others,
possibly because of modern supportive measures.6
SYNERGISTIC NECROTIZING CELLULITIS
(NECROTIZING CUTANEOUS MYOSITIS,
SYNERGISTIC NONCLOSTRIDIAL ANAEROBIC
MYONECROSIS)
This variant of necrotizing fasciitis is unique in that all
soft-tissue structures, including muscle, can be involved in
a painful, progressive, and polymicrobial infection that is
highly lethal. This infection generally occurs in patients
who are elderly, obese, or wasted, and have chronic illnesses, such as diabetes mellitus or various renal or cardiac
diseases. The disease begins with a slow pain. Individuals are often afebrile or have only a low-grade fever, lacking systemic toxicity in the early stages. The initial skin
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281
ological studies confirm that this infection is usually associated with a microaerophilic Streptococcus or anaerobic Streptococcus at the advancing margin and S. aureus in the central,
ulcerated area.2
This infection typically is seen in a drain site following
an abdominal operation, in an incision in the chest wall
following abdominal or thoracic infection, at the exit site
of a fistulous tract, or in a chronic ulcer. Rarely, it may be
seen in the perineum.2
The process usually begins with local redness, tenderness, and swelling that develops into a painful, superficial enlarging shaggy ulcer. Three zones of involvement
become apparent: a central area of necrosis; a surrounding
zone of violaceous, tender, edematous tissue with necrotic
margins; and an outer zone of bright erythema and edema
(Figure 28.3). Fever and systemic toxicity are minimal or
absent. The process progressively enlarges if it is not treated
with appropriate therapy as soon as possible. Treatment
includes excision of the shaggy ulcer and necrotic margins
and appropriate antimicrobials, guided by Gram stains and
cultures.2
FIGURE 28.3: Synergistic gangrene, following drainage of perianal abscess. (Photo courtesy of Hasan Kalafat, MD, Istanbul,
Turkey.)
lesion is a small area of necrosis or a reddish-brown blister with extreme local tenderness. Then a foul-smelling
draining ulcer that rapidly expands is seen. Gram stain of
the drainage reveals both gram-positive and gram-negative
organisms and rare or absent neutrophils. Extensive gangrene of the superficial tissues and fat can be visualized by
direct inspection through open areas or with skin incisions.
Gas can be palpated in the tissues in approximately one
quarter of patients. Organisms frequently isolated include
anaerobes and facultative bacteria.2,5,7
The most common site of involvement is the perineum. The major predisposing factors are perirectal and
ischiorectal abscesses. Treatment is similar to that for
group A  hemolytic streptococcal necrotizing fasciitis,
except that the antibiotic regimen must be adjusted to the
culture results.2,5,7
PROGRESSIVE BACTERIAL SYNERGISTIC
GANGRENE (MELENEY GANGRENE)
The name, synergistic gangrene, was coined by Meleney in
the 1930s, based on studies done in vivo in rabbits. Microbi-
REFERENCES
1. Bunker CB, Neill SM. The genital, perianal and umbilical
regions. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s textbook of dermatology. Vol. 4, 7th ed. Oxford:
Blackwell; 2004. pp. 68.1–68.104.
2. Odom RB, James WD, Berger TG, editors. Andrews’ diseases
of the skin clinical dermatology. Philadelphia: WB Saunders;
2000. pp. 307–57.
3. Matz H, Orion E, Wolf R. Bacterial infections: uncommon
presentations. Clin Dermatol. 2005; 23:503–8.
4. Weinberg AN, Swartz MN, Tsao H, Johnson RS. Softtissue infections: erysipelas, cellulitis, gangrenous cellulitis,
and myonecrosis. In: Freedberg IM, Eisen AZ, Wolff K,
Austen KF, Goldsmith LA, Katz SI, editors. Fitzpatrick’s dermatology in general medicine. 6th ed. New York: McGrawHill; 2003. pp. 1883–95.
5. Braun-Falco O, Plewig G, Wolff HH, Burgdorf WHC, editors. Dermatology. 2nd ed. Munich: Springer; 2000. pp. 128–
244.
6. Cabrera H, Skoczdopole L, Marini M, et al. Necrotizing gangrene of the genitalia and perineum. Int J Dermatol. 2002;
41:847–51.
7. Bostancı S. Acil cerrahi tedavi gerektiren dermatozlar. Türk
Klin J Surg Med Sci. 2006; 2:74–80.
CHAPTER 29
Emergency Management of Sexually
Transmitted Diseases and Other
Genitourethral Disorders
Michael Waugh
THIS CHAPTER is based on practical clinical experience of the author in the management of sexually transmitted diseases since 1969 in the United Kingdom (UK).
In the UK, genitourinary medicine (sexually transmitted
infections [STI] covers human immunodeficiency virus/
acquired immune deficiency syndrome (HIV/AIDS) as well
as does sexually transmitted diseases (STDs). It is a separate specialty and requires very considerable postgraduate
study in all aspects of sexual health. Although emergencies in the acute internal or medical sense are rare, rapid
and astute clinical management of many of the conditions
encountered is necessary.
Patients are usually concerned when they think that
they might have contracted an STD. Accurate diagnosis is
needed so that necessary medication (whether it be antimicrobial, antifungal, or antiviral) may be given. Fast diagnosis is needed to abort infection, wherever possible, and
to prevent immediate and long-term consequences to the
patient. When an STI has been contracted, it is imperative
that an easily understood explanation and education also
be given to the patient with the reasons given why contact
tracing (partner notification) must be pursued for sexual
contacts. Follow-up is necessary not only to make sure that
any immediate infection or infections are cured, but also to
make sure that adequate care is taken to test for infections
such as syphilis and HIV, which may well require testing
not only on immediate presentation but also 1 month and
3 months after initial presentation. It is essential under any
public health and legal system to maintain confidentiality
of the patient and to explain, if necessary, to the patient
what that means.
Many patients will nowadays use resources on the Internet to gain information. This method is frequent, and the
good physician will work with that system and help the
patient to enhance his or her knowledge rather than decrying Internet information. In the UK, the Department of
Health has recognized the importance of early access to
STD services and has set a goal that any patient should
be offered an appointment within 48 hours of contracting
the service, which must have well-publicized easy accessibility.1
NON-STD CONDITIONS
Conditions that are not STDs but that may present to
venereologists and must never be missed include the following items.
Torsion of the Testicle
Torsion of the testis is not a common condition. The author
has only seen one case presenting in almost 50 years in
practice. It occurs with equal frequency in incompletely
and fully descended testes. Taking into consideration that
incomplete descent is present in less than 1% of men, it
is obvious that torsion of an incompletely descended testis
occurs relatively more frequently than that of a completely
descended testis. The highest incidence is in men between
15 and 25 years old, and the second most common incidence
is in infants.
The symptoms vary with the degree of torsion present.
Most commonly the patient experiences sudden and agonizing pain in the groin and lower abdomen and vomits.
In about one quarter of patients, the first symptom is a
dull ache in the loin or hypogastrium. It is insufficiently
appreciated that true testicular pain is situated in the lower
abdomen at the level of the internal inguinal ring. It might
be considered that the diagnosis is simple. It can be impossible to distinguish torsion of an imperfectly descended
testicle from a strangulated inguinal hernia until the parts
have been displayed by operation. Torsion of a completely
descended testicle is a less difficult problem; sometimes,
the actual twists in the cord can be felt thus establishing
the diagnosis.
Torsion of the testicle may stimulate an acute
epididymo-orchitis; after approximately 6 hours the skin of
the scrotum becomes reddened and the temperature may
be raised 37.2◦ C. Elevation of the scrotum usually relieves
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Emergency Management of Sexually Transmitted Diseases and Other Genitourethral Disorders 283
the pain in epididymitis but increases it in torsion.2 Scrotal
ultrasound is not a satisfactory way to make a diagnosis of
torsion of the testicle, and if mumps and an acute infectious epididymo-orchitis are excluded surgical exploration
should not be delayed by diagnostic imaging.3
Ectopic Pregnancy
Various degrees of pelvic inflammatory disease (PID),
caused mainly by Chlamydia trachomatis and Neisseria gonorrhoeae, but also by Mycoplasma hominis and anaerobes, are
frequently seen, but a condition in which there should be a
high index of suspicion is ectopic pregnancy.4
By definition, ectopic pregnancy refers to any nonintrauterine pregnancy. Although ectopic pregnancies may
be ovarian, cervical, or intraabdominal, the vast majority
are tubal, having an incidence of 1:200–400 pregnancies.
There may be a history of a previous ectopic pregnancy,
previous surgery, pelvic infection, endometriosis, or in vitro
fertilization, but approximately half occur with no predisposing cause.
Clinical Features. Clinical features range from no symptoms at all; to right, left, or bilateral lower abdominal pain;
bleeding per vagina; intraabdominal hemorrhage (peritonism and shoulder tip pain); and collapse. Pelvic examination
should be gentle to avoid tubal rupture. An ultrasound
investigation is often useful. It should be noted that a gestational sac may be confused with a pseudosac (due to fluid
in the thickened endometrium), which is seen in 20% of
ectopic pregnancies and which lacks the echogenic ring of
a gestational sac. A true sac is usually smooth with a double
rim, is eccentrically placed, and may contain a yolk sac.
Management. Immediate referral for acute emergency
gynecological assessment is essential. The management of
shock and the setting up of two intravenous (IV) lines is
urgent as is the setting up and patient cross-matching for 6
units of red cell concentrate.
PARAPHIMOSIS
Although this condition has none of the serious consequences of the previous two conditions, it is not infrequently seen turning up in young men attending STD
clinics, especially in countries where men are uncircumcised. The tight prepuce has been retracted but cannot be
returned, and it is constricting the glans, which is engorged
and edematous. The patient is usually frightened. The diagnosis is apparent at a glance.
The surgical textbooks recommend injection of normal saline containing 150 turbidity units of hyalurodinase
injected into each lateral aspect of the swollen ring of the
prepuce. Usually, within 15 minutes the swelling is much
reduced; this is, however, not always available. Soaking
the swollen parts in ice water for the same amount of time
and giving the patient 5 mg of diazepam while lying down
usually allows the doctor to reduce the paraphimosis by
bilateral gentle pressure of the thumbs on the glans while
holding firmly but not painfully the prepuce proximal to
the paraphimosis. The paraphimosis disappears. If that is
impossible, or if the paraphimosis has been there too long or
the patient will not relax, a urologist needs to be consulted
for reduction under anesthetia and later circumcision.
SQUAMOUS CELL CARCINOMA OF THE PENIS
Although rare, this is a condition that must not be missed;
it is a serious cancer with a high mortality. In STD clinics
for men, one or two cases will turn up annually, usually
in older men, often having noticed something wrong for
some length of time but for one reason or another not having sought help from a doctor. Risk factors include being
uncircumcised, smoking, and having contact with carcinogens such as oil, tar, and/or arsenic. There is a link with the
human papillomavirus, and the condition may be found
after phototherapy for psoriasis. I have seen it in three
patients followed up for more than 20 years for lichen sclerosus et atrophicus (LSA). It accounts for approximately
0.5% male malignancies in western countries.
Symptoms often have been present for many years.
Patients complain of itching, bleeding, irritation, and foreskin problems such as tethering and phimosis. Tumors may
involve the glans penis in approximately 50% and prepuce
in 20%, and in some patients both glans and prepuce are
affected. There may be small nodules, nonhealing areas,
and ulceration as well as phimosis and LSA. Palpable lymph
nodes may be the first place for metastases. Referral to a
urologist and specialist treatment center is needed. Diagnosis is by biopsy. Treatment is resection followed by radiotherapy and chemotherapy. Prognosis is poor.5
STDS
Although only a few complications of STDs could be considered to be emergencies, symptoms and signs suggestive of an STD should always be taken seriously. Accurate
history taking and diagnosis or multiple diagnoses are necessary both for the purposes of effective therapy and appropriate partner notification (contact tracing), with follow-up
to make sure the patient has been adequately cured. As
the condition is infective, there is all the more reason why
good diagnosis and treatment as a public health measure
are imperatives. In many localities, there are also civil regulations that differ from country to country on treatment
of STDs, aspects concerning confidentiality, their notification to public health authorities, and their situation within
the legal framework of that country.
Here concise guidelines are given for management
of gonorrhea, genital tract infection with C. trachomatis,
284 E MERGENCY D ERMATOLOGY
FIGURE 29.1: Urethral gonorrhea.
herpes genitalis, and syphilis, which may all have emergency elements in their presentations. These guidelines will
generally follow those of the Clinical Effectiveness Group
of British Association for Sexual Health.
Gonorrhea
Gonorrhea is an STD resulting from infection with N. gonorrhoeae, a gram-negative diplococcus. The primary sites of
infection are the mucous membranes of the urethra (Figure 29.1), endocervix (Figure 29.2), rectum (Figure 29.3),
pharynx (Figure 29.4), and conjunctiva. Transmission is by
direct inoculation of infected secretions from one mucous
membrane to another.6
In men, 80% have a mucopurulent urethral discharge
and approximately 50% have dysuria if the urethra is
infected. Most specialists will be only too aware of the man
with acute gonorrhea entering the consulting room with
a yellowish catarrhal urethral discharge. In a few, asymptomatic infection may occur. Pharyngeal infection is usually
asymptomatic. Rectal infection in men who have sex with
men (MSM) may be asymptomatic, but approximately 20%
have anal discharge or perianal pain or discomfort.
In women, up to 50% with infection of the endocervix
have no symptoms. Up to 50% may also have an increased
vaginal discharge. If there is a degree of PID, lower abdominal pain may be found in up to 25%. Gonorrhea is also a rare
cause of intermenstrual bleeding or menorrhagia. Twelve
percent of women complain of dysuria but not frequency.
FIGURE 29.2: Purulent cervicitis in gonorrhea.
FIGURE 29.4: Pharyngeal gonorrhea after fellatio.
FIGURE 29.3: Anorectal gonorrhea.
Chapter 29
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Emergency Management of Sexually Transmitted Diseases and Other Genitourethral Disorders 285
Rectal infection may occur after anal sexual intercourse or
by spread from genital secretions. As with men, pharyngeal
infection is usually asymptomatic.
It is important to realize that N. gonorrhoeae may coexist with C. trachomatis, Trichomonas vaginalis, and Candida
albicans. If signs are present at all, up to 50% may have
an endocervical discharge, but there may be few positive
signs, the patient either presenting as a sexual partner of a
man infected or presenting for a genital diagnostic check.
Complications are transluminal spread of N. gonorrhoeae
from the urethra to involve the epididymis and prostate in
men (≤1%) and endometrium and pelvic organs (PID) in
women, probably less than 10%. Hematogenous dissemination may also occur from infected mucous membranes
(it is worth considering infection of the pharynx when
this occurs), resulting in skin lesions, arthralgia, arthritis, and tenosynovitis. Disseminated gonococcal infection
is uncommon, but in the 1960s outbreaks of gonococcal
dermatitis arthritis syndrome were seen.7
Gonococcal Infection of the Eye. In adults, this infection
is rare. It may occur from fomites but more likely as the
result of sex play. The conjunctiva is swollen, red, edematous, and painful, and pus is pouring out. The possibility
should always be considered that it was caught as a strain of
penicillinase-producing N. gonorrhoeae and adequate cultures taken. It responds rapidly to appropriate antibiotics,
and an ophthalmologic opinion should always be requested
to exclude corneal ulceration.
In children, this infection is usually caught in places with
poor hygiene, such as crowded tenements and refugee and
nomad camps, but of course it may be after sexual interference with that child. Its appearance will be similar to that
found in an adult.
Ophthalmia neonatorum in the UK is defined as a purulent discharge from the eyes of an infant within 21 days of
birth. It is now much more common in babies infected with
C. trachomatis than in those infected with N. gonorrhoea.
Diagnosis is made by identification of N. gonorrhoeae
from an infected site. Microscopy with visualization of
gram-negative diplococci is obviously the fastest way of
making a presumptive diagnosis in men with symptomatic
urethral gonorrhea, but in women microscopy from endocervical smears even with skilled technicians will pick up
only approximately half the cases. Thus, cultures are also
needed. Here again, specimens need to be adequately collected and selective culture medium containing antimicrobials are recommended to reduce contamination.8 Culture
tests help very much in diagnosis of gonorrhea from the
pharynx, cervix, and anorectal canal as well as the urethra,
and are the only way to monitor sensitivity and resistance
patterns to antimicrobials in gonorrhea.
Nucleic acid amplification tests (NAATs) and nucleic
acid hybridization tests are more sensitive than cultures
and can be used for screening urine samples and self-taken
vaginal swabs. Although probably adequate for pharyngeal and rectal specimens, long-term reliability still needs
to be completely proven. Confirmation, especially in
medical–legal cases, still requires adequate culture sampling. NAATs also do not show sensitivity patterns for
antimicrobials. Screening for coincident STDs should
always be performed in patients with gonorrhea.
Treatment. For 60 years since penicillin was first used, N.
gonorrhoeae has shown capacity to develop reduced sensitivity and resistance to many antimicrobials. For instance,
resistance to penicillin, tetracyclines, and ciprofloxacin is
common.9 Therapy should eliminate at least 95% of those
presenting in the local community.10
Generally, the following treatments will work unless
resistance has developed:
●
Ceftriaxone 250 mg intramuscularly in or after (IM),
●
Cefixime 400 mg orally with or after (PO),
●
Spectinomycin 2 g IM.
Azithromycin is not recommended for the treatment
of gonorrhea due to reports of developing resistance
to it.11
Co-Infection with C. trachomatis. Between 20% and
40% of men and women with gonorrhea will also be
infected with C. trachomatis, so often combined therapy for
both N. gonorrhoea and C. trachomatis is given at the same
time. Thus, for the latter, azithromycin 1 g PO or doxycycline 100 mg twice daily for 7 days is recommended. When
prescribing antibiotics, care should always be taken in pregnant women, patients with known antibiotic sensitivities or
allergies, patients who are taking other medications, and
(in the case of doxycycline) patients exposed to sunlight.
Sexual Partners. Partner notification is needed. It is a skill
that requires diplomacy, and the patient will often be helped
by a professional health adviser. Sexual partners should be
treated for gonorrhea, preferably after evaluation as for
STI.
Genital Tract Infection with C. trachomatis
This is the most common nonviral STD found in industrialized countries. It is thought that 5%–10% of sexually active women younger than 24 years and men in their
late teens and early twenties may be currently infected.12
Risk factors are being a young adult, having a new sexual partner in the last year, and lack of consistent use of
condoms. There has been a pattern of serial monogamy.
Although it usually causes a mild urethral discharge in men
with variable dysuria (Figure 29.5), there may be few adequate symptoms in some men, and it is frequently asymptomatic in women. In women, when there are symptoms,
286 E MERGENCY D ERMATOLOGY
be a proctitis with anal discharge and anorectal discomfort.
It is the complications that will cause the patient to seek
help as an emergency.
Pelvic Inflammatory Disease (PID)
PID results when infections ascend from the cervix or
vagina into the upper genital tract.13 It includes endometritis, salpingitis, tubo-ovarian abscesses, and pelvic peritonitis. The main causes are C. trachomatis and N. gonorrhoeae,
but M. hominis and anaerobes are also found. Even after
laparoscopy, no bacterial cause may still be found.
Lower abdominal pain is the most common symptom,
with increased vaginal discharge, irregular bleeding, deep
dyspareunia, and dysuria also present in some women. The
cervix may have a mucopurulent discharge with contact
bleeding, indicative of a cervicitis. Adnexal and cervical
motion tenderness on bimanual examination is the most
common sign, but pyrexia and a palpable adnexal mass may
also be present.
Diagnosis. Laparoscopy with microbiological specimens
from the upper and lower genital tracts is considered
the gold standard for diagnosis, but this is not always
available. If laparoscopy is not available, the presence of
lower abdominal pain, increased vaginal discharge, cervical motion, and adnexal tenderness on bimanual examination, together with confirmatory subsequent diagnosis
from swabs taken from the lower genital tract, will give a
diagnosis but only with a specificity of approximately 70%.
FIGURE 29.5: Chlamydial urethritis with molluscum contagiosum.
they are variable and may include postcoital or intermenstrual bleeding, lower abdominal pain, purulent vaginal discharge, mucopurulent cervicitis, and dysuria. Babies may be
infected from mothers via the birth process (Figure 29.6).
In men and women, after anal sexual intercourse there may
FIGURE 29.6: Chlamydial ophthalmia in an infant.
Treatment of PID. Prompt diagnosis and early treatment
should reduce the risk of tubal damage and should be started
before microbiology results are known. Regimens should
cover all bacterial causes and may need to be given IV for
the first few days.
A suitable regimen would be ceftriaxone 2 g IM plus
doxycycline 100 mg twice daily or ofloxacin 400 mg twice
daily plus metronidazole 400 mg twice daily for 14 days.
Appropriate analgesia should be given. Partner notification
is essential to prevent reinfection.
Other complications of genital C. trachomatis infection
include Fitz–Hugh–Curtis syndrome (perihepatitis), transmission to the neonate (neonatal conjunctivitis, pneumonia), epididymo-orchitis, adult conjunctivitis, and sexually
acquired reactive arthritis (SARA)/Reiter syndrome (more
common in men). Of the complications mentioned, both
epididymo-orchitis and SARA may present as emergencies
and are discussed here.
Epididymo-Orchitis. An acute epididymitis may occur in
older men (generally at least 35 years old) due to urinary tract infection usually caused by coliform organisms,
although age does not preclude sexual activity and sexually transmitted causes of epididymitis should always be
Chapter 29
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Emergency Management of Sexually Transmitted Diseases and Other Genitourethral Disorders 287
considered if there is an active sex life. In younger men
under age 35, more frequently C. trachomatis and less frequently N. gonorrhoeae are the cause, although urinary tract
infection, especially if there are underlying genital tract
anomalies, should be considered. Rarer causes, but those
still found in developing countries, are tuberculosis and
leprosy. Mumps, especially where there are many youngsters living closely together, also should be considered. The
differential diagnosis from torsion of the testicle has already
been described. There does need to be a planned approach
in centers where the symptomatic patient may well get to a
venereal disease clinic but the asymptomatic patient gets to
an urologist. Treatment includes excluding a urinary tract
infection, giving necessary analgesics and scrotal support,
and administering appropriate antibiotic therapy for either
N. gonorrhoeae or C. trachomatis (in the latter case doxycycline 100 mg twice daily for 14 days). Partner notification
for STD causes of epididymo-orchitis is a requisite.
If any group of young men presenting with epididymoorchitis is analyzed, annually, there will be one or two
who do not have an epididymo-orchitis but have, in fact, a
malignant tumor of the testicle. The skilled clinician usually develops a sixth sense, and a high index of suspicion
is needed for these cases when not presenting to an urologist. In my practice malignant tumors of the testicle are also
more common in men with HIV infection. The usual signs
of testicular cancer include a lump in the testicle, painless
swelling, or altered consistency of the testis; any of these
may be found on a medical examination. Ultrasound and
nuclear magnetic resonance help in the diagnosis, and the
patient needs to be seen rapidly by the appropriate team in
a center that has specialist knowledge of testicular tumor
management.
SARA/Reiter Syndrome. SARA/Reiter syndrome has
been included as an emergency, as it may well have an
insidious onset that can present to a variety of clinicians.
It is often missed in its early stages; in practice, less would
be seen if more often the early diagnosis of C. trachomatis
(often asymptomatic in young men) was considered and
appropriate therapy (best given as azithromycin 1 g PO)
was instituted. Missing SARA may have disastrous effects
in sportsmen with active sex lives when damages to the
hip, knee, ankle, and small joints of the foot, as well as
tenosynovitis, are short- and long-term side effects.
Circinate balanitis (Figure 29.7) may well occur a few
weeks before other major symptoms and should act as a trigger for the dermatologist to screen for STDs (especially C.
trachomatis) and to give appropriate antibiotic therapy with
doxycycline or azithromycin. As any mucosa may well be
affected, there is a need to look further than the genitals.
Conjunctivitis occurs in approximately 30% of cases in the
early stages as well as usually mild oral and buccal lesions
in early SARA. In chronic SARA obviously the well-known
classical signs of chronic arthritis, serious skin lesions, ker-
FIGURE 29.7: Circinate balanitis.
atoderma blenorrrhagica, onycholysis, and eye complications (such as an anterior uveitis) are all known but are not
part of emergency presentation. The condition is far from
common in women, but a vulvitis may occasionally present.
When considering the consequences and the differential
diagnosis of C. trachomatis genital infection, it is necessary
to consider the much more common and very frequently
seen uncomplicated C. trachomatis genital infection.
Diagnosis and Treatment of C. trachomatis Genital
Infection. Diagnostic tests are changing rapidly for C. trachomatis.13 The tests for standard of care are NAATs. These
are more sensitive and specific than enzyme immunoassays
(EIAs). Suboptimal EIAs are no longer appropriate. No
test, be it NAAT or EIA, is 100% sensitive or specific. The
field of diagnosis changes so rapidly that ongoing specialist
advice should be considered by those whose main specialty
is not STDs.
It should be noted that, as yet, NAATs have not had
U.S. Food and Drug Administration approval for specimens from rectal, pharyngeal, and conjunctival specimens
288 E MERGENCY D ERMATOLOGY
hepatitis B and C – all of which should be investigated in
this group of patients.
Treatment of Uncomplicated Genital C. Trachomatis
Infection. Recommended treatment includes doxycycline
100 mg twice daily for 7 days, ofloxacin 200 mg twice a day
for 7 days, or azithromycin 1 g PO, the latter being recommended by the World Health Organisation for pregnant women but not completely passed as being safe by all
national health agencies, although it probably is.
In my own clinical practice, I have found azithromycin,
although more expensive than doxycycline, much more
acceptable for young adults. It needs to be taken only once,
and, provided the partner is treated at the same time, a
sex life will be started faster and safer without the risk of
recurrent infection in one or the other (as may happen with
doxycycline, where a week seems an incredibly long time
for the eager young man to avoid sex).
Herpes Genitalis
As this condition is so often not only painful but comes as
a most unpleasant shock to self-esteem in a world where
young people are so media aware, it is the STD that most
often gets the venereologist called outside his normal working day (Figures 29.8 and 29.9). Over the years it is often
the parent of young persons who has realized that they are
suffering from genital herpes who calls so often at weekends
and public holidays.
FIGURE 29.8: Painful ulcer on penis, syphilis excluded, but herpes simplex virus type 2 isolated.
in men or women; in the absence of culture tests, however,
NAATs are usually taken from these sites. In Europe, in
the last 5 years rectal lymphogranuloma venereum (LGV)
has been seen not infrequently in MSM, and British guidelines recommend that when a rectal NAAT is found to be
positive, it is sent for further testing for LGV typing to the
appropriate laboratory. Rectal LGV was in recent years
first seen in The Netherlands occurring in MSM who had
passive anal sex without the use of a condom for protection against STIs. Since then, it has been found in MSM
throughout Western Europe. The most common sign is a
proctitis that may be not only purulent but bloody. There
may be considerable alteration of bowel habits, perhaps
being mistaken for irritable bowel syndrome, ulcerative
colitis, or Crohn disease. There may be a fever, a general
feeling of malaise, and inguinal regional lymphadenopathy. In contrast, there may be few symptoms. As would be
expected, it may be found with other STIs in this region –
namely, syphilis, rectal gonorrhea, anorectal herpetic
infection, anal condyloma acuminata, HIV infection, and
Etiology. The two forms are herpes simplex virus type 1
(HSV-1), the usual cause of orolabial herpes and herpes
simplex virus type 2 (HSV-2).
Natural History: What Do We Know about Herpes
Genitalis? Infection may be primary or nonprimary. Disease episodes may be initial or recurrent and symptomatic
or asymptomatic. Prior infection with HSV-1 modifies the
clinical manifestations of first infection by HSV-2. After
FIGURE 29.9: Acute herpes genitalis in a woman.
Chapter 29
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Emergency Management of Sexually Transmitted Diseases and Other Genitourethral Disorders 289
childhood, symptomatic primary infection with HSV-1
is equally likely to be acquired in the genital or oral
areas.
Following primary infection, the virus becomes latent
in local sensory ganglia, periodically reactivating to cause
symptomatic lesions or asymptomatic (but infectious) viral
shedding.
New diagnoses of genital herpes are equally likely to
be caused by HSV-1 or HSV-2; the median recurrence
rate, after a symptomatic first episode, however, is 0.34
recurrences per month for HSV-2 and 0.08 recurrences per
month for HSV-1.14 Recurrence rates decline over time in
most individuals, although the pattern is variable.
The majority of individuals found to have asymptomatic HSV-2 infections subsequently develop symptomatic lesions. Asymptomatic perianal HSV shedding in
HIV-negative HSV-2–seropositive MSM is common.15
In HIV HSV-2–seropositive men, both symptomatic and
asymptomatic shedding are increased, especially in men
with low CD4 counts and in men who are also seropositive for HSV-1.16
As most modern information is available on the Internet,
no wonder patients, their families, and friends get upset,
when herpes genitalis is considered. So what are the clinical features, including ones that could be considered an
emergency? In both sexes, there is painful genital ulceration
often with local dysuria and urethral or vaginal discharge.
There may be fever and myalgia. Unpleasant symptoms
are more common in primary infection. Some patients are
asymptomatic. Genital ulceration begins with an itchy vesicle that breaks down to form a shallow superficial painful
ulcer, often in groups, on the genitals or cervix or in the
anorectal canal (often very painful indeed). Complications
include autonomic neuropathy resulting in retention of
urine and aseptic meningitis.
Confirmation of Diagnosis. It is necessary but often difficult to isolate HSV from genital lesions. Successful diagnosis depends on using swabs taken directly from the base of
the lesion, maintaining the cold chain (4◦ C), rapidly transporting specimens to the laboratory, and avoiding freeze–
thaw cycles.
Serology. Most commercial tests for HSV antibodies are
not type specific and are of no value in the management
of genital herpes. Type-specific EIAs based on glycoprotein G (gG1, gG2) or western blot assays are becoming available. Type-specific immune responses can take
8–12 weeks to develop following primary infection. It is
now becoming possible for serological evaluation of genital herpes, but that needs access to both HSV-1 and
HSV-2 type-specific assays. Caution is needed in interpreting results because even highly sensitive and specific assays have poor predictive values in low-prevalence
populations.
The clinical utility of these tests has not been fully
assessed. Virus detection remains the method of choice,
but the tests may be useful for the following conditions:
●
Recurrent genital ulceration of unknown cause;
●
Counselling patients with initial episodes of disease;
●
Investigating asymptomatic partners of patients with
genital herpes; and
●
Evaluating genital herpes in pregnancy.
The Management of Genital Herpes and
Its Complications
First Episode of Genital Herpes. The faster oral antiviral drugs are given preferably within hours of lesions forming. Acyclovir, valacyclovir, and famcyclovir all reduce
the severity and duration of episodes. The availability of
these drugs depends on local conditions. Manufacturers’
recommendations regarding dosage should be followed.
Antiviral therapy does not alter the natural history of the
disease. Topical agents are less effective than oral ones. IV
therapy is only indicated when the patient cannot swallow
or tolerate oral medication because of vomiting. In addition, local bathing with normal saline solution and analgesia helps. Some clinicians recommend topical anesthetic
agents, but then there is the danger of potential sensitization.
Regimens recommended for adults (all for 5 days) are
acyclovir 200 mg five times a day; famciclovir 250 mg three
times a day, or valacyclovir 500 mg twice daily.
Management of Complications. Hospitalization may
be needed for urinary retention, meningism, and severe
constitutional symptoms. If catheterization is needed,
suprapubic catheterization is preferred because it prevents
the risk of ascending infection and allows normal micturition to be restored without multiple removals and
recatheterizations. Always, however, try sitting the patient
in a warm bath and allowing him or her to try to pass urine
in it before catheterization is attempted. It often works.
HIV-Positive Patients. In the early days of HIV,
especially when dealing with gay men before the advent
of highly active antiretroviral therapy (HAART), when
often enormous painful and distressing perianal herpes was
found, resistance of HSV to antivirals was found. With
HAART, however, this condition is far less frequently seen.
Recurrent Genital Herpes. Although causing much
personal distress to some patients, genital herpes cannot
really be considered as an emergency. Most recurrences are
self-limiting, but a good doctor–patient relationship can be
supportive for the patient. Strategies for treatment include
general support, treatment with antivirals episodically, and
suppressive therapy. All of these management techniques
need working out for each individual patient.
290 E MERGENCY D ERMATOLOGY
Management of Genital Herpes in Pregnancy.
Guidelines for genital herpes in pregnancy are categorized
into management of first episodes and recurrent episodes.
Accurate clinical classification is difficult. Viral isolation
and typing and the testing of paired sera (if a booking specimen is available) may be helpful. There are guidelines for
management depending on when genital herpes was first
acquired and in what trimester.17 Basically, all guidelines
suggest continuous acyclovir in the last 4 weeks of pregnancy and an elective Caesarean section despite lack of evidence for its effectiveness. The risks of vaginal delivery for
the fetus are small and must be set against the risks to the
mother of Caesarean section.18
Syphilis
In this section, some of the pitfalls (mistakes) in making
a diagnosis and some of the side effects that may occur
in treatment are discussed. There are several good descriptions of syphilis in many dermatology and venereology textbooks that can be used for reference.
It was once said, “Always consider syphilis” (Sir William
Osler, 1909). That may well be almost as true now, but also
add on HIV infection. There are three main reasons why
syphilis is missed:
1) The patient does not know about it or fails to ask for
medical advice;
2) the clinician (and this is far more serious) does not consider it in his differential diagnosis; and
3) public health authorities do not stress its importance.
For the last 20 years the focus has been on HIV disease
as the number one STI to consider.
Like much of medicine, a good history will consider
syphilis. Always take a sexual history in a quiet place out of
the earshot of others. Let the patient know that you will
keep confidences and be discreet. Do not show any surprise at what you are told; all things human are within the
knowledge of a good clinician. Be candid and ask if the
patient is not forthcoming about his or her sexual practices. Start with simple questions, such as “Was a condom used?” If the patient is a man, find out if he had sex
with another man, a woman, or both sexes (if that has not
already been proffered). There has been a rise in homosexually (Figure 29.10) contracted early primary and secondary
syphilis in MSM in Europe, North America, and parts of
East Asia recently, often with HIV infection and pharyngeal and rectal gonorrhea. Early syphilis remains common
in Eastern Europe in heterosexuals and has been seen in
pockets all over Western Europe, often in groups related
to street drugs and/or prostitution (where sex workers are
brought in from Eastern Europe). Syphilis is no respecter
of social position, and perhaps the more money a person
has the easier it is to travel and meet others for sexual purposes. Always consider any genital sore to be syphilis until
proven otherwise (herpes genitalis is much more common),
FIGURE 29.10: Anal chancre.
and always consider syphilis in the differential diagnosis
of eruptions. Remember that most dermatology textbooks
in industrialized countries have used as photographs white
skins; presentation in brown, yellow, or black skins may
look different. The eruption may last for weeks but may be
fleeting and disappear before the patient has had a chance
to see a physician if the appointment is delayed. Remember
that the patient with secondary syphilis may feel unwell, be
running a fever, or even be jaundiced. Secondary syphilis
(Figure 29.11 and 29.12) may present with many different signs, some of them rare: meningism, uveitis, deafness,
arthralgia, periostitis, as well as skin signs easily missed such
as alopecia, snail track ulcers (buccal mucosal patches), and
condyloma lata around the mouth, axillae, inguinal regions,
and anus and toe webs. Generally, unless the patient is
severely immunocompromised standard serological tests
for syphilis will be reactive in secondary syphilis.
The Diagnosis of Primary Syphilis. The ulcer (chancre)
is said to be painless with rolled indurated edges but,
like many classical descriptions, this is not always so. If
the patient has applied antiseptic lotion or cream or has
Chapter 29
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Emergency Management of Sexually Transmitted Diseases and Other Genitourethral Disorders 291
way of making a fast diagnosis, but it requires skill and much
practice and is time consuming. Serological tests for syphilis
need to be performed. If there is any doubt about syphilis,
they need to be repeated at 1 month and 3 months. The
initial test is likely to be an EIA; if reactive, the Venereal
Disease Research Laboratory test or rapid plasma regain
test, T. pallidum hemagglutination test, and fluorescent treponemal antibody absorption (FTA-ABS) test should be
performed. It has to be remembered that, in the early stages
of syphilis, there may be only T. pallidum seen on dark-field
microscopy. One of the first blood tests to become reactive
is FTA-ABS at about 2 weeks.
Remember that it may be difficult to tell if the patient
has had either syphilis or a nonvenereal treponematosis
(such as yaws or pinta) treated in the past, whether or not
serological tests refer to the present or past infection. If in
doubt, it is best to treat again.
FIGURE 29.11: Secondary syphilis.
taken an antibiotic such as penicillin, tetracycline, or erythromycin prior to being seen, dark-field examination for
Treponema pallidum is a waste of time as it will not be found.
Dark-field examination for T. pallidum by a skilled observer
when the chancre has not been modified is still an effective
Treatment. In parts of the world where there are good
public health facilities staffed by specialists for the treatment of STDs, syphilis is best treated in such facilities; in
other parts of the world, however, the dermatovenereologist will be responsible for treatment.
For early syphilis that is primary, secondary, or early
latent, the following treatment is recommended: either
benzathine benzylpenicillin 2.4 million units IM or procaine penicillin 0.6 million units IM daily for 10 days. If the
patient is allergic to penicillin, doxycycline 100 mg twice
daily for 14 days is recommended. The patient should be
seen after a week to make sure that he or she is taking
prescribed medication. T. pallidum is highly susceptible to
penicillin – not requiring a high level, but rather a prolonged level of penicillin in tissues for it to be bactericidal,
as penicillin only acts on dividing cells. Studies on doxycycline, tetracycline, erythromycin, azithromycin, and ceftriaxone all show efficacy in syphilis, but often the trials
have been in the past and not conducted to modern criteria.
There have also been reports of resistance to azithromycin,
so it can not be recommended.
ANTIBIOTIC THERAPY AND SIDE EFFECTS
Acute Anaphylaxis after Treatment with Penicillin
This side effect is rare, and no patient should be given penicillin if there is any history of allergy to it. Desensitization
takes time and is inappropriate in a busy clinic. Staff should
be trained in resuscitation, and there should be the drugs
and equipment present to give emergency treatment for
acute anaphylaxis as well as the ability to summon immediate aid from resuscitation emergency services.
Jarisch–Herxheimer Reaction
FIGURE 29.12: Secondary syphilis, palms
This reaction occurs in more than half of patients when
penicillin is given for early treatment of syphilis. Within
292 E MERGENCY D ERMATOLOGY
8 hours of an injection, the patient notices a febrile illness
with malaise, headache, chills, and rigors. It clears quickly,
but the patient should be told about it beforehand that it is
not an allergic reaction. It is thought to be due to release
of lymphokines including tumor necrosis factor and interleukins. In late syphilis, although rare, it may be potentially
life threatening, so steroid cover is given for 3 days before
treatment.
Procaine Reaction
This reaction will become rarer the more often benzathine
benzylpenicillin is used instead of procaine penicillin. It is
more common in men and is a sort of anaphylactoid reaction. The patient experiences auditory symptoms, a fear of
impending death, seizures, and a violent behavioral reaction. It is thought to be due to inadvertent IV administration. It is much less common than it was 40 years ago when
procaine penicillin was the treatment for gonorrhea. Most
of the patients recovered without any therapy, although it
usually needed all the clinic staff to hold the patients down
in their struggles.
Stevens–Johnson Syndrome
Again, this has become infrequent in the treatment of
STDs, because the use of sulfonamides (especially the longacting ones) and cotrimoxazole has declined in the day-today treatment of conditions presenting in clinics. It is still
seen, however, in the treatment of HIV disease after the
use of non-nucleoside reverse transcriptase inhibitors such
as nevirapine.
REFERENCES
1. British Association for Sexual Health and HIV: Department of Health. Genito-Urinary Medicine Clinics and the 48
hour Access Target. London: Department of Health, 2007.
Gateway ref: 8930 [cited 2008 April 26]. Available from:
http://www.bashh.org/whatsnew.asp
2. Bailey H. The testes and scrotum. In: Bailey H, Love McNeill,
editors. A short practice of surgery. 12th ed. London: H.K.
Lewis; 1962. pp. 1266–96.
3. Robertson DHH, McMillan A, Young H. Clinical practice in
sexually transmitted diseases, 2nd ed. Edinburgh: Churchill
Livingstone; 1989. pp. 244–53.
4. Drife J, Magowan BA. Clinical obstetrics and gynaecology.
Edinburgh: W.B. Saunders Ltd.; 2004. pp. 171–3.
5. Shah M, De Silva A. The male genitalia: a clinician’s guide
to skin problems and sexually transmitted infections. Oxford:
Radcliffe Publishing; 2008. pp. 60–2.
6. British Association for Sexual Health and HIV. National
guideline on the diagnosis and treatment of gonorrhoea in
adults 2005 [cited 2008 April 26]. Available from: http://
www.bashh.org
7. Ackerman AB, Miller RC, Shapiro L. Gonococcemia and its
cutaneous manifestations. Arch Dermatol. 1965; 91:227–32.
8. Jephcott AE. Microbiological diagnosis of gonorrhoea. Genitourin Med. 1997; 73:245–52.
9. Health Protection Agency (HPA). GRASP (The Gonococcal Resistance to Antimicrobials Surveillance Programme) – Annual Report 2004. London: Health Protection
Agency, August 2005 [cited 2008 April 26]. Available from:
http://www.hpa.org.uk/infections/topics az/hiv and ati/stigonorrhoea/publications/ GRASP 2004 Annual Report.pdf
10. FitzGerald M, Bedford C. National standards for the management of gonorrhoea. Int J STD AIDS. 1996; 7:298–
300.
11. Tapsall JW, Schultz TR, Limnios EA, et al. Failure of
azithromycin therapy in gonorrhoea and discorrelation with
laboratory parameters. Sex Trans Dis. 1998; 25:505–8.
12. Fenton KA, Korovessis C, Johnson AM, et al. Sexual
behaviour in Britain: reported sexually transmitted infections and prevalent genital Chlamydia trachomatis infection.
Lancet. 2001; 358:1851–4.
13. Drife J, Magowan BA. Clinical obstetrics and gynaecology.
Edinburgh: W.B. Saunders Ltd.; 2004. pp. 198–200.
14. British Association for Sexual Health and HIV. 2006 UK
national guideline for the management of genital tract infection with chlamydia trachomatis [cited 2008 April 26]. Available from: http://www.bashh.org
15. Krone MR, Wald A, Tabet SR, et al. Herpes simplex virus type
2 shedding in human immunodeficiency virus-negative men
who have sex with men; frequency, patterns and risk factors.
Clin Infect Dis. 2000; 30:261–7.
16. Schaker T, Zeh J, Hu HL, et al. Frequency of symptomatic
and asymptomatic herpes simplex virus type 2 reactivations
among human immunodeficiency virus-infected men. J Infect
Dis. 1998; 121:847–54.
17. British Association for Sexual Health and HIV. 2001 National
guidelines for the management of genital herpes [cited 2008
April 26]. Available from: http://www.bashh.org
18. Mindel A, Taylor J, Tideman RL, et al. Neonatal herpes prevention: a minor public health problem in some communities.
Sex Transm Infect. 2000; 76:287–91.
CHAPTER 30
Emergency Management of Environmental
Skin Disorders: Heat, Cold, Ultraviolet
Light Injuries
Larry E. Millikan
ENVIRONMENTAL SKIN disorders usually are associated with ambient changes (heat, humidity, intensity of
ultraviolet [UV] solar rays) and new environments (ski
slopes, beaches, jungles/rainforests, and areas with exotic
animals unfamiliar to patients). Many of these new surroundings cause unique dermatologic reactions familiar to
natives who understand the need for avoidance but unfamiliar to others who must seek dermatologic care.
PROPER AND EARLY MANAGEMENT
Proper and early management of skin disorders due to environmental factors might avert the ruin of a long anticipated
trip or vacation. In some instances, the environmental exposure occurs at home before departure and then is manifested during travel to – or at – the destination. Such environmental exposures from contact allergens, toxins, and
infections or infestations can be delayed. As a result, clinical manifestations are delayed and may not appear until
several days after the return home. Likewise, the necessary therapy may be required in that wide window – the
so-called incubation period. The challenge of many of the
environmentally associated emergencies is to initiate therapy early, to achieve the best possible outcome, and, in some
infectious complications, to be able to institute the nowdelayed therapy to avoid great increases in morbidity and
mortality.
HEAT EMERGENCIES
These emergencies are largely associated with ecotourism
where the traveler is truly out in the environment – a
marked departure from the usual life in “civilization” with
its air-conditioned environment, dehumidification, and
general protection from extremes.1 These exposures, coupled with the “holiday” conditions of food and beverage
excess (i.e., alcohol), impair the body’s ability to maintain
homeostasis, and, in extremes, regulation of body core temperature is lost. The resultant elevation of core temperature
can reach a potentially fatal level. Immediate care may
be life saving. Simple measures – rehydration, cool water
immersion, ice packs, and limiting of activities – are essential. Newer approaches (electrolyte replacement fluids and
some drugs) reported in Olympic and world class sports
may be the prevention as well as treatment in the future.2
As these conditions are largely in primitive/remote areas,
where access to professional assistance is limited if available
at all, anticipation of heat stress is the primary step to avoid
the serious sequelae (coagulopathy, etc.).3 Obviously, these
scenarios are not the domain of the dermatologist, but one
should be aware of risk to encourage the patient to be alert
to the symptoms and seek care, should they appear.
UV LIGHT
Here again, the key is environmental change. Essentials
to anticipate include the enhanced UV exposure closer
to the tropics and the effect of altitude on intensity of
UV, especially with a pale, light-skinned traveler seeking
respite from winter. The temptation of the sun during the
long dark days is often too great, and careful planning and
prevention are ignored or forgotten. Lower latitudes and
higher altitudes are key to risk in the environment, as each
enhances the intensity. The higher altitudes have thinner
air filtering and less of the incoming sunlight, whereas the
nearer the equator, the greater the direct effect of the rays.
An essential key is education in the use of sunscreens
prior to departure and gradual increase of exposure to
induce melanin formation. In addition, the late Harry
Arnold who practiced for years in Hawaii was a proponent of planned/controlled tanning in his office prior to
exposure to avoid the chance of burning (personal communication). Others (including myself) use this approach in
certain selected cases (types 1 and 2 skin in particular).
Additionally, the present world of polypharmacy has
greatly expanded the list of photosensitizing drugs, particularly for hypertensive and/or diabetic patients. The prototype in the past has been the group of furocoumarins and
page 293
294 E MERGENCY D ERMATOLOGY
FIGURE 30.1: Phototoxic reaction to a topical antibiotic.
the sulfa-related drugs (Figure 30.1). Whereas the former
group were used therapeutically, the latter are omnipresent
in the treatment of infections, diabetes, and hypertension
(diuretics) (Figure 30.2). The traveler should be aware of
any drugs taken with such potential and use extra care. The
personal physician and the pharmacist should be the best
source for this information and obtain it before the patient
travels. It should be noted that many busy general practitioners may not have the most recent information, whereas
the pharmacist will have this information, usually on a computer program.4
Modern sunscreens are the real answer.5 New guidelines
for protection (sun protection factor [SPF]) are imminent
and long overdue, as a consensus on UVA protection is
essential for the informed and concerned consumer. The
significance of UVA grows as data accumulate in its role in
carcinogenesis, a far more insidious and significant “thief
in the night” because of its much less obvious impact without the “sunburn” that inspires caution with UVB.6 The
significance of UVA relates to its greater penetration into
the dermis (whereas UVB only penetrates superficially) and
the immunosuppression it can cause. This problem is not
emergent/acute but it is the cumulative exposure that is the
major cause/factor in the carcinogenesis. The acute problems are less associated with the risk for carcinogenesis; the
immediate discomfort is the primary reason for the need
for suncreens.
The early agents were effective protection but not aesthetically desirable and hence not well accepted. These
agents included Red Vet Pet (red veterinary petrolatum),
which had very good sunscreening properties and hence
was standard in water survival kits when I was a flight surgeon in the U.S. Navy. Sudden loss of your ship put you
on the open ocean in a life raft (if you were lucky) but often
exposed to intense sunlight and sunburn. In this scenario,
it could be life saving, and the greasy aspects of petrolatum
were not a great concern – much different than applying it
while on the sandy beach or by the pool. The total blockers such as titanium and zinc oxide have many, if the same,
problems and hence are used primarily in medical conditions of very severe photosensitivity.
The first chemicals other than physical sunscreens
such as para-aminobenzoic acid were primarily protective
against UVB (and the sunburn sequelae) as that was the
easiest to measure with SPF testing. Furthermore, it represented our best knowledge of the situation at the time.
Of course, important prevention from UVB sunburn is the
acute concern and would be key to avoid acute problems for
the traveler. Much of the literature on sunscreens to date
has dealt with UVB protection preventing sunburn, but it
now is appreciated that the deeper penetration of the UVA
rays into the dermis greatly enhances risk for carcinogenesis but poses a lesser risk for sunburn.
Newer agents such as avobenzone (Parsol 1789), one of
the first with UVA screening, are now preferred because of
broader spectrum A/B effect. They have greater acceptance
but, in all instances, need to be used expectantly to prevent
future acute episodes. This field is rapidly changing with
R
R
the newer agents Helioplex
,Tinosorb M
, and Mexoryl
R
XL , which are just a few examples of this growing field.
Even and repeat application is essential for protection, and
the effectiveness is seen in Figure 30.3. The irregular tanning attests to protection potential.
Total disregard for usual “sun sense” can produce an
emergency situation, especially when the results are nearsecond-degree burns, enhanced risk for infection, and significant morbidity. Acute treatment is instituted to prevent
usual burn complications, fluid loss, infection, and systemic
sequelae. Steroids may be of assistance in the first few hours,
and nonsteroidal antiinflammatory drugs may be helpful in
stopping the progression. These are primarily administered
orally, but some newer preparations and concentrations of
diclofenac gel are showing promise.7
CONTACT DERMATITIS
FIGURE 30.2: Sulfonamide-associated photoreaction.
There are several groups of plants causing type 4 reactions
that can be encountered, and most are widespread, if not
Chapter 30
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Emergency Management of Environmental Skin Disorders: Heat, Cold, Ultraviolet Light Injuries
295
FIGURE 30.4: Classical presentation of Rhus dermatitis.
FIGURE 30.3: Irregular pigmentation after uneven application
of a sunscreen.
worldwide, in distribution. The compositae group of plants
are the most widespread, but fortunately only few persons
have allergic potential, and these are ones with extensive
exposure, usually occupational, floriculture, and/or agriculture. The hallmark of the group is the daisy-like composite
flower; the group also includes some popular herbal sources
such as Echinacea. Even the common dandelion is in the
same group. It is a vast group found everywhere, so they are
difficult to avoid. The sesquiterpene lactones are the common antigens, and it has been recently documented with a
higher incidence in children (4.2%) and adolescents (2.6%),
primarily in those who are atopic.8 This allergy further
increases the risk, as atopic children are those with greatest
morbidity in tropical dermatology from impetiginization
and secondarily infected miliaria, seeming to double the
risk for such children in the tropics.
The Rhus/Toxicodendron group has a much higher
incidence of allergy but fortunately has a smaller range of
distribution. Norman Goldstein wrote a classical article in
Cutis documenting related plants that result in worldwide
exposure – the very sensitive subject commences extensive
travel, arrives in the tropics, and gets a perioral contact
dermatitis from eating mango. Then on to the Orient,
where dermatitis on the buttocks results from toilet seats
finished with lacquer (the related Japanese lacquer tree as
the source). In India, a dermatitis on the neck from laundry
ink in the collar (the Indian marking nut tree). The different
species have definite and limited range, but the oleoresin
cross-reacts, and sensitivity then can even be widespread.
Even cashews are related, but fortunately the usual processing inactivates the allergen.9 Although frequently presenting as simple vesicles in a linear display (Figure 30.4), this
allergen also can result in the most dramatic vesicular and
vesiculobullous reactions that can be widespread and are
a frequent site for impetiginization. This secondary infection is the most frequent reason for emergency care as it
progresses erysipelas and with certain nephritogenic streptococci symptomatic renal disease. As mentioned earlier
in this chapter, exposure to contact dermatitis can be initiated even before departure or while on the trip. Either
way, the morbidity can be such that it can nearly ruin the
vacation/trip.
Alstroemeria is a newer problem largely due to the popularity of the plants in the flower and greenhouse industry.
Although previously limited in range, the artificial nature
of growth in the trade has greatly increased the exposure for
persons in the business of floriculture. Previous sensitization and subsequent reexposure usually in the wild (primarily southern hemisphere) can give the same scenario as in
the preceding paragraph in the seriously allergic individual.
Primula sensitivity seems to be largely limited to the
United Kingdom, in gardeners, floriculturists, and so forth.
The limited range of this group of plant species in cooler
climes lessens the exposure to primulin and, furthermore,
the cool environment usually results in clothing that limits the amount of bare skin exposure. Similar complications
seen with other allergic contact dermatitis reactions are still
possible. The usual clinical presentation with all of the previously mentioned allergens is so similar that often careful
history taking and even patch testing may be necessary to
discern the source of the contact dermatitis. Identification
is essential to both educate the patient and prevent future
exposure. Although some new barrier creams seem to have
promise, there are none universally in use at present.
BEACH AND REEF: AQUATIC EXPOSURES
There are a few significant aquatic exposures that one can
encounter; fortunately, most of the areas involved are well
equipped to handle the problems as the shore, surf, and the
coral reefs are primarily developed as resort facilities with
296 E MERGENCY D ERMATOLOGY
FIGURE 30.5: Local reaction from toxins in spines of a scorpionfish.
FIGURE 30.6: Linear reaction to nematocysts.
all the amenities, medical included. The reefs are associated
with many fish having toxic spine, such as the scorpionfish
(Figure 30.5).
The “aquatourists” also are usually well educated in risk,
emergency care, and first aid – all part of the basic exposure
to water safety, scuba diving, surfboarding safety, and, in
some areas, the swimming education program. Perhaps, the
primary impetus is the periodic headline on shark attacks
and the previously mentioned death of Steve Irwin. He was
an individual well versed in proper safety in such hostile
environments. One can never be too prepared!
Although these large animals get the headlines, the
smaller creatures – seeming innocents such as jellyfish –
are the real cause of most problems.
Among coelenterates, two have the greatest impact. In
the Western hemisphere, the Portuguese Man o’ War
(Physalia physalis) is a cause of reported deaths. The long
tentacles of this creature can break off, and the unsuspecting
swimmer suffers the consequences of the contact and subsequent reaction from the multiple nematocyst toxicity. This
usually happens to swimmers with lack of knowledge of the
problem; they get extensive stings and improper care (by
fresh water exposure, massage, and other amateur first aid
remedies), which results in continued “firing” of the nematocysts deposited in the characteristic linear arrays (Figure 30.6). The resort staff are usually available to assist.
When managing these patients, it is also important to realize that broken tentacles can maintain toxicity for months,
allowing for exposure over a broader window of time. Also,
the nematocysts in the patient’s dermis can fire off for variable periods of time after emergent care has been completed, a cause for morbidity in some patients.
In Southeast Asia, a much more serious threat is
Chironex fleckeri (also occasionally reported in the
Caribbean, but most of the publicity is from Australia). It
is estimated that the fatality rate is between 15% and 20%.
The beaches in Australia (Queensland) have jugs of alcohol or vinegar strategically placed to provide emergency
neutralization of the nematocysts – a potentially life-saving
maneuver. Alternatively, experienced swimmers carry meat
tenderizer as another approach to minimize morbidity.
These creatures, colloquially sea nettles and sea wasps, are
appropriately named.
The other headliner in this environment is the “deadly”
cone shell. Here again, it has an estimated 15%–20% fatality rate that should be diminished by education. These
attractive shells are sought by collectors in Australia,
California, and Florida, often by occasional collectors
unaware of the risk. With education on precautions (gloves,
etc.), emergency symptoms from the neurotoxin can be
avoided. Definitive treatment is still not standardized. The
unusual nature of the venom is sparking interest to utilize it therapeutically and to approach better therapeutic
avenues.10
Many other dermatoses have been described, from coral
dermatitis to sea bathers eruption, which are acute, usually
minor, and rarely prompt a visit to the emergency room.
Alexander Fisher added a useful small atlas to the dermatologic literature,11 which, when used along with the classic
reference by Halstead,12 one can easily master the dermatologic significance of these clinical challenges.
REFERENCES
1. Laws J. We’re hot and unbothered. Occup Health Saf. 2008;
77:68–70.
2. von Duvillard SP, Arciero PJ, Tietjen-Smith T, Alford K.
Sports drinks, exercise training, and competition. Curr Sports
Med Rep. 2008; 7:202–8.
3. Levi M. Burning issues surrounding inflammation and coagulation in heatstroke. Crit Care Med. 2008; 36:2455–6.
4. Stein KR, Scheinfeld NS. Drug-induced photoallergic and
phototoxic reactions. Expert Opin Drug Saf. 2007; 6:431–4.
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Emergency Management of Environmental Skin Disorders: Heat, Cold, Ultraviolet Light Injuries
5. Lautenschlager S, Wulf H, Pittelkow M. Photoprotection.
Lancet. 2007; 370:528–37.
6. Antoniou C, Kosmadaki M, Stratigos A, Katsambas A. Sunscreens – what’s important to know. J Eur Acad Dermatol
Venereol. 2008; 22(9):1110–18.
7. New treatments for actinic keratoses. Med Lett Drugs Ther.
2002; 44:57.
8. Paulsen E, Otkjaer A, Andersen K. Sesquiterpene lactone dermatitis in the young: is atopy a risk factor? Contact Derm.
2008; 59:1–6.
297
9. Goldstein N, The ubiquitous urushiols, contact dermatitis
from mango, poison ivy, and other “poison” plants. Hawaii
Med J. 2004; 63:231–5.
10. Lewis RJ. Ion channel toxins and therapeutics: from cone snail
venoms to ciguatera. Ther Drug Monit. 2000; 22:61–4.
11. Fisher AA. Atlas of aquatic dermatology. New York: Grune
& Stratton; 1978.
12. Halstead BW. Poisonous and venomous marine animals of
the world. Vol 1. Invertebrates. Washington, DC: US Government Printing Office; 1965.
CHAPTER 31
Endocrinologic Emergencies
in Dermatology
Margaret T. Ryan
Vincent Savarese
Serge A. Jabbour
ENDOCRINE AND METABOLIC DISEASES, besides
affecting other organs, can result in changes in cutaneous
function and morphology and can lead to a complex symptomatology. Dermatologists may see some of these skin
lesions first, either before the endocrinologist, or even after
the internist or specialist has missed the right diagnosis.
Because some skin lesions might reflect a life-threatening
endocrine or metabolic disorder, identifying the underlying
disorder is important, so that patients can receive corrective
rather than symptomatic treatment.
In this section, we review a few endocrine and metabolic
disorders in which patients may present to the dermatologist with various skin lesions and in which the diagnosis of
the underlying condition must be made in a timely fashion
before the patient ends up with complications that could
be fatal.
HYPERPIGMENTATION AND ADDISON DISEASE
Addison disease, or primary adrenal insufficiency, can
be caused by either infiltrative disorders that invade the
adrenal cortex or by destructive disorders that attack the
adrenal cells. In either etiology, the adrenal cortex is unable
to produce and secrete adequate amounts of glucocorticoid
and mineralocorticoid hormones. The most common etiology of Addison disease used to be tuberculous granulomatous disease, but with declining infection rates in the
developed world, the most common cause of Addison disease today is autoimmune destruction of the adrenal glands.
Other less common causes of Addison include other granulomatous fungal infections (histoplasmosis, coccidiomycosis), metastatic carcinoma infiltration of the adrenals, or
bilateral adrenal hemorrhage.1 Rarely, autoimmune Addison disease can be seen in association with certain inherited
autoimmune polyglandular syndromes.
Clinical Features
The hallmark dermatologic feature of Addison disease is
a darkening of the skin, particularly in sun-exposed areas.
The hyperpigmentation of Addison disease is due to the
melanocyte-stimulating activity of the high plasma levels
of adrenocorticotropic hormone (ACTH).2 This skin darkening may be homogeneous or blotchy and is observed
in all racial groups, although it can be more difficult to
see in darker-skinned individuals. Also seen is significant
increased pigmentation in the palmar creases, the vermillion border of the lips, flexural areas, in recent scars,
and in areas of friction such as pant waistlines. Mucous
membranes such as the buccal, periodontal, and vaginal
mucosa may show patchy areas of increased pigmentation.
Women may have diminished axillary and pubic hair as
their androgen production occurs primarily in the adrenal
glands.3,4 Patients with autoimmune Addison disease may
also present with vitiligo or alopecia areata, from a similar
autoimmune destruction of melanocytes and hair follicles,
respectively.
Diagnosis
Diagnosis should be based on clinical presentation confirmed by laboratory testing. The presentation of a patient
with chronic primary adrenal insufficiency is that of longstanding vague symptoms such as malaise, anorexia, joint
aches, nausea, and fatigue, in addition the skin findings
mentioned earlier. Patients may also report craving highsalt foods.1 The acute presentation of adrenal insufficiency
is that of orthostatic hypotension, confusion, circulatory
collapse, and abdominal pain. This acute presentation is
frequently precipitated by an acute infection.
Biochemical testing to confirm the diagnosis is done
with a cosyntropin (synthetic ACTH) stimulation test. In
page 298
Chapter 31
this test, serum cortisol is measured immediately prior to
and 60 minutes following injection of 250 g of cosyntropin. A cortisol level at 60 minutes of 18–20 g/dL or
greater is considered a normal adrenal response. If the
serum cortisol at 60 minutes is less than 18–20 g/dL, the
patient is diagnosed with adrenal insufficiency; however,
this may be primary or secondary (pituitary/hypothalamic
mediated).5 Plasma ACTH should then be measured.
In Addison disease (primary adrenal insufficiency), the
ACTH will be elevated (>100 pg/mL) whereas in secondary adrenal insufficiency, the ACTH will be normal
to low.5 Other biochemical findings supporting a diagnosis of Addison disease include hyperkalemia, elevated
renin activity, hyponatremia, hypoglycemia, and hyperchloremic metabolic acidosis. Measurement of a morning
plasma cortisol is sometimes done instead of a cosyntropin
stimulation test, as a morning serum cortisol greater than
18–20 g/dL rules out the diagnosis of adrenal insufficiency and a value of less than 3 g/dL makes it very
likely. In many patients, serum cortisol falls within the
intermediate range and further testing is required, making
cosyntropin stimulation the preferred testing method for
diagnosis.5
Treatment
Treatment of Addison disease includes replacing both glucocorticoids and mineralocorticoids. Typical dosing of glucocorticoids is prednisone 5–7.5 mg daily or hydrocortisone 15–20 mg in the morning and 5–10 mg in the
evening. For mineralocorticoid replacement, fludrocortisone is given at a dose of 0.05–0.3 mg/day.4 The fludrocortisone dose can be adjusted to normalize renin plasma
activity, and the required dose is typically slightly lower
in patients on hydrocortisone as opposed to prednisone,
as hydrocortisone has some mineralocorticoid activity
itself.6 There is no easy way to assess the appropriateness of the glucocorticoid replacement dose as ACTH
levels, although they do decline with appropriate treatment, generally do not normalize. Recurrent symptoms
of adrenal insufficiency may suggest underreplacement
whereas development of Cushingoid features may suggest
overreplacement. Patients are typically advised to increase
their dose of glucocorticoids during stressful events such
as illnesses or surgery. The hyperpigmentation seen in
untreated Addison disease should resolve with appropriate
treatment.
Patients with Addison disease are also dehydroepiandrosterone (DHEA) deficient, and some studies show
symptomatic improvement in women who are given
DHEA replacement as well.7 These findings, however,
have not been consistently shown, and there is as of yet
no consensus on whether DHEA replacement is appropriate.1
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Endocrinologic Emergencies in Dermatology
299
FIGURE 31.1: Necrolytic migratory erythema on the foot, showing indurated areas with blistering, crusting, and scaling.
NECROLYTIC MIGRATORY ERYTHEMA
IN GLUCAGONOMA
Glucagonoma is a pancreatic tumor arising from the α cells
of the pancreatic islets and causing increased secretion of
the pancreatic hormone glucagon. The clinical syndrome
classically associated with glucagonoma includes necrolytic
migratory erythema (NME), cheilitis, diabetes mellitus,
anemia, weight loss, venous thrombosis, and neuropsychiatric symptoms. Weight loss and NME are the most prevalent symptoms, occurring in approximately 65%–70% of
patients by the time of diagnosis. The dermatitis may occasionally appear, prior to the onset of systemic symptoms,
but most patients with rash usually have weight loss, diarrhea, sore mouth, weakness, mental status changes, or diabetes mellitus as well as hypoaminoacidemia and zinc deficiency on laboratory analysis.8
Clinical Features
NME is considered the hallmark feature of the glucagonoma syndrome8,9 and is the clinical feature that leads
to the diagnosis of glucagonoma syndrome in the majority
of cases. NME is characterized by a painful and pruritic
polymorphous rash. It begins as an erythematous macular and papular skin eruption that later develops into welldemarcated plaques with variable scaling and finally progresses to centrally forming vesicles and bullae that rupture
leaving a crusted and eroded surface8,9 (see Figure 31.1).
NME has a relapsing remitting course. Individual lesions
typically evolve over a period of time lasting 1–2 weeks,
and patients will have multiple lesions in various stages of
the cycle. These lesions are usually seen first in the groin,
later progressing to the perineum, the buttocks, and the
extremities.
300 E MERGENCY D ERMATOLOGY
NME is frequently complicated by secondary skin infections with Candida albicans or Staphylococcus aureus and, in
fact, some patients are diagnosed incorrectly with chronic
candidosis years before eventually being diagnosed with
NME.9
the liver with liver transplant in addition to resection of
the primary tumor. The role of liver transplantation in
patients with metastatic glucagonoma is, however, not yet
clear.17 Other treatments that have been tried with mixed
results include intravenous amino acid and aggressive zinc
supplementation.18
Diagnosis
The differential diagnosis for NME is large and includes
acrodermatitis enteropathica (AE), pemphigus foliaceus,
psoriasis, and chronic mucocutaneous candidosis,10,11 and
should be differentiated on the basis of the larger clinical picture, histologic analysis, and laboratory findings. In
patients in whom NME is suspected, one should check a
glucagon level, and, if elevated, imaging should be done to
look for a neuroendocrine tumor. Glucagon levels may be
elevated in several conditions besides glucagonoma, including liver or kidney disease, prolonged starvation, or acute
myocardial infarction, but a level greater than 1000 pg/mL
is highly suggestive of glucagonoma.9 Given the often long
delay in diagnosis from initial presentation of NME, some
authors argue that glucagon levels should be checked in
all patients with diabetes mellitus and a chronic cutaneous
eruption.9
Skin biopsy specimens should be taken from the inner
edge of an advancing lesion. The characteristic finding is
necrosis of the upper layers of the stratum spinosum with
separation from the underlying epidermis, which is less
affected.8
NME occasionally has been reported in patients without
any evidence of glucagonoma. These patients, however,
typically have hyperglucagonemia or amino acid deficiency
of some other etiology and are often referred to as having
pseudoglucagonoma syndrome.12
Treatment
The treatment of choice for NME is complete surgical
removal of the α-cell tumor and is the only chance for
a cure of the disease. After surgical resection, there is normalization of glucagon levels. The rash typically resolves
rapidly, often within days, after removal of the tumor.13
Unfortunately, the majority of glucagonomas are either
too large for curative surgery or already metastatic at the
time of diagnosis. Due to the slow growth of these tumors,
even in metastatic disease, debulking surgery may achieve
a prolonged resolution of symptoms although there is no
evidence of prolonged survival.14 If full surgical resection is not possible due to the size of tumor or distant
metastases, chemotherapy is added to decrease tumor bulk
and a long-acting somatostatin analog (a glucagon antagonist) such as octreotide is used to relieve symptoms of
NME.15,16 There have been case reports of successful surgical treatment of glucagonomas that are metastatic to
THYROID DYSFUNCTION
Thyroid disorders are common in the general population and can have varied dermatologic presentations based
on the type and the severity of the thyroid dysfunction.
Hyperthyroidism may be due to a transient thyroiditis,
toxic nodules (either single or multiple), or, most commonly, Graves autoimmune thyroid disease. Hypothyroidism may be autoimmune Hashimoto, iodine-deficiency
related, radiation induced, or postsurgical.
Clinical Features
Patients with hyperthyroidism have warm, moist, erythematous skin. Many patients develop onycholysis, and a significant percentage of them complain of scalp hair loss.
Alopecia areata and loss of body hair may also be noted, but
are less common.4,19 In addition, patients with Graves disease may show evidence of Graves ophthalmopathy, pretibial myxedema, or acropachy. Pretibial myxedema can occur
anywhere on the body but most commonly affects the anterior tibia and the dorsum of the feet. It is characterized by
a nonpitting thickening and induration of the skin, and
is present in 0.5%–4% of patients with Graves disease.19
Acropachy is even less common, occurring in just 0.1%–
1% of patients with Graves, and consists of a triad of digital clubbing, soft tissue swelling of hands and feet, and
periosteal new bone formation.19 Both pretibial myxedema
and acropachy are seen almost exclusively in patients with
Graves ophthalmopathy, and these two dermatologic manifestations are considered indicators of more severe autoimmune disease.20 Vitiligo, a marker of autoimmune disease,
is also frequently seen in Graves disease.21
Patients with hypothyroidism, by contrast, have pale
cold skin that is typically dry, rough, scaly, and hyperkeratotic.19 The skin may appear to have a yellowish discoloration, particularly in the palms, soles, and nasolabial
folds, due to carotene deposition, and approximately 50%
have a malar flush.4,19 Myxedema, caused by mucopolysaccaride deposition in the dermis, is most pronounced in the
periorbital regions, leading to nonpitting swelling around
the eyes. Loss of sympathetic tone may lead to a drooping of the upper eyelid. Patients may lose hair on the
outer third of their eyebrows, and scalp hair loss has
been reported in about half of all hypothyroid patients.
Hair becomes dry and brittle and nails are thin and
grooved.19
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301
Diagnosis
Clinical Features
Serum TSH (thyroid-stimulating hormone) is the initial
diagnostic test for either hyperthyroidism or hypothyroidism. In most cases of hyperthyroidism, the TSH will
be suppressed, whereas in hypothyroidism the TSH will be
elevated.22 Thyroid peroxidase antibody may be checked in
hypothyroid patients to evaluate for Hashimoto (autoimmune) thyroiditis. After a laboratory diagnosis of hyperthyroidism is made, patients should be sent for a 24-hour
radioactive iodine uptake and scan to determine etiology, as
an uptake and scan can differentiate between Graves, toxic
nodules, and thyroiditis.
Episodic cutaneous flushing is the hallmark of the carcinoid syndrome and is seen in 85% of patients.25 The flushing of carcinoid is typically confined to the face, neck, and
upper trunk. Carcinoid tumors originating in the midgut
(appendix, ileum, jejunum) produce what is known as the
classical carcinoid flush, which is a rapid-onset cyanotic
flush lasting approximately 30 seconds and associated with a
mild burning sensation. Foregut carcinoids (stomach, lung,
pancreas, biliary tract) produce a brighter pinkish-red flush
that may be pruritic and can be more difficult to differentiate from physiological flushing. Flushing episodes may
occur spontaneously or may be provoked by certain triggers, similar to the triggers of physiologic flushing (alcohol, cheese, coffee, exercise, or emotional stressors).26,27
Carcinoid flushing often is associated with diarrhea and
breathlessness or wheeze, and these associated symptoms
are a method of differentiating the flushing of carcinoid
from physiologic flushing.28 Features of rosacea or vascular
telangiectasias may develop after years of flushing. Severe
flushing can be associated with a drop in blood pressure
and tachycardia. A phenomenon known as carcinoid crisis
can be precipitated by anesthesia or an interventional procedure and is characterized by a profound and prolonged
hypotension with tachycardia.
Other clinical features of the carcinoid syndrome
include niacin deficiency and hypoproteinemia from diversion of tryptophan for the synthesis of serotonin. Pellagra
(glossitis, scaly skin, angular stomatitis, and confusion) as
well as dependent edema may develop secondary to these
deficiencies but are usually a later presentation of the carcinoid syndrome.24,25,28 Scleroderma, without Raynaud phenomenon, also has been described in association with the
carcinoid syndrome and is considered a poor prognostic
indicator.28
Treatment
Treatment of hypothyroidism is with levothyroxine
weight-based dosing, typically 1.6 g/kg/d, titrated to
achieve a euthyroid state with TSH in the normal range.4
Any symptomatic patient with hyperthyroidism may be
given a beta blocker if there is no contraindication. Definitive treatment of hyperthyroidism varies depending on
the etiology of the disorder. Thyroiditis typically resolves
without treatment. In Graves disease or toxic nodules,
radioactive iodine treatment is effective but frequently
leads to hypothyroidism requiring levothyroxine therapy.
In patients with Graves disease, antithyroid agents such
as methimazole and propylthiouracil are other options;
the remission rates after 18 months of medical treatment, however, are only 30%–40%, and these medications do come with the risk of allergic reactions or
agranulocytosis.23
FLUSHING AND CARCINOID SYNDROME
Carcinoids are slow-growing tumors arising from the enterochromaffin or Kulchitsky cells and in most cases originate
in the gastrointestinal (GI) tract or the lungs. Carcinoid
tumors can secrete any number of bioactive substances,
and their presentation is dependent on both the type of
substances secreted as well as the location of the original
tumor and any metastases. Carcinoid tumors typically produce large amounts of serotonin. In addition, they may also
secrete histamine, corticotropin, dopamine, substance P,
neurotensin, prostaglandins, kallikrein, and tachykinins.24
Carcinoid syndrome is the term used to describe a constellation of symptoms caused by the secreted bioactive substances and is present in less than 10% of patients with
carcinoid tumors. The bioactive products produced by carcinoid tumors are inactivated in the liver, so patients with
GI carcinoids develop the carcinoid syndrome only if they
have hepatic metastases leading to secretion of the substances into the hepatic veins, whereas patients with carcinoid of the lung can develop the carcinoid syndrome in the
absence of metastatic disease.
Diagnosis
Symptoms of flushing, diarrhea, and bronchospasm, typically paroxysmal, may raise the suspicion for the carcinoid
syndrome. Additional less specific symptoms may include
GI discomfort, a palpable abdominal mass, GI bleeding,
or heart failure. The symptoms of carcinoid are protean
as they vary depending on the type of bioactive substances
secreted and the location of the tumor. As such, patients are
often initially misdiagnosed with other conditions, such as
irritable bowel syndrome, asthma, or anxiety, and accurate
diagnosis and treatment are delayed.
Although carcinoid may be suspected from the clinical
presentation, the diagnosis must be confirmed with biochemical tests. The most specific test is a measurement
of 24-hour urinary excretion of 5-hydroxyindoleacetic acid
(5-HIAA), a degradation product of serotonin. The test
for urinary 5-HIAA has a sensitivity of 75% and a specificity of 88%,24 but there are some drawbacks. Certain
302 E MERGENCY D ERMATOLOGY
serotonin-rich foods such as bananas, avocados, and tomatoes, can increase urinary 5-HIAA and lead to false-positive
results. Serum chromogranin A (CgA) is another biochemical test commonly used for the diagnosis of carcinoid. CgA
is a constitutive secretory product of most neuroendocrine
tumors, and plasma CgA levels have a sensitivity of up to
99% in diagnosing carcinoid. Plasma CgA is thus a sensitive, but not specific, marker for carcinoid tumors as it may
be elevated in several other neuroendocrine tumors as well
as in cases of renal impairment, liver failure, and inflammatory bowel disease24 or in patients on proton pump
inhibitors.29 A single recent study of the efficacy of plasma
5-HIAA in detecting carcinoid tumors demonstrated a sensitivity of 89% and a specificity of 97%,30 but this test is
not yet part of the standard armamentarium.
After carcinoid is confirmed by biochemical testing,
localization of the primary tumor as well as any metastasis
must be done; there are several different imaging modalities from which to choose. Octreotide scintigraphy, using
In-111, is the initial modality of choice if it is available.
Octreotide scintigraphy has an overall sensitivity of 80%–
90% based on various studies.31 In addition to the high sensitivity, octreotide scintigraphy allows imaging of the entire
body in one session, thereby detecting primary tumors as
well as metastasis (which may be missed with conventional
imaging). Bone scintigraphy is used to detect bone metastases if they are suspected and 123 I-MIBG scintigraphy also
can be used to localize carcinoid, although it appears to
be less sensitive than octreotide scintigraphy, especially in
detecting metastases.31 Computed tomography and magnetic resonance imaging scans are frequently used for initial localization with a sensitivity for both of approximately
80%. Radiographic findings include mass lesions with calcification and stranding fibrosis. Other modalities frequently
used for localization include positron emission tomography
scan (sometimes in combination with octreotide scintigraphy), endoscopic ultrasound, and endoscopy.
symptomatic relief, leading to resolution of flushing and
diarrhea in 70%–80% of patients. In addition, urinary
5-HIAA levels were halved in 72% of patients.33 Intravenous octreotide infusion has been used to successfully
treat carcinoid crisis. The somatostatin analogs do not,
however, appear to have any effect on tumor size or growth
rate.24,26 Other medical treatments commonly employed in
metastatic carcinoid include interferon-α and chemotherapy agents. Lifestyle modifications to avoid the triggers of
flushing episodes, such as alcohol, exercise, and spicy food,
are also encouraged, and diet supplementation with nicotinamide may prevent the symptoms of niacin deficiency.
URTICARIA PIGMENTOSA AND MASTOCYTOSIS
Mastocytosis is a group of rare disorders affecting adults
and children and is distinguished by a pathologic increase
in mast cells.25 This increase in mast cells may be seen in a
variety of tissues including the skin, bone marrow, GI tract,
spleen, liver, and lymph nodes. The symptoms of mastocytosis are heterogeneous25 and tend to be related to the
level of mast cell burden and the tissue type involved. Symptoms are typically related to mast cell mediator release. The
mediators found within mast cells are legion, including
histamine, prostaglandin D2, leukotrienes, interleukin-6,
and many more. Patients with mastocytosis tend to experience symptoms in discrete attacks when mast cell mediators
are released. Symptoms typically include pruritus, whealing, flushing, palpitations, and tachycardia. Bone marrow
involvement, common in adult cases of mastocytosis, can
lead to anemia and low bone density. If there is GI involvement, patients may experience diarrhea and abdominal
pain. Strong stimuli of mast cell release can lead to anaphylactoid reactions with severe, prolonged hypotension.
Mastocytosis can also present as idiopathic anaphylaxis in
previously undiagnosed patients.
Clinical Features
Treatment
Surgery is the only curative treatment for carcinoid tumors.
Unfortunately, curative surgery is possible only with nonmetastatic disease or in resectable nodal or hepatic metastases, and most patients have significant metastatic disease
at the time of presentation. Even in patients who have
metastic disease, surgery has a role for relief of mechanical
obstructions and, in cases of carcinoid syndrome, debulking causes significant relief of symptoms. Similarly, reduction of hepatic metastases, via surgical resection or hepatic
artery occlusion (ligation, embolization, or chemoembolization), has been shown to give symptomatic relief from
the carcinoid syndrome, and some studies have shown survival benefits of up to 2 years.32
Medical treatment with somatostatin analogs (octreotide and lanreotide) has proven extremely efficacious for
The characteristic feature of mastocytosis is a rash known
as urticaria pigmentosa (UP). UP is the presenting feature in the majority of patients with systemic mastocytosis
but can also be present as a cutaneous mastocytosis, without any extracutaneous involvement. The classical lesion34
is a hyperpigmented reddish-brown macule or papule (see
Figure 31.2). Another feature seen in UP is the local whealing and development of edema around the lesions when
rubbed or scratched. This is known as the Darier sign. In
typical UP in adults, the lesions measure 3–4 mm individually and are symmetrically and randomly distributed, with
the highest density of lesions seen on the trunk and thighs
and with relative sparing of the palms, soles, and face. In
extensive cutaneous disease, the lesions may become confluent. Children tend to present with larger lesions (5–15
mm), and their lesions are most prominent on the trunk.34
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303
TABLE 31.1: Diagnostic Criteria for Systemic Mastocytosis
Major criteria:
Multifocal infiltrates of mast cells in bone-marrow biopsy or in
other extracutaneous organs
Minor criteria:
>25% of mast cells in bone-marrow biopsy or tissue specimens
are spindle shaped or atypical
Detection of a codon 816 c-kit point mutation in blood, bone
marrow, or lesional tissue
Mast cells in blood, bone marrow, or lesional tissue expressing
CD25 or CD2
Baseline total tryptase level >20 ng/mL
FIGURE 31.2: Urticaria pigmentosa on the back with hyperpigmented reddish-brown macules and papules.
Pruritus is typically associated with UP. Less common
presentations of UP include telangiectatic, nonpigmented,
nodular or plaque-like variations of the rash.34 In rare cases,
mastocytosis can present as a single large mastocytoma
instead of the diffuse rash.
Diagnosis
The diagnosis of UP is based on clinical suspicion from
the maculopapular lesions and a Darier sign, and is confirmed by histopathologic examination of a tissue specimen. Skin biopsy of a UP lesion typically shows aggregates
of mast cells within the papillary dermis and extending into
the reticular dermis,35 particularly around blood vessels.
Mast cells within skin biopsies show a characteristic spindle
shape with metachromatic granules. Another characteristic
of UP on skin biopsy is the absence of any inflammatory
cells other than mast cells in the dermal infiltrate.36 The
most specific stain for mast cells in any tissue is immunohistochemical staining with tryptase.37 The diagnosis of
mastocytosis is occasionally made in patients lacking the
typical rash, by bone marrow biopsy, typically done after
unexplained anaphylaxis or flushing or for peripheral blood
abnormalities.
When the diagnosis of UP is made, it is important to
determine whether the patient has cutaneous mastocytosis
alone or whether there is systemic involvement. A set of
major and minor diagnostic criteria exist to diagnose systemic mastocytosis (see Table 31.1). A diagnosis of systemic
mastocytosis requires the fulfilment of either one major
criterion with one minor criterion or three minor criteria.38,39 More extensive cutaneous disease tends to correlate with increased risk for systemic mastocytosis. Elevated
levels of mast cell mediators such as tryptase and histamine
also can be used to support the diagnosis of systemic mastocytosis. Serum tryptase levels greater than 20 ng/mL are
suggestive of systemic mastocytosis, whereas patients with
only cutaneous mastocytosis tend to have levels less than
14 ng/mL.40 Histamine metabolites in a 24-hour urine
collection also tend to be increased in systemic mastocytosis.41 This test, however, is neither more sensitive nor
more specific than the serum tryptase level.42 Bone-marrow
involvement is seen in the vast majority of patients with
adult-onset mastocytosis. Thus, a bone-marrow biopsy is
recommended in the evaluation of all patients with adultonset disease, whereas in children with cutaneous disease
bone-marrow biopsy is recommended only in the presence
of other abnormal findings suggesting systemic involvement such as an abnormal complete blood count or an
enlarged spleen or liver.
Treatment
Most patients, be they children or adults, have an indolent
course and a good prognosis; however, there is no definitive
treatment for mastocytosis. Treatment instead is directed
toward the amelioration of symptoms related to the release
of mast cell mediators and must be tailored to each patient’s
specific symptoms and organ involvement. All patients may
be counseled in the avoidance of triggers such as exercise, rapid temperature changes, skin rubbing, or certain
drugs including anesthesia medications. Histamine receptor blockers (H1 and H2) along with cromolyn are effective for pruritus and for episodes of flushing, diarrhea, or
abdominal pain.35 Topical glucocorticoids can be used for
symptomatic skin lesions. Ultraviolet light irradiation (psoralen plus ultraviolet A) is used in the treatment of UP
to decrease pruritus, whealing, and flare reactions.43 Bone
disease from marrow involvement can be treated similarly
to osteoporosis of other etiologies, with calcium, vitamin
D, and bisphosphonates. Patients with anaphylactic reactions are treated with epinephrine and should be given
an epinephrine emergency pen to carry with them. For
patients with more aggressive systemic disease, other treatments (such as chemotherapy, interferon-α, and splenectomy) have been tried with mixed results.
304 E MERGENCY D ERMATOLOGY
DIABETES MELLITUS
Diabetes mellitus is a group of disorders characterized by
hyperglycemia due either to a deficiency of insulin secretion (type 1 diabetes), a resistance to insulin, or both (type
2 diabetes). Classic symptoms of diabetes include polyuria,
polydipsia, and weight loss, but diabetes can be associated
with several skin disorders both infectious and noninfectious in etiology.
Clinical Features
Common noninfectious skin findings in diabetics include
acanthosis nigricans (AN), skin tags, vitiligo, necrobiosis
lipoidica, and diabetic dermopathy. AN presents as hypertrophic, hyperpigmented velvety plaques seen in the body
folds, most commonly in the axillae and the posterior neck.
AN is generally asymptomatic and is more common in
patients with type 2 diabetes, but it can be seen in other diseases that cause insulin resistance, such as acromegaly and
Cushing disease. Skin tags, or acrochordons, are another
skin manifestation of insulin resistance and 66%–75% of
patients with skin tags have diabetes.44 The skin tags are
found most frequently on the eyelids, neck, and axilla.
Vitiligo is an autoimmune disorder and, due to similar etiologies, is seen more frequently in type 1 (autoimmune)
diabetes. Necrobiosis lipoidica (NL) is a rare but specific
skin manifestation of diabetes. It occurs in only 0.3% of
all diabetic patients, most of whom are insulin dependent
at the time of presentation, and is more common in men.4
NL consists of distinctive oval or irregularly shaped plaques
with red or violaceous borders, central atrophy, and yellow
pigmentation, typically occurring on the anterior shins. Up
to 35% of these lesions result in ulceration.4 Diabetic dermopathy, or shin spots, is seen in 40% of diabetic patients
and is more common in men and in patients with evidence of other end-organ damage such as retinopathy, neuropathy, or nephropathy. The lesions of diabetic dermopathy begin as groups of red macules on the anterior shins
that over time become shallow or depressed and hyperpigmented.
Skin infections are also common in diabetics, occurring
in 20%–50% of all diabetic patients, more commonly in
patients with type 2 diabetes and in patients with poor
glycemic control, and can vary in severity from a simple
superficial cellulitis to a necrotizing fasciitis.44 Patients with
poor diabetic control have both higher rates of colonization
and higher rates of skin infection with C. albicans, Staphylococcus species, and Streptococcus species. Women with hyperglycemia and glycosuria frequently complain of recurrent vaginal yeast infections. Elderly diabetics can develop
malignant external otitis, an invasive infection of the external auditory canal that typically occurs in immunocompromised patients, and Pseudomonas aeruginosa is the causative
organism in more than 95% of cases.45
Diagnosis
The diagnosis of diabetes can be made one of three ways.
The preferred method is the use of a fasting plasma glucose
of 126 mg/dL (7.0 mmol/L) after a fast of at least 8 hours.
Other acceptable criteria for diagnosing diabetes include
symptoms of hyperglycemia (polyuria, polydipsia, weight
loss) along with a random plasma glucose greater than or
equal to 200 mg/dL (11.1 mmol/L) or an oral glucose tolerance test using a 75-g glucose load with a 2-hour plasma
glucose level greater than or equal to 200 mg/dL.46 The
use of hemoglobin A1c for the diagnosis of diabetes is not
currently recommended.
On histopathologic examination, acanthosis nigricans
lesions appear hyperkeratotic with papillomatosis. The
dark color of the lesions is due to the thickness of the superficial epithelium, but there is no change in melanocyte number or melanin content.47 The lesions of diabetic dermopathy show basement membrane thickening, whereas NL is
characterized by a degeneration of collagen with granulomatous inflammation of the subcutaneous tissues and blood
vessels.48,49 The yellow central area of the necrobiot lesions
is believed to be due to the thinning of the dermis, making
subcutaneous fat more visible.50
Treatment
The treatment of diabetes focuses on normalization of
blood glucose levels as well as aggressive management of
known complications of diabetes, such as cardiovascular
disease. Type 2 diabetes can be treated with oral medications (e.g., secretagogues, biguanides, and thiazolidinediones), with injectable drugs (e.g., exenatide, insulin, or
pramlintide), or with a combination of both. Type 1 diabetes, however, must be treated with insulin; sometimes
pramlintide is added. Improved glycemic control decreases
the incidence of skin infections and delays progression to
microvascular disease complications such as retinopathy
and nephropathy.
Most of the noninfectious skin manifestations of diabetes are asymptomatic and do not require treatment.
Acanthosis nigricans, diabetic dermopathy, and skin tags
are generally asymptomatic and require no treatment. If
desired, however, skin tags can be removed with laser or
shave biopsy, and acanthosis may be ameliorated by weight
loss. Necrobiosis lipoidica has no standardized treatment;
however, most treatments use some form of glucocorticoid
in topical, intralesional, or systemic form.50
PORPHYRIA CUTANEA TARDA
Porphyria cutanea tarda (PCT) is the most common of the
porphyrias and is caused by a disruption of heme biosynthesis due to decreased activity of the enzyme uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme
biosynthetic pathway. PCT may be sporadic, inherited, or
Chapter 31
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Endocrinologic Emergencies in Dermatology
305
increase in urinary uroporphyrins. An analysis of urinary
porphyrins showing greater amounts of uroporphyrin versus coproporphyrin is consistent with PCT.59
Treatment
FIGURE 31.3: Porphyria cutanea tarda with hand lesions presenting as vesicles, bullae, blisters, and sores.
toxic in origin. Sporadic PCT makes up 80% of cases and is
caused by an acquired deficiency of UROD activity in the
liver, but not in any other tissues.51 Twenty percent of cases
are inherited as an autosomal dominant trait with low penetrance, and there are reports of PCT developing after exposure to certain chemicals such as fungicides, herbicides, and
polyhalogenated hydrocarbons.52–54 Most cases of PCT
are associated with some sort of precipitant. Precipitants
for PCT in susceptible individuals include alcohol, estrogens, viral infections (specifically, hepatitis C and human
immunodeficiency virus [HIV]), and iron overload.55 In
addition, an association has been found between PCT and
the hemochromatosis gene mutation C28Y.56
Clinical Features
PCT is characterized by photosensitive cutaneous lesions
with increased skin fragility manifesting as vesicles, bullae,
blisters, and sores (see Figure 31.3). The bullae rupture easily, crust over, and frequently become secondarily infected.
Lesions are seen most commonly on the hands and forearms but can be found on any sun-exposed area and may
heal with areas of hypopigmentation or hyperpigmentation
or sclerodermatous changes.57 Milia are frequently seen on
the hands and fingers. Increased facial hair is common and
is more noticeable in women.
Diagnosis
The characteristic finding of PCT on histopathologic
examination is subepidermal bullae with minimal inflammation. The dermal papillae have an undulating base
and are referred to as “festooned.”57 Liver biopsy findings include red autofluorescence under a Wood lamp as
well as mild steatosis, siderosis, and focal lobular necrosis
with pigment-laden macrophages. Birefringent needle-like
cytoplasmic inclusions may be present in hepatocytes and
are specific for PCT.58 Serum iron levels are elevated in
most patients with PCT. Urine studies will show a marked
General measures in the management of PCT include
avoidance of precipitating factors such as alcohol, estrogens, iron, and strong sunlight. If these measures are not
sufficient, then phlebotomy is the treatment of choice for
PCT. The goal of phlebotomy is to deplete body iron stores
and produce a mild iron deficiency. Clinical improvement
is typically seen starting 2–3 months after initiation of phlebotomy. If phlebotomy is contraindicated or unsuccessful,
then chloroquine is an alternative treatment.60
CONGENITAL ICHTHYOSIS AND TYPE II
GAUCHER DISEASE
Gaucher disease is the inherited autosomal recessive deficiency of lysosomal glucocerebrosidase. There is significant
clinical heterogeneity within Gaucher disease related to the
severity of the mutations affecting the glucocerebrosidase
gene located at 1q21.61 The disease is divided into three
different types based on phenotypic presentation, including
progression to neurologic manifestations. Type I is known
as nonneuronopathic Gaucher disease. It is by far the most
common type, and patients may remain asymptomatic or
may present with cytopenia, hepatosplenomegaly, or bone
involvement. Type II, acute neuronopathic Gaucher disease, is uniformly fatal with death typically occurring by
early childhood; it is within this type that one can see presentations of congenital ichthyosis, or collodion baby syndrome. Type III, chronic neuronopathic Gaucher disease,
presents with variable degrees of systemic involvement plus
one or more neurologic manifestations.
Clinical Features
Type II Gaucher disease is the rarest and most severe form
of the disease, and it is within this type that one can see
presentations of congenital ichthyosis, or collodion baby
syndrome. Congenital ichthyosis presents in neonates with
red, dry, tight, hyperkeratotic, scaling skin throughout the
body, often associated with joint abnormalities and contractures as well as other systemic signs of Gaucher such
as hepatosplenomegaly and neurologic changes.62 There
have been case reports of patients presenting with congenital ichthyosis prior to neurologic deterioration that develop
in subsequent months.63
Diagnosis
The skin changes in type II Gaucher disease are related
to the loss of glucocerebrosidase leading to an increased
306 E MERGENCY D ERMATOLOGY
ratio of glucosylceramide to ceramide in the lipid makeup
of epidermal cells.64 Ceramides are major components of
the lipid bilayer in the normal epidermis, necessary for permeability barrier homeostasis. A paucity of ceramides leads
to an inability to form a competent epidermal barrier, and,
as a result, the lipid bilayer has a serrated, abnormal appearance.64,65 Epidermal hyperplasia and hyperproliferation are
also seen and have been hypothesized to be due to stimulation of cellular proliferation by the accumulated glucosylceramide.66
Histologic examination of skin from patients with congenital ichthyosis shows dense hyperkeratosis, epidermal
hyperplasia, and inflammation. Ultrastructural examination reveals disruptions in the normal lamellar bilayer in
the stratum corneum as well as a reversal of the normal
ratio of sphingolipids in the stratum corneum, with much
higher levels of glucosylceramide to ceramide in the type
II Gaucher patients.62,64 Significantly, these ultrastructural
skin changes can be seen in all patients with type II Gaucher
disease, whether or not they show skin changes clinically.
In addition, these changes are seen only in type II Gaucher
disease and are not present in type I or type III. These skin
findings, thus, represent a method for early discrimination
of type II from the other, milder types of Gaucher disease.
Early differentiation of type II disease can aid in appropriate management and counseling, as neither enzyme activity
nor genotypic analysis is able to determine the specific type
of Gaucher disease.64
Clinical Features
The characteristic dermatologic manifestation of Fabry
disease is angiokeratoma. These lesions can occur at any
time but typically first appear between 5 and 13 years of
age.67,68 The initial lesion is dark red, telangiectatic, and up
to 4 mm across and does not blanch with pressure. Overlying hyperkeratosis may or may not be present. Lesions typically occur in symmetrical clusters and are seen most commonly in the areas between the umbilicus and the knees. In
men, the first lesions are frequently seen on the scrotum.
The number of lesions increases with age in the majority
of patients, and the extent of cutaneous involvement correlates with the severity of the systemic manifestations of
the disease.69
Other cutaneous findings in Fabry disease include
telangiectasias, disorders of sweating, decreased body hair,
and edema. Telangiectasias are characteristic of Fabry disease but are not specific as they can be seen in several other
conditions. The most commonly reported sweating disorders are hypohidrosis or anhydrosis, associated with heat
and exercise intolerance; hyperhidrosis has been reported
as well.
In addition to cutaneous manifestations, several systemic effects are frequently seen, including multiple cardiac and cardiovascular manifestations such as hypertension, cardiomegaly and stroke, renal failure, neuropathic
pain attacks, cataracts, and corneal dystrophy.
Diagnosis
Treatment
There is, unfortunately, no treatment to halt or reverse the
effects of type II Gaucher disease. Placental human glucocerebrosidase and recombinant glucocerebrosidase have
been used as enzyme replacement therapy in type I and
type III disease and have been effective at treating the
visceral and hematologic manifestations, but these treatments have shown disappointing results in type II disease and do not appear to alter the course of neurologic
deterioration.62
FABRY DISEASE
Fabry disease is a rare, X-linked lysosomal storage disease.67
Patients with Fabry disease are deficient in the enzyme
α-galactosidase A (α-gal A), which leads to the buildup
of neutral glycosphingolipids in a range of tissues within
the body. The clinical manifestations of Fabry disease are
seen primarily in affected hemizygous men and to some
extent in heterozygous women. The disease is slowly progressive; affected men have a shortened life expectancy of
approximately 50 years, and heterozygous women have a
life expectancy of 70 years with the main causes of death
being renal failure, heart disease, or stroke.
In men, the diagnosis can be made based on the presence of
cutaneous angiokeratomas in the setting of a positive family
history, specifically of early deaths due to kidney or heart
disease. Under light microscopy, angiokeratoma lesions are
composed of a thin epidermis, below which the upper dermis is filled with dilated blood-filled vessels.70 A hyperkeratotic stratum corneum may or may not be present. Further testing will reveal a deficiency of α−gal A in several
tissues including serum, tears, and tissue specimens. Lipid
inclusions with birefringent “Maltese crosses” as well as
fat-laden epithelial cells may be seen in the urine.
In female heterozygotes, symptoms are seen only in
a minority of affected patients and tend to be milder.
The variability of presentations in female heterozygotes is
believed to be due to variations in selective X-chromosome
inactivation. Affected women may have α−gal A levels
within the normal range, so genetic analysis is recommended.67
Treatment
Treatment of Fabry disease has been focused mainly on
symptomatic relief up to this point; there is now, however, growing evidence of the effectiveness of enzyme
replacement therapy. The mainstay of treatment for
Chapter 31
angiokeratomas has been the application of various types of
laser systems. Recent trials of enzyme replacement therapy
with two different preparations of bioengineered enzyme
have shown beneficial effects on signs and symptoms such
as pain, renal and cardiac complications, and overall quality
of life.71 In addition, enzyme replacement therapy has been
shown to clear the deposits of neutral glycosphingolipids
from the kidneys, hearts, and skin of patients with Fabry
disease.72
ZINC DEFICIENCY
Zinc is an essential mineral for humans. It is present in more
than 100 metalloenzymes, such as alkaline phosphatase and
carbonic anhydrase, and appears to play an important role
in protein and carbohydrate metabolism as well as cell proliferation, healing and tissue repair, and growth and development. Zinc is absorbed from the proximal small intestine
and is excreted through intestinal and pancreatic secretions.
It is also present in human breast milk.
Zinc deficiency can be either acquired or inherited.
The inherited congenital form is known as acrodermatitis
enteropathica (AE) and is a rare autosomal recessive partial defect in zinc absorption occurring in approximately 1
in 500,000 children.73 In AE, patients present in infancy,
within days if the infant is bottle fed and at the time of
weaning if breast fed. Most acquired forms of zinc deficiency, however, do not present until later in development. Acquired zinc deficiency can be caused by inadequate
dietary intake of zinc or from malabsorption of zinc, usually
due to diseases such as celiac sprue, Crohn disease, cystic
fibrosis, or short gut syndrome. Dietary zinc deficiency is
common in certain parts of Southeast Asia and sub-Saharan
Africa, but it is rare in the developed world. There are certain subpopulations, however, that are at increased risk;
these include vegetarians, alcoholics, premature infants,
and malnourished persons.74
Endocrinologic Emergencies in Dermatology
307
Diagnosis
Histopathologic examination of skin biopsy specimens is
nonspecific and, again, indistinguishable from other vitamin deficiency dermatoses and glucagonoma. The most
common findings are parakeratosis and necrolysis, the cytoplasmic pallor, vacuolization, and ballooning degeneration
also seen in the NME of glucagonoma.73 Diagnosis instead
must be based on clinical suspicion and confirmed by laboratory testing. Plasma zinc level is the most commonly
used test, although because only 0.1% of the body’s total
zinc stores is manifested in plasma zinc, it is an imperfect measure of total body zinc. A fasting morning plasma
zinc level less than 50 g/dL is suggestive of zinc deficiency. Other laboratory tests to support the diagnosis
include a low level of serum alkaline phosphatase, a zincdependent metalloenzyme, and a low level of urinary zinc
excretion.77–79
Treatment
Treatment of zinc deficiency is with zinc supplementation.
It is important to distinguish acquired zinc deficiencies
from AE because acquired deficiencies require only limited treatment durations, whereas inherited AE requires
lifelong treatment. In AE, the recommended initial dosing starts at 3–10 mg/kg/d and maintenance dosing of 1–2
mg/kg/d, whereas the recommended dose for dietary deficiency is lower, at approximately 0.5–1 mg/kg/d.73,80 Zinc
can be administered in many preparations, but zinc sulfate
appears to be the best tolerated.75 Clinical improvement is
typically seen within days to weeks of initiating zinc replacement therapy,81 often long before a change in the plasma
zinc levels can be seen. The most common side effect of zinc
supplementation is GI irritation with resultant symptoms
of nausea, vomiting, and gastric hemorrhage. Zinc has also
been implicated in impaired copper absorption, so copper
serum levels must be monitored as well in these patients.
Clinical Features
The dermatitis seen in zinc deficiency is similar in both the
acquired and inherited forms and is also largely indistinguishable from the rash seen in glucagonoma, vitamin B3
(niacin) deficiency, and in other vitamin deficiencies. The
dermatitis is characterized by eczematous, erythematous
scaly plaques over the acral and periorificial areas. These
plaques may become vesicular, bullous, or desquamative.
The skin can become secondarily infected, typically with
C. albicans. Other commonly seen features include angular
cheilitis, stomatitis, and nail changes such as onychodystrophy, onycholysis, and paronychia.75 If left untreated, these
patients will go on to develop generalized alopecia as well as
diarrhea.76 Other possible findings are photophobia, irritability, loss of appetite, poor wound healing, growth retardation, and hypogonadism.
●
VITAMIN DEFICIENCY
Vitamin A
Vitamin A is a fat-soluble vitamin found in meats, dairy
products, and certain vegetables (e.g., carrots, spinach, kale,
peas, cantaloupe). Because of the abundance of vitamin A
in the food supply, deficiency of vitamin A is quite rare
in Western countries, but is common in developing countries where malnutrition is prevalent. It also can be seen
in patients with anorexia nervosa; in those with fat malabsorption syndromes, such as Crohn disease, celiac disease,
pancreatic insufficiency, biliary disease, and cystic fibrosis;
and in persons who have had GI surgery.82–84
Clinical Features. Deficiency of vitamin A typically
presents with ocular findings, such as conjunctival xerosis,
308 E MERGENCY D ERMATOLOGY
white patches on the sclera (known as Bitot spots), and
night blindness, but it also can present with cognitive
disturbances or growth failure.82 Cutaneous manifestations of vitamin A deficiency may overlap with features of
other nutritional deficiencies. The most common finding
is phrynoderma, a form of follicular hyperkeratosis characterized by hyperkeratotic papules on the extensor surfaces
of the limbs, shoulders, and buttocks. These papules tend to
coalesce to form plaques, and, in severe phrynoderma, they
can cover the entire body.83 Phrynoderma was previously
thought to result exclusively from vitamin A deficiency, but
studies in recent years have associated the disease with deficiencies in B vitamins, vitamin E, essential fatty acids, and
general malnutrition.83–86
Diagnosis and Treatment. Diagnosis of vitamin A deficiency is typically made by identification of typical ocular findings and confirmed by laboratory testing of serum
vitamin A levels. Symptoms of deficiency typically resolve
with vitamin A replacement. Phrynoderma traditionally has
been treated with cod liver oil (which contains vitamin A),83
and more recently treatment with safflower oil, vitamin B
complex, and vitamin E have been associated with improvement in phrynoderma as well as visual symptoms.86
Riboflavin (Vitamin B2 )
Riboflavin deficiency is rare in developed countries, due to
the abundance of this water-soluble vitamin in the food
supply. Riboflavin is found in meats, fish, green leafy
vegetables, dairy products, and fortified cereals. Riboflavin
deficiency is typically seen in malnutrition states, and in
Western countries it can be seen in liver disease and
in infants treated with phototherapy for neonatal jaundice.82,84
Clinical Features. Typical cutaneous features of riboflavin
deficiency involve the mucous membranes and frequently
overlap with signs and symptoms of other vitamin deficiencies. Cutaneous manifestations of chronic deficiency
include scaling of the lips, angular stomatitis, glossitis,
monilial intertrigo, and scrotal dermatitis.82,84,87
Diagnosis and Treatment. Diagnosis can be made with
plasma riboflavin concentration or erythrocyte glutathione
reductase activity.82,84 As other nutritional deficiencies may
coexist, however, the diagnosis of riboflavin deficiency is
commonly made based on clinical suspicion and confirmed
by rapid improvement in symptoms and signs after repletion of riboflavin stores. Replacement of riboflavin is given
as 1 mg/d in infants and 3 mg/d in children.82
Niacin (Vitamin B3 )
Similar to riboflavin, niacin is found in meats, dairy products, fortified cereals, and legumes, and is synthesized in
the body from dietary tryptophan in the setting of vitamins
B1 and B6 .83 In developed countries, niacin deficiency is
typically seen in malabsorption syndromes, such as Crohn
disease, anorexia nervosa, HIV, carcinoid syndrome, Hartnup syndrome, malnutrition secondary to alcoholism, and
with use of medications such as isoniazid, 5-fluorouracil,
and 6-mercaptopurine.82,83
Clinical Features. The clinical manifestation of niacin
deficiency is pellagra. This is classically described in terms
of the “three Ds”: dermatitis, diarrhea, and dementia. The
rash of pellagra is typically symmetric and in areas of sun
exposure or friction. It tends to be erythematous and then
hyperpigmented and scaly. A classic finding is Casal necklace – a scaling, hyperpigmented rash around the neck and
chest. Bullous and depigmenting lesions also have been
described,83 as well as glossitis, stomatitis, and a facial rash
with a butterfly distribution.82
Diagnosis and Treatment. Diagnosis of niacin deficiency
is typically made after rapid improvement in clinical features with niacin supplementation, recommended at 50–
100 mg/d.
Vitamin B6 (Pyridoxine)
Vitamin B6 , or pyridoxine, is a water-soluble vitamin found
in meats, bananass, and vegetables such as beans and potatoes. Deficiency in Western countries is typically seen in
malnourished patients, chronic alcoholics, and patients taking isoniazid, penicillamine, or hydralazine.82
Clinical Features. Pyridoxine deficiency manifests as perioral and perianal skin changes similar to those seen in vitamin B2 or zinc deficiency, and may resemble seborrheic
dermatitis, stomatitis, or glossitis. GI symptoms and neurologic symptoms (such as weakness, confusion, or peripheral
neuropathy) may be seen as well.82,84 Blepharoconjunctivitis and atrophic tongue also have been described.88
Diagnosis and Treatment. Similar to that of other watersoluble vitamins, diagnosis can be made by serum levels,
but may be made more commonly by prompt resolution of
symptoms after treatment.
Vitamin C
Vitamin C, or ascorbic acid, is a water-soluble vitamin
found in many citrus fruits, vegetables, and organ meats. It
is obtained exclusively in the diet, as humans are unable to
synthesize vitamin C. Like the deficiencies of other watersoluble vitamins, vitamin C deficiency is rare in developed
countries, and is found in conditions of general malnutrition, such as in patients with alcoholism and/or drug addiction and in rare socially isolated elderly patients.
Chapter 31
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309
TABLE 31.2: Toxicity of Commonly Used Vitamins
Vitamin
Clinical features of vitamin toxicity
Minimum daily dose associated with adverse effect93
Vitamin A
Liver toxicity, cirrhosis, birth defects, benign intracranial
hypertension93,94
Cirrhosis: 25,000 IU
Niacin (B3 )
Flushing, nausea, vomiting, diarrhea, liver toxicity,
fulminant hepatic failure (at least one case report)93
Flushing/gastrointestinal side effects: 10 mg
Vitamin B6
Sensory neuropathy, photoallergic drug rash, acneiform
rash, contact dermatitis93,95–97
300 mg
Vitamin C
Nausea, abdominal cramping, diarrhea; reports of
increased incidence of oxalate kidney stones have not
been substantiated93,98,99
1000 mg
Clinical Features. Deficiency of vitamin C causes the clinical entity of scurvy, with several classic cutaneous findings:
follicular hyperkeratosis, perifollicular hemorrhages, and
corkscrew-like, coiled hairs embedded in the hyperkeratotic follicular material. Also seen are petechiae and ecchymoses in dependent and friction-prone areas and swollen,
inflamed gums (hemorrhagic hyperplastic gingivitis). Also
seen in chronic vitamin C deficiency is a woody edema of
the legs.89–91
Birth defects: 10,000 IU
Hepatotoxicity reported with 500 mg/d, but generally
seen in doses >1000 mg/d
Diagnosis and Treatment. Diagnosis is made with the
appropriate history and clinical findings, along with prolonged prothrombin time. The coagulopathy of vitamin
K deficiency can be corrected with oral or subcutaneous
supplementation. Cases with severe bleeding may require
parenteral vitamin K supplementation and possibly transfusion of fresh frozen plasma.
VITAMIN TOXICITY
Diagnosis and Treatment. Serum levels of ascorbic acid
fall to almost zero rapidly after failing to meet sufficient
dietary requirements, limiting the diagnostic value of serum
testing. Diagnosis is typically made on clinical grounds,
such as with a patient having signs of scurvy, or with
improvement of symptoms with supplementation of vitamin C. In addition to its role in treatment of clinical deficiency, vitamin C, along with zinc and arginine, has been
associated with improvement in the treatment of pressure
ulcers.92
Vitamin K
Vitamin K is a fat-soluble vitamin found in green leafy vegetables and legumes. It is also synthesized by bacteria in the
digestive tract. Deficiency is seen in malabsorptive states,
such as Crohn disease, pancreatic insufficiency, and with
medications such as antibiotics, anticonvulsants, isoniazid,
rifampin, and cholestyramine.89 It is also seen in patients
with liver disease and in patients with poor diet.
Clinical Features. Deficiency of vitamin K is manifested by
coagulopathy caused by deficiency of vitamin K–dependent
clotting factors II, VII, IX, and X. As a result, patients
with deficiency in vitamin K present with coagulopathy,
with easy bruising, ecchymoses, or bleeding from the GI or
genitourinary tract, or with excessive bleeding after injury,
trauma, or surgery.
Potentially toxic levels of vitamins can be achieved easily in
people who take very high potency vitamins. Water-soluble
vitamins have an extraordinarily broad therapeutic ratio,
with toxicity occurring only at doses thousands of times the
daily value. Fat-soluble vitamins are generally more toxic
than water-soluble vitamins. Table 31.2 summarizes some
important points related to some vitamin toxicities.
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CHAPTER 32
Emergency Management of Skin Torture
and Self-Inflicted Dermatoses
Daniel H. Parish
Hirak B. Routh
Kazal R. Bhowmik
Kishore Kumar
TORTURE WRIT broadly is the intentional infliction of
physical or psychological pain.1 The term includes a wide
variety of conduct ranging from that instigated by authorities to gain confessions or information to that caused by
private actors in the course of domestic abuse or in the
intimidation of neighbors or disliked ethnic or religious
minorities. Most legal definitions of torture, however,
restrict its definition by requiring an element of state action.
Thus, for example, the United Nations Convention against
Torture defines it as:
and devastating to the victim, are expressly designed to
leave no visible mark on the skin whatsoever, in large part
to allow the torturer to deny the torture. Without in any
way diminishing the severity, horror, and tragedy of the
latter, this chapter focuses on the former in the context of
addressing such injuries in an emergency situation.
any act by which severe pain or suffering,
whether physical or mental, is intentionally inflicted on a person for such purposes as obtaining from him or a third person information or a
confession, punishing him for an act he or a third
person has committed or is suspected of having
committed, or intimidating or coercing him or a
third person, or for any reason based on discrimination of any kind, when such pain or suffering
is inflicted by or at the instigation of or with the
consent or acquiescence of a public official or
other person acting in an official capacity. It does
not include pain or suffering arising only from,
inherent in or incidental to lawful sanctions.2
In most cases that will fall under the rubric of torture,
an especially detailed dermatologic history should be performed, as the exact location and description of wounds and
scars can prove significant both for treatment and further
legal proceedings. Any history of skin disease and lesions
that predate the described torture should be noted. Lesions
more consistent with torture will include those that are
asymmetric, irregular linear lesions and those with welldemarcated borders.3 All of this should be directed, in addition to providing treatment, to determining whether the
physical findings on examination are consistent with a history of torture as presented.4 A thorough examination of
all skin areas should be conducted to the extent permitted,
as a patient may have passed out during an episode of torture and not even know all affected portions of his or her
body. It should be noted that torture, from the point of
view of skin damage, will tend to be most extensive when
the torturer did not expect that the patient would be leaving
custody any time soon, if ever, and less so if a known court
date or its equivalent had to be kept in the near future.5
The exception, of course, lies in those cases where the visible damage is meant to frighten others or permanently scar
the victim. Additionally, although one might suspect that
a person in the position of potential asylum seeker or victim seeking redress might seek to overattribute every scar to
torture, at least one physician who treats asylum candidates
Similarly, the damage done by torture and the evidence
of the same range widely. On the one hand, some persons torturing others seek to injure their victims in a way
that is highly visible and consequently damaging to the victim’s psyche (and serve as a threat to anyone who sees the
victim). Cases in which perpetrators burn women chemically or thermally for failing to accept proposals or in
defense of a family’s “honor” will fall into this category.
Such injuries can also lead to secondary complications such
as skin infection and scar-related contractures. On the other
hand, other forms of torture, although extremely painful
CLINICAL AND LABORATORY AIDS REQUIRED
FOR DIAGNOSIS
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314 E MERGENCY D ERMATOLOGY
has noticed the exact opposite and that such victims tend to
minimize rather than exaggerate.5 Patients who have been
brutalized and shamed may also be reluctant to permit full
examinations, and although the wishes of the patient must
ultimately be respected, the limitations of such an examination need to be noted.
The type of torture inflicted is also likely dependent
upon the country or circumstances in which the torture
took place. Although no fully accurate statistics of torture
methods exist, one study found, for example, that electrical burns were extremely common in Bangladesh but
not present in Iran, whereas foot beatings were the rule
in Bangladesh and Syria but largely absent in Peru and
Uganda.6 A study of Sri Lankan victims showed that torturers beat nearly all victims with blunt weapons and burned
57% with cigarettes, whereas chemical and electrical burns,
for example, were far less frequent.7 The point is, however,
that the examiner may detect patterns and injury based on
the country or location in which the torture occurred.
Probably the most common form of injury in torture is
that from blunt trauma, be it from stick, club, rod, or fist.
Danielsen and Rasmussen3 provide an excellent review of
the consequences and manifestations of this form of torture.
From the dermatologic perspective, such beatings may
result in lacerations, abrasions, ecchymoses, and edema,
although it may be rare for a torture victim to present with
the immediate aftereffects of such trauma. Consequently,
unless a wound reaches full thickness, there may well be
little evidence of the trauma at the time the patient is
brought to medical attention.8 As is the case with suspected
domestic abuse, it may be necessary to evaluate and document the trauma to the extent necessary to distinguish
trauma from an accidental fall or other injury from more
wanton and intentional violence (e.g., the custodial claim
that the victim “simply fell” on his way out of the police car
or “tripped” on his way into the interrogation room and hit
his head on the table). Scars produced here will often appear
nonspecific, although linearly patterned, hyperpigmented
scars, such as from trauma from whippings or beatings with
rods, may point strongly toward torture. Similarly, the tight
binding of a victim around his or her arms or legs may
produce characteristic linear scarring around the arms and
ankles. In evaluating damage from possible blunt force with
respect to scars, it must be kept in mind that a huge variety
of causes can produce scarring throughout the body, from
accidents at home and work and on playing fields to acne to
earlier infections to stretch marks to vaccinations to prior
surgery to ritual wounds, and although many of these scars
are easily distinguished, it is not always the case; it is hard to
tell if a kick to the legs came from torture or a soccer tackle.
The practice of bastinado (also known as falaka or
falanga), the systematic beating of the feet, qualifies as a
subset of blunt trauma and is another common torture
with occasional dermatologic implications.6 The practice
is common among torturers, probably because it is easy to
carry out, is exquisitely painful, and generally produces little visible injury; nonetheless, above and beyond the pain
of walking due to trauma to the soles, cases of atraumatic
necrosis of the toes and necrotic ulcers on the feet also have
been reported. The necrosis is, in part, a consequence of
the damage to the subcutaneous tissue pads of the feet that
can no longer cushion them while a patient is walking or
standing.4,9
Moving along on the realm of blunt trauma, torturers
will also often crush or remove nails, both because of the
terrible pain such damage inflicts and because of the relatively minimal damage to the rest of the body. The consequence of such damage, after it heals, is a damaged nail bed
that produces distorted nail growth, although such changes
are not easy to distinguish from general nail trauma.5 A differential of such damage may include, for example, psoriatic
nail disease.
The various forms of burning – be they thermal, chemical, or electrical – are the most likely types of torture to
produce skin damage and changes. Direct application of
heat with a metal rod will tend to cause a brand, resulting
in a full-thickness burn that demonstrates the shape of the
object that caused the damage, with a scar forming in that
shape.
Cigarette burns are likely the most common source of
skin damage from burning. They follow the damage patterns of burns on any scale, ranging from superficial burns
akin to moderate sun damage to full-thickness burns of
the dermis and epidermis, albeit in circular patterns of 5–
20 mm in diameter.10 The damage caused will generally
depend on the length of time the cigarette is applied to
the skin, and may or may not be accompanied by a blister.
The time needed to achieve the damage of a full-thickness
burn is longer than the reflex time for withdrawal, indicating that such burns should be accompanied by a story of
the affected body part being held in place while the burn
was inflicted. Such injuries will generally heal in weeks to
months, depending on the depth of injury, but are at risk for
secondary infection. Cigarette burns inflicted in the course
of torture are more likely to be on surfaces of the body
visible to the victim, as no small portion of the pain and
trauma from such burns comes from witnessing the event.
Torturers also often burn victims this way in tight patterns as opposed to haphazard and irregular burns.5,10 A
differential diagnosis, depending on the case, may include
impetigo, abscess formation, and pyoderma gangrenosum.
Chemical burns are an invidious form of torture, frequently associated with attempted disfigurement of a
woman for refusal to marry or for some supposed disgrace
visited on her family.11 Such torture has been reported in
India, Bangladesh (Figures 32.1–32.8), and Uganda, where
sulfuric acid is the most common agent. In most cases, the
face is involved, as the goal of the torture is, in no small part,
to render the victim permanently disfigured, in order both
to render her socially unacceptable and to let the victim
Chapter 32
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Emergency Management of Skin Torture and Self-Inflicted Dermatoses 315
FIGURE 32.1: Domestic violence manifested by acid burns due
to 50% sulfuric acid being thrown on the victim.
FIGURE 32.4: Domestic violence manifested by acid burns due
to 50% sulfuric acid being thrown on the victim.
FIGURE 32.2: Domestic violence manifested by acid burns due
to 50% sulfuric acid being thrown on the victim.
FIGURE 32.5: Domestic violence manifested by acid burns due
to 50% sulfuric acid being thrown on the victim.
FIGURE 32.3: Domestic violence manifested by acid burns due
to 50% sulfuric acid being thrown on the victim.
FIGURE 32.6: Domestic violence manifested by acid burns due
to 50% sulfuric acid being thrown on the victim.
316 E MERGENCY D ERMATOLOGY
FIGURE 32.7: Domestic violence manifested by acid burns due
to 50% sulfuric acid being thrown on the victim.
serve as a warning to others. When the burn is extensive,
cosmetic surgery may have a role to play in ameliorating
the damage, albeit not typically in the emergency context.
Electrical burns can occur when a torturer attaches electrodes to various parts of a person’s body and runs current
through the circuit, although such burns are usually incidental to the torture intended rather than its aim. These
burn marks are usually small circular lesions that leave fine
scars, although the wound will depend on the type of current and attachment used. Danielsen and Rasmussen3 again
provide an excellent overview of these differences. Broadening the foci of charge entry and emergence through the
use of gels will render these marks even harder to find,
if they exist at all.4 A particular form of electrical torture common in Peru and other parts of South America
(“picana,” involving a wand that delivers a high-voltage
but low-current shock) leaves clusters of tiny lesions covered with brown crusts and sometimes surrounded by a
FIGURE 32.8: Domestic violence manifested by acid burns due
to 50% sulfuric acid being thrown on the victim.
small erythematous ring. A differential diagnosis of such
lesions may include contact dermatitis.4 Biopsy and histological examination may have a role to play in the investigation of electrical torture. In the case of electrical burns,
recently inflicted damage may show deposits of calcium
salts on cellular structures that accords with the flow of an
electric current, while perhaps also showing signs of burn
damage due to the heat produced by the current.3 One
case series involving histologic examination of 11 patients
seen after burns from defibrillation, however, showed no
such evidence, implying that such evidence may be present
less frequently.12 Another study of 11 patients who suffered electrical fatalities (also not torture related) showed
deposition of copper and iron on the skin in a significant
number of histologic specimens from these patients, suggesting that staining for these metals might help to support
a case of electrical torture.13
Torture can also potentially, as a result of stress induced,
make a patient susceptible to flares of skin diseases from
which he or she already suffers. Psoriasis and other diseases induced by various sorts of skin trauma may arise
in response to torture via the Koebner phenomenon,
while the psychological stress of the same may either provoke urticaria or the uncontrolled repetitive self-rubbing
that can exacerbate or introduce disease.3 Patients with
other underlying diseases, such as diabetes mellitus and
peripheral arterial disease, may also be more susceptible to ongoing effects from trauma to limbs and reduced
healing. Patients who tend toward hypertrophic healing
may develop keloids as a consequence of torture wounds.
Finally, evidence of severe damage to the skin through torture may well indicate more internal damage that could
result in rhabdomyolysis and consequently could warrant a
check of renal function for signs of failure.14
THERAPY
Patients with extensive skin damage due to chemical or
physical burns should be referred to a burn unit and ultimately for appropriate surgical intervention, if necessary.
Care is otherwise commensurate with the damages and normal wound care. Depending on the age of the skin damage
and how it was inflicted, it is also important to look for signs
of infection and to treat the same if discovered.
In almost every situation in which a patient was the
possible victim of torture, thorough documentation of
the history and examination becomes extremely important, whether for asylum claims or conceivable future legal
actions against a perpetrator. In some cases and countries, for example, it is essential for a physician to identify
the victim through specific means for any possible legal
redress to follow. One U.S. study has found that individuals who received medical evaluations from Physicians for
Human Rights have obtained asylum at statistically significant higher rates than have those without similar documentation.15
Chapter 32
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Emergency Management of Skin Torture and Self-Inflicted Dermatoses 317
It is also important to ensure that social workers and psychiatrists or psychologists are involved in treatment whentorture is suspected.9 Similarly, a physician dealing with a
patient who is suspected of suffering or claiming to be the
victim of torture should be treated with great care. No matter how much the physician wishes to help, a person who
has just been utterly mistreated by an authority figure and
has suffered under questioning may be reflexively suspicious of answering the questions of a new authority figure.
Women (and men) who may have been sexually brutalized
may be ashamed to tell their whole story. Various forms of
torture may also lead to impaired memory of the event. In
any case, it may be necessary for additional visits for an adequate documentation of what has happened to the patient.
Although these visits obviously should not take place in the
emergency department setting, such a course of aftercare
should be established to the extent possible.
COURSE AND PROGNOSIS
In cases of intentional mutilation, whether through chemical, electrical, thermal, or mechanical destruction of the
skin, the patient’s course and prognosis depend heavily
on the extent of damage inflicted. Unless the patient was
severely and significantly burned, most scars will follow
a normal course of healing absent secondary infection or
other complication. For the purposes of documenting torture, damage to the skin should be evaluated as near in time
to the event as possible.
Of course, the goal of torture is ultimately not the infliction of the pain or disfigurement, per se, but the psychological repression of the victim. As such, much treatment
will lie beyond the expert purview of the dermatologist and
depend on ongoing social and psychological assistance. It is
essential, therefore, that the patient does not simply shuttle
through for evaluation of his or her skin condition.
The evaluation, depending on the situation, as noted
previously, may be important for a patient’s possible need
or desire to seek asylum. All relevant symptoms should
be documented, of course, and if there is no examination
beyond the dermatologic that should be noted, lest evidence of the absence of such complaints be used against
the patient. Even when treatment is being offered in situations where some limitations may be present in how far
the patient may explain the torture (e.g., a prisoner brought
in by his captors/torturers to seek medical treatment after
a session of interrogation has gone too far) or the physician may express his or her opinions, documentation to the
fullest extent, as well as an acknowledgment of any limitations, should be included.16 Similarly, a full examination for
the purposes of an asylum claim likely may well lie beyond
the purview and time constraints of the physician delivering emergency care, and arrangements for a more extensive
examination by someone more familiar with medical (and
legal) aspects of such claims is likely in order.17
REFERENCES
1. Peel M. History of torture. In Payne-James J, Byard R, Corey
T, Henderson C, editors. Encyclopedia of forensic and legal
medicine. 1st ed. Amsterdam: Elsevier; 2005. pp. 520–4.
2. United Nations Convention against Torture and Other
Cruel, Inhuman or Degrading Treatment or Punishment,
Art. 1.
3. Danielsen L, Rasmussen OV. Dermatological findings after
alleged torture. Torture. 2006; 16:108–27.
4. Pounder DJ. Torture: physical findings. In Payne-James J,
Byard R, Corey T, Henderson C, editors. Encyclopedia of
forensic and legal medicine. 1st ed. Amsterdam: Elsevier;
2005. pp. 297–302.
5. Forest DM. Examination for the late physical after effects of
torture. J Clin Forensic Med. 1999; 6:4–13.
6. Moisander PA, Edston E, Torture and its sequel – a comparison between victims from six countries. Forensic Sci Int.
2003; 137:133–40.
7. Perera P. Physical methods of torture and their sequelae: a Sri
Lankan perspective. J Forensic Leg Med. 2007; 14:146–50.
8. Forrest D. The physical after-effects of torture. Forensic Sci
Int. 1995; 76:77–84.
9. Richey SL. Assessment and management of survivors of torture in the emergency department. J Emerg Nurs. 2007;
33:484–7.
10. Faller-Marquardt M, Pollak S, Schmidt U. Cigarette burns in
forensic medicine. Forensic Sci Int. 2008; 176:200–8.
11. Routh HB, Parish LC, Sen SL, Bhowmik B. Skin torture. Clin
Dermatol. 2005; 23:307–9.
12. Danielsen L, Gniadecka M, Thomsen HK, et al. Skin changes
following defibrillation: the effect of high voltage direct current. Forensic Sci Int. 2003; 134:134–41.
13. Jacobsen H. Electrically induced deposition of metal on the
human skin. Forensic Sci Int. 1997; 90:85–92.
14. Naqvi R, Ahmed E, Akhtar F, et al. Acute renal failure due to
traumatic rhabdomyolysis. Ren Fail. 1996; 18:677–9.
15. Lustig SL, Kureshi S, Delucchi KL, et al. Asylum grant rates
following medical evaluations of maltreatment among political asylum applicants in the United States. J Immigr Minor
Health. 2008; 10:7–15.
16. Perera C. Review of initiatives adopted for effective documentation of torture in a developing country. J Clin Forensic
Med. 2006; 13:288–92.
17. Forrest D, Knight B, Hinshelwood G, et al. A guide to writing
medical reports on survivors of torture. Forensic Sci Int. 1995;
76:69–75.
CHAPTER 33
Skin Signs of Poisoning
Batya B. Davidovici
Ronni Wolf
CUTANEOUS POISONING syndromes produce a myriad of signs and symptoms. Poisoning may be acquired
either accidentally or deliberately through inhalation,
ingestion, or percutaneous contact of the toxic substances.
It can affect all age groups, but children have an increased
risk for adverse effects of these toxic agents.
Early diagnosis and therapeutic support may not always
be achieved due to poor recognition of signs and symptoms. This realization emphasizes the importance of recognizing the signs of cutaneous poisoning syndromes and
initiating adequate systemic therapy when indicated. The
initial approach to poisoning entails a thorough clinical history, detailed physical examination, and institution of basic
supportive measures. Primary and secondary prevention by
way of public education and vigilant observation are essential.
One of the challenges in managing these patients is to
identify the “needle in the haystack,” the small percentage that may develop potentially serious clinical effects and
require specific management without subjecting them to
unnecessary procedures.
The focus of this review is on four major cutaneous poisoning syndromes, namely metallic poisoning
(arsenic, mercury); excessive -carotene (carotenoderma),
which may present with diagnostic and therapeutic difficulties; carbon monoxide (CO) poisoning; and dioxin
poisoning.
ARSENIC POISONING
Arsenic is a well-recognized poisonous metal due to its inexpensive cost, lack of odor, and tasteless quality. Arsenic
can be contacted during the smelting of copper, gold, lead,
and other metals. In smelting operations and in the manufacture of pesticides and herbicides, considerable contamination of the environment can be present, requiring extensive preventive measures. In the semiconductor
industry, exposure to arsenic can occur during maintenance
activities and especially during the handling of raw materials.
In children, the most common arsenic sources are
medicinal and environmental.1 Chronic arsenic toxicity due
to drinking arsenic-contaminated water is a major environmental health hazard. Many aquifers in various parts
of the world are contaminated with arsenic. Of these, the
most noteworthy occurrences are in large areas of India,
Bangladesh, Taiwan, and Northern China.2 Although
arsenic poisoning has been rarely reported in the pediatric
population, a recent work analyzing the acute effects of
arsenic poisoning showed that children as young as 1 year
old may be affected.3
Arsenic can cause a persistent folliculitis, in addition to
systemic poisoning. An increased incidence of skin cancer was also reported following ingestion of seafood and
drinking water containing more than 0.6 mg of arsenic per
liter.4 There is additional evidence from human studies that
chronic ingestion of inorganic arsenic causes skin, bladder,
and lung cancer in adults.5 Skin abnormalities, such as pigmentation changes and keratosis, have long been known
to be hallmark signs of chronic arsenic exposure in adults.
These lesions are the most common health effects found
in populations exposed to arsenic-contaminated drinking
water.
Clinical Manifestations
Arsenic poisoning may be classified as either acute
or chronic. In a study on acute arsenic poisoning in
Wakayama, Japan,3 cutaneous manifestations from arsenic
exposure in both children and adults appeared as soon as 3
months after exposure. Cutaneous findings, although rarely
documented after acute arsenic poisoning, include facial
edema and a mildly pruritic maculopapular eruption in the
intertriginous areas, as well as acral hyperkeratosis with
lamellar peeling. Transverse 1- to 2-mm-wide whitish fingernail bands, called Mees lines, become apparent after
a 2-month incubation period and tend to be broader in
children. Other cutaneous lesions such as urticaria, erythema multiforme lesions, a morbilliform eruption, periungual pigmentation, acral desquamation, and postinflammatory hyperpigmentation have also been reported.6 With
chronic low-level arsenic exposure, clinical signs and symptoms are subtle and difficult to detect initially but later
can manifest as systemic signs and symptoms, including
page 318
Chapter 33
benign skin changes, skin cancer, or internal malignancy.
Cutaneous signs from chronic arsenicism may present as
facial and eyelid edema and blushing. Cutaneous melanosis
with hyperpigmented patches has also been reported in the
nipples, axillae, groin, and other pressure points.7 . A 2003
study of an Argentinian population1 showed that chronic
arsenic exposure from contaminated well water ingestion
presented with the principal skin manifestations of distinctive pigmentation and keratoses. The hyperpigmentation is marked by raindrop-shaped discolored spots, diffuse
dark brown spots, or diffuse darkening of the skin on the
limbs and trunk. Simple keratosis usually appears as bilateral thickening of the palms and soles, whereas in nodular
keratosis, small protrusions appear in the hands, feet, or
legs. Spotty depigmentation (leucomelanosis) also occurs
in arsenicosis. In contrast to cancer, which takes decades
to develop, these skin lesions are generally observed 5–
10 years after exposure commences. The cutaneous malignancies reported were Bowen disease, basal cell carcinoma
(BCC), and squamous cell carcinoma (SCC) with BCC
being more common than SCC.1
Although limited epidemiological data exist, other
reported clinical manifestations resulting from ingestion
of arsenic-contaminated drinking water in adults include
weakness, conjunctival congestion, hepatomegaly, portal
hypertension, lung disease, polyneuropathy, solid edema
of limbs, and anemia.5
Occurrence of chronic lung disease including pulmonary interstitial fibrosis was described in arsenicexposed children in Chile. Influence on intellectual function is also reported from Thailand, Bangladesh, and India.
Diagnosis
Several diagnostic aids are available in detecting the presence of arsenic. Urine arsenic levels may be useful for acute
poisoning due to rapid clearance of arsenic from the blood.
Deposition of arsenic in hair and nails begins within 2 weeks
of exposure and remains in the tissues for the next 1–2 years
of life.8 A few strands of hair, preferably from the pubic area,
are necessary to reduce the likelihood of environmental
contamination. Ancillary tests should also be done to rule
out systemic involvement.
Management
Environmental control of arsenic exposure remains the
major preventive measure against arsenic poisoning or
morbidity. Seasonal variation, specifically dry periods,
enhances toxicity. Chelation therapy with dimercaprol may
enhance excretion of arsenic from the system. When carcinogenic effects of arsenic are evident, arsenic levels are
minimal and chelation may prove to be inadequate treatment.9 Oral retinoids have been used to reduce the risk of
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Skin Signs of Poisoning
319
internal malignancies as well as decrease the induction of
multiple BCC formation.
MERCURY POISONING
Poisoning with mercury is now fortunately rare although
it is still the second most common cause of heavy metal
poisoning.10 For more than 3000 years, mercury and its
derivatives have been used in a variety of systemic medications, dermatologic creams, dental amalgams, and medications.11,12 In addition, compounds of mercury have been
widely used as fungicides, bactericides, and catalysts and in
electrical parts, antifouling paints, and pulp and paper manufacturing. It is also found in a variety of household items,
such as thermometers, light bulbs, batteries, and seafood
products.13 The reports highlighting the toxicity of mercury ranged from contaminated fish (Minamata disease–
Japan, 1960)14,15 to infected grains (Iraq, 1971).16
Clinical manifestations may vary, depending on the
dose, type of mercury, method of administration, duration
of exposure, and individual sensitivity.17 Mercury toxicity
can also cause a variety of cutaneous signs and manifestations. The effect of mercury on the skin depends on the
mode of poisoning and extent of involvement. Mercury is
also a moderate sensitizer and leads to contact sensitivity.
Elemental Mercury
Elemental mercury is commonly found in thermometers, mercury-laden latex paint, and dental amalgams. It
is rapidly oxidized to mercuric ions and has a half-life of 60
days.17 In pediatric patients, exposure to accidental breakage of thermometers is one of the common routes of mercury toxicity. Children are at a higher risk for elemental
mercury poisoning because they attain much higher body
concentrations of the element compared with adults for the
same amount of exposure.10 Clinical signs and symptoms
are minimal after ingestion of elemental mercury because
gastrointestinal absorption is negligible. Up to 80% of elemental mercury that is inhaled, however, is absorbed and
diffuses rapidly across membranes, including the blood–
brain barrier and placenta.10 Acute toxicity results in three
symptomatic stages.18 Initially, a flu-like syndrome with
fever, myalgia, and dryness of the mouth and throat occurs.
After 2 weeks, the second stage ensues, mainly affecting the
gastrointestinal and respiratory tracts. Symptoms include
a metallic taste in the mouth, nausea, and vomiting. Fulminant interstitial pneumonitis, pulmonary edema, and
even pulmonary failure may occur. Nephrotic syndrome
has also been reported.10 Chronic exposure to mercury
produces a classic triad of intentional tremors, erethism
(increased excitability), and gingivitis. Cutaneous manifestations include an erythematous papular eruption and
bluish discoloration of the gingiva.
320 E MERGENCY D ERMATOLOGY
Organic Mercury
Organic mercury, in the form of methylmercury, is the
most toxic form of mercury and is commonly found in
processed wood, plastics and paper, insecticides, and vaccines containing thimerosal. It may also be found in
seafoods that are exposed to mercury-contaminated water.
Clinically, it causes irreversible damage to the central nervous system due to its lipid solubility allowing passage
through the blood–brain barrier.19 Demyelination, autonomic dysfunction, mental retardation, ataxia, and cerebral
palsy have all been reported in methylmercury toxicity.10
Inorganic Mercury
Inorganic mercury is found in topical medications, such as
antiseptic face creams and bleaching creams. Percutaneous
absorption of lethal doses is possible. Women of childbearing age who use mercury-based skin whiteners may
cause toxic effects on their unborn fetus.20 Application of
a mercury-containing cream to the face over many years
can produce slate-gray pigmentation, especially on the eyelids, nasolabial folds, and neck folds (exogenous ochronosis),21–23 and mercury granules lie free in the dermis or
within macrophages.24
Inorganic mercury exposure sometimes causes a bluish
linear pigmentation on the gums and tongue, which should
be considered a marker for systemic poisoning.
Acrodynia
As early as the 1890s, a disease entity called “pink disease” was recognized in Australia, characterized by diffuse painful, occasionally itchy, redness of the hands, feet,
and trunk.11 Acrodynia or pink disease is a hypersensitivity condition of infancy and early childhood, which
presents with both systemic and cutaneous symptoms
due to chronic mercury exposure.18 Acrodynia has been
reported in some patients who were chronically exposed
to calomel-containing teething and diaper powders, diaper rinses, termite-protected wood (mercury bichloride),
batteries, cathartics, antihelminthics, ammoniated mercury ointments, wart treatment pills, antisyphilitic agents,
and/or mercurial preservatives.11 Acrodynia was also seen
in a patient after inhalation of an accidental spillage of mercury onto the carpet where the child played frequently. In
the more recent years, stricter industrial and commercial
manufacturing measures have eliminated mercury in the
production of many of these items, leading to a significant
decline in the prevalence of acrodynia.
Clinical presentations may vary with children initially
presenting with irritability, lethargy, and anorexia, as well
as painful swelling of the hands and feet. Tips of the fingers
and toes acquire a pink color and later become dusky, hence,
the name “pink disease.” Acrodynia is pathognomonically
described as patients with “puffy, pink, painful, paresthetic,
perspiring, and peeling hands.”18 Occasionally, excruciating pain of the digits leads to sleep deprivation, whereas
persistent pruritus leads to lichenification and less often,
trichotillomania. The skin is cool and moist due to hyperhidrosis. Patients also develop alopecia, photophobia, muscle weakness, excessive salivation with gum swelling, and
diffuse hypotonia.
Mercury poisoning should be included in the differential diagnosis of atypical Kawasaki disease, although high
fever pathognomonic for Kawasaki disease is the major differentiating factor.
The natural course of acrodynia is prolonged, although
the prognosis is often good. A delayed presentation appears
to be a good prognostic sign. Mortality approximates
10%.11 Elevated urinary mercury level confirms the diagnosis. Treatment mainly involves removal of mercury from
the patient’s circulation and avoiding mercury exposure
from the environment.
Mercury Poisoning from Fish Ingestion
Aside from neurotoxic effects associated with ingestion of
mercury-containing food products, a recent report of a
new cutaneous sign of mercury poisoning has been documented. Dantzig25 described the appearance of nonpruritic
or mildly pruritic, discreet, small (1–2 mm), flesh-colored
or slightly erythematous papules and papulovesicles that
correlated with blood mercury levels and responded well
to lowering of the blood mercury levels. Children are
2–3 times more prone to mercury poisoning from seafood
ingestion because of a higher food intake per kilogram of
body weight.19 Lesions are mostly found on the palms,
soles, arms, and trunk. Lowering of blood mercury levels
with a seafood-free diet in all patients and chelation therapy
in seven patients resulted in clearing of the lesions.
Other Cutaneous Manifestations
In 2004, two distinct clinical patterns were reported in two
pediatric patients in the form of acute generalized exanthematous pustulosis (AGEP) and symmetric flexural exanthema “baboon syndrome.”26
AGEP is characterized by an acute eruption of
widespread, nonfollicular pustules with underlying edematous erythema associated with fever (>38◦ C) and leukocytosis.27 It is most frequently seen in association with
drugs such as penicillins and macrolides. Although cases
of mercury-related eruption have been reported, there is
no definite conclusion regarding the existence of a cause–
effect relationship. The baboon syndrome is a diffuse, symmetric, erythematous, maculopapular eruption of the flexural areas with a V-shaped pattern on the medial thighs
and diffuse erythema of the buttocks. The syndrome occurs
within a few days of exposure to mercury with no systemic
Chapter 33
symptoms.28 Mercury exposure from topical disinfectants, ophthalmologic preparations, and antiparasitic powders was also reported to produce systemic reactions.13,29
Patients recover with extensive exfoliation, particularly of
the palmoplantar surfaces, after 2 weeks. Positive patch
tests for delayed-type hypersensitivity were seen in 80%
of cases, but serum mercury levels and cutaneous disease
failed to show a correlation.13,29
Vaccine-Related Mercury Exposure
Neurodevelopmental disabilities, such as language delay,
attention deficit hyperactivity disorder, and especially
autism spectrum disorder30,31 have been reported in vaccines containing thimerosal, a vaccine preservative.
Thimerosal is 49.6% ethylmercury,20 which may be found
in diphtheria–tetanus–acellular pertussis, hepatitis B, and
some Hemophilus influenzae type B vaccines.32–34 It has
emerged as a major source of mercury in children in their
first 2 years of life.17 Reports that idiopathic autism may
be induced by early mercury exposure from vaccines that
exceed the safety guidelines of thimerosal determined by
the U.S. Food and Drug Administration (FDA) and the
American Academy of Pediatrics34 prompted studies validating this hypothesis. To date, there is no causal relationship between the timing of mercury administration
via vaccines and the onset of autistic symptoms.32 In July
1999, however, based on the rationale that cumulative doses
of ethylmercury from multiple vaccinations may potentially exceed the recommended safety levels of mercury,
the Environment Protection Agency responded by requesting manufacturers to remove thimerosal from vaccines.
Although thimerosal has been recently removed from most
children’s vaccines, it is still present in flu vaccines given to
pregnant women, elderly persons, and to children in developing countries.31
Diagnosis
An environmental history should be obtained when there
is a high index of suspicion. Mercury intoxication can be
identified with mercury-level assays from both blood and
hair. Hair mercury analysis is a reliable and more acceptable
means of detecting tissue mercury levels in children with
chronic exposure because it reflects tissue accumulation
of mercury for the past 2–3 months, whereas blood levels
reflect a more recent exposure to mercury.35 Histopathology is nonspecific. Urinary levels of vanillylmandelic and
homovanillic acid are increased in acrodynia due to inhibition of catechol methyltransferase.
Management
Management mainly involves identifying and eliminating
the source of mercury exposure. Removing the patient from
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321
the source of exposure alone may be sufficient to ameliorate or reverse the symptoms.36 Chelation is recommended
for symptomatic patients and those with toxic mercury
levels in the blood or urine. Dimercaprol, which was
previously the agent of choice, has now been found to
exacerbate neurotoxicity and deemed unsuitable.18 DMSA
(2,3-dimercaptosuccinic acid), a water-soluble analog of
dimercaprol, and/or D-penicillamine increase mercury
excretion and are employed for aggressive elimination of
serum mercury compounds. DMSA is, however, the only
chelating agent approved by the FDA for use in the pediatric population.36 There is a growing concern among
some clinicians with regard to the use of chelation therapy in the treatment of mercury poisoning because of the
lack of guidelines available to physicians and the paucity
of controlled studies that show a clinical beneficial longterm outcome among patients.36 The teratogenic effects of
these agents also limit the use among pregnant women.
Hemodialysis, peritoneal dialysis, and plasma exchange
have been shown to have beneficial effects in previous
reports.37 Most patients improve after treatment, but longterm morbidity and death have been reported.11 Treatment
should be individualized, depending on severity and presentation.
CAROTENODERMA
Carotenoderma is a phenomenon, characterized by orange
pigmentation of the skin, resulting from carotene deposition mainly in the stratum corneum. It is associated with a
high blood -carotene value and is regarded as a significant
physical finding, but a harmless condition.
Von Noorden38 described carotenemia in 1907. While
investigating diabetes mellitus and its treatment, he
noticed a carroty pigmentation in patients whose treatment involved special diets. A year later, Moro39 noted
the condition in infants. In 1919, Hess and Meyers40 gave
the term “carotenemia” to the condition consisting of
increased carotene blood levels and yellow skin pigmentation.
During the last century, epidemics of carotenemia have
occurred, usually as a result of carotene-rich diets. Food
rationing during the Second World War forced the public
to consume large quantities of carrots, which were nutritious and inexpensive. It was found to be transferred to
infants by breast-feeding.41 During the 1970s, carotenoderma was observed in many Japanese infants and in children who consumed high amounts of tangerines or tangerine juice.42 Carotenemia is endemic in West Africa as
a result of frequent use of red palm oil, which is rich in
carotenoids.43
On histology, the stratum corneum has a high lipid
content that has an affinity for carotene, so the carotene
pigment is concentrated in the stratum corneum. On
direct immunofluorescence it can autofluoresce in a
322 E MERGENCY D ERMATOLOGY
pemphigus-like intercellular pattern, and thus be mistaken
for pemphigus vulgaris.44
Carotenoids are found in a complex with proteins or in
crystalline carotenoid complexes in vegetables and fruits.45
-carotene is not synthesized in the human body. Its source
is food. It gives some fruits and vegetables their orange–
yellow hue. In green vegetables, the yellow pigment is
masked by chlorophyll. In a study done in a Brazilian population in 2005,46 the authors showed that green vegetables, such as lettuce, contain a considerable amount of
carotenoids.
About one third of ingested -carotene is absorbed.47
Absorbance is affected by the fiber content of food and
by food processing. Mashing, cooking, and pureeing of
fruits and vegetables cause rupture of cells and enhance
the availability of -carotene.47 In the presence of bile
acids it becomes incorporated into mixed micelles, from
which it is absorbed by passive diffusion into the enterocytes in the small intestine mucosa. In the enterocyte,
most of the -carotene is converted into retinal by the
enzyme 15,15 -dioxygenase.48 Retinal reductase converts
retinal to retinol49 (vitamin A), which is then complexed
with long-chain fatty acids to be transported to the liver as
chylomicrons.50 It is not clear how much intact -carotene
is absorbed. In the literature, estimates vary between 10%
and 80%. The amount of intact -carotene absorbed
is affected by -carotene intake and vitamin A stores.
-carotene that is directly absorbed, however, is transported to the liver via the portal circulation.51,52 Although
-carotene is fat soluble, eating it with as little as 3–5 g
of fat per meal can still increase its plasma levels.53 Absorption is also enhanced by pancreatic lipase, bile acids, and
probably by the thyroid hormone. Disturbance of fat
absorption, infection, and intestinal disease may all impair
-carotene absorption.54 High gastric pH levels interfere
with absorption, probably by inhibiting passive diffusion
into the enterocyte.55 Certain constituents of food, such
as sulfides and acids,56 can destroy -carotene. Pectin
interrupts micelle formation and hence interferes with
-carotene absorption.57 Lutein and canthaxanthin inhibit
the conversion of -carotene to retinal.58
-carotene is stored in the liver and adipose tissues, and
can also be found in high concentrations in the testes and
in the adrenal glands. In healthy persons, there is a linear relationship between serum -lipoprotein and serum
-carotene levels.59
Excretion of -carotene occurs mainly through the
colon and epidermis through sebaceous glands. A small
amount is excreted through the urine.60
A number of mechanisms are presumed to be responsible
for carotenemia. The most common is excessive dietary
consumption of -carotene. Carotenemia may be observed
4–7 weeks after initiation of a diet rich in carotenoids.42
In these cases of carotenemia, serum levels of vitamin A
may be normal or elevated, although never high enough
to cause hypervitaminosis A. High blood levels of carotene
are never high enough to cause hypervitaminosis A because
conversion of carotene to vitamin A is slow.47
The linear relationship between -lipoprotein and
-carotene may cause carotenemia in hyperlipidemiaassociated disorders, such as diabetes mellitus, nephrotic
syndrome, and hypothyroidism.61,62 Carotenemia in
anorexia nervosa is chiefly related to a diet that is rich in carotene sources. Some consider the cause to be an acquired
defect in the metabolism or utilization of vitamin A. It may
also be related to abnormalities of lipid metabolism, such as
the decreased catabolism of -lipoprotein63 and hypothyroidism, which are observed in this disease.64
Liver disease may cause carotenemia due to impaired
conversion of -carotene into vitamin A. In these cases
carotenoderma may be masked by jaundice.54
Kidney diseases, particularly nephrotic syndrome and
chronic glomerulonephritis, may be associated with elevated serum levels of -carotene. In nephrotic syndrome
it is attributed to hyperlipidemia. An interesting finding is
the absence of carotenoderma in patients who suffer from
renal disease despite elevated serum -carotene.54
Metabolic (idiopathic) carotenemia is thought to
result from a relative or absolute deficiency of 15,15 dioxygenase, which leads to accumulation of -carotene
and to low to normal vitamin A levels. This enzyme defect
may be familial.59 High -carotene levels in Alzheimer disease are also suggested to arise from an abnormality in the
conversion of -carotene to vitamin A.65
Hypopituitarism and male castrates are conditions that
have also been reported to be associated with carotenemia.47 There is an anecdotal report of carotenemia and
Simmonds disease.54
Clinical Manifestations
The yellow pigmentation of -carotene appears when its
concentrations in serum exceed 250 g/dL. It is deposited
mainly in the stratum corneum, in sweat, and in sebum,
and hence pigmentation is noted in areas where sweating
is marked, such as the nasolabial folds, palms, and soles. It
can extend to the entire body. The sclerae are not affected,
and this helps to distinguish carotenoderma from jaundice. Another typical sign of carotenoderma is its enhanced
appearance under artificial light.66
Complications
There is a debate as to whether carotenemia is a harmless condition. Some authors report that long-standing
carotenemia has been associated with weakness, weight
loss, hepatomegaly, hypotension, neutropenia,67 and
amenorrhea.68 Others report no abnormality with high
serum -carotene.69 There is, however, an agreement that
carotenemia is not associated with vitamin A toxicity.
Chapter 33
Treatment
Treatment begins with reassurance that this is a benign
condition. Dietary carotenemia is easily manageable within
weeks to months on a low--carotene diet.48 Carotenemia
associated with hyper--lipoproteinemia is reversible by
treatment of the underlying cause or with a lipid-lowering
diet. There is not yet a satisfactory treatment for metabolic
carotenemia.50
CO POISONING
CO poisoning causes organ damage as a result of cellular hypoxia. The toxic effects of tissue hypoxia were first
described by Bernard in 185770 ; then, in 1895, Haldane71
described the underlying mechanism of CO toxicity. CO
poisoning affects nearly all organs, including the central and
peripheral nervous system, heart, kidney, skeletal, muscle,
and skin. The clinical manifestations are diverse, and various complications and sequelae may develop following CO
poisoning. Cardiac arrhythmias, such as ventricular fibrillations, however, constitute the major threats to life during
acute exposure.72–75
Symptoms and signs become increasingly apparent as
circulating levels of carboxyhemoglobin rise. Severe CO
poisoning can also produce several types of lesions of the
skin.76–80 The lesions vary in degree from erythema and
edema to marked vesicle and bulla formation. Vivid erythematous or edematous plaques appear, especially at pressure
sites, within hours after CO poisoning.81 Vesicles and bullae may develop, often in a geographical pattern.82,83 The
scalp lesion of edema and erythema may evolve into areas
of alopecia.77
The lesions simulate those seen in burns, trauma, or
barbiturate poisoning or after cerebral vascular accident or
drug-induced coma. Histologically, the bullae show epidermal necrosis, intraepidermal vesiculation, and necrosis of
the secreting portions of the sweat glands.81 Pressure and
hypoxia are probably the main factors in the pathogenesis.79
Spontaneous resolution occurs in persons who survive,
in about 15 days.81,84
DIOXIN POISONING (CHLORACNE)
Chloracne is a rare, follicular, acneiform eruption that is
a characteristic symptom of dioxin poisoning. Dioxins are
polyhalogenated aromatic hydrocarbons that can be found
in herbicides and wood preservatives.85
Dioxins are a group of chemicals, which include
75 different chlorinated molecules of dibenzo-p-dioxin
and 135 chlorinated dibenzofurans. Some polychlorinated
biphenyls are referred to as dioxin-like compounds. Of the
chloracnegenic compounds, 2,3-tetrachlorodibenzo-paradioxin (TCDD), or dioxin, is regarded to be the most harmful, associated with many harmful health effects, possessing
potentially carcinogenic and teratogenic properties.86 It is
●
Skin Signs of Poisoning
323
a normal by-product of numerous manufacturing processes
and waste incineration.
Small amounts of TCDD (15–45 U/g body fat) are seen
normally in humans because of its use in many common
industries. It is tasteless but highly toxic.
More than 95% of human exposure to dioxin is through
the diet. Air emissions of pollutants, including dioxin, settle on vegetation that is fed to livestock. Dioxin then accumulates in animal fatty tissue and is conveyed to humans
through meat and dairy products. Fish and other aquatic
organisms ingest dioxin that is washed into bodies of water
from land, providing another potential pathway into the
food chain. The average dietary intakes of dioxins have
declined dramatically over the past 20 years in the United
States and Western Europe due to better environmental
regulations. As a result of this dramatic improvement in
dioxin contamination, the average person born today in the
Western world will receive his or her highest exposure to
dioxins as a developing fetus and as a nursing infant. Much
of that exposure comes from breast milk as the mother
mobilizes fatty acids, where dioxin is sequestered, to form
breast milk.
Acute dioxin poisoning is rare. Most of the experience
with acute dioxin poisoning resulted from industrial accidents. In 1976, a large number of people in Seveso, Italy,
were exposed to high levels of dioxins through contaminated cooking oil.
There is also the “Ranch Hand” study that examined
the health of more than 1200 U.S. Air Force personnel
who worked with Agent Orange. Dioxin was an ingredient in Agent Orange, a defoliant used during the Vietnam
War. These servicemen have been followed for many years
by the Department of Veterans Affairs and are still being
monitored today. Many of them, particularly the ground
technicians who loaded spray planes with Agent Orange,
developed chloracne. Other episodes of dioxin poisoning
occurred several years ago at places such as Love Canal,
where hundreds of families needed to abandon their homes
due to dioxin contamination, and Times Beach, Missouri,
a town that was abandoned as a result of dioxin.
Dioxin, however, made worldwide headlines in September 2004, when Ukrainian President Viktor Yushchenko
had been poisoned. His blood samples contained an abnormally high level of dioxin, 1000 times the accepted level.
One year later, Yushchenko’s face, with its strong jaw and
movie-star features, remained badly pockmarked.
Clinical Findings
Dioxin taken in through the human diet dissolves in the
fatty components of blood, eventually accumulating in fatty
tissue. The human body eliminates dioxin slowly; at any
given time, the dioxin concentration in the fatty tissue
of a human body is a function of the competing rates of
accumulation and elimination. Half a dose of dioxin gets
324 E MERGENCY D ERMATOLOGY
eliminated every few years but never completely rids itself.
Dioxin is eliminated also through sebaceous glands; as a
result, the skin grows oily or pimply, resulting in chloracne.
Chloracne is considered to be the hallmark of dioxin poisoning and represents a symptom of systemic poisoning by
chemical chloracnegens and not just a cutaneous disorder.87
It has been found to be 4 times more frequent in persons
with plasma dioxin levels greater than 10 ppt.88 Chloracne
clinically presents a few months after ingestion, inhalation,
or manipulation of the toxic agent. Cutaneous findings of
chloracne include open and closed comedones and noninflammatory nodules and cysts, mostly on the malar crescent and in postauricular, axillary, and inguinal areas. With
more severe dioxin exposure, cysts become inflammatory
and may spread to the trunk and genitalia. The nose and
limbs are usually spared. Scarring may be severe. It differs
from acne vulgaris because of the paucity of pustules or
nodules, atrophy of sebaceous glands, sparseness of Propionibacterium acnes,87 frequent involvement of meibomian
glands, and occurrence in any age group.85
A follow-up study on the Seveso, Italy, dioxin accident of 1976 done 20 years after the incident showed that
dioxin toxicity was confined to acute dermatotoxic effects.
Increased dioxin levels were still seen in 26.6% of the
affected population – particularly in women, in persons who
had ingested home-grown animals, and in individuals with
older age, higher body mass index, and residence near the
accident site. There was, however, an association between
chloracne risk and light hair color as well as younger age
(<8 years old) at the time of the accident.88
Dioxin also binds to cellular hormone receptors; thus, it
has the potential to modify the functioning and genetic
mechanism of the cell, causing a wide range of effects,
from cancer to reduced immunity to nervous system disorders to miscarriages and birth deformity. Indeed, systemically chloracne may be associated with abnormal liver
function, hyperhidrosis, conjunctivitis, transient peripheral
neuropathy, encephalopathy, and porphyria cutanea tarda–
like-features (pigmentation, hirsutism). In a study on the
effects of dioxin in children involved in a major environmental accident near Seveso, Italy, in 1976, those exposed
to the highest concentration of TCDD showed alterations
in serum ␥ -glutamyltransferase and alanine aminotransferase activity compared with the control group. These
changes were mild and disappeared with time.89 In higher
quantities, however, severe effects, such as spina bifida
(split spine) and other birth defects, autism, endometriosis,
reduced immunity, chronic fatigue syndrome, psychological disorders, and other nerve and blood disorders, have
been reported.
Management
Management of chloracne may be challenging. It is important to identify and remove the source of exposure. Some
lesions clear up spontaneously within 2 years while others
may continue for decades. Persistent cases may be treated
similarly to acne with topical retinoids, oral antimicrobials,
or oral isotretinoin. A nondigestible, lipophilic dietary fat
substitute called olestra has shown promise in reducing systemic dioxin levels by eightfold to tenfold and reducing the
half-life from 7 to 1–2 years.90 The most important means,
however, is preventing contamination of the environment
by strict legislation.
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CHAPTER 34
Disaster Planning: Mass Casualty
Management
Lion Poles
DISASTERS AND OTHER emergencies can strain and
even damage – at least transiently – a health care system.
The increased awareness of natural and manmade disasters
has created a relatively new need for health care providers:
preparedness and response for medical emergencies. To
remain both robust and flexible, the medical systems must
establish protocols, perform exercises, and learn from the
experience of others. Facing threats since it was born 62
years ago, the Israeli medical system has conducted a comprehensive preparedness activity that has been tested in
large-scale exercises and in large- and small-scale violent
conflicts.
AN OVERVIEW OF THE ISRAELI MEDICAL SYSTEM
Israel has 24 public acute care hospitals in addition to its
geriatric, psychiatric, and private hospitals. The hospital
system serves both the civilian and the military population.
Six are trauma centers (level 1) located in densely populated
urban areas; 14 others are acute care medical centers without cardiosurgery or neurosurgery services (level 2), and the
rest are relatively remote community hospitals (level 3) that
can offer triage and limited surgical and surge capacity. All
Israeli hospitals maintain continuous alert for mass casualty
incidents (MCIs) in line with a unified national doctrine.
Thus, we regard the hospitals as part of the first-responders
system. In the extrahospital arena, there is a highly developed network of outpatient clinics, part of the four health
maintenance organizations’ (HMOs’) network of primary
care clinics.
As for other first-responders systems, Israel has a single national emergency medical service (EMS), a national
police system, and a regionally based firefighting system.
The national search-and-rescue unit and air evacuation
systems are operated by the Israel Defense Forces (IDF).
The leader of the medical system, which sets priorities
in peacetime, during major disasters, and during wars,
is the Supreme Health Authority (SHA); it is headed by
the Director General of the Ministry of Health (MOH),
the Surgeon General (member, IDF Medical corps) and
the chief executive officer (CEO) of the largest HMO
(member). An advisory committee comprising the MOH
senior executive officials, EMS, the Home Front Command (HFC) medical officer, and other organizations is
consulted if necessary. The HFC medical department acts
as an operational arm of the SHA. Main budgets of medical
preparedness for MCIs originate from the MOH: Specific
facilities such as decontamination sites, equipment (e.g.,
physical protection, respirators), pharmaceuticals, and new
infrastructure are funded by the MOH.
EVOLUTION OF OPERABILITY OF
THE HOSPITAL SYSTEM
The general hospitals have always been an integral part of
Israel’s national emergency response system. Most hospitals have participated in the management of injured soldiers
and civilians during and between wars. Historically, lessons
learned during wartime and through isolated conventional
MCIs were gathered, but no comprehensive doctrine was
established. In the 1980s, as lessons emerged from the war
of 1973 and the perceived threat of chemical warfare (CW)
increased, the heads of the medical system decided that a
fundamental change was needed in the way hospitals prepare for crises.
Under the auspices of the SHA, a trilateral system was
founded. The Emergency Division of the MOH was given
overall responsibility and funding for infrastructure and
procurement; and the IDF medical corps – acting on behalf
of the MOH through a newly established Hospital Contingency Branch (HCB) and the Nuclear, Biological, and
Chemical Medical Branch – led the development of doctrine and the implementation of new procedures. Representatives of the public general hospitals participated
in planning and implementation through several steering
committees. These committees were headed by hospital
executives and were composed of subject-matter experts
and representatives of the trilateral preparedness organization. Nominated specific committees included a contingency committee for conventional MCIs, a similar committee for CW hospital preparedness, and committees for
human resources and for procurement. End products were
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328 E MERGENCY D ERMATOLOGY
presented and approved by the SHA, becoming official policies and backed up by the necessary budgets.
After Israel was attacked by Iraqi missiles during Operation Desert Storm in the Persian Gulf (1991), the HCB was
designated as the leader for CW preparedness. Thereafter,
new steering committees developed new directions, such
as preparing for an accident at a nuclear reactor (1994) and
preparing for a mass toxicological incident (1997, following the release of the nerve gas sarin by terrorists in Japan
in 1994–1995). The principles of preparedness and the
interrelationships of groups involved have remained since.
Concomitantly, operational missions were transferred to
the medical department of the HFC (established in 1994),
which incorporated HCB in 1999. The emerging threat
of biological warfare (BW) and a new crisis alert regarding Iraq in 1998 led to the development of an entirely new
preparedness initiative – the “unusual biological incident.”
The evolving threats of BW, bioterrorism, and emerging
infectious diseases necessitated different kinds of response
and new partners, including the public health system, laboratory network, surveillance system, and ambulatory medical services. In the biological threat scenario, hospitals
changed their role; rather than being the key factor, as
in previous threats, they became just one component of
a national interrelated response system that was developed
within the MOH.
COMPONENTS OF PLANNING FOR EMERGENCY
RESPONSE IN THE ACUTE CARE HOSPITAL
Israeli hospitals are regarded as part of the first-responder
system because most of the medical management of victims and nearly all decontamination procedures are planned
and actually have taken place within hospitals. In addition, the last decade’s experience of the EMS has shown
that, for most urban incidents, evacuation of all victims can
last up to 90 minutes after the incident. Because natural
and man-made MCIs can occur after hours, all hospital
contingency plans base initial response on the emergency
department, which is reinforced by any in-house staff available during those hours. Hospitals have developed redundant telecommunications and staff notification capabilities. The hospital standard operating procedure (SOP) plan
is to provide effective triage, decontamination, and treatment in the first hour with these resources, until additional
staff arrive and are incorporated into the crisis management activities. Specific means provided to hospitals by the
MOH include decontamination infrastructure (e.g., communication, decontamination sites, and negative–positive
pressure environments); power-driven level 3 respiratory
protection sets with universal canisters (ABEK P3 type);
mission-oriented protective posture 4 (MOPP4) protective
garments or, alternatively, standard kits to protect against
airborne biological agents; and specific sets of antidotes
sufficient for the first 8–24 hours of treatment (to be supplemented from national stockpiles).
All prehospital and interhospital activities in times of
large-scale emergencies are supervised and coordinated by
the chief medical officer of the HFC (on behalf of the
MOH) through a command and control center. Within
the hospital, all emergency contingency activity is coordinated and supervised generally by a senior physician and
nurse. Because emergency preparedness is principally a
nonprofit activity funded by the hospital, in many places
this physician is one of the hospital’s deputy general managers. He or she heads an advisory committee – an emergency contingency committee – with representatives from
nursing, logistics, security, and administration. Subcommittees are often established for specific scenarios (e.g., a
bioevent committee comprising the infectious disease unit,
the director of the microbiological laboratory, a security
officer, and logistics and nursing executives). These subcommittees define and help to execute annual and ad hoc
plans, updated according to MOH directives. As these officials are not primarily assigned to emergency preparedness, their activities usually reach a peak before planned
or anticipated exercises or inspections of the regulatory
bodies. Their most difficult task is maintaining continuous
readiness among the staff, through intermittent individual
or institutional training and small-scale drills.
In Israel, the public, the media, and the MOH expect
hospitals to be able to handle any emergency, and hospital
managers perform accordingly perhaps as a matter of selfesteem. Only recently has systematic analysis been done
for the most likely wartime scenarios with which hospitals should prepare to cope. There is still no official specific analysis of hospitals’ missions during terrorist events
and natural disasters, and no procedures have been established for assessing hospitals’ individual vulnerabilities to
internal hazards. With respect to MCIs, all Israeli hospitals are expected to provide medical assessment, treatment,
and continuing care for large numbers of patients and to
identify and manage contaminated patients and patients
who have been exposed to an unusual biological agent (this
management includes protecting the hospital staff, patients,
and others within the hospital). In general, such response
and mitigation activities should not interfere with everyday
emergency care.
According to lessons learned in Israel from mass casualty event MCIs, following a terrorist incident three waves
of casualties arrive at emergency rooms: the most severely
injured arrive by EMS ambulances or by private cars within
45 minutes in an urban location. Moderately or mildly
injured victims arrive within 2 hours. The third wave consists of patients mildly injured and those experiencing acute
stress reaction, all who arrive within 24 hours. Three systems of resources are involved in managing these patients:
operational, medical, and informational. Hospitals need
Chapter 34
to assemble, evaluate, implement, and disseminate information quickly and accurately and deliver it to various
internal and external customers, including local and state
agencies.
To be efficient in response during a crisis, the hospital
must be a part of a coordinated collaborative effort. Other
members include other first responders, the media, local
communities, the National Institute for Forensic Medicine,
other hospitals, the MOH, and the HFC. Ideally, there
should be one risk communication system for the public, for both informative and directive purposes. Practically, the media provide a medium for conveying information and sometimes directions to the public by senior
officials in the hospital system or the MOH. As the hospitals’ CEOs may be forced to address the media and share
information with the public, providing updates on the situation, it is beneficial to train them in “risk communication”
skills.
Target allocation and evacuation from the disaster or
mass emergency area is done by the HFC’s medical and the
EMS control centers. They are also responsible for alerting
hospitals of casualties that are on the way. This notification
leads to activation of the hospitals’ SOP.
Throughout the emergency, every hospital is planning
to host a designated EMS liaison officer in its control
center. His or her duty is to coordinate the activities of
ambulances in the hospital both primarily from the scene
and later for secondary allocation of victims. Another liaison is an officer from the HFC medical department who
works with the hospital’s incident command system to
assist the hospital’s needs – disseminate information within
the hospital, the MOH, and the EMS networks; coordinate the air evacuation missions; and communicate about
resources and support needed from other authorities and
agencies.
The Israeli media plays a role in medical response in
times of emergency, serving as a “first responder” for information. Hospital emergency plans incorporate designated
areas for the media.
CURRENT POLICIES
Current policies – including policies for hospital emergency preparedness – are dictated by economic pressures
and tight budgets, especially in the medical system. Moreover, there is a huge array of possible manmade and natural
disasters. Consequently, there is a clear need for a costeffective approach that can find a common denominator
among many threats, so as to concentrate on generic solutions. Such denominators might include decontamination;
surge capacity; multifaceted, multilevel triage; communication regarding risks and crises; and public relations. It
is vital to consent on low- versus high-probability scenarios, so that preferences and resources can be allotted to
●
Disaster Planning: Mass Casualty Management
329
the latter (in toto) and critical steps in the response plan
to the former. Hospital-specific hazards – both external
and internal – should be analyzed, and emergency missions
should be tailored accordingly and supported by appropriate resources.
Emergency scenarios can be classified as “rapid” or
“slow” types. Rapid scenarios involve conventional events
(e.g., mass trauma from explosives or airplane crashes),
chemicals (including toxins), and quickly identifiable radiological exposure. These scenarios tend to be clearly
bounded in time and place, with distinct victims or exposed
individuals. Most of the rapid scenarios are easily perceived
by human senses or simple monitoring equipment. Victims
are managed mainly within the hospital system. The initial
response phase is expected to be limited to 24 hours. Common problems in rapid scenarios include surge capacity,
triage, decontamination, identification of hazards, treatment protocols, control and communication, public relations, intensive care, and personnel recruitment and management. The main principles of response planning for
rapid scenarios are to apply the experience gained from the
terror campaign of the last 15 years and to apply the conventional MCI model (modified as necessary for victims of
contamination). It is pertinent that hospitals will maintain
readiness for these type of emergencies, among others, by
maintaining “just in case” annual training programs.
Slow scenarios include biological outbreaks and unidentified radiological exposure. These scenarios are not clearly
bounded in space or time nor are the victims or exposed
individuals distinct. Slow scenarios are not perceptible by
human senses; thus relatively advanced or sophisticated
diagnostic procedures are necessary. The response to a slow
scenario is beyond the scope of the hospital system, and
the response phase will last for several days or weeks. The
main problems are similar to those in rapid scenarios: surge
capacity, triage, contaminated victims, and so forth. Special consideration should be given, however, to detecting
the event, to notification, to diagnostic procedures, and to
relationships with external entities such as public health and
ambulatory medical services. Specific criteria for a hospital’s preparedness should be established. Local planning,
staff training, and maintenance of emergency equipment
are not funded by the MOH (preparedness activities tend to
add expense but not to produce revenue); still, any new standards should be accompanied by appropriate resources or
budget allocations. Finally, emergency contingency units
should be founded and funded within the general hospital, ambulatory, and public health systems to ensure
real commitment and productivity on the part of nonemergency medical organizations. For the slow scenarios,
it is reasonable to maintain limited readiness – for the initial
response only – and to prepare resources such as materials
(manuals, presentations, etc.) for providing “just-in-time”
training.
330 E MERGENCY D ERMATOLOGY
CONCLUSIONS
Some of these principles are already implemented or
are expected to be implemented in the strategy of the
MOH.
FURTHER READING
Hughes JM. The emerging threat of bioterrorism. Emerg infect
Dis. 1999; 5:494–5.
Poles L. Contingency of the national hospitalization system for peacetime emergencies. Harefuah. 2001; 130:817–20.
(Hebrew)
Shalala DE. Bioterrorism: how prepared are we? Emerg Infect Dis.
1999; 5:492–3.
Torok TJ, Tauxe RV, Wise RP, et al. A large cummunity outbreak of salmonellosis caused by intentional contamination of
restaurant salad bars. JAMA. 1997; 278:389–95.
WuDunn S, Miller J, Broad WJ. How Japan germ terror alerted
world. New York Times, 26 May 1998; Sect A: 1 (col 1),
A: 10 (col 1–5).
CHAPTER 35
Catastrophes in Cosmetic Procedures
Marina Landau
Ronni Wolf
DERMATOLOGISTS HAVE performed surgery and
cosmetic invasive procedures on the skin since the 19th
century. They are responsible for developments in chemical peels, hair transplantation, dermabrasion, sclerotherapy, laser surgery, and liposuction. As with any medical
treatment, those procedures carry inherent risk for possible complications.
“If you’ve been thinking of having your face or body
rejuvenated, but have been scared off by the thought of
major surgery, then maybe it’s time to think again. A wealth
of new techniques and technologies have transformed the
field of cosmetic treatment. The common feature of all
these new treatments is ‘minimally invasive’ – that is, less
cutting, less open surgery, less risk and less downtime.
Not only that – the cost is often far lower,” says one
(of many) Web sites (see http://www.shanghaiexpat.com/
Article1103965.phtml accessed March 10, 2010). For individuals who choose a minimally invasive cosmetic procedure aimed at improving appearance, fighting the signs of
aging, and restoring their youthful looks (as opposed to
treating a “real” disease), any visual side effect is considered a “catastrophe.” Therefore, we include in this chapter,
aside from “true emergencies/catastrophes,” what we call
“aesthetic catastrophes.”
formation of such scars include race (skin of color and
Asian), heredity, excessive wound tension, excessively deep
dermal injury, wound infection, and foreign body reaction.
The concomitant or recent use of oral vitamin A derivatives
has been traditionally considered as a risk factor for bad
scarring.1,2 This opinion has been recently challenged.3,4
Despite the high prevalence of keloids in the general
population, they remain one of the more challenging dermatologic conditions to manage. Because patients with
a previous personal or family history of keloids are at
increased risk for developing abnormal scars, they should
avoid elective cosmetic procedures with a risk for scarring.
If such a procedure is performed, wounds should be closed
with minimal tension and the immediate use of silicone gel
sheets should be started.
A wide range of therapies exists for keloids, with the
most commonly used modalities being intralesional steroid
injection, surgical excision, cryotherapy, laser therapy,
radiation therapy, and the application of silicon gel sheets.
Other treatments that have been used with variable success rates include imiquimod, 5-fluorouracil, bleomycin,
retinoids, calcium channel blockers, mitomycin C, and
interferon-␣ 2b. A recent meta-analysis of 39 studies, representing 27 different treatments, reported a 70% chance
of clinical improvement with any type of treatment.5
SCARRING
A significant number of procedures in dermatology carry
a risk of scarring. In some procedure scarring is inevitable,
such as in surgical rhytidectomies and hair transplantations,
whereas in others scarring is considered a complication,
such as in chemical peels or laser surgery. The ultimate goal
of a physician performing these interventions is to create a
superior cosmetic outcome by avoiding or minimizing the
scar.
Unfortunately, some cases result in hypertrophic scarring or keloids instead of a minimal scar. Those abnormally thickened scars are often painful or pruritic. The
common locations for keloids and hypertrophic scars are
on the upper trunk, neck, and upper extremities and over
bony prominences of the face. Factors predisposing to the
INFECTIONS
Because dermatologic procedures disrupt skin integrity,
they alter the body’s protective barrier and predispose
theoretically to cutaneous infections. Surprisingly, postoperative wound infections seldom complicate dermatologic procedures, ranging from 1% to 3%;6 however, they
have been rarely reported to complicate simple procedures
such as excisions, biopsies, skin grafts, chemical peels, dermabrasion, laser resurfacing, liposuction, blepharoplasty,
and filler injections.
Antimicrobials continue to be widely used in the setting of dermatologic surgery for the prevention of surgical wound infection, endocarditis, and late prosthetic joint
infections. Debate regarding routine use of topical and
page 331
332 E MERGENCY D ERMATOLOGY
systemic antibiotics is still ongoing. The literature suggests that, for most routine skin procedures, antibiotic
use is probably not warranted. During prolonged Mohs
procedures, delayed repairs, grafts, or any procedure that
breaches a mucosal surface, decisions should be made on
a case-by-case basis. Systemic prophylactic antibiotics for
laser resurfacing and liposuction are also not routinely
necessary.7 For the prevention of surgical site infections,
antimicrobials may be indicated for procedures on the
lower extremities or groin, for wedge excisions of the lip
and ear, skin flaps on the nose, skin grafts, and for patients
with extensive inflammatory skin disease.8
Pooled data from four studies on the risk of bacteremia
during dermatologic surgery including scalpel excision,
electrodesiccation and curettage, Mohs surgery, hair transplantation, and flaps and grafts on clinically noninfected
skin revealed a risk of bacteremia at 1.9%.9–12 Despite
a strong shift away from administration of prophylactic
antibiotics in many dermatologic surgery settings, it is still
needed for patients with high-risk cardiac conditions and
for a defined group of patients with prosthetic joints at high
risk for hematogenous total joint infection.8
BLEEDING
Although the overall incidence is low, bleeding complications in dermatologic surgery can occur and be the source
of patient morbidity. It is particularly important because
the use of blood thinners has increased dramatically in
recent years among the general, and especially among the
elderly, population. In addition, many patients are taking
dietary supplements that may alter coagulation.13 When
these patients need to undergo cutaneous surgery, the
surgeon might encounter a problem of increased bleeding tendency. Discontinuation of these medications may
increase the risk of cerebral and cardiovascular complications; therefore, a question of safe continuation or discontinuation of anticoagulant and antiplatelet medications
before surgery might be a major issue in dermatologic
surgery.
Meta-analysis of controlled studies reporting bleeding and other complications among patients undergoing
cutaneous surgery who were taking anticoagulant medications suggests that although low, the risk of bleeding among anticoagulated patients may be higher than
baseline.14 Until recently, discontinuation of anticoagulation and antiplatelet therapy before surgery was a
rule.
In recent years, dermasurgeons have been more likely to
continue medically necessary aspirin and warfarin, but to
discontinue prophylactic aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and vitamin E.15,16 There are no
studies in the literature that examined the effects of combination anticoagulant therapy or the effect of herbal agents
on postoperative risk of bleeding.
PROCEDURE-SPECIFIC COMPLICATIONS
Dermal Fillers
In 1899, Robert Gersuny, a Viennese surgeon , introduced
R
) for correction of soft-tissue defects.
mineral oil (Vaseline
The principle of the technique consisted in the injection of
a product that becomes semiliquid by heating but solidifies
R
when cooled. Later, Vaseline
was replaced with paraffin.
Although serious complications were reported, it remained
popular for the first 20 years of the 20th century. Unfortunately, even with initial good results, secondary or late
severe complications appeared due to the dispersion of
paraffin. There was formation of nodules, the paraffinomas
that were very difficult to remove. The sequelae of paraffin
injections were observed for several years.17
Since that time, soft-tissue augmentation using autologous or synthetic products has become the cornerstone of
facial beautification and of antiaging treatment. The choice
of commercially available dermal fillers is growing constantly.18,19
In the European Union, injectable fillers are certified as
medical devices. Depending on the potential risk of each
substance, a controlled clinical trial may be performed during the certification process; nevertheless, the process is
completely different from that applied for U.S. Food and
Drug Administration (FDA) approval. Not infrequently,
the safety and efficacy of many CE-certified injectables are
assessed only in the postmarketing process.
No matter what the origin of the fillers is, they are
usually classified into resorbable and permanent groups.
Resorbable materials, such as collagens and hyaluronic
acids, are removed from the tissue by phagocytosis. PerR
manent fillers, such as silicone and ArteFill
, cannot be
removed efficiently. Large microspheres of nonresorbable
fillers are encapsulated with fibrous tissue and escape
phagocytosis.
In 2004, a new classification of dermal fillers, taking
into account the long-term safety and reversibility of the
side effects, was proposed.20 According to this classification, dermal fillers are nonpermanent and biodegradable (e.g., collagens and hyaluronic acids), semipermanent
and biodegradable (e.g., polylactic acid), permanent and
reversible (e.g., expanded poly tetrafluoroethylene), or permanent and nonreversible (e.g., liquid injectable silicone,
polymethylmethacrylate).
Complications and adverse reactions can occur with
all fillers and all filler procedures. The most common
side effects include hematomas, ecchymoses, swelling, erythema, discoloration, visibility, or palpability of the filler.
Hypersensitivity and tissue necrosis are rare and most distressing. Filler migration, granuloma formation, infection,
and delayed inflammatory reactions do not usually occur
with nonpermanent biodegradable fillers.
Hematoma and ecchymosis are due to extravasation of
blood cells into the tissue due to needle injury of blood
Chapter 35
vessels. Alcohol consumption, blood thinners, NSAIDs,
aspirin, vitamin E, omega 3, and probably other herbal
agents facilitate the occurrence of hematoma. If these drugs
are used prophylactically, proper discontinuation of their
intake prior to the procedure, and refraining from alcohol
consumption, may prevent some of the bleeding events.
Firm pressure immediately after the injection and ice-pack
application may minimize the bleeding, if it occurs. In general, collagen-based fillers (Zyderm, Evolence) are associated with less bleeding due to induction of platelet aggregation.
Transient swelling and redness occur immediately after
a filler injection and usually last a few hours to a few days.
These phenomena are probably secondary to the inflammation induced by the product itself, injection trauma, and
tissue manipulation by massaging or molding. Some products are more prone to induce tissue swelling due to their
hygroscopic properties (e.g., hyaluronic acid–based products). Certain facial areas, such as the lips, are specifically
sensitive to injections and inevitably swell after the procedure. Prolonged icing of the area without direct contact
between the ice cube and the skin can assist to diminish this
phenomenon.
More prolonged swelling can signal overcorrection.
Tear trough depression is especially sensitive to overcorrections. Permanent or periodic (usually in the mornings)
swelling in this area may require dissolving the filler by
enzyme hyaluronidase.21
Discoloration in the injection site is either induced by
hemosiderin deposits following postprocedural hematoma
or due to superficial implantation of the filler in a way
that the original color of the product or its interaction
with the tissue shows. A bluish tint in the areas where
hyaluronic acid was implanted too superficially is known as
the Tyndall effect.22 This can be also successfully treated
by hyaluronidase.
Visibility and palpability of the filler are also related to
a bad injection technique.
R
injection are
Palpable nodularities after ArteFill
observed as a result of uneven delivery of material due
to clumping of the polymethylacrylate microspheres. This
finding has nothing to do with granuloma formation.23
R
Superficial implantation of Radiesse
may also create a visible whitish cord along the implantation route. To avoid this
happening, an adequate practitioner’s training is needed
prior to the clinical work with the fillers. A physician has to
adopt a proper technique of even delivery of the product to
the mid-dermis or subdermally. In most cases, immediate
postprocedural vigorous molding of the tissue will diminish
filler palpability.
When a relationship between dermal filler injection
methods and the incidence of the local adverse events
was assessed, a higher rate of side effects was found with
more tissue-traumatizing techniques, such as fanning, rapid
injection rate, and higher volumes of the product.24
●
Catastrophes in Cosmetic Procedures
333
Necrosis of the overlying tissues after dermal filler
implantation is elicited by vascular embolism, vascular
injury, or compression. The overall estimate for necrosis with bovine collagen is 0.09% of treated individuals.
R
Most of the cases were seen after injection of Zyplast
in the glabellar area.25,26 The manifestations of intravascular injection are immediate blanching and pain. Completely identical symptoms and outcome are observed with
hyaluronic acid.27,28 When injecting into glabellar, periorbital, or nasal regions with any filler, caution is necessary
to avoid intravascular injection. Aspiration when injected in
these areas might be helpful. Different treatment modalities have been suggested to treat imminent necrosis, such as
massaging, warm compresses, nitroglycerin paste, and systemic steroids, but their efficacy is not well established.29
Local wound care, after necrosis settles in, is of paramount
importance to reduce the extent of scar formation.
Hypersensitivity reactions and granuloma formation
are the most distressing adverse effects occurring with
soft-tissue augmentation. Every single filler material can
cause this complication, but the risk rate differs among
products. There are also patient-related factors that affect
the incidence of the hypersensitivity. Allergic reactions to
bovine collagen are well known (Figure 35.1). The colR
lagen component of ArteFill
may evoke the same type
of reactions in sensitive individuals. Since introduction of
a double skin pretesting, the incidence of localized hypersensitivity at the test sites is 3%, and in treated patients, the
numbers dropped to 1%–2%. These reactions resolve with
time as the implant material is resorbed by the host. Circulating antibodies to bovine collagen can be demonstrated
in the sera of a majority of patients (90%–100%) with local
hypersensitivity. These antibodies are specific for bovine
collagen and do not cross-react with human type I, II, or
III collagen.30
The hypersensitivity reaction rate seems to be significantly lower with the recently developed cross-linked,
R
porcine collagen implant, Evolence
. Because this implant
has a low potential for hypersensitivity, intradermal skin
testing before its use appears unnecessary.31
The rate of hypersensitivity reaction with most of the
hyaluronic acid –based fillers is less than 1%. So far, approxR
were
imately 40 cases of hypersensitivity to Restylane
reported, and the global risk of sensitivity is estimated as
0.8%. Since 2000, the amount of protein in the raw product
has decreased, and the incidence of hypersensitivity reactions has decreased to approximately 0.6%. Fifty percent of
these reactions are immediate and resolved within less than
3 weeks. The risk of strong but transient, delayed reaction
is approximately 0.3%.32–35
Whereas hypersensitivity reactions are self-limited with
nonpermanent fillers, a completely different course is
expected when such a reaction develops with permanent
and nonreversible products (Figure 35.2). The liquid form
of silicone, called dimethicone (dimethylpolysiloxane), has
334 E MERGENCY D ERMATOLOGY
R
FIGURE 35.3: Bio-Alkamid
-induced delayed inflammation.
R
FIGURE 35.1: Zyderm
-induced granulomatous reaction.
been used extensively in some countries. Although considered biologically inert, this material has been reported
as potentially inducing a granulomatous inflammatory
response of variable severity. A remarkable paucity of
reports about the development of complications after
injections of liquid silicone is probably related to its illegal
or semilegal use in most countries.36 When using silicone
in a microdroplet technique for lip enhancement, the incidence of granuloma formation is estimated to be approximately 2%.37
R
Nonreabsorbable gel polymers (Bio-Alkamid
, AquaR
mid ) are approved for use in Europe, but have not
been released by the FDA. Those products may induce
severe inflammatory/infectious granulomatous reactions
at any point from the implantation time. In some cases,
treatment of these adverse effects is extremely difficult
(Figure 35.3).38–41
Botulinum Toxin A
R
FIGURE 35.2: ArteFill
-induced granuloma in the lip.
Botulinum toxin A (BTXA) has become a widely used drug
in cosmetic dermatology to treat hyperkinetic facial and
neck lines and focal hyperhidrosis. The spectrum of possible adverse effects of BTXA is broad, but the effects are
generally mild and transient. The major tools for preventing adverse effects from BTXA are knowledge and
skill. Knowledge of the facial and extrafacial muscles allows
physicians to select the optimal dose, time, and technique.
The most common adverse effects of BTXA injections are
pain, hematoma, flu-like syndrome, headaches, focal facial
paralysis, and muscle weakness.42,43 Severe side effects with
Chapter 35
A
●
Catastrophes in Cosmetic Procedures
335
B
FIGURE 35.4: Brow ptosis due to inadequate injection of botulinum toxin A to forehead before injection (panel A) and after injection
(panel B).
cosmetic use of BTXA are rare and related to extreme overdosing or illegal use of an unapproved toxin.44–46
The majority of BTXA-associated adverse reactions
remain to be local and transient. In the glabellar area, the
most important potential side effects used to be blepharoptosis and diplopia reaching approximately 5% in the early
period of BTXA use. With better understanding of glabellar complex muscle function and a more precise dosing, this
adverse effect had become extremely rare recently.47 If it
R
ophthalmic solution 0.5% is useful
occurs, IOPIDINE
until the ptosis resolves.
While treating the forehead wrinkles, eyebrow ptosis
and asymmetry are the major potential side effects.48 A
thorough analysis of the face animation is crucial to avoid
injecting patients whose forehead wrinkles are related to
the use of frontalis muscle to keep visual acuity (Figure
35.4). In most cases, co-injection of the forehead depressors (glabella complex) minimizes the risk of brow ptosis.
Careful planning of injection doses and sites will decrease
the risk of eyebrow position asymmetry. If it happens,
additional injection of the less deactivated muscle will
correct it.
In the periorbital region, partial lip ptosis resulting from
weakening of the zygomaticus major muscle is the most
devastating complication, because it affects smile symmetry
(Figure 35.5).49
FIGURE 35.5: Lip ptosis due to paresis of left zygomaticus
muscle by periorbital botulinum toxin Ainjection.
336 E MERGENCY D ERMATOLOGY
A
B
C
FIGURE 35.6: Reactive hyperpigmentation after deep chemical peel in dark-skin patient before (panel A), 3 weeks after the peel
(panel B), and 4 weeks after introduction of topical bleaching preparation (panel C).
To avoid this happening, no toxin should be injected
behind the zygomatic bone. BTXA can be used in the
lower eyelid to improve wrinkles and widen the eye. In
these cases, minute doses of the toxin are recommended
because higher doses induce lower eyelid edema and incomplete sphincter function of the eyelids.50 Although BTXA
for lateral canthal rhytids usually does not suppress tear
production, dry eye is a possible complication of this
procedure. Treatment of dry eye and exposure keratitis is
symptomatic and includes lubrication.51 Another rare complication reported recently after BTXA injection in the lateral canthal area is proptosis associated with thyroid disease.
Although proptosis represents progression of the patient’s
preexisting thyroid eye disease, cosmetic use of BTXA
unmasks it.52
Procedures for the lower third of the face require a
higher level of expertise because all the muscles there have
specific functions. Different muscles in this zone interdigitate with others and, in some cases, act as antagonists. Thus,
this region requires a rigorous evaluation by the physician,
with precise diagnosis and technique of BTXA application.
Platysmal bands can be temporarily improved by BTXA
with redundant skin being a limiting factor of this treatment success. Dysphagia and airway obstruction are the
potential side effects related to the toxin dosing and
diffusion.53
Hyperhidrosis refers to excessive and uncontrollable
sweating beyond that required to return body temperature
to normal. Although a broad spectrum of treatment modalities are available, including topical and systemic therapies,
chemodenervation using botulinum toxin has emerged as
a safe and effective treatment for both primary palmar and
axillary hyperhidrosis in several clinical trials. This treatment is highly effective with a paucity of side effects. Fine
motor impairment after palmar injection of BTXA has been
rarely reported.54
Chemical Peels
Chemical peeling is a procedure used for cosmetic improvement of skin or for treatment of some skin disorders.
A chemical exfoliating agent is applied to the skin to
destroy portions of epidermis and/or dermis with subsequent regeneration and rejuvenation of the tissues. Chemical peels are divided into three categories, depending on
the depth of the wound created by the peel. Superficial peels
penetrate the epidermis only, medium depth peels damage
the entire epidermis and papillary dermis, and deep peels
create a wound to the level of midreticular dermis.
The list of potential complications of chemical peels
includes pigmentary changes, infections, milia, acneiform
eruption, scarring, and cardiotoxicity.
Reactive hyperpigmentation can occur after any depth
of chemical peels (Figure 35.6). Usually lighter complected
patients have a lower risk for hyperpigmentation, but
genetic factors play an important role, and sometimes light
patients with “dark genes” hyperpigment unexpectedly.
Skin priming using a combination of hydroquinone and
tretinoin cream (Kligman’s formula) before the superficial
and medium depth peels and early introduction of this
Chapter 35
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Catastrophes in Cosmetic Procedures
337
FIGURE 35.7: Disseminated herpes simplex infection in patient
after chemical peel.
preparation after deep peels reduces the rate of this complication. Demarcation lines can be avoided if the boundaries
of the peeling area are hidden under the mandibular line
and feathered gradually to the normal skin. Hypopigmentation after phenol peels is proportional to the depth of
the peel, amount of the solution used, number of drops of
croton oil in the solution, inherent skin color, and postpeel
sun-related behavior. Intradermal nevi can hyperpigment
after deep peels.
Bacterial and fungal complications in chemical peels are
rare. Patients with a positive history of herpes simplex infection are treated prophylactically with acyclovir or valacyclovir during medium and deep peels until full reepithelialization is achieved (Figure 35.7). Toxic shock syndrome
has been reported after chemical peels.55
Milia or epidermal cysts appear in up to 20% of patients
after chemical peels, usually 8–16 weeks after the procedure
(Figure 35.8). Electrosurgery is simple and effective to treat
this postpeel complication.
Acneiform eruption after chemical peels is not rare and
usually appears immediately after reepithelialization. Its
etiology is multifactorial and is either related to exacerbation of previously existing acne or is due to overgreasing of newly formed skin. Short-term systemic antibiotics
together with discontinuation of any oily preparations will
usually provide satisfactory results.
Scarring remains the most dreadful complication of
chemical peels. The contributing factors are not well
understood. The most common location of such scars is in
the lower part of the face, probably due to more aggressive
treatment in this area or to the greater tissue movement,
because of eating and speaking, during the healing process. Delayed healing and persistent redness are important
alarming signs for forthcoming scarring. Topical antibiotics and potent steroid preparations should be introduced
as soon as this diagnosis is made.
The most important potential complication exclusive to
phenol-based peels is cardiotoxicity. Phenol is directly toxic
FIGURE 35.8: Postpeel milia.
to the myocardium. Studies in rats have shown a decrease in
myocardial contraction and in electrical activity following
systemic exposure to phenol.56 Because fatal doses ranged
widely in these studies, it seems that individual sensitivity
of the myocardium to this chemical exists. In humans, sex,
age, previous cardiac history, and blood phenol levels are
not accurate predictors for cardiac arrhythmia susceptibility.57 Cardiac arrhythmias in less than 30 minutes have been
recorded in up to 23% of patients, when full face peel was
performed.58 Adequate patient management reduces this
complication to less than 7%.59 No hepatorenal or central
nervous system toxicities have been reported in the literature with properly performed chemical peels.
CONCLUSIONS
Each one of the procedures in dermatology carries a risk of
potential complications. They can be mild and reversible
or severe and permanent. Most of them are avoidable and
treatable.
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Dermatol Surg. 2007; 33:190–3.
CHAPTER 36
Life-Threatening Dermatoses in Travelers
Larry E. Millikan
SEVERE SKIN reactions/conditions are of particular
concern when the traveler is away from home and
medical care is unfamiliar or of uncertain caliber. Perhaps the most significant of these conditions is Stevens–
Johnson syndrome, which may occur after the use of
R
antimalarials such as Fansidar
as prophylaxis while
traveling in Africa. Travel remains a rapidly growing enterprise with more remote destinations appearing on the radar
screen each year, making the previous review a basis for this
update.1
More commonly, a serious dermatosis begins before the
trip, progresses, and becomes significant while the traveler
is away from usual medical care, not following his or her
usual dietary and health habits, and often has a difficult
time finding and/or communicating with medical personnel. Older patients (often the usual travelers with both time
and means) have particular challenges – daunting lists of
drugs and potential interactions, as well as the possibility
of new drugs (and side effects) beginning around the time
of the travel. The pediatric population is part of this new
trend, and the smaller patients have higher risk in both
toxic (venoms) and drug reactions.1 The occasional traveler rarely keeps important medical documents with him or
her, but they are necessary during an acute/life-threatening
event, as the following example demonstrates.
there is minimal ascites. To obtain more information,
the patient’s wallet is examined, and of interest are the
addresses of the two premier oyster houses in the New
Orleans French Quarter. With this information and little
else of medical history – plus signs of hypotension, fever,
and sepsis – the dermatological consultants suggest the likelihood of infection from Vibrio vulnificus due to oysters.
Intravenous ciprofloxacin is started approximately 3 hours
after arrival at the hospital, when all of the preliminary
data and consultations had been collated. Six hours later,
after an up- and-down course during the night, the patient
expires without ever regaining consciousness. On autopsy,
V. vulnificus is confirmed with a septic vasculitis and
advanced liver and kidney disease, as well as advanced coronary disease – all typical for the usual patient with lifethreatening and usually fatal Vibrio sepsis.2 More recently,
Hurricane Katrina prompted other travel on the part of
rebuilders of the Gulf Coast and at the same time resulted
in a resurgence of the Vibrio problem.3,4
These types of events may have different outcomes if
medical histories are made available when patients present
to a major hospital in North America or Europe. Much
more tenuous events can transpire in remote sites for ecotourism and in marginal medical facilities in so many developing countries.
CASE REPORT
A male tourist in his 50s is brought to the emergency room
from the French Quarter in New Orleans, having been
found confused, weak, tremulous, and unable to walk with
a steady gait. He is placed in an emergency cubicle, where
he is found to be hypertensive with a temperature of 38.5◦ C.
As history taking commences, he becomes incoherent and
lapses into a coma. Examination reveals moderate obesity,
hypertension, and spreading waxy urticarial plaques (Figure 36.1) over most of his trunk.
He responds to pain and pressure with withdrawal,
but otherwise he is unresponsive to verbal commands and
questions. Preliminary laboratory studies reveal glycosuria,
hyperglycemia, polymorphonuclear leukocytosis, and elevated erythrocyte sedimentation rate and C-reactive protein. The exam of the protuberant abdomen shows slight
organomegaly of the liver and possibly the spleen, but
FIGURE 36.1: Enlarging waxy plaques of Vibrio vulnificus.
page 340
Chapter 36
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Life-Threatening Dermatoses in Travelers
341
FIGURE 36.2: Severe bullous erythema multiforme.
Infectious Dermatoses
Infectious dermatoses are the first and most serious risk for
the traveler, especially for one partaking of the exotic “out
of the way” trips becoming in vogue as well as the popular
ecotourism ventures, which as a routine are far from the
fringes of civilization.
Food-Borne Infections
The case report underscores serious dermatologic conditions from food-borne infectious agents. Although it is
more common to have the famous gastrointestinal (GI)
sequelae – Montezuma’s revenge, Tut’s curse, and Delhi
Belly are common descriptors – the primary challenge with
these food-borne GI reactions is to restore fluid balance,
which is difficult to do in some patients without hospitalization. Very young or infirm patients can be at mortal risk unless proper support is available. Of greater concern is the increase of contamination of the food chain in
modern countries with various pathogenic agents, such as
Escherichia coli, with widespread exposure in various fast
food chains, where the usual assumption is safety and therefore caution is at a lower level. These same persons are
ordinarily more careful while traveling, but as this evolves,
concern that such adulteration of foodstuffs (as seen in animal foods in which potential toxic “expanders” were resulting in many pet deaths from renal failure) perhaps equals
infection is a major concern.
It is reminiscent of the “porphyria Turcica”5 from the
ingestion of seed grains containing toxic antifungal powders – marked “not for ingestion” (in English), unintelligible to the rural people who desperately needed food
and assumed that the grains were safe for cooking.2 In
the treatment phase, cutaneous sequelae may be an additional reason for the hospitalization – a result of reaction to
the drugs prescribed (erythematous [EM] vide infra; Figure 36.2), sudden systemic collapse and sepsis complica-
FIGURE 36.3: Petechial lesions of drug vasculitis.
tions such as vasculitis (Figure 36.3) and mechanobullous
eruptions. These results are usually indicative of multiorgan involvement and potential organ failure and death.
Cholera and typhoid fever are always risks to travelers,
whether in the “first world” or “third world” because global
sources of foods compromise the safety of the food chain,
even in Europe and the Americas. An “ecotourist” may take
all the right precautions in the country, only to become
seriously ill on the way home!!!
ENVIRONMENTAL SOURCES
Traveling away from cities and civilization exposes one to
many native infections and infestations that can be serious
to those who are not natives and lack acquired immunity.
Particularly susceptible are older patients, persons with
immune deficiencies from pharmacotherapy (transplants,
certain chemotherapy, etc.), and persons with infectious
immunodeficiencies. The cutaneous presentations of these
include petechiae (Rickettsia, Meningococcus, and some gram
negatives – palpable purpura, ecthyma gangrenosum, and
ulcers such as those seen in Mycobacterium ulcerans infections) (Table 36.1).1
This caveat is important: In an abnormal host, classical presentations seldom occur and diagnosis in atypical
presentations requires a high index of suspicion and compulsive use of all diagnostic tests to provide confirmation of
diagnosis. Many of these conditions require early aggressive
treatment to ensure survival. Rickettsioses, as an example,
respond best with early systemic therapy; late therapy is
associated with a much lower survival rate.3
342 E MERGENCY D ERMATOLOGY
TABLE 36.1: Petechial/Purpuric Presentations
Rickettsia
Meningococcemia
Henoch–Schönlein purpura
Morbilliform
Rubella
Morbilla
Other viruses
Staphylococcal scalded skin syndrome
Many of the herpes viruses1−9
Drug eruptions
CASE REPORT
The patient is a 24-year-old former Peace Corps worker
seen because of recurring problems in the amputee stump.
He was working in Africa in the 60s during a time of
increased greenery due to a wet phase in the weather. It
was assumed that the initial event was trauma to the left
leg from the sharp margins of the local grasses. The infection proceeded to an ulcer unresponsive to therapy: Thus
began a scenario of repeated debridement, grafting, and
recurrence – then ultimately amputation, below the knee,
then above the knee, then at the hip. On examination, he
appeared normal for his age except for his left lower quarter,
where there were several EM and granulomatous arcuate
lesions surrounding the scar from the last hip procedure.
Biopsy of these granulomatous areas revealed heavy cellular infiltrate that was nearly magenta on the acid-fast stain,
being loaded with organisms. Further surgery and trials of
new antimicrobials were started.
Many of the atypical acid-fast organisms also are found
on vegetation where they come in contact with animals.
Many infections remain a challenge for chemotherapy.
Although the effectiveness of clarithromycin has been documented, it usually needs some surgical assistance for the
best results. This concerns life-threatening conditions; the
prolonged course is debilitating to the patient – the only
respite being the cryophilic nature of M. ulcerans, which
does limit its spread to the body’s core while the host
remains in good health. Much later it has become apparent, concerning the extensive deforming spread of Mycobacterium cheloniae and Mycobacterium avium intracellulare, that
it begins to impinge on vital structures – thus a threat to
life in addition to limb!
So the traveler can acquire infectious organisms that
slowly destroy life as well as have much more acute episodes
with infectious vasculitis, sepsis, and a stay in the intensive
care unit (ICU)! Some of these organisms are from vegetation and others are from arthropods – Plasmodia, Rickettsia,
and many others.3
Malaria remains a risk in much of the developing world,
although the newer insecticidal curtains have been helpful in limiting the spread after the great increase without
dichloro-diphenyl-trichloroethane (DDT) use. Cutaneous
sequelae are less frequent. Usually, the patient in good
health will usually survive and clear with appropriate treatment. Much more of a risk are the potential reactions to
antimalarial prophylaxis. These have been documented –
erythema multiforme, agranulocytosis with subsequent
sepsis, and the dapsone syndrome. All of these outcomes
have become serious if not treated early, intensively,
and usually with hospitalization. The seriousness is compounded by the fact that the patient on malaria prophylaxis
is usually far from medical care.
The most serious of infections are those of the filovirus
group. They present with impressive cutaneous hemorrhagic findings, associated with a high mortality from, for
example, the Marburg and Ebola viruses.3 Fortunately,
these infections are in remote areas and occur rarely in
areas that are common tourist destinations. Hospitalization, isolation, and intensive care with precautions for the
health care team (due to the high mortality and infectivity potential) are needed. Therapy is still on a case-by-case
basis due to the lack of definitive antiviral therapy. Support
therapy is the only usual approach, maintaining essential
organ function until the patient recovers.
The usual bacterial and rickettsial infections also need to
be considered for patients ill with petechial and/or morbilliform exanthems. The differential diagnoses need always
to be reviewed to be sure that the diagnosis is not missed
(Table 36.1). It is critical to establish the diagnosis and treat
expectantly to be certain that the patient survives. Many
of these infections respond only with early therapy. Early
aggressive diagnosis and therapy are key!!8
Allergic/Immunologic Reactions
Immediate/Immunoglobulin-Mediated Type I
Anaphylactic/Immunoglobulin E. Anaphylaxis is the most
significant of disorders affecting travelers and may result
in death in a very short span of time. It may also be so
sudden that more sophisticated medical facilities are not
close enough to be able to offer their life-saving expertise.
Patients who know of their risk are often prepared for emergencies with injectables, such as epinephrine carried with
the person. This type of reaction (usually immunoglobulin
E [IgE] mediated) can result from reexposure to antigens
such as insect venom, drugs, or even contact antigens (usually environmental but can be due to personal care products
including creams, sunscreens, and lotions). Initial presentation may be that of angioedema.2,9,10
When anaphylaxis occurs, the events are too rapid
in sequence for dermatitis to appear, but the usual previous antigenic exposure is either urticarial or EM in
nature. The patient’s physician should alert the future
traveler to reexposure risk and recommend prophylaxis
such as antihistamines or epinephrine/antihistamine injection kits. Whereas the patient may be aware of the agent
Chapter 36
FIGURE 36.4: Multiple pustules – Solenopsis/fire ant.
(arthropod, etc.) in the home environment, there may be
related causes/agents encountered while traveling that are
unfamiliar. It is important that the physician make an effort
to educate the patient to these new threats (in other words,
the different species of Vespa, Apis, Latrodectus, Solenopsis,
etc. [Figure 36.4], the botflies, and other groups). This
education can be life saving in the case of bee/hornet/wasp
allergies. Avoidance is often far better than the prevention
of anaphylaxis after exposure.11,12
Whereas airborne arthropods are the main cause for
these venom reactions, there are others found at the seaside that vary from minor localized reactions to widespread
skin involvement, predisposing to serious (and occasionally life-threatening) skin infections. Coelenterates are perhaps the most significant in this category and they can be
ubiquitous and a serious health problem on the shores of
Australia, where emergency care is available at the beach
to neutralize the toxins and to avoid a trip to the hospital. Far more dramatic are the larger animals – sea snakes,
giant clams (Figure 36.5), moray eels, barracuda, sharks,
and various rays (such as the one that killed the zoologist
Steve Irwin) – but it should be emphasized that these are
extremely rare, and the morbidity is from trauma or venoms
(not anaphylactic in nature). Most exposures at the beach –
sea bathers eruption, swimmers itch, creeping eruption, and
so forth – are sources of minimal morbidity unless large
areas of skin are involved or an unusual allergic reaction
occurs.
Type 2 or 3. Type 2 (vasculitis and the immuno-/
mechanobullous dermatoses) and 3 (immune complex reactions) are rare in environmental exposure but hypothetically can occur after hypersensitivity to various venoms
such as solenopsis4 and subsequent exposure with possible
intravascular dissemination of the venom with extensive
immune complex formation and cascades of inflammatory
mediators. These types can cause acute organ failure (liver,
●
Life-Threatening Dermatoses in Travelers
343
FIGURE 36.5: Giant clam at the Great Barrier Reef.
kidney) and a picture not unlike infectious sepsis. These are
rare and, in extreme cases, result in ICU stays.
Delayed/Cell Mediated. Delayed reactions can be just as
serious as immediate reactions under the proper circumstances. Whereas atopic dermatitis is generally considered
to be related to IgE, atopic patients seem to develop type
4 reactions to plants in increasing amounts as they age.
The timing may be the significant factor. Many travelers
have a vacation ruined by widespread rhus contact dermatitis (Figure 36.6); the patient, even under the best of care,
cannot enjoy the destination city and its charms. Without
proper care, and in certain climates, the heat and humidity can lead to secondary infection and the end result can
approach the morbidity of a second-degree burn or worse.
There are well-documented cases of nephrogenic streptococcus, resulting in acute renal complications, hospitalization, and rarely dialysis.
When the exposure takes place during the trip, the rapidity of the reaction often relates to the degree of sensitivity
FIGURE 36.6: Typical vesicular and linear lesions of rhus dermatitis.
344 E MERGENCY D ERMATOLOGY
and the breadth of exposure. In many cases, the source
is a related species unfamiliar to the traveler. The possibilities are immense. The main plant groups are Primula
(mostly the in United Kingdom), Compositae (worldwide),
Alstroemeria (largely acquired in the floral trades), Rhus
(United States), Allium, and certain legumes that can be a
source of allergy, largely manifested by food allergy, but
occasionally cause type 1 and type 4 reactions. With a high
degree of sensitivity, widespread vesiculobullous lesions
increase the risk of infection and sepsis requiring hospitalization. The treatment varies with the infecting organism,
but parenteral antibiotics are the main indication for hospitalization and are the most rapid means for quick recovery.
CONCLUSIONS
The current most significant trend in travel is “ecotourism,” which places the traveler directly in the environment and often in remote areas that make rapid
response to severe and potentially life-threatening reactions a big challenge. Furthermore, travel is now more
accessible to patients with significant morbidities such as
diabetes, immunosuppression in transplant patients, and
even advanced malignancies under chemotherapy. Minor
environmental dermatoses and infections easily addressed
at home can drastically evolve to threaten life when one is
away from the usual medical support system. Evacuation
and inherent delays in transfer can allow a minor and local
condition to spread, impetiginize, and possibly secondarily involve internal organs mandating hospitalization. Dermatoses that respond to simple local measures normally
become life threatening when care is delayed or complicated by measures in evacuation. The prepared traveler
should have significant medical information available, especially when morbidities such as diabetes or other metabolic
conditions predispose the traveler to greater risk and complicate usual recovery. Similarly, patients with a long list of
medications need to have documentation of it as well as an
understanding of potential risks such as photosensitivity.
Most major medical institutions now have travel medicine
units that should be the first stop after the trip is finalized.
This consultation educates the traveler as to risks and the
necessary preparations, vaccinations, prophylactic drugs, as
well as preparing him or her for environmental exposures.
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Index
Note: The page numbers with “f ” indicate the references to Figures, and the page numbers with “t” indicate the references to Tables.
abacavir hypersensitivity reaction, HIV patients, 192
ABC algorithm
burn patients, 273
carbon monoxide poisoning, 274
overview of, 51
ablative regimens, graft versus host disease, 199–200
acanthosis nigricans
diabetes and, 304
malignant form, 265–266, 268
ACD. See autophagic cell death (ACD)
acetylcholine sensitivity, 178–179
acid burns, 314, 315f, 316
acne
chemical peels, 337
treatment complications, 173
acquired immune deficiency syndrome (AIDS). See AIDS
acrochordons, 304
acrocyanosis, 102t
acrodermatitis enteropathica (AE)
erythroderma and, 207
zinc deficiency and, 307
acrodynia, 320
acrokeratosis paraneoplastica, 266
acute generalized exanthematous pustulosis (AGEP), 320
acute graft versus host disease. See graft versus host disease
(GVHD)
acute skin failure, 62–64.See also life-threatening bacterial
infections; neonatal cutaneous emergencies
complications, 63, 63t, 64
defined, 62
etiology, 62, 62t, 63
management, 63, 63t, 64, 64t
overview of, 62, 64
pharmacology, 63t
risk factors, 63
types of, 62
acyclovir, herpes simplex and, 117
Addison disease, 298–299
adenosine, 54
advanced cardiopulmonary life support (ACLS), 50–51
adverse (cutaneous) drug reactions (ADRs), 154–159, 162–165
drug rash with eosinophilia and systemic symptoms syndrome,
162–164
overview of, 154, 159
serum sickness/serum sickness-like reaction, 164–165
Stevens-Johnson syndrome/toxic epidermal necrolysis,
154–159
vasculitis, 165
AE. See acrodermatitis enteropathica (AE)
Aeromonas hydrophila infection, 92
diagnosis, 92
overview of, 92
prognosis, 92
treatment, 92
Agent Orange, 323
AGEP. See acute generalized exanthematous pustulosis (AGEP)
AIDS, 188–193
fungal infections, 137f, 138f
Kaposi sarcoma, 121
malignant (necrotizing) external otitis, 82
overview of, 188–189, 189f
AIF. See apoptosis-inducing factor (AIF)
airway, breathing, and circulation (ABC)
burn patients, 273
carbon monoxide poisoning, 274
overview of, 51
alcohol, 13
alcohol-based hand rubs, 14
allergic granuloma, 234–235
allergic reactions, 178–183.See also anaphylaxis; urticaria;
venomous exposures
angioedema, 178, 180–182
contact dermatitis, 294–295, 295f, 343, 343f, 344
as cosmetic procedure complication, 333–334
hypersensitivity, 184–186, 333–334
mastocytosis, 178, 180–183, 302–303
page 345
346 I NDEX
allergic reactions (cont.)
overview of, 178
travel-related, 342–344
Alstroemeria species, 295
amebiasis, 141
American trypanosomiasis. See Chagas disease
amino-acid disorders, erythroderma and, 207
amiodarone, 53–54
analgesics, 60
anaphylaxis
clinical features, 178, 180, 184–185
diagnosis, 181
penicillin, 291–292
prognosis, 183
travel-related, 342–343
treatment, 183
venomous exposures, 146–147
anemia
in adverse (cutaneous) drug reactions, 157
hemolytic, efalizumab association, 171
angioedema
described, 178, 180
diagnosis, 181
hereditary, 180–182
with hypereosinophilia, 35t, 43
treatment, 182
angiokeratoma, in Fabry disease, 306
angioneurotic edema, 180.See also angioedema
anidulafungin, 29t, 30, 30f, 31
anorectal regions, dermatoses of, 278–281.See also sexually
transmitted diseases (STDs)
ecthyma gangrenosum, 278–279
necrotizing infections, 278–279, 279f, 279t, 280f, 281f
overview of, 278, 279t
perianal abscess, 278
staphylococcal cellulitis, 278
streptococcal dermatitis, 278
anoxia, 273
anthrax, 87, 88f, 89
diagnosis, 87–88
overview of, 87
prognosis, 89
treatment, 88–89
antibiotics, 18, 19t, 31.See also specific drug names and
groups
resistance, malignant (necrotizing) external otitis,
82–83
acute skin failure, 63t
antifungals, 29, 29f, 29t, 30f, 31
antivirals, 31, 31t
burn injuries and, 275
cellulitis, periorbital and orbital, 82
cosmetic procedures and, 331–332
daptomycin, 22, 22f, 24
in development, 26f, 27–28
fluoroquinolones, new indications for, 28, 28f, 29, 82–83
Gram-positive drug resistance, 18
linezolid, 18, 19f, 20
necrotizing soft-tissue infection, 77–79
overview of, 18
quinupristin/dalfopristin, 20, 21f, 22
retapamulin, 25, 25f, 27
selection of, 15–16
tigecycline, 24, 24f, 25
toxic epidermal necrolysis risk, 157
antibody deficiency, 188
antibody-dependent hypersensitivity, 186
anticoagulant drugs
cosmetic procedures, 332
in purpura fulminans, 240–241
in purpura fulminans treatment, 240t
antifungals, 29, 29t, 31, 128
anidulafungin, 30, 30f, 31
posaconazole, 29–30, 30f
voriconazole, 29, 29f, 30
antihistamines, in urticaria treatment, 181–182
antimicrobials. See antibiotics
antiretroviral therapy
drug classes, 189t
overview of, 188–189
antiseptic detergents, 14
antiseptics, 13–14
antisynthetase antibodies, 250, 250t
antithrombin III (AT III ), purpura fulminans, 240
antivirals, 31, 31t
aplasia cutis, 74
apoptosis. See also necrosis; programmed cell death
(PCD)
vs. autophagic cell death, 6–7
bcl-2 protein family, role of, 5–6
cancer and, 8
caspases, role of, 4–5
characteristics of, 6t
extrinsic cell death pathway, 4, 5f
intrinsic cell death pathway, 4–5, 5f
model overview, 6t
morphology of, 3, 3f, 4, 4f
vs. necrosis, 1–2, 7–8
overview of, 2–6
vs. paraptosis, 7
term, origins of, 2
apoptosis-inducing factor (AIF ), 4–5
apoptotic bodies, 3, 3f
aquagenic urticaria, 178
aquatic venomous exposures, 150–151, 178, 295–296, 296f, 343,
343f
arrhythmias, 52–53
arsenic poisoning, 318–319
arterial blood gases, 60
aseptic meningitis, drug-induced, 175
aseptic technique, 12–16
antibiotic selection, 15–16
overview of, 12, 16
preoperative skin antisepsis, 13–15
risk factors, environmental, 13
risk factors, patient, 13
skin preparation, 14
surgical equipment, 13
surgical site infections, 12–13
wound classification, 15
Index
Aspergillus fumigatus. See antifungals
asystole, 52
AT III. See antithrombin III (AT III)
atopic allergic reactions. See anaphylaxis
atopic dermatitis
erythroderma and, 204–205, 206f
travel-related, 343–344
atrioventricular (AV ) block, 52–53
atropine, 53–54
autism spectrum disorder, 321
autoantibodies
in chronic urticaria, 179
targeted immune modulators and, 171
autoimmune bullous diseases, 69
autoimmune disorders, cell death and, 9
autophagic cell death (ACD), 6, 6t, 7
autophagy, 6–7
baboon syndrome. See symmetric flexural exanthema
bacillary angiomatosis, HIV and, 191–192
Bacillus anthracis, 87, 88f, 89
diagnosis, 87–88
overview of, 87
prognosis, 89
treatment, 88–89
bacteremia, 15
background, 98
diagnosis, 101, 102t
overview of, 98–99
pathogens, 99t
pathophysiology, 100–101
prognosis, 106–107
symptoms, 101–103
terminology, 98t
treatment, 105
bacterial infection. See infection; life-threatening bacterial
infections; specific bacterium and infection names
basic life support (BLS), 50–51
Bazex syndrome, 266, 266f
B-cell defects, 188
bcl-2 protein family, 5–6
Beclin 1, 7
bee and wasp stings, 185, 342–343
ß-adrenergic blockers, 54
ß-carotene toxicity, 321–323
bilharziasis. See schistosomiasis
biological agents, 34, 35t, 43
etanercept, 37–38
infliximab, 34–37
intravenous immunoglobulin, 39–43
overview of, 34, 35t
rituximab, 38–39
biologics. See targeted immune modulators (TIMs),
complications of
bioterrorism
anthrax, 87, 88f, 89
tularemia, 89–90
black widow spider bites, 147–148, 148f
bleaching. See topical lighteners and bleaches
blistering, causes of, 216t
blood pressure, 59–60
blunt trauma, from torture, 314
body surface area (BSA)
in adverse (cutaneous) drug reactions, 155
calculation of, in burn injuries, 271
bone marrow toxicity. See pancytopenia
boric acid toxicity, erythroderma and, 207
botulinum toxin A (BTXA), complications, 334, 335f, 336
Boutonneuse fever, 86–87
diagnosis, 86–87
overview of, 86
prognosis, 87
treatment, 87
bovine collagen injections, reactions to, 333, 334f
BP. See bullous pemphigoid (BP)
bradyarrhythmia, 52–53
brands, from torture, 314
brow ptosis, botulinum toxin, 335, 335f
brown recluse spider bites, 147, 147f, 148
BSA. See body surface area (BSA)
BTXA. See botulinum toxin A (BTXA)
bubonic plague, 260
“budding phenomenon.” See apoptotic bodies
bullous dermatoses, 215–229.See also pemphigus
autoimmune subepidermal, 222–229
blistering, causes of, 216t
dermatitis herpetiformis, 227, 228f, 229
epidermolysis bullosa acquisita, 226, 226f, 227, 227f
histopathology, 215–216, 218f, 219f
linear IgA disease, 225–226, 226f
overview of, 215–216, 222
pemphigoid group, 222, 223f, 224f, 225
bullous impetigo, 66–67
bullous pemphigoid (BP), 222–223, 223f, 224f
biological agents for, 35t
etanercept, 37
intravenous immunoglobulin, 41
Burkholderia pseudomallei, 256.See also melioidosis
burn injuries, 271–277
baseline determination regarding, 273, 273t, 274
chemicals, 276, 314, 315f, 316
cigarettes, 314
clinical features, 271–272, 272f, 273t
complications, 275–276
depth of, 271–272, 272f, 273t
electrical, 276–277, 316
extent, 271
and fungal infection risk, 135
from lightning strikes, 277
from metal (brands), 314
non-thermal, 276–277
overview of, 271
pathophysiology of, 271
prognosis, 275
Rule of Nines, 271, 272f
surgery and, 275
torture, 314
from torture, 314–316
vs. toxic epidermal necrolysis, 158
treatment, 272, 273t, 275, 275t
347
348 I NDEX
burn units
in adverse (cutaneous) drug reaction treatment, 157–158
management, 273–274
referral to, 275, 275t
calcium channel blockers, 54
calpains, 6
cancer
anorectal infections, 278
autophagy and, 7
cell death and, 8–9
dermatoses associated with, 265–267, 268t, 269
dioxin association, 323
erythroderma association, 203–204
morphological changes, 3f
paraneoplastic cutaneous syndrome association
skin metastases, 265
ultraviolet exposure, 293–294
viral disease associations, 122–123
Candida species, 126, 127t.See also antifungals; oral-esophageal
candidiasis; systemic candidiasis
C. albicans, 70, 70f
candidosis, 126.See also systemic candidosis
carbon monoxide poisoning, 274, 323
carcinoid syndrome, 301–302
cardiac arrest, 51–52
drug administration, 52
survival, 51
cardiac arrhythmias, 52–53
cardiogenic shock, 57
cardiopulmonary resuscitation (CPR), 50–51
cardiac arrest and, 51–52
endotracheal intubation, 57
pulse monitoring, 60
pulseless electrical activity, 52
cardiotoxicity, as cosmetic procedure complication, 337
cardiovascular dysfunction
intravenous immunoglobulin complication, 174–175
system procedures, 59
systemic lupus erythematosus, 245–246
targeted immune modulator complication, 170
carotenoderma, 321–323
Casal’s necklace, 308
caspase-activated DNAse (CAD), 3
caspases, 1, 4–5, 5f
caterpillars, venomous exposures, 147–148
celiac disease (CD), 227–229.See also dermatitis herpetiformis
(DH )
cell death. See programmed cell death (PCD)
cell injury, 1–6.See also programmed cell death (PCD)
apoptosis and, 2–6
exposure time, 2
overview of, 1
responses to, 1–2, 2f
severity, 2
types, 2
cell-mediated hypersensitivity, 186
cellulitis, periorbital and orbital, 81, 81f, 82
diagnosis, 81–82, 102t
prognosis, 82
treatment, 82
centipede bites, 147
central nervous system procedures, 59
central venous catheterization (CV ), 57
cephalosporins
malignant (necrotizing) external otitis, 82–83
surgical prophylaxis, 16
Vibrio vulnificus, 91
ceramides, 305–306
Chagas disease, 137, 139f, 140
chelation therapy, mercury toxicity, 321
chemical burns, 276, 314, 315f, 316
chemical peels, complications of, 336, 336f, 337, 337f
CHF. See congestive heart failure (CHF)
CHG. See chlorhexidine gluconate (CHG)
chickenpox. See primary varicella
chimeric antibodies, 168
Chlamydia trachomatis infections, 285–288
complications of, 286–287, 287f
diagnosis, 287–288
gonorrhea, co-infection with, 285
overview of, 285–286, 286f
treatment, 288
chlamydial ophthalmia, 286, 286f
chloracne, 323–324
chloramphenicol, Mediterranean spotted fever, 87
chlorhexidine gluconate (CHG), 14
cholera, exposure risks, 341
cholinergic urticaria, 178–179
Chromobacterium violaceum infection, 92–93, 93f
diagnosis, 92–93
prognosis, 93
treatment, 93
chronic graft versus host disease. See graft versus host disease
(GVHD)
chronic skin failure, 62
Churg-Strauss syndrome (CSS), 233t, 234–235, 238
cicatricial pemphigoid (CP), 223–224
biological agents for, 35t
etanercept, 37
infliximab, 35
intravenous immunoglobulin, 41
cigarette burns, 314
ciprofloxacin
anthrax, 88–89
tularemia, 90
ciprofloxacin, malignant (necrotizing) external otitis, 82–83
circinate balanitis, 287, 287f
clean technique. See aseptic technique
clean wounds (class I), 15
clean-contaminated wounds (class II), 15
cleaning, surgical equipment, 13
Clostridium infection, 77
clubbing, digital, 268
CMV. See cytomegalovirus (CMV)
Cockayne-Touraine type (dominant dystrophic epidermolysis
bullosa), 68
collagen injections, reactions to, 333, 334f
collagen vascular diseases. See connective tissue disorders
collodion baby syndrome, 71, 72f, 305–306
Index
combination therapy. See highly active antiretroviral therapy
(HAART)
common variable immunodeficiency (CVI ), 188
community-acquired bacteremia, 99t
community-acquired pneumonia, 106t
community-associated methicillin-resistant Staphylococcus aureus
(CA-MRSA), 77–78
compartment syndrome, 276
complement deficiency, 187
complicated infection, 18
cone shells, venomous exposures, 150, 296
congenital ichthyosis, 305–306
congenital infection
candidosis, 70, 70f
candidosis, cutaneous, 70, 70f
candidosis, neonatal, 207
erythropoietic porphyria, 69
hemangioma, 73f
melanoma, 73–74
syphilis, 69
varicella, 70
congenital rubella syndrome (CRS), 120
congestive heart failure (CHF ), as targeted immune modulator
complication, 170
connective tissue disorders, 245–252
dermatomyositis, 246f, 249, 249t, 251
mixed connective tissue disease, 252
neonatal lupus erythematosus, 248, 248t, 249
overview of, 245, 252
scleroderma, 251, 251f, 252, 301
systemic lupus erythematosus, 219, 245, 245t, 249, 249f
Conradi-Hünermann syndrome, 208
contact dermatitis, from plants, 294–295, 295f, 343, 343f, 344.See
also urticaria
contaminated wounds (class III), 15–16
continuous bacteremia, 99
corticosteroid treatment
adverse (cutaneous) drug reactions, 158–159
drug rash with eosinophilia and systemic symptoms syndrome,
164
graft versus host disease management, 200
pemphigus treatment, 221–222
cosmetic procedure complications, 331–337
bleeding, 332
botulinum toxin A, 334–336
chemical peels, 336, 336f, 337, 337f
dermal fillers, 332–334, 334f
infections, 331–332
overview of, 331, 337
scarring, 331
cosmetic procedures, burn injury, 275
cosyntropin stimulation test, 298–299
Cowden syndrome, 267
cranial nerve neuropathy, 83
critical care, 50–60
asystole and pulseless electrical care, 52
basic life support, 51
bradyarrhythmia, 52–53
cardiac arrest, 51–52
cardiovascular system procedures, 59
central nervous system procedures, 59
central venous catheterization, 57
complications, 59
endotracheal intubation, 57
foreign body airway obstruction, 55
glucose control, 58
hypertensive crisis, 56–57
induced hypothermia, 58
medications for, 53–55
myocardial infarction, 55–56
organ-specific support, 58
overview of, 50–51
patient monitoring, 59–60
post-resuscitation support, 57–58
prognosis, 59
pulmonary edema, 55
pulmonary embolism, 55
respiratory dysfunction, 58–59
shock, 57
stroke, 56
tachyarrhythmia, 52–53
CRS. See congenital rubella syndrome (CRS)
crusted scabies
erythroderma, 205–206
HIV patients, 191
cryptococcosis, HIV patients, 191
CsA. See cyclosporine A (CsA)
CSS. See Churg-Strauss syndrome (CSS)
CTCL. See cutaneous T-cell lymphoma (CTCL)
cultured epithelial autografts, 275
cutaneous anthrax, 87–88, 88f
cutaneous T-cell lymphoma (CTCL), erythroderma, 206
cutaneous tumors, in neonates, 72–74
hamartomas, 72
hemangiomas, 72, 73f
mastocytosis, 72–73, 73f
neoplastic diseases, 73, 73f, 74
CVI. See common variable immunodeficiency (CVI)
cyclosporine A (CsA), 172–173
cystic fibrosis dermatitis, erythroderma, 207
cytochrome c, 4–5
cytomegalovirus (CMV ), 71f, 119–120
dalbavancin, 19t, 26f, 28
dalfopristin (quinupristin/dalfopristin), 19t, 20, 21f, 22
cellular mechanism, 20
contraindications, 22
dosage, 22
indications, 21–22
pharmacokinetics, 20
in vitro activity, 20
daptomycin, 19t, 22, 22f, 24
cellular mechanism, 23
contraindications, 23
dosage, 23
indications, 23
pharmacokinetics, 23
in vitro activity, 23
Darier sign, 302–303
death inducing signaling complex (DISC), 4
349
350 I NDEX
death receptors (DRs), 4
death stimuli, 1–2, 2f
debridement. See necrotizing fasciitis, treatment
decoy receptors (DcRs), 4
deep partial-thickness burns, 272
DEET. See N,N-diethyl-3-methylbenzamide (DEET )
deferoxamine, zygomycosis infections and, 135
demyelination, as targeted immune modulator complication,
170–171
dengue fever, 121
dermal fillers, complications of, 332–334, 334f
dermatitis herpetiformis (DH ), 227, 228f, 229
dermatologic therapy complications, 168–175
cyclosporine A reactions, 172–173
intravenous immunoglobulin reactions, 173–175
isotretinoin reactions, 173
methotrexate reactions, 171–172
overview of, 168, 175
targeted immune modulator reactions, 168–171
dermatomyositis (DM), 249–251
cardiovascular dysfunction and, 250–251
gastrointestinal dysfunction and, 249
malignancy association, 268
overview of, 246f, 249, 249t
pulmonary dysfunction and, 249–250, 250t
desensitization, 185
detergents, 14
dextran, purpura fulminans, 241
DH. See dermatitis herpetiformis (DH)
diabetes mellitus, 135, 137, 304
diabetic dermopathy, 304
DIAS. See drug-induced aseptic meningitis (DIAS)
N,N-diethyl-3-methylbenzamide (DEET ), 150
DIF. See direct immunofluorescence (DIF)
diffuse cutaneous mastocytosis, 72–73, 73f, 205
DiGeorge syndrome, 188, 206
digital clubbing, 268
diltiazem, 54
dimethicone fillers, reactions to, 333–334
dioxin poisoning, 323–324
direct immunofluorescence (DIF )
bullous pemphigoid, 223f
dermatitis herpetiformis, 228f
described, 215
pemphigus, 217–218, 218f
dirty wounds (class IV ), 15–16
disaster planning. See mass casualty management
DISC. See death inducing signaling complex (DISC)
discoloration. See pigmentation, changes in
disinfection, surgical equipment, 13
disinfection procedure. See aseptic technique
disseminated herpes, 69
DM. See dermatomyositis (DM)
DNA laddering, 3, 4f
documentation
allergy-related, 183
torture cases, suspected, 316–317
travel-related, 341, 344
domestic violence, 314, 315f, 316
dominant dystrophic EB (Cockayne-Touraine type), 68
Dorfman-Chanarin syndrome, erythroderma and, 208
Dowling-Meara variant, epidermolysis bullosa, 67–68
doxycycline
anthrax, 88–89
Lyme disease, 149, 149f
Mediterranean spotted fever, 87
Rocky Mountain spotted fever, 85–86
DRESS. See drug rash with eosinophilia and systemic symptoms
(DRESS) syndrome
DRs. See death receptors (DRs)
drug hypersensitivity syndrome, 162.See also drug rash with
eosinophilia and systemic symptoms (DRESS) syndrome
drug rash with eosinophilia and systemic symptoms (DRESS)
syndrome, 162–164
causative drugs, 162
diagnosis, 163, 163f, 164
overview of, 162
vs. serum sickness, 162, 162t
vs. Stevens-Johnson syndrome/toxic epidermal necrolysis, 163
treatment, 164
drug reactions
adverse cutaneous reactions, 154–159, 162–165
anaphylaxis, 184–185
as dermatologic therapy complication, 168–175
erythroderma, 203, 203t
in HIV patients, 192–193
phototoxic, 293–294, 294f
in sexually transmitted disease treatments, 291–292
travel-related, 341, 341f, 342
drug resistance, 18, 276.See also methicillin-resistant Staphylococcus
aureus (MRSA)
drug-induced aseptic meningitis (DIAS), 175
drug-induced disorders
aseptic meningitis, 175
erythroderma, 207–208
linear IgA disease, 225
pemphigus, 221
Duhring-Brocq disease. See dermatitis herpetiformis (DH)
Duncan syndrome, 188
dystrophic epidermolysis bullosa, 68
Dystrophic Epidermolysis Bullosa Research Association
(DEBRA), 67
EBA. See epidermolysis bullosa acquisita (EBA)
EBV. See Epstein-Barr virus (EBV)
ecchymosis, cosmetic procedures and, 332–333
echinocandins, fungal infection, 128
ecthyma gangrenosum, 102t, 278–279
ectodermal dysplasias, erythroderma and, 208
eczema herpeticum, 116
efalizumab, 171
electrical burns, 276–277, 316
electrolyte replacement, acute skin failure, 64t
elemental mercury, 319
emergency preparedness. See mass casualty management
encephalitis
herpes simplex, 69, 116
rubella, 120
Index
endocarditis, 15
endocrine disorders, 298–306, 309.See also mastocytosis
Addison disease, 298–299
carcinoid syndrome, 301–302
diabetes mellitus, 304
Fabry disease, 306–307
glucagonoma, 299–300
overview of, 298
porphyria cutanea tarda, 304–305
thyroid dysfunction, 300–301
vitamin deficiencies, 307–309
vitamin toxicity, 309, 309t
zinc deficiency, 307
endoplasmic reticulum, cell death pathway, 6
endotracheal intubation, 57
end-stage skin failure, 62
end-tidal CO2 monitoring, 60
Entamoeba histolytica, 141.See also amebiasis
entomophthoromycosis, 134
environmental risk factors, 13
environmental skin disorders, 293–296.See also travel-related
dermatoses; venomous exposures
contact dermatitis, 294–295, 295f
heat emergencies, 293
management, 293
overview of, 293, 296
ultraviolet exposure, 293–294, 294f, 295f, 298
eosinophilic folliculitis, HIV patients and, 192
epidermal burns, 272
epidermal cysts
as cosmetic procedure complication, 337f
epidermal cysts, cosmetic procedures and, 337
epidermolysis bullosa acquisita (EBA), 226, 226f, 227, 227f
epidermolysis bullosa (EB), 68f
description of, 67
management principles, 68
in neonates, 67
subtypes of, 67–68, 68f
epidermolysis bullosa simplex, 67–68
epididymo-orchitis, 286–287
epinephrine, 53.See also anaphylaxis
oral, 147
syringes, pre-loaded, 183
epoprostenol, purpura fulminans, 240–241
Epstein-Barr virus (EBV ), 188
oncogenic potential, 122
erythema gyratum repens, 266, 266f
erythema infectiosum, 119, 122
erythema migrans, Lyme disease, 149f
erythema multiforme (EM)
classification, 154–155, 155t
clinical features, 341f
hypersensitivity reaction, 184–185
overview of, 154
erythroderma, 62t, 72f, 202–211
clinical features, 204–207
complications, 211
cutaneous disorders and, 204, 204f, 205f, 206, 206f
diagnosis, 209–210, 210t
drug reactions, 203t, 207–208
etiology, 202, 203t, 204
hemodynamic/metabolic disturbances, 208
histopathology, 209, 209t
immunologic disorders, 206
infections and, 207
management, 210–211, 211t
metabolic/nutritional disorders and, 207
in neonates, 71, 72f
overview of, 202
pathogenesis, 204
pediatric considerations, 203t, 210–211
from pemphigus, 218, 220f
prognosis, 211
syndromes associated with, 208
ET. See exfoliative toxin (ET)
etanercept, 35t, 37–38
bullous pemphigoid, 37
cicatricial pemphigoid, 37
dosage, 37
graft versus host disease, acute and chronic, 37–38
indications, 37
side-effects, 37
exfoliative dermatitis. See erythroderma
exfoliative toxin (ET )
staphylococcal scalded skin syndrome and, 110–112
extrinsic cell death pathway, 4, 5f
eye infections. See also ocular difficulties
chlamydial ophthalmia, 286, 286f
gonococcal, 285
ophthalmia neonatorum, 285
Fabry disease, 306–307
famciclovir, 31, 31t
familial reticuloendotheliosis, erythroderma and, 206
fibrinolytic therapy, 56
filovirus exposure risk, 342
fire ant stings, 146–147, 342–343, 343f
fish
mercury poisoning, 320
venomous exposures, 150–151, 296, 296f
5-hydroxyindoleacetic acid (5-HIAA) test, 301–302
“5t’s”, 52
fleas, as disease vectors, 149
fluconazole, 128
fluid electrolyte replacement, acute skin failure, 64t
fluid replacement, burns and, 273–274
fluoroquinolones
malignant (necrotizing) external otitis, 82–83
new indications for, 28, 28f, 29
tularemia, 90
Vibrio vulnificus, 91
flushing, cutaneous, 301
fogo selvagem, 219
food allergens, 179t
food-borne infections, 340f, 341
foreign body airway obstruction (FBAO), 51, 55
Fournier gangrene, 280, 280f
Francisella tularensis infection, 89–90, 90f
351
352 I NDEX
full-thickness burns, 272
fungal infections, 126–137
histoplasmosis, 137
overview of, 126
paracoccidioidomycosis, 128
sporotrichosis, 132–133
systemic candidosis, 126–129
as targeted immune modulator complication,
169–170
zygomycosis, 134–137
Gardner syndrome, 267
gastrointestinal dysfunction
dermatomyositis, 249
isotretinoin complication, 173
systemic lupus erythematosus, 248
gatifloxacin, 19t, 28, 28f, 29
Gaucher disease, 305–306
gel polymer fillers, reactions to, 334
genetic associations, adverse drug reactions, 157
genital herpes, 288–290. See herpes simplex virus (HSV )
genitourethral disorders, 282–283.See also sexually transmitted
diseases (STDs)
ectopic pregnancy, 283
paraphimosis, 283
penis, squamous cell carcinoma of, 283
schistosomiasis infections, 140, 140f, 141, 141f
testicles, torsion of, 282–283
genodermatoses, associated with malignancies,
267
German measles. See rubella
Gianotti-Crosti disease, 122–123
glucagonoma
clinical features, 299f
necrolytic migratory erythema in, 267, 299–300
glucose control, 58
glycylglycine. See tigecycline
gonorrhea, 284–285
Chlamydia trachomatis, co-infection with, 285
clinical features, 284, 284f, 285
diagnosis, 285
eye, infection of, 285
treatment, 285
Gottron sign, 246f
graft versus host disease (GVHD), 29–30, 194–200
acute, 194–195, 195f, 196f, 197, 199
biological agents for, 35t
chronic, 194, 197, 197f, 198f, 199, 199f
clinical features, 195–198
cutaneous manifestations, 195, 195f, 196f, 197
diagnosis, 196, 198
erythroderma and, 206
etanercept, for acute, 37
etanercept, for chronic, 37–38
extracutaneous manifestations, 195, 197
histological changes, 196, 198
infliximab, for acute, 35–36
infliximab, for chronic, 36
lichenoid form, 197, 197f, 198, 198f
management, 199–200
overview of, 194, 200
pathophysiology of, 194–195
prognosis, 196–199
prophylaxis and therapy, 199
rituximab, 39
sclerodermiform, 197–198, 198f, 199, 199f
grafts, burn injuries and, 275
Gram-positive drug resistance, 18
daptomycin, 23
linezolid, 19–20
quinupristin/dalfopristin, 20
retapamulin, 25
tigecycline, 24
granuloma formation, cosmetic procedures and, 333
granulomatous disease, chronic, 187
group A streptococcus (GAS), 75, 77, 100
Günther’s disease, 69
HAART. See highly active antiretroviral therapy (HAART )
hair removal, 14
Hallopeau-Siemens type (recessive dystrophic epidermolysis
bullosa), 68
hamartomas, 72
hand washing, 14
agents used for, 14
scrubbing and, 14–15
HCC. See hepatocellular carcinoma (HCC)
heat emergencies, 293
hemangiomas, 72, 73f
hematological dysfunction
in systemic lupus erythematosus, 247
as targeted immune modulator complication, 171
hematomas, cosmetic procedures and, 332–333
hemodynamic disturbances, erythroderma and, 208
hemodynamic instability, 59
hemolytic anemia, efalizumab and, 171
hemorrhagic bullous, 102t
hemorrhagic fever, 121
Henoch-Schönlein purpura, 233, 233t, 234, 237–238
hepatitis B, oncogenic potential, 122–123
hepatobiliary side effects, isotretinoin and, 173
hepatocellular carcinoma (HCC), hepatitis B association,
123
hepatotoxicity, as targeted immune modulator complication,
171
Herlitz type, epidermolysis bullosa, 68, 68f
herpes simplex encephalitis (HSE), 116
herpes simplex virus (HSV ), 69, 115–117
chemical peel complications and, 337, 337f
clinical features, 115–117
genital herpes, 288–290
diagnosis, 289
in HIV patients, 289
overview of, 288, 288f, 289
pregnancy, 117, 290
treatment and management, 289–290
eczema herpeticum, 116
encephalitis and, 116
Index
immunocompromised patients and, 116, 191
neonatal, 69f, 115–116, 116t
treatment, 31t, 117
visceral infections, 116–117
herpes zoster, 117–118
HHV-5. See cytomegalovirus (CMV)
highly active antiretroviral therapy (HAART )
in Kaposi’s sarcoma treatment, 121
overview of, 188–189
histocompatibility leukocyte antigen (HLA)
graft versus host disease and, 194
histoplasmosis, 137
clinical features, 137f, 138f
diagnosis, 138f
as targeted immune modulator complication, 169–170
HIV, 188–193
anti-retroviral therapy, 188–189, 189t
cutaneous manifestations of, 189f, 190, 190f, 190t, 192,
193f
drug reactions, 192–193
fungal infections and, 135
herpes infections and, 289
overview of, 188–189, 189f
schistosomiasis infections and, 140
seroconversion illness, 189–190
hives. See urticaria
HLA. See histocompatibility leukocyte antigen (HLA)
hospital preparedness, in mass casualty management,
327–329
hospital-acquired infection. See aseptic technique; nosocomial
infections
hospital-acquired bacteremia, 99t
HPV. See human papilloma virus (HPV)
HSR. See hypersensitivity reaction (HSR)
HSV. See herpes simplex virus (HSV)
human cytomegalovirus (HCMV ). See cytomegalovirus (CMV)
human granulocytic anaplasmosis (HGA), 84–85
human herpesvirus 5 (HHV-5). See cytomegalovirus (CMV)
human immunodeficiency virus (HIV ). See HIV
human monocytic ehrlichiosis (HME), 84–85
human papilloma virus (HPV )
in HIV patients, 191
oncogenic potential, 122
5-hydroxyindoleacetic acid (5-HIAA) test, 301–302
hyperbaric oxygen therapy, 78, 82–83
hypereosinophilia, intravenous immunoglobulin and, 35t, 43
hyperglycemia, 58
hyperhidrosis, botulinum toxin A and, 336
hyper-IgE syndrome, 187
hyperpigmentation
in Addison disease, 298–299
reactive, as chemical peel complication, 336, 336f, 337
hypersensitivity reaction (HSR), 184–186.See also anaphylaxis;
venomous exposures
to abacavir, 192
as complication of cosmetic procedures, 333–334
drug rash with eosinophilia and systemic symptoms syndrome,
162–164
types of, 184, 184t, 186
353
hypertension
as cyclosporine A complication, 172
hypertensive crisis, 56–57
intracranial, as isotretinoin complication, 173
hyperthyroidism. See thyroid dysfunction
hypertrichosis lanuginose, 268–269
hypogammaglobulinemia
antibody deficiency and, 188
erythroderma and, 206
hypoglycemia, 58
hypopigmentation, 336–337
hypothermia, induced, 58
hypothyroidism. See thyroid dysfunction
hypoxia, carbon monoxide poisoning, 323
IBD. See inflammatory bowel disease (IBD)
ichthyosis
congenital, 305–306
erythroderma and, 205, 208
IgA. See immunoglobulin A (IgA)
IgE. See immunoglobulin E (IgE)
IIF. See indirect immunofluorescence (IIF)
immune complex hypersensitivity, 186
immune deficiencies, 186–193
acquired, 186t, 188–193
B-cell defects, 188
combined B- and T-cell defects, 188
complement deficiency, 187
congenital, 186, 186t, 188
ecthyma gangrenosum, 278–279
fungal infections, 126, 132–133
histoplasmosis, 137
HIV and AIDS, 188–193
neutrophils, defects in, 187
opportunistic infection association, 187t
T-cell defects, 188
warning signs of, 187t
immune restoration inflammatory syndrome (IRIS), 192–193,
193f
immunoblot analysis, 218, 219f
immunocompromised patients
crusted scabies
ecthyma gangrenosum, 278–279
Fournier’s gangrene, 280
Pneumocystis carinii pneumonia, 170
surgical site infections, 13
viral infections, 116, 118–120
immunoglobulin A (IgA), 188.See also linear IgA disease
immunoglobulin E (IgE). See anaphylaxis; hyper-IgE
syndrome
immunomodulators, 34–43.See also biological agents
incontinentia pigmenti, 70
indirect immunofluorescence (IIF )
of bullous pemphigoid, 224f
described, 215
of epidermolysis bullosa acquisita, 227f
pemphigus, 217–218, 218f
induced hypothermia, 58
infantile myofibromatosis, 72
354 I NDEX
infection, 18.See also life-threatening bacterial infections
in burn injuries, 276
classification of, 15
as cosmetic procedure complication, 331–332
diabetes, 304
HIV, 190–192
opportunistic, in immune deficiencies, 187, 187t, 188
systemic, 256–261
as targeted immune modulator complication, 168–170
infection control. See aseptic technique
Infectious Disease Society of America (IDSA), on necrotizing
soft-tissue infection treatment, 77–78
inflammatory bowel disease (IBD), isotretinoin complication, 173
infliximab, 34, 35t, 37
cicatricial pemphigoid, 35
contraindications, 36
dosage, 34
graft versus host disease, acute and chronic, 35–36
indications, 34
pemphigus vulgaris, 34
side-effects, 34
Stevens-Johnson syndrome, 36–37
toxic epidermal necrolysis, 36–37
infusion reactions, 168
inhalation anthrax. See anthrax
inhalation injuries, 273
inorganic mercury, 320
insect and arachnid venom exposures, 147–148.See also
vector-borne diseases
anaphylaxis and, 146–147, 343
bee and wasp stings, 185, 342–343
clinical features, 147–148
fire ant stings, 146–147, 342–343, 343f
overview of, 147, 147f, 148f
treatment, 148
intermittent bacteremia, 98–99
intracranial hypertension, isotretinoin complication, 173
intravenous immunoglobulin (IVIg), 35t, 39–43
angioedema with hypereosinophilia, 43
bullous pemphigoid, 41
cicatricial pemphigoid, 41
complications, 173–175
dosage, 40
indications, 40
mechanism, 39
necrotizing soft-tissue infection, 78
pemphigus foliaceus, 41
pemphigus vulgaris, 40–41
side-effects, 40
Stevens-Johnson syndrome and toxic epidermal necrolysis, 42
in toxic epidermal necrolysis, 159
intrinsic cell death pathway, 4–5, 5f
intubation, 57
invasive fungal dermatitis, 70, 70f
invasive fungal infection (IFI ) treatment, 29, 29t
iodophors, 14
IRIS. See immune restoration inflammatory syndrome (IRIS)
isotretinoin, complications, 173
Israel, mass casualty management in, 327–330
Italy, dioxin poisoning incident, 323–324
IVIG. See intravenous immunoglobulin (IVIG)
Jarisch-Herxheimer reaction, 291–292
jellyfish stings, 150, 296, 296f, 343
Job syndrome. See hyper-IgE syndrome
junctional epidermolysis bullosa, 68, 68f
Kaposi sarcoma, 121, 192
Kawasaki disease (KD)
vs. mercury poisoning, 320
purpura, 233t, 236
vs. staphylococcal scalded skin syndrome, 113–114
treatment, 239
keloids, cosmetic procedures and, 331
keratitis-ichthyosis-deafness (KID) syndrome, erythroderma and,
208
KID syndrome. See keratitis-ichthyosis-deafness (KID) syndrome
Kindler syndrome, 68–69
Klebsiella spp. infection, 78
Koebner type, epidermolysis bullosa, 67–68
kwashiorkor cryoglobulins, erythroderma and, 207
LAD. See linear IgA disease (LAD)
Langerhans cell histiocytosis (LCH ), 73–74
latent tuberculosis infection (LTBI ), 169
Leiner disease
erythroderma and, 207
vs. staphylococcal scalded skin syndrome, 113
leishmaniasis. See mucocutaneous leishmaniasis
Leptospira interrogans, 258.See also leptospirosis
leptospirosis, 258–259
leukemia, 73–74
leukoplakia, oral hairy. See oral hairy leukoplakia
lice, as disease vectors, 149
Lichtenberg figures, 277
lidocaine, 53–54
life-threatening bacterial infections, 81–93.See also bacteremia;
sepsis; septic shock; toxic shock syndrome (TSS)
Aeromonas hydrophila infection, 92
anthrax, 87, 88f, 89
cellulitis, periorbital and orbital, 81, 81f, 82
Chromobacterium violaceum infection, 92–93, 93f
malignant (necrotizing) external otitis, 82–83
Mediterranean spotted fever, 86–87
meningococcemia, 83, 83f, 84
overview of, 81
Rocky Mountain spotted fever, 84, 85f, 86
tularemia, 89–90, 90f
Vibrio vulnificus infection, 78–79, 90, 91f, 92
lightning strike injuries, 277
linear IgA disease (LAD), 225–226, 226f
linezolid, 18, 19f, 19t, 20
cellular mechanism, 18
contraindications, 20
dosage, 20
indications, 19–20
pharmacokinetics, 18–19
in vitro activity, 19
Index
lip ptosis, as botulinum toxin A complication, 335, 335f
lipid metabolism, isotretinoin complications in, 173
lipopolysaccharide, sepsis and, 100–101
Listeria monocytogenes (listeriosis), 69
local wheals, 178.See also urticaria
LTBI. See latent tuberculosis infection (LTBI)
lupus erythematosus, in neonates, 71.See also systemic lupus
erythematosus (SLE)
Lutz-Splendore-Almeida disease. See paracoccidioidomycosis
Lyell disease. See toxic epidermal necrolysis (TEN)
Lyme disease, 149, 149f
lymphopenia, in adverse (cutaneous) drug reactions, 157
macrolides, surgical prophylaxis, 16
macular/papular eruption, in neonates, 70
magnesium, 54
major histocompatibility complex (MHC) class II molecules, 101
malaria exposure risk, 149–150, 342
malignant (necrotizing) external otitis, 82–83
diagnosis, 82
prognosis, 83
treatment, 82–83
Marburg virus, 122
marine venomous exposures. See aquatic venomous exposures
mass casualty management, 327–330
hospital preparedness, 327–329
media role, 329
overview of, 327
policy considerations, 329
rapid vs. slow scenarios, 329
mastocytosis, 72–73, 73f, 302–303
clinical features, 181, 302–303, 303f
diagnosis, 303, 303t
diffuse cutaneous, erythroderma and, 205
and insect venom exposures, 146
overview of, 178, 180, 302
prognosis, 183
treatment, 182, 303
measles, 120
media role, in mass casualty management, 329
Mediterranean spotted fever, 86–87
diagnosis, 86–87
overview of, 86
prognosis, 87
treatment, 87
Mees lines, 318
melanoma, 8–9, 73–74
Meleney gangrene, 281
melioidosis, 256–257
meningococcemia, 83, 83f, 84
diagnosis, 83–84
overview of, 83
prognosis, 84
treatment, 84
menstrual toxic shock syndrome. See toxic shock syndrome (TSS)
mercury poisoning, 319–321
diagnosis, 321
management, 321
overview of, 319
355
types of/exposure risks, 319–321
metabolic disturbances, erythroderma and, 208.See also endocrine
disorders
metastases, 265
methicillin-resistant Staphylococcus aureus (MRSA), 114.See also
antibiotics; Staphylococcus aureus
cellulitis, periorbital and orbital, 82
daptomycin, 23
linezolid, 20
necrotizing soft-tissue infection, 77–78
oritavancin, 27–28
quinupristin/dalfopristin, 20
tigecycline, 24
methicillin-susceptible Staphylococcus aureus (MSSA), 23
retapamulin, 25
tigecycline, 24
methotrexate (MTX), complications, 171–172
methylmercury, 320
microscopic polyangiitis (MPA), 233t, 235–236, 239
milia, cosmetic procedures and, 337, 337f
mites, as disease vectors, 149
mitochondrial-mediated intrinsic cell death pathway, 4–6
mixed connective tissue disease, 252
molluscum contagiosum, in HIV patients, 191
mononucleosis
cytomegalovirus, 119–120
Epstein-Barr infections, 122
mosquito-borne diseases, 121–122, 149–150
moxifloxacin, 19t, 28, 28f, 29
MPA. See microscopic polyangiitis (MPA)
MS. See multiple sclerosis (MS)
MTX. See methotrexate (MTX)
mucocutaneous leishmaniasis, 141–143
clinical features, 142
diagnosis, 142, 142f, 143, 143f
overview of, 141–142
treatment, 143
mucormycosis, 134
mucous membrane pemphigoid, 223–224, 224f.See also cicatricial
pemphigoid (CP)
Muir-Torre syndrome, 266–267
multiple organ dysfunction syndrome (MODS), 99–100
multiple sclerosis (MS), targeted immune modulators and, 170
multi-resistant organisms, 276
mycobacterial adenopathy, suppurative, 192–193, 193f
myeloablative regimens, graft versus host disease, 199–200
myocardial infarction (MI ), 55–56, 174
myonecrosis, 75
nails, removal of, in torture, 314
necrobiosis lipoidica, 304
necrolysis, toxic epidermal, erythroderma and, 205
necrolytic migratory erythema, glucagonoma and, 267, 299, 299f,
300
necrosis. See also apoptosis; programmed cell death (PCD)
vs. apoptosis, 1–2
atraumatic
cosmetic procedure complication, 333
model overview, 6t, 7–8
356 I NDEX
necrosis (cont.)
vs. oncosis, 8
programmed, 6t
term, meaning and origin, 7–8
necrotizing cutaneous myositis, 280–281
necrotizing external otitis, 82–83
diagnosis, 82
prognosis, 83
treatment, 82–83
necrotizing fasciitis (NF ). See also necrosis
anorectal region, 279, 279f, 280
antibiotic selection, 77–79
classification, 75
clinical presentation, 76, 76t, 77, 79
diagnosis, 77
misdiagnosis of, 76
prognosis, 78
treatment, 77
Vibrio vulnificus, 78–79, 90, 91f, 92
necrotizing infections, 279–281
Fournier gangrene, 280, 280f
necrotizing fasciitis, 279, 279f, 280
overview of, 279, 279t
progressive bacterial synergistic gangrene, 281, 281f
synergistic necrotizing cellulitis, 280–281
necrotizing soft-tissue infection (NSTI ), 75–79
antibiotic selection, 77–79
classification, 75
clinical presentation, 76, 76t, 77, 79
diagnosis, 77
incidence, 75
overview of, 75
prognosis, 78
term, meaning of, 75
treatment, 77
Vibrio vulnificus, 78–79, 90, 91f, 92
Neisseria gonorrhoeae, 284.See also gonorrhea
Neisseria meningitidis. See meningococcemia
nematocysts, 296, 296f
neonatal cutaneous emergencies, 66–74
aplasia cutis, 74
Candida infection, 70, 70f
epidermolysis bullosa, 67
erythroderma, 71, 72f
hamartomas, 72
hemangiomas, 72, 73f
herpes, 69, 69f
incontinentia pigmenti, 70
listeriosis, 69
lupus erythematosus, 71
macular/papular eruption, 70
management principles, 68
mastocytosis, 72–73, 73f
neoplastic diseases, 73, 73f, 74
nodular eruptions, 71
overview of, 66
prematurity, 74
purpura, 70–71
S. aureus, 66–67, 67f
scabies, 70
sepsis, 69
syphilis, 69
TORCH syndrome, 71, 71f
varicella, 70
neonatal herpes simplex virus, 115–116, 116t
neonatal lupus erythematosus (NLE), 71, 248, 248t, 249
neonatal varicella, 117
neoplastic diseases, neonatal, 73–74
nephrotoxicity, cyclosporine A complication, 172
Netherton syndrome, 71, 72f, 208
neuroblastoma, 73, 73f, 74
neurological events
cyclosporine A complication, 173
targeted immune modulator complication, 170–171
neurotoxicity, cyclosporine A complication, 172–173
neutral lipid storage disease, erythroderma and, 208
neutrophils, defects in, 187
nevirapine rash, in HIV patients, 192
niacin deficiency, 308
Nikolsky sign, 112, 113f
nodular eruptions, in neonates, 71
nodularities, palpable. See palpable nodularities
nonmenstrual toxic shock syndrome. See toxic shock syndrome
(TSS)
nonmyeloablative regimens, graft versus host disease, 199–200
nonreabsorbable gel polymer fillers, reactions to, 334
nonsteroidal antiinflammatory drugs (NSAIDs)
acute skin failure, 63t, 64
toxic epidermal necrolysis risk, 157
nosocomial infections. See also aseptic technique
hospital-acquired bacteremia, 99t
pneumonia and sepsis, 106t
surgical site infections, 12–13
NSAIDs. See nonsteroidal antiinflammatory drugs (NSAIDs)
NSTI. See necrotizing soft-tissue infection (NSTI)
nutrition, acute skin failure, 64t
octopuses, venomous exposure to, 150
ocular difficulties. See also eye infections
in adverse (cutaneous) drug reactions, 158
as isotretinoin complication, 173
oculoglandular disease, 90
Ofuji disease. See eosinophilic folliculitis
Omenn syndrome, erythroderma and, 206
oncogenic viruses, 122–123
oncosis, 8
ophthalmia neonatorum, 285
oral hairy leukoplakia, in HIV patients, 191
oral-esophageal candidiasis, 70, 190–191
orbital cellulitis, 81–82
diagnosis, 102t
vs. periorbital, 81, 81f, 82
prognosis, 82
treatment, 82
organ transplantation, herpes zoster infections and, 117–118
organic mercury, 320
oritavancin, 19t, 26f, 27–28
osteomyelitis, 83
Index
otitis, malignant external, 82–83
diagnosis, 82
prognosis, 83
treatment, 82–83
outpatient surgery, 12.See also aseptic technique
oxazolidinones. See linezolid
oximetry, 60
p53 tumor suppressor gene, 5–6
palpable nodularities, cosmetic surgery and, 333
palpable purpura, 102t
PAN. See polyarteritis nodosa (PAN)
pancytopenia, methotrexate and, 172
pandemics, of plague, 260
papular purpuric syndrome, 119
Paracoccidioides brasiliensis, 129.See also paracoccidioidomycosis
paracoccidioidomycosis, 129–132
clinical features, 129, 129t, 130, 130f
diagnosis, 130–131, 131f
overview of, 129
treatment, 131–132
paraffin, as dermal filler, 332
paraneoplastic autoimmune multiorgan syndrome, 221
paraneoplastic cutaneous syndromes, malignancy association,
265–269
highly associated, 265, 266f, 267
overview of, 265, 265f, 268t
possibly associated, 267–269
paraneoplastic pemphigus (PNP), 35t, 39, 219–221, 267
paraphimosis, 283
paraptosis, 6t, 7
parasitic diseases, 137–143
amebiasis, 141
Chagas disease, 137–140
mucocutaneous leishmaniasis, 141–143
overview of, 126
schistosomiasis, 140–141
PARP. See poly adenosine diphosphate-ribose polymerase
(PARP)
parvovirus B19 (PVB 19), 118–119
PCD. See programmed cell death (PCD)
PCP. See Pneumocystis carinii pneumonia (PCP)
PCT. See porphyria cutanea tarda (PCT)
pediatric considerations. See also pregnancy
burn injuries, 271
Chagas disease, 139
dioxin poisoning, 323
erythroderma, 203t, 210–211
eye infections, 285–286, 286f
insect repellant use, 150
insect venom exposures, 146
mercury toxicity, 319–320
staphylococcal scalded skin syndrome, 109–114
streptococcal dermatitis, 278
pellagra, 301, 308
pelvic inflammatory disease (PID), 283, 286
pemphigoid gestationis (PG), 224, 224f, 225
pemphigoid group, of autoimmune bullous dermatoses, 222–225
bullous, 222–223, 223f, 224f
mucous membrane, 223–224, 224f
pemphigoid gestationis, 224–225, 225f
pemphigus, 216–222
drug-induced, 221
erythematosus form, 219, 220f
foliaceus form, 218–219, 220f
histopathology, 217–218, 218f, 219f
overview of, 216
paraneoplastic, 219–221, 221f, 267
prognosis, 216–217
treatment, 221–222
vegetans form, 218, 219f, 220f
vulgaris form, 217, 217f, 218, 218f
pemphigus foliaceus (PF )
biological agents for, 35t
intravenous immunoglobulin, 41
vs. staphylococcal scalded skin syndrome, 111, 111t, 112,
112f
pemphigus vulgaris (PV ), 9
biological agents for, 35t
infliximab, 34
intravenous immunoglobulin, 40–41
in neonates, 69
rituximab, 38–39
penicillins
anaphylaxis, 291–292
meningococcemia, 84
surgical prophylaxis, 16
penis
herpes and, 288f
squamous cell carcinoma of, 283
perianal abscess, 278
perianal cellulitis, 278
perinatal varicella, 70
periorbital cellulitis, 81, 81f, 82
diagnosis, 102t
vs. orbital, 81–82
prognosis, 82
treatment, 82
permeability transition (PT ) pore, 4
permethrin insect repellant, 150
petechiae, 102t
Peutz-Jeghers syndrome, 267
PF. See pemphigus foliaceus (PF ); purpura fulminans (PF)
PG. See pemphigoid gestationis (PG)
phagocytosis, initiation of, 3
pharmacokinetics
of daptomycin, 23
of linezolid, 18–19
of quinupristin/dalfopristin, 20
of retapamulin, 25
of tigecycline, 24
phenol-based chemical peels, cardiotoxicity, 337
phosphatidylserine receptor (PS-R), 3
phototoxic reactions, 293–294, 294f
phrynoderma, 308
phytophotodermatitis, 181
picaridin insect repellent, 150
PID. See pelvic inflammatory disease (PID)
357
358 I NDEX
pigmentation, changes in
Addison disease and, 298
carotenoderma, 321–323
as cosmetic procedure complication, 333, 336–337
pink disease, See acrodynia
pityriasis rubra pilaris (PRP), erythroderma and, 205, 205f
plague, 259–261
bubonic, 260
overview of, 259–260, 260f
pneumonic, 261
septicemic, 261
treatment, 261
plasminogen activators, purpura fulminans, 240
Pneumocystis carinii pneumonia (PCP), as targeted immune
modulator complication, 170
Pneumocystis jiroveci. See Pneumocystis carinii pneumonia
(PCP)
pneumonic plague, 261
pneumonitis, methotrexate-induced, 172
PNP. See paraneoplastic pemphigus (PNP)
poisoning, cutaneous signs of, 318–324
arsenic, 318–319
carbon monoxide, 274, 323
carotenoderma, 321–323
dioxin, 323–324
food-borne, 341
mercury, 319–321
overview of, 318
poly(adenosine diphosphate-ribose) polymerase (PARP), 4
polyarteritis nodosa (PAN), 233t, 235, 239
porcine collagen injections, reactions to, 333
porphyria, 69
porphyria cutanea tarda (PCT ), 304–305, 305f
posaconazole, 29, 29t, 30, 30f
post-resuscitation support, 57–58
PPE. See pustular pruritic eruption (PPE)
pregnancy
cytomegalovirus infections, 119–120
ectopic, 283
herpes infections, 115–117, 290
neonatal lupus erythematosus, 248, 248t, 249
parvovirus infections, 119
pemphigoid gestationis, 224–225
rubella infections, 120
varicella zoster infections, 117
prematurity, in neonates, 74
preoperative skin antisepsis, 13–15
scrubbing, 14–15
septics, 13–14
skin preparation, 14
preseptal cellulitis, 81, 81f, 82, 102t
vs. orbital, 81–82
prognosis, 82
treatment, 82
primary varicella, 117
primula sensitivity, 295
procainamide, 54–55
procaine reaction, 292
programmed cell death (PCD). See also apoptosis
autoimmune disorders and, 9
autophagic cell death, 6–7
cancer and, 8–9
cell injury and, 1–6
vs. necrosis, 7–8
overview of, 6t, 9
paraptosis, 7
pathways of, 1–2, 2f, 6t
purpose of, 1
programmed necrosis, 6t
progressive bacterial synergistic gangrene, 281, 281f
prophylactic antibiotics, 15–16
proptosis, as botulinum toxin A complication, 336
protein C, purpura fulminans and, 240
PRP. See pityriasis rubra pilaris (PRP)
Pseudomonas aeruginosa, 82, 278–279.See also ecthyma
gangrenosum
Pseudomonas pseudomallei, 256.See also melioidosis
psoriasis
erythroderma and, 205
in HIV patients, 191
methotrexate complications, 171–172
psoriatic erythroderma, 204f, 205
psychiatric disorders, isotretinoin and, 173
psychological considerations, torture cases and, 316–317
ptosis, botulinum toxin A, 335, 335f
pulmonary dysfunction
dermatomyositis and, 249–250
leptospirosis and, 259
methotrexate and, 172
scleroderma and, 251
in systemic lupus erythematosus, 246–247
pulmonary edema, 55
pulmonary embolism (PE), 55
pulse oximetry, 60
pulseless electrical activity (PEA), 52
pulses, 60
purpura, 70–71, 233–241
etiology, 233–237
overview of, 233, 233t, 241
treatment and management, 237, 237t, 241
purpura fulminans (PF )
etiology, 233, 233t, 236, 236f, 237
treatment and management, 239, 240t, 241
pustular pruritic eruption (PPE). See eosinophilic folliculitis
PVB 19. See parvovirus B19 (PVB 19)
pyoderma gangrenosum, 267–268
pyridoxine deficiency, 308
QRS complex, 53
Quinke edema. See angioedema
quinolones, new indications for, 28, 28f, 29
quinupristin/dalfopristin, 19t, 20, 21f, 22
cellular mechanism, 20
contraindications, 22
dosage, 22
indications, 21–22
pharmacokinetics, 20
in vitro activity, 20
Index
reactive hyperpigmentation, 336, 336f, 337
recessive dystrophic EB (Hallopeau-Siemens type), 68
Reiter’s syndrome. See sexually acquired reactive arthritis (SARA)
renal dysfunction/insufficiency
acute, as intravenous immunoglobulin complication, 174
leptospirosis and, 259
scleroderma and, 252
staphylococcal scalded skin syndrome and, 109
in systemic lupus erythematosus, 247–248
resistant organisms. See drug resistance
respiratory dysfunction, 58–59
resuscitation, 50–51
retapamulin, 19t, 25, 25f, 27
cellular mechanism, 25
contraindications, 26–27
dosage, 26
indications, 25
pharmacokinetics, 25
in vitro activity, 25
retinoids, complications, 173
return of spontaneous rhythm circulation (ROSC), 58–59
rhabdomyosarcoma, 73–74
rhus dermatitis, 295, 295f, 343, 343f, 344
riboflavin deficiency, 308
Rickettsia conorii, 86–87
Rickettsia rickettsii, 84, 85f, 86
risk factors
environmental, 13
surgical site infections, 13
travel-related, 340–341, 344
for viral infection, 123
Ritter’s disease, 114.See also staphylococcal scalded skin syndrome
(SSSS)
rituximab, 35t, 38–39
dosage, 38
graft versus host disease, chronic, 39
indications, 38
pemphigus vulgaris, 38–39
side-effects, 38
RMSF. See Rocky Mountain spotted fever (RMSF)
Rocky Mountain spotted fever (RMSF ), 84, 85f, 86, 149
diagnosis, 84–85
prognosis, 86
treatment, 85–86
Romaña sign, 139, 139f
rose spots, 258
rubella, 120–121
rubeola. See measles
Rule of Nines, 271
Salmonella typhi, 257.See also typhoid fever
“Samurai law of biology”, 26f
SARA. See sexually acquired reactive arthritis (SARA)
scabies, crusted
erythroderma and, 205–206
in HIV patients, 191
scabies, in neonates, 70
scalding. See burn injuries
scarlet fever
erythroderma and, 207
staphylococcal, 112
scarring, cosmetic procedures and, 331, 337
schistosomiasis, 140, 140f, 141, 141f
Schwartzman phenomenon, 236–237
SCID. See severe combined immunodeficiency syndrome
(SCID)
scleroderma
carcinoid syndrome, 301
overview of, 251, 251f
pulmonary dysfunction, 251
renal dysfunction, 252
systemic lupus erythematosus, 251–252
scorpion stings, 147
scorpion fish, venomous exposures, 296, 296f
SCORTEN. See severity-of-illness score for toxic epidermal
necrolysis (SCORTEN)
scrubbing, 14–15
SCT. See stem cell transplantation (SCT)
scurvy, 309
seborrheic dermatitis
erythroderma, 205
in HIV patients, 190, 190f
sedatives, 60
seizures
cyclosporine A complication, 173
targeted immune modulator complication, 170
Senear-Usher syndrome, 219
sepsis
background, 98
diagnosis, 101, 102t
laboratory findings, 103, 103t
neonatal, 69
overview of, 99
pathophysiology, 100–101
prognosis, 106–107
symptoms, 101–103, 103t
terminology, 98t
treatment, 105–106, 106t
septic shock
background, 98
diagnosis, 101, 102t
laboratory findings, 103, 103t
overview of, 99–100
pathophysiology, 100–101
prognosis, 106–107
symptoms, 101–103, 103t
terminology, 98t
septicemic plague, 261
seroconversion illness, HIV, 189, 189f, 190
Serratia marcescens, 14
serum chromogranin A (CgA) test, 302
serum sickness (SS), 162, 162t, 164–165
serum sickness-like reaction (SSLR), 164–165
severe combined immunodeficiency syndrome (SCID), 188
severity-of-illness score for toxic epidermal necrolysis
(SCORTEN), 63t, 64, 159
Seveso, Italy, dioxin poisoning incident, 323–324
sexually acquired reactive arthritis (SARA), 287, 287f
359
360 I NDEX
sexually transmitted diseases (STDs), 282–292.See also
genitourethral disorders
Chlamydia trachomatis infections, 285–288
drug reactions and side effects, 291–292
genital herpes, 288–290
gonorrhea, 284–285
overview of, 282–284
partner notification, 283, 285
syphilis, 290–291
shaving, 14
Shibasaburo Kitasato, 259–260
shin spots, 304
shingles. See herpes zoster
shock, 57
side effects. See drug reactions; specific drug names
sign of Leser-Trelat, 267
silicone fillers, reactions to, 333–334
Sister Mary Joseph nodule, 265, 265f
“6 H’s”, 52
Sjögren syndrome, erythroderma and, 208
SJS. See Stevens-Johnson syndrome (SJS)
skin and soft tissue infections (SSTIs), 19, 19t, 20, 23
skin failure, acute, 62–64.See also life-threatening bacterial
infections; neonatal cutaneous emergencies
complications, 63, 63t, 64
defined, 62
etiology, 62, 62t, 63
management, 63, 63t, 64, 64t
overview of, 62, 64
pharmacology, 63t
risk factors, 63
types of, 62
skin frailty syndrome, 68–69
skin preparation, 14
skin tags, 304
skin torture. See torture
SLE. See systemic lupus erythematosus (SLE)
Smac DIABLO, 4–5
smallpox, 118
smoke inhalation, 273–274
soap, 14
solar urticaria, 178
Solenopsis species. See fire ant stings
soles, of feet, blunt trama to,
South American blastomycosis. See paracoccidioidomycosis
spider bites, 147, 147f, 148, 148f
sponge dermatitis and sponge diver’s disease, 150
sporotrichosis, 132–133
clinical features, 132, 132f, 133
diagnosis, 133, 133f
overview of, 132
treatment, 133, 134t
squamous cell carcinoma, of penis, 283
SS. See systemic sclerosis (SS)
SSI. See surgical site infections (SSIs)
SSSS. See staphylococcal scalded skin syndrome (SSSS)
staphylococcal cellulitis, of anorectal region, 278
staphylococcal scalded skin syndrome (SSSS), 66–67, 67f,
109–114
clinical features, 112, 113f
diagnosis, 113–114
epidemiology, 109
vs. erythroderma, 71, 72f
erythroderma and, 207
etiology, 109–110, 110f
management, 114
in neonates, 71
overview of, 109, 114
pathogenesis, 110–112
pathology, 112–113, 113f
vs. pemphigus foliaceus, 111, 111t, 112, 112f
prognosis, 114
Staphylococcus aureus
bacteremia, 99
cellulitis, periorbital and orbital, 82
malignant (necrotizing) external otitis, 82
necrotizing soft-tissue infection, 77
in neonates, 66–67
staphylococcal scalded skin syndrome and, 109–110
surgical site infections, 12.See also methicillin-resistant
Staphylococcus aureus (MRSA)
toxic shock syndrome, 100, 104, 104t, 105, 105t
STDs. See sexually transmitted diseases (STDs)
stem cell transplantation (SCT ), 194.See also graft versus host
disease (GVHD)
sterile technique. See aseptic technique
sterilization, surgical equipment, 13
Stevens-Johnson syndrome (SJS), 36–37, 154–159
acute skin failure, 62t, 63t, 64
biological agents for, 35t
causative drugs, 157
classification, 154–155, 155t
clinical features, 155–156
corticosteroids, 158–159
diagnosis, 157
vs. drug rash with eosinophilia and systemic symptoms
syndrome, 163
hypersensitivity reactions, 184–185
intravenous immunoglobulin, 42
overview of, 154, 159
prognosis, 159
sexually transmitted diseases and, 292
treatment, 157–159
stratum corneum, 63, 64t
streptococcal dermatitis, of anorectal region, 278
streptococcal gangrene, 279–280
Streptococcal pyogenes, toxic shock syndrome, 104t, 105, 105t
streptomycin, tularemia and, 90
stroke, 56, 174
sucrose, intravenous immunoglobulin and, 174
sulfonamides, toxic epidermal necrolysis risk, 157
sun exposure. See ultraviolet (UV ) exposure
sunscreens, 294, 295f
superficial herpes simplex, 69
superficial partial-thickness burns, 272
surgery. See also cosmetic procedures
surgical equipment, 13
surgical site infections (SSIs), 12–13, 15–16
Index
antibiotic prophylaxis, 15–16
overview of, 12
preoperative skin antisepsis, 13–15
risk factors, environmental, 13
risk factors, patient, 13
skin preparation, 14
surgical technique. See aseptic technique
surgical wound infection. See aseptic technique
symmetric flexural exanthema, 320–321
synergistic necrotizing cellulitis, 280–281
synergistic nonclostridial anaerobic myonecrosis, 280–281
syphilis, 290–291
diagnosis, 290–291
in neonates, 69
overview of, 290, 290f, 291f
treatment, 291
systemic candidosis, 126–129
clinical features, 126–127, 127f
diagnosis, 127
overview of, 126
treatment, 127, 127t, 128t, 129
systemic infections, 256–261
leptospirosis, 258–259
melioidosis, 256–257
overview of, 256
plague, 259, 260f, 261
typhoid fever, 257–258
systemic inflammatory response syndrome (SIRS), 98t, 99–100
systemic lupus erythematosus (SLE), 245–249
cardiovascular dysfunction, 245–246
drug-induced, 171
gastrointestinal dysfunction, 248
hematological dysfunction, 247
neurological dysfunction, 247
overview of, 245, 245t, 249f
pemphigus and, 219
pulmonary dysfunction, 246–247
renal dysfunction, 247–248
systemic neoplastic diseases. See paraneoplastic cutaneous
syndromes, malignancy association
systemic sclerosis (SS), 252.See also scleroderma
tachyarrhythmia, 52–53
tanning, controlled, 293
targeted immune modulators (TIMs), complications of, 168–171
congestive heart failure, 170
hepatotoxicity, 171
histoplasmosis, 169–170
infections, 168–170
infusion reactions, 168
neurological events, 170–171
vasculitis, 171
Tay’s syndrome. See trichothiodystrophy
T-cell defects, 188
T-cell receptors (TCRs), 101
TEN. See toxic epidermal necrolysis (TEN)
testicles
torsion of, 282–283
tumor of, 287
361
thermal injuries. See burn injuries
thimerosal, 321
thrombocytopenia, efalizumab and, 171
thromboembolic disease, 276
thrombotic complications, of intravenous immunoglobulin,
174–175
thrush, 70, 190–191
thyroid dysfunction, 300–301
ticks. See also Rocky Mountain spotted fever (RMSF )
as disease vectors, 148f, 149, 149f
Lyme disease, 149, 149f
Mediterranean spotted fever, 86–87
tularemia, 89–90
venomous exposures, 146, 148
tigecycline, 19t, 24, 24f, 25
cellular mechanism, 24
contraindications, 24–25
dosage, 24
indications, 24
pharmacokinetics, 24
in vitro activity, 24
TIMs. See targeted immune modulators (TIMs), complications of
tissue plasminogen activator (tPA), 56
TNF-a. See tumor necrosis factor-a (TNF-a)
TNF-R. See tumor necrosis factor receptor (TNF-R)
toll-like receptors (TLRs), 100
topical lighteners and bleaches
hyperpigmentation and, 336f
mercury toxicity and, 320
TORCH syndrome, 71, 71f
torture, 313–317
clinical features, 313, 315f, 316
defined, 313
prognosis, 317
therapy, 316–317
toxic epidermal necrolysis (TEN), 36–37, 154–159
acute skin failure, 62t, 63t, 64
biological agents for, 35t
causative drugs, 157
classification, 154–155, 155t
clinical features, 155–156, 156f
corticosteroids and, 158–159
diagnosis, 157
vs. drug rash with eosinophilia and systemic symptoms
syndrome, 163
erythroderma and, 205
intravenous immunoglobulin, 42
overview of, 154, 159
prognosis, 159, 159t
vs. staphylococcal scalded skin syndrome, 113
treatment, 157–159
toxic shock syndrome (TSS)
background, 98
chemical peels, 337
diagnosis, 101
erythroderma and, 207
overview of, 100
pathophysiology, 100–101
prognosis, 106–107
362 I NDEX
toxic shock syndrome (cont.)
staphylococcal, 104, 104t, 105, 105t
streptococcal, 104t, 105, 105t
symptoms, 103–105
terminology, 98t
toxin 1 (TSST-1), 101
treatment, 106
transient bacteremia, 98
travel-related dermatoses, 340–344.See also environmental skin
disorders
allergic reactions, 342, 343f, 344
case reports, 340, 342
drug reactions, 341, 341f
infections, 340f, 341–342
medical history documents, importance of, 341, 344
overview of, 340–341, 342t, 344
from viral infections, 123
treatment. See specific drug names and groups
Treponema pallidum. See syphilis
trichothiodystrophy, erythroderma and, 208
tripe palms, 268
Trypanosoma cruzi, 139, 139f.See also Chagas disease
trypanosomiasis, 137.See also Chagas disease
TSS. See toxic shock syndrome; toxic shock syndrome (TSS)
tuberculosis, as targeted immune modulator complication, 169
tularemia, 89–90, 90f
diagnosis, 89–90
prognosis, 90
treatment, 90
tumor necrosis factor receptor (TNF-R), 4
tumor necrosis factor-a (TNF-a), 100–101, 168–170.See also
targeted immune modulators (TIMs), complications of
tumor necrosis factor-alpha (TNF-a)
etanercept, 37
graft versus host disease, 35
infliximab, 34
Stevens-Johnson syndrome and toxic epidermal necrolysis, 36
Tyndall effect, 333
type I cell death. See apoptosis
type I hypersensitivity. See anaphylaxis
type II cell death. See autophagic cell death (ACD)
typhoid fever, 257–258, 341
ulceroglandular disease, 90.See also tularemia
ultraviolet (UV ) exposure
Addison disease, 298
overview of, 293–294
phototoxic reactions, 294f
sunscreens, 295f
uncomplicated infection, 18
UP. See urticaria pigmentosa (UP)
urticaria
acute/physical, 178, 178t, 179, 181, 183
aquagenic, 178
chronic/non-physical, 179, 179t, 181–183
described, 178–179, 179f
diagnosis, 180–181
prognosis, 183
treatment, 181–182
vasculitis and, 181
urticaria pigmentosa, 72–73
urticaria pigmentosa (UP), 302–303, 303f.See also mastocytosis
UV. See ultraviolet (UV ) exposure
vaccinations
measles, 120
mosquito-borne diseases, 122
rubella, 121
smallpox, 118
varicella zoster virus, 118
vaccine-related mercury exposure, 321
vaccinia, 118
valacyclovir, 31, 31t
vancomycin, 77–78
vancomycin-resistance, 18, 21–22
vancomycin-resistant enterococci (VRE), 19–20
vancomycin-resistant Enterococcus faecium (VREF ) infections, 18
quinupristin/dalfopristin, 20–22
tigecycline, 24
varicella zoster virus (VZV ), 70, 117–118
clinical features, 117–118
herpes zoster, 117–118
in HIV patients, 191
primary varicella, 117
treatment, 118
variola, 136–137
variola major. See smallpox
vasculitis, 233–241
from drug reactions, 165, 341f
etiology, 233–237
malignancy association, 269
overview of, 233, 233t, 241
targeted immune modulator complication, 171
treatment and management, 237, 237t, 241
urticaria, 181
vasopressin, 53
vector-borne diseases, 149–150.See also insect and arachnid
venom exposures
Chagas disease, 137, 139f, 140
clinical features, 149
Lyme disease, 148f, 149f
mosquito-borne, 121–122
mucocutaneous leishmaniasis, 141, 142f, 143, 143f
overview of, 149
venom desensitization immunotherapy, 185
venomous exposures, 146–151
anaphylaxis and, 146–147
aquatic, 150–151, 178, 295–296, 296f, 343, 343f
from insects and arachnids, 147–148, 185, 342–343, 343f
overview of, 150
travel-related, 342–343, 343f
treatment, 147–148, 151
ventricular fibrillation (VF ), 51–52
verapamil, 54
vesicular/pustular eruptions, neonatal, 69–70
Candida infection, 70, 70f
herpes, 69
incontinentia pigmenti, 70
Index
listeriosis, 69
scabies, 70
sepsis, 69
varicella, 70
Vibrio vulnificus infection, 90, 91f, 92, 340, 340f
background, 90–91
clinical presentation, 79
diagnosis, 91
epidemiology of, 79
necrotizing soft-tissue infection, 78–79
prognosis, 91–92
treatment, 91
viral diseases, 115–123
cytomegalovirus, 119–120
herpes simplex virus (HSV ), 115–117
Kaposi sarcoma, 121
Marburg/Ebola, 122
measles, 120
mosquito-borne, 121–122
oncogenic, 122–123
overview of, 115, 123
parvovirus B19, 118–119
rubella, 120–121
smallpox, 118
varicella zoster virus, 117–118
visual loss. See ocular difficulties
vitamin A. See also isotretinoin
conversion of, in carotenoderma, 322
deficiency, 307–308
in measles treatment, 120
vitamin deficiencies, 307–309
B vitamins, 308
vitamin A, 307–308
vitamin C, 308–309
vitamin K, 309
vitamin toxicity, 309, 309t, 321–323
vitiligo, 304
voriconazole, 29, 29f, 29t, 30
VREF. See vancomycin-resistant Enterococcus faecium (VREF )
infections
wasps. See bee and wasp stings
water contaminants, arsenic, 318
Wegener granulomatosis (WG), 233t, 234, 238
West Nile virus, 122
WG. See Wegener granulomatosis (WG)
wheals, local, 178.See also urticaria
Whitmore disease, 256
Wiskott-Aldrich syndrome, 188
wound classification, 15.See also antibiotic selection
wound management, burns, 274–275
xenodiagnosis of Brumpt, 140
X-linked hypogammaglobulinemia, 188
yellow fever, 121–122
Yersin, Alexandre, 259–260
Yersinia pestis, 259–260.See also plague
Yushchenko, Viktor, 323
zinc deficiency, 307
zygomycosis, 134–137
clinical features, 135, 136t
diagnosis, 134f, 135–136, 136f
overview of, 134–135, 135t
treatment, 136–137
363