Medstudy im core curriculum, 16e book 1 gastroenterology & infectious disease unitedvrg by Amran Hajjaj

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Integrate and demonstrate increased overall knowledge of Internal Medicine

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16th Edition Internal Medicine Review Core Curriculum Robert A. Hannaman, MD

Editor in Chief MedStudy Colorado Springs, CO

Medical Editors

Yasmine Subhi Ali, MD, MSCI, FACC, FACP*

Donald Venes, MD, MSJ

President, Nashville Preventive Cardiology, PLLC

Medical Editor

Nashville, TN

Taber's Cyclopedic Medical Diction01y Brookings, OR

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University of Colorado Denver School of Medicine

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York Hospital

Orlando, FL

York, PA

Section Editors and Reviewers

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Thomas L. Abell, MD*

Arthur M. Schoen, MD Chair in Gastroenterology

University of Louisville

Aaron J. Calderon, MD, FACP, SFHM*

Associate Program Director Internal Medicine Residency

Division of GI, Hepatology and Nutrition

Exempla Saint Joseph Hospital

Louisville, KY

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University of Colorado Denver Denver, CO

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Internist, Pediatrician Oxford Pediatric Group, PLLC Oxford, MS

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Rush University Medical Center

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Director, New England Thyroid and Endocrine Center

Associate Training Program Director

Assistant Professor of Medicine,

Division of Allergy & Immunology

Tufts University School of Medicine

University of Texas Medical Branch

Longmeadow, MA

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MedStudyÂ® INTERNAL MEDICINE REVIEW

SIXTEENTH

EDITION

CURRICULUM

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Topics in this volume:

Gastroenterology

Infectious Disease

Robert A. Hannaman, MD Editor in Chief

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NOTICE: Medicine and accepted standards of care are constantly changing. We at MedStudy do our best to review and include in this publication accurate discussions of the standards of care and methods of diagnosis. However, the editor in chief, the reviewers, the section editors, the publisher, and all other parties involved with the preparation and publication of this work do not guarantee that the information contained herein is in every respect accurate or complete. MedStudy further disclaims any and all liability for damages and claims that may result from the use of information or viewpoints presented. We recommend that you confirm the material with current sources of medical knowledge whenever considering presentations or treating patients.

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Kathryn H. Dao, MD, FACP, FACR*

N. Kevin Krane, MD, FACP

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Department of Internal Medicine

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Program Director, Internal Medicine Residency Program

State University of New York at Buffalo

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Department of Neurology

University of South Carolina School of Medicine -

Western New York Healthcare System

Greenville

Buffalo, NY

Greenville, SC Leonard Mankin, MD, FACP Norton Greenberger, MD

Associate Program Director,

Professor of Medicine

Legacy Health IM Residency

Harvard Medical School

Associate Professor of Medicine

Gastroenterology Division

Oregon Health & Science University

Brigham & Women's Hospital

Portland, OR

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Boston, MA John P. Higgins, MD, MBA (Hons), MPHIL, FACC, FACP, FAHA, FACSM, FASNC, FSGC

Chief of Cardiology,

Memorial Hermann lronman Sports Medicine Institute Associate Professor, The University of Texas Health Science Center at Houston (UTHealth)

Associate Professor of Medicine

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University of South Florida Morsani College of Medicine

Houston, TX

Program Director, Nephrology Fellowship Lehigh Valley Health Network

Edward Hu, MD

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Assistant Professor of Clinical Medicine

Medical Director, Center of Asthma, Allergy & Clinical Immunology

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Keck Medical Center of University of Southern California Los Angeles, CA

Clinical Physician of Allergy and Immunology

Christopher L. Knight, MD, F ACP

Associate Professor of Medicine University of Washington Medical Center Seattle, WA Fredric B. Kraemer, MD

Professor of Medicine Chief, Division of Endocrinology, Gerontology and Metabolism Stanford University School of Medicine Stanford, CA VA Palo Alto Health Care System Palo Alto, CA

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Chicago, IL

Sharon Maynard, MD

Division of Cardiovascular Medicine

Panorama City, CA

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Rush University

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Kaiser Permanente

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Bosko Margeta, MD

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Infectious Disease Specialist Infectious Disease Consultants Medical Group Glendale, CA Juan G. Ochoa, MD

Associate Professor of Neurology Residency Director University of South Alabama Health System Mobile, AL Melba Iris Ovalle, MD

Assistant Program Chair & Medical Director Associate Professor, Nova Southeastern University Physician Assistant Program-Orlando Campus Associate Professor University of Central Florida College of Medicine Orlando, FL

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Manish Suneja, MD

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Diseases Program

The Warren Alpert Medical School of Brown University Medical Director, Comprehensive Cancer Center

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Jeffrey L. Williams, MD, MS, FACC, FHRS

of Rhode Island

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Providence, RI

The Good Samaritan Hospital Lebanon, PA

Abigail M. Stocker, MD

University of Louisville Hospital

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Fred Arthur Zar, MD, FACP

Louisville, KY

Professor of Clinical Medicine

Vice Chair of Education, Department of Medicine Program Director, Internal Medicine Residency University of lllinois at Chicago

Chicago, IL

Note: Those reviewers with an asterisk(*) after their names have disclosed relationships with entities producing,

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Disclosures: The following editors and reviewers have openly indicated affiliation with commercial entities.

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Yasmine Subhi Ali, MD, MSCI, FACC,

Consultant: MCG Health, LLC

FACP

Other: Intellectual property rights for About.com

Thomas L. Abell, MD

Robert A. Balk, MD, FCCP

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Grant Support: Medtronic, NIH Consultant: Medtronic, Rhythm Speakers' Bureau: Medtronic Other: Reviewer for UpToDate, Licensor to Medtronic and ADEPT-GI Speakers' Bureau: Practice Point Communications CF Educational Program Stockholder/Stock Options: Pfizer, Merck, Abbott, Medtronic

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For Further Study

MedStudy Internal Medicine Board Review Core Curriculum, 161" Ed. MedStudy Corporation, 2014.

MedStudy 2014 Internal Medicine Board-Style Questions & Answers. MedStudy Corporation, 2014. ÂŽ MedStudy Internal Medicine Core Scripts Flash Cards, 2014-2015 Ed. MedStudy Corporation, 2014. Heart SoundsTM (MedStudy Interactive), MedStudy Corporation, Colorado Springs, CO, 2012. Skin Signsâ&#x201E;˘ (MedStudy Interactive), MedStudy Corporation, Colorado Springs, CO, 2012.

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Longo DL, Fauci AS, Kasper DL, et al (eds). Harrison's Principles of Internal Medicine, 18'" Ed. McGraw-Hill Medical, 2012.

Goldman L, Schafer AI. Cecil Medicine, 24'" Ed. Saunders Elsevier, 2012.

Web-based:

National Guideline Clearinghouse: http://www.guideline.gov/

American College of Physicians Guidelines: http://www.acponline.org/clinical_information/guidelines/

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Gastroenterology GI PROCEDURES ESOPHAGUS

. ..

............ . . . ........

1-1

................................... ...................................

1-1

.............................................. .

. .

......... ..

...

DYSPHAGIA

............. ................................................................

ACHALASIA

......

............................................

DIFFUSE ESOPHAGEAL SPASM

. 1-1 .

1-2

...........................

.............................................

1-3

.....................................................

1-3

ANATOMIC OBSTRUCTION

Lower Esophageal Ring (Schatzki Ring) Esophageal Stricture

ULCERATIVE COLITIS

...................

Extraintestinal Manifestations of UC ..

1-21 1-22

Treatment of UC .

.... ................................................

1-23

................................. . . ..... ..............................................

1-23

....... ......

DIARRHEA

Introduction

..............

1-4

Diagnosis of Acute Diarrhea

......................................................

1-4

Treatment of Acute Diarrhea

NEUROLOGIC DYSFUNCTION

............ ...................................

1-4

1-21 1-21

..........

.....................................

1-4

........................................................................

......................... . . ......................................

.. ...........................................

. ...

Cancer in UC .

1-4

Malignant Obstruction . .

.. ...................................

.. ..............................................................

.................................

Plummer-Vinson Syndrome

... .

Overview . .

ACUTE DIARRHEA

1-23

....... ....................

1-23

...................................................

1-23

................................................

CHRONIC DIARRHEA

. .

..............

..........................................

.. .....

..................................................

. ..

... .. .

1-24

.......

1-24

........................................

............. ... ..

......................

SCLERODERMAAND SYSTEMIC SCLEROSIS . .

. .................

1-4

Mechanisms of Chronic Diarrhea .

1-24

EOSINOPHILIC (ALLERGIC) ESOPHAGITIS

.......................

1-5

Causes of Chronic Diarrhea

1-25

1-5

Chronic Loose Stools

MISCELLANEOUS CAUSES OF ESOPHAGITIS

...................

Pill-Induced Esophagitis ........................................................... I-5 Opportunistic Infections

............................................................

PROTON PUMP INHIBITORS

. .... ..

GE REFLUX DISEASE (GER0) Overview

...........................

1-6

......

1-26 1-26

Loose Stools and Fecal Tmpaction MALABSORPTION

. .. .. .

................................................................

1-6

Malabsorption Due to Decreased Digestion

1-7

Diagnosing the Cause: Transport vs. Digestion ..

Treatment of GERO

...............................

... . ..

.............................

.................................. . . ........................

ESOPHAGEAL CANCER

...................................... ....................

ZENKER DIVERTICULUM

1-7

Bacterial Overgrowth

Bowel Resection and Diarrhea CONSTIPATION

1-9

CAUSES

DIAGNOSIS

1-9

TREATMENT

DYSPEPSIA GASTRITIS

....

1-10

......... .................................................................

1-10

.................. ..............................................................

Classification Schemes

1-10

........................................... ................

Classification by Histology

1-10

.....................................................

Classification by Etiology .

1- I 0

.. ....................................................

Erosive Gastropathy Testing for H. pylori H. pylori Treatment

.........................................................

.......................................

......

.. .

.......................

FECAL IMPACTION DIAGNOSIS OF JBS

1-11

COLON CANCER OVERVIEW

FOBT

.................................... .............................

1-14

Treatment of Bleeding Peptic Ulcers

NON-ULCER CAUSES OF UGI BLEEDS ZOLLINGER-ELLISON Sï¿½DROME GASTRIC CARCINOIDS

1-14

......................................

1-15

..............................

...............

.............. ........... ...............

1-33

................................................................

1-33

.. .. .. .

............

1-34

............................................................

1-34

.......

. .. .. .

................................

...

....

...

............ ...................

1-35 1-35

.... .............................. ..................................................

1-35

.......................................................................................

1-36

....................................................... ..................................

1-36

STAGING OF COLON CANCER TNM Classification

...

1-36

...................................... .......................

1-36

TREATMENT OF COLON CANCER

1-37

........... . . . .. . . . . . . . . . . . . . . . . ......................

1-37

...................................

1-16

Symptomatic Diverticulosis

1-16

Diverticular Bleeding

....................

Other Causes of Gastroparesis

1-3 8

. . . . . . . . . . . . . . . . . . . .........................................................

ANGIODYSPLAS!AAND LOWER GI BLEED

......................

1-38

..................................................................

1-39

ISCHEMIC COLITIS

VIDEO CAPSULE ENDOSCOPY

1-17

BALLOON-ASSISTED ENTEROSCOPY.

...

...................................

...............................

1-39 1-39

. . . ......................................

1-17

BOWEL OBSTRUCTION

..............................................................

1-39

...................................... . . . . ....................

1-17

INTESTINAL ISCHEMIA

..............................................................

1-39

............................................................. . . . ...............

1-39

COMMON DRUGS FOR IBD CROHN DISEASE

.. 1-37 1-37

1-17

COMMON FACTORS . .

.....

1-38

1-17

1-37

.........

....................................................

............................

.................. ........ . . . . . . . . .............

INFLAMMATORY BOWEL DISEASE

Diverticulitis

. . . . . . . . ..... .................................................

.................................

........ . . . . .............................

Gastroparesis in Diabetics

1-16 1-17

............................. ........ . . . . . .............

.......

.....

................................................................

DIVERTICULAR DISEASE

1-37

.......................................

DIVERTICULAR DISEASE AND LOWER GI BLEED

......................................

....................................... . . . . . . . ............

......

......................................

........................................

1-35

Asymptomatic Diverticulosis

Blind Loop Syndrome .

1-35

........................................ ......................................

Types of Diverticular Disease

Afferent Loop Syndrome

.......

................................ ......

1-16

................................................

. ..

1-16

.....

1-32 1-33

..........................................................

.......................................................................

Dumping Syndrome

........

Diagnosis

1-32 1-32

1-15

POSTGASTRECTOMY SYl\1DROMES

...

.................

......................................

OTHER GASTRIC SYNDROMES

Gastroparesis

1-15

...................

CEA

..............................................

...........................................

............ ..

DUODENAL vs. GASTRIC ULCER

GASTRIC CANCER

1-32

Hereditary Nonpolyposis Colon Cancer Review

1-32

1-13

1-14

......................................................

Look for Characteristic Symptoms

1-14

1-31

.......

................................................................

.........................................

..................................................................

TREATMENT OF IBS

1-13

l-3I

.. ...

.............................................................

Exclude Other Diseases

SCREENING

...

IRRITABLE BOWEL SYNDROME

1-13

.................

....

Familial Polyposis Syndromes

Workup of Bleeding Peptic Ulcers

1-31

FECAL INCONTINENCE

.................. ...............................

1-30

................

.........................................................................

TREATMENT OF NONBLEEDING PUD .

NSAIDs

1-31

INHERITED COLON CANCER

....

1-12

.........................................

1-29 1-30

... .. ..

1-12

BLEEDING PEPTIC ULCERS

....

............................ ...................... .....

1-12

...............................

.........

1-27

............................. ...................................................

........................

...............................

................................................

.................................................

DIAGNOSIS OF PUD

1-11

...............................................................

PEPTIC ULCER DISEASE.. ETIOLOGY

1-11

................................................................

MORE ON H. PYLORI Overview H.

pylori infection can cause gastnt1s, PUD, gastric

adenocarcinoma, and gastric B-cell (MALT) lymphoma.

MedStudy

94% & 98%).

•Serologic tests are no longer recommended due to their low PPV (positive predictive value;< 50%). Also, serum tests are poor for checking effectiveness of treatment as they can stay positive for years after eradication.

1-11

1-12

PEPTIC ULCER DISEASE

Again:

PEPTIC ULCER DISEASE

PPis interfere with any urease test (CLOtest and urease breath test). Stop PPls 2 weeks before the breath test.

ETIOLOGY

Serologic tests are discouraged due to poor positive

Peptic ulcer disease (PUD) has 4 well-confirmed causes:

predictive value for H. pylori. PPls and H. pylori pangastritis cause decreased gastric acid production which, in tum, interferes with absorp tion of some medications (thyroxine, azole antifungals).

l ) Helicobacterpylori infection is still the most common cause of PUD-especially duodenal ulcer disease (50%, but incidence is decreasing in the U.S.). Life time ulcer risk for a person with H. pylori infection is

10-15% (higher for men). If H. pylori can be eradi cated, ulcers virtually never recur, and the H. pylori

H. pylori Treatment H. pylori treatment is the same whether the patient has gastritis or PUD: Usually, triple-drug therapy is used-2 antibiotics and a PPL A good one with an erad ication rate of� 80% is 0-CLAM (omeprazole 20 mg + clarithromycin 500 mg + amoxicillin l g-all bid x

recurrence rate is very small. The trouble is getting rid of it! If the ulcer does recur, suspectNSAIDs. See earlier discussion of H . pylori testing. 2) NSAIDs cause the majority of peptic ulcers not caused by H. pylori. The prevalence of ulcers in patients on

10--14 d).

NSAIDs is� 25% (!) although many are

Recurrence rate is very low. Increasing resistance to

duodenal ulcers-but typically gastric. IfNSAIDs are

clarithromycin is leading to increasing numbers of treatment failure.

5 mm

and asymptomatic. NSAIDs cause both gastric and required, and the patient is having or has had trouble, use any of the following:

Because of resistance to clarithromycin, levofloxacin is

•

Nonacetylated NSAIDs (e.g., salsalate).

now being substituted on a 3-day regimen. Sequential

•

NSAIDs that are non-acidic prodrugs

•

NSAIDs with a PPI or prostaglandin E analog (e.g.,

therapy with a PPI and amoxicillin for 7 days followed by a PPI, metronidazole, and clarithromycin for 7 days has been shown to be superior to a 3-day regimen. A

(e.g., nabumetone; Relafen®). misoprostol). PPis are superior to H2 blockers and

4-drug regimen (PPI, tetracycline, metronidazole, and bismuth) is also effective. [Know:]

The

more drugs

the

better! Single-

and

dual-drug therapies are ineffective. and clarithromycin. Previous macrolide antibiotic use precludes the use of clarithromycin. Metronidazole resistance can be overcome with increased dose (500 mg bid). If the first course of therapy (PPI and 2 antibiotics) fails to eradicate H. pylori, then some recommend PPI + amoxicillin + levofloxacin or quadruple therapy using

bismuth+ 2 antibiotics + PPL The accepted indications include the following:

4) Crohn disease of the duodenum/stomach. Enteric-coated NSAIDs have been recommended in the past; but the 2008 ACC/ACG guidelines on NSAIDs in patients with coronary artery disease highlights data that demonstrates no increased benefit of enteric-coated formulations in reduction of GI adverse events.

history of ulcer disease or prior UGI bleed, cardiac concurrent ASA use.

•

Persistent dyspepsia despite the test-and-treat strategy

•

H. pylori-associated MALT lymphoma

•

Resection of early gastric carcinoma testing

include: first 3 months of use, high doses, elderly patient, disease, concurrent steroid use, serious illness, and

History of H. pylori-associated ulcer

necessary,

3) High acid-secreting states, such as Zollinger-Ellison

Risk factors for conventional NSAID-induced PUD

Universal post-treatment testing is not recommended.

When confirmation is

COX-2 NSAIDs (see page 1-14).

(1-3% of duodenal ulcers).

Note: H. pylori develops resistance to metronidazole

•

sucralfate in the prevention ofNSAID-induced ulcers. •

What about smoking? In gastric and duodenal ulcer dis ease, smoking exacerbates the ulcer. For non-H. pylori ulcers, smoking also decreases the healing rate and

should

increases recurrence and perforation rate. Commonly,

performed no sooner than 4 weeks after the completion of

these recurrences are asymptomatic.

therapy. In general, noninvasive tests (not serology) should

Previously, the incidence of PUD was higher in men, but

be done for post-treatment testing unless there is a need for

now the male-to-female ratio is approaching 1. Type of

repeat EGD.

diet, personality, and occupation are not significant risk factors for PUD! Weight loss is uncommon in PUD. Notes: Alcohol is not ulcerogenic! Corticosteroids alone are not ulcerogenic, but they double the risk of serious NSAID-associated gastrointestinal complication-risk of bleeding may be 10-fold!

PEPTIC ULCER DISEASE

TREATMENT OF NONBLEEDING PUD Treatment of PUD targets combinations of

3 mam

strategies: •

•

What is a common medical regimen for

I) H. pylori treatment

H. pylori infection?

2) Decrease acid secretion (H2 receptor antagonists, PPis)

What is the most common cause of peptic

3) Stop

ulcer disease? •

What is the relationship between NSAIDs and PUD?

•

processes

(smoking,

taking

Less frequently used are mucosa! protection (sucralfate) and acid neutralization with antacids.

How does smoking affect PUD?

Treat

What is the relationship of steroids to PUD? Alcohol?

•

exacerbating

NSAIDs)

H. pylori infection associated with PUD. This is 1-12.

discussed on page

If the patient tests negative for

How are peptic ulcers diagnosed? If perforated? Name at least 3 indications for surgery in a patient with PUD.

H. pylori infection, and

if exacerbating factors such as NSAIDs have been addressed, then use antisecret01y drugs and antacids. Sucralfate is an effective treatment of non-H.

pylori

PUD, but patients do not care for the qid dosage; so

DIAGNOSIS OF PUD

PPis are preferred. Sucralfate binds bile salts and forms

The following are currently approved strategies for

Sucralfate is a short-term drug of choice in renal patients

diagnosing PUD:

a barrier at the ulcer site that prevents acid penetration. because it also binds P04. However, it should not be

• For the younger, healthy patient with classic symp

used long term in patients with advanced chronic kidney

toms, no diagnostic protocol is required-empiric

disease because it can cause aluminum accumulation

treatment with an H2 blocker or PP! is acceptable.

and metabolic bone disease.

• For this same younger, healthy group,

H. pylori

"test-and-treat" also is acceptable. • EGD is done for all other patients, particularly in older patients or in patients of any age who present with melena, heme+ stools, early satiety, or iron deficiency anemia. EGD is always indicated in the workup of PUD in the following situations: •If symptoms include dysphagia and odynophagia

Stop smoking-smoking increases the risk of recurrence and perforation in ulcers not associated with II. pylori or in untreated H.

pylori ulcers.

Indications for surgery in PUD: • UGI bleed-most common-active bleed unable to stop via endoscopic therapy. Surgery is required in

5% of UGI bleeds. •Gastric outlet obstruction-initial treatment is balloon dilation. Surgery required in�

25%.

•UGI bleeding

• Pe rfo ration-laparoscopic repair may be possible.

•Abnormal UGI (barium swallow) or CT scan

• Recurrent/refractory ulcers (rare).

•Family history of duodenal ulcer disease

• Zollinger-Ellison syndrome (ZES)-surgery is for

(EGO is also done for follow-up of a healing gastric ulcer and for evaluation of a swallowed foreign body.) The upper gastrointestinal series (UGI) is less sensitive than the EGD and rarely done today to diagnose PUD. If an ulcer is found, serum gastrin levels may be indicated (specifics discussed under the type of ulcer). Diagnose

H. pylori, as described in the Gastritis 1-10.

the presence of section, page

Perforated gastric and duodenal ulcers often cause free air

underlying gastrinoma.

DUODENAL vs. GASTRIC ULCER Duodenal ulcers: Again, the common causes are NSAIDs and H.

pylori, and only 1-3% are due to increased acid 1-8 and Image 1-9.

secretion (ZES). See l mage

H. pylori are treated 3 months. PPis and misoprostol (a synthetic prosta

Gastric ulcers not associated with for

glandin) are superior to H2 blockers and sucralfate in the

in the peritoneal space, which can be seen on an upright

prevention ofNSAID-induced ulcers.

abdominal x-ray. If a perforated ulcer is suspected, do

Although gastric ulcers were once thought to increase

the upright x-ray first! EGD and UGI are contraindicated

gastric cancer risk, studies have not shown this to be

until perforation is excluded.

true! On the other hand, examine all nonhealing gastric

[Know:] The pain of an ulcer tends to be gnawing,

ulcers via endoscopy with a cytologic exam of at least

whereas that of a perforated ulcer is usually severe.

MedStudy

6 biopsy samples to rule out gastric cancer.

1-13

1-14

PEPTIC ULCER DISEASE

BLEEDING PEPTIC ULCERS

Workup of Bleeding Peptic Ulcers

NSAIDs

Signs indicating a severe bleed and high risk of rebleed:

NSAIDs are the leading cause of bleeding ulcers in

•Hemodynamic instability

the U.S. Gastrointestinal bleeding may be the only

• Recurrent red-colored hematemesis or hematochezia

presenting related.

symptom.

The

mentioned

bleeding

previously,

risk

dose

corticosteroids

alone are not ulcerogenic, but they may increase the NSAID-associated bleeding I 0-fold!

EGD is the diagnostic and treatment procedure of choice for UGI bleeding. It should be done emergently if the patient has any of the above findings. EGO is done for 2 reasons:

Risk of bleeding with conventional NSAIDs:

1) To treat the current bleed

•General population: 1%

2) To assess the risk for rebleed

•In those using aspirin concurrently as preventive medicine: 1.5%

EGD

•History of PUD/UGI bleed: 3%

findings

that

indicate

increased

chance

of rebleeding:

NSAID-related ulcer risk is higher in females and in any patient> 70 years of age.

1) Larger size of the ulcer. 2) Active bleeding at time of endoscopy (risk of

If you add cardiac disease to any of the above factors, the risk increases 3-fold. Note that there is no perfectly safe dose of aspirin.

rebleed 55%). 3) Visible vessels on a non-bleeding ulcer (increase the risk for rebleed to 43%). See Image 1-10.

Risk of bleeding with COX-2 NSAIDs:

4) Visible clot= 22%.

•COX-2 used alone has close to normal risk of GI

Conversely, an ulcer with a clean base (i.e., no bleeding,

bleeding (0.5%). •COX-2 with low-dose (81 mg) aspirin has the same

no clot, and no visible vessels) has a very low chance of rebleed

(< 10%). These patients are typically sent home 1 of the 4 signs

risk as regular doses ofNSAIDs (1%)! Baby aspirin

the same or next day-unless they have

used alone has near-nonnal risk of GI bleeding.

of severe bleed mentioned above.

COX-2 NSAIDs block the action of cyclooxygen ase (COX), an enzyme that converts arachidonic acid to prostaglandin. COX- I is the constitutive enzyme, while COX-2 is inducible. COX- I produces protective prostaglandins in the stomach, whereas the inducible COX-2 is involved in inflammatory response. COX-2

Treatment of Bleeding Peptic Ulcers What does not work: Gastric lavage does not stop bleed ing or prevent rebleeding. IV vasoconstrictors also are ineffective.

inhibitors (celecoxib, Celebrex®; meloxicam, Mobic®)

The purpose of gastric lavage is to look for blood in the

appear to have decreased GI side effects (compared to

effluent. Blood in the effluent indicates that the stom

conventional nonselective NSAIDs), while retaining the

ach is the source of bleeding. But, remember that the

antiinflammatory and pain relief effects.

absence of blood does not rule out peptic ulcer as the

All NSAIDs (including COX-2 inhibitors) appear to

source, because it may have stopped bleeding.

have some dose-related cardiovascular risks (thrombosis

Increasing the gastric pH to > 6.0 reduces the risk of

and Mis).

rebleeding-PPis given either IV or orally bid achieve

All NSAIDs now have an FDA-mandated boxed warn ing highlighting the potential for increased risk of death from cardiovascular events and GI bleeding.

Image 1-8: Duodenal ulcer

Image 1-9: Gastric ulcer

this. Most patients with a bleeding ulcer get prompt IV PPI treatment before endoscopic therapy; this is contin ued until they are able to switch to oral bid therapy.

Image 1-10: Ulcer with visible vessel

GASTRIC CARCINOIDS

• Recurrent ulcers and no other risk factors • Recurrent complicated ulcers

uiz •

•Post-bulbar duodenal ulcers To evaluate ZES, first order a serum gastrin while

What is the main cause of bleeding ulcers

patient is off PPI therapy. If the gastrin level is elevated

in the U.S.? •

in a patient with gastric ulcer, workup typically requires

Name 4 EGO findings that indicate increased

abdominal CT, endoscopic ultrasound, and somatostatin

risk for rebleed of a peptic ulcer.

receptor imaging.

•

What is the most common presentation of ZES?

•

What is the usual cause of gastric carcinoid?

Treatment: All patients with

newly diagnosed ZES

without evidence of metastatic disease warrant surgical exploration. 112 are cured by resection of the primary

Initial treatment of actively bleeding ulcers (or adherent clot/visible vessel) shows best results with combination therapy consisting of injection (epinephrine or scle rosant) followed by either thermal/laser coagulation or a hemoclip.

tumor. Even with metastatic disease, treat ZES aggres sively with resection of the primary tumor, because the mass effect of the tumor tissue can eventually cause problems (obstruction). A PPI is the drug of choice for medical treatment of ZES, although the dose is higher than usual and often must be increased with long-term therapy.

NON-ULCER CAUSES OF UGI BLEEDS Osler-Weber-Rendu (hereditary hemorrhagic telangiec

tasia) causes telangiectasias on the skin, buccal and nasal mucosa, and throughout the GI tract, lungs, and brain. Occasionally,

arteriovenous

malformations

(AVMs)

occur and have the propensity to bleed. In the GI tract,

Remember: Other conditions associated with an elevated gastrin level are vitiligo, renal failure, hyperthyroidism, and achlorhydria caused by PPI use or chronic Type A gastritis (see page 1-10). Also remember that persistent high gastrin levels can cause gastric carcinoids.

these AYMs are generally in the stomach or duodenum. Peutz-Jeghers syndrome (PJS) causes dark melanin

GASTRIC CARCINOIDS

spots on the lips, buccal mucosa, and the hands and feet. Most patients have hamartomatous polyps that can occur anywhere from the stomach to the rectum. These polyps may cause acute or chronic GI bleeds.

Gastric carcinoids are rare (0.5% of gastric tumors) and typically caused by chronic hypergastrinemic states. The types of carcinoids are based on the causes of the hyper gastrinemic state:

ZOLLINGER-ELLISON SYNDROME Zollinger-Ellison gastrinoma,

syndrome

which

(ZES)

produces

occurs

gastrin

•Type 1 (70-80%): Autoimmune gastritis/pernicious when

continuously,

causes refractory (usually duodenal bulb) ulcers and diarrhea +/- steatorrhea. The most common presen tation of ZES is diarrhea. The diarrhea/steatorrhea is from the large volume of gastric juice causing acidifi cation of duodenal contents and resultant inactivation

anemia •Type 2 (5%): ZES, when it occurs as part of multiple endocrine neoplasia-MEN I •Type 3 (20%): Spontaneous (most aggressive) Sometimes gastric carcinoids occur in patients with vitiligo.

of pancreatic enzymes and damage to the intestinal villi

Gastrin is trophic to the enterochromaffin-like (ECL)

(maldigestion/malabsorption).

cells

Gastrinomas most frequently occur in the duodenum

of the

stomach,

leading

hyperplasia

and

occasionally to gastric carcinoids.

(- 50%) or pancreas (- 25%), and less frequently in

Note: The PPI omeprazole has not been shown to

the stomach, lymph nodes, and spleen. 90% are found

cause carcinoids in humans

in what is called the "ZE triangle"-which includes

although it does increase the circulating gastrin level.

the porta hepatis, mid-duodenum, and the head of the pancreas. 80% are of the sporadic form; 20% are associated with MEN Type 1. Consider ZES in patients with: •Severe esophagitis and chronic diarrhea •Ulcer (especially duodenal ulcer) and chronic diarrhea •Duodenal ulcer and big folds in the stomach (from parietal cell hyperplasia)

(> I 0

years worth of data),

It is unusual for gastric carcinoids to metastasize or to be symptomatic. They are slow growing and almost never cause carcinoid syndrome. See page 1-26 for more on carcinoids.

1-15

1-16

GASTRIC CANCER

Neither alcohol consumption nor gastric ulcers has been

GASTRIC CA NCER There are

proven to cause gastric cancer-as previously thought

4 significant malignancies of the stomach:

1) Adenocarcinoma (most common-95%!)

up on EGD or barium contrast study (double contrast of gastric ulcers is recommended, especially nonhealing

3) Lymphoma stromal

tumors;

e.g.,

leiomyosarcoma) There are 2 distinct forms of gastric adenocarcinoma: a proximal diffuse type and a distal intestinal type. The incidence of distal gastric cancer had been decreas ing until about 20 years ago; since then, its incidence has been holding steady. The proximal type has been steadily increasing. See Image

Diagnosis of gastric cancer: Often an ulcer is picked is better). If it appears benign, it can be treated. Biopsy

2) Carcinoids (just discussed)

4) GIST (gastrointestinal

even though gastric cancer can present as an ulcer.

1-11.

The risk factors and associations with gastric cancer include:

ulcers, if clear etiology is not found For

nonhealing

ulcer,

(H. pylori/NSAID).

endoscopy

with

multiple

biopsies is the diagnostic procedure of choice. Tumor markers, such as carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP), are not useful as early markers for gastric cancer. Prognosis is determined by stage (TNM classification), using CT scan and endoscopic ultrasound. Because it is largely asymptomatic until advanced,

10% are found

in the early gastric cancer stage (EGC, confined to the mucosa and submucosa, T l NOMO).

• Chronic

H. pylori infection

The 5-year survival rate is 85-90% for treated EGC and

• Metaplastic(chronic) atrophic gastritis

only 3% for treated invasive, metastatic gastric cancer.

• Menetrier disease(= large stomach folds

Treatment consists of surgical removal of the cancer

from epithelial cell hyperplasia)

and

•Adenomatous gastric polyps(rare)

adjacent

lymph

nodes.

Adjuvant

combination

chemoradiation prolongs survival.

It appears that distal gastric cancer is most strongly associated and observed with environmental factors, especially: • A diet low in fruits and vegetables and high in dried, smoked, and salted foods

OTHER GASTRIC SYNDROMES POSTGASTRECTOMYSYNDROMES Overview

•Foods rich in nitrates and nitrites(animal studies) Acanthosis nigricans is a reactive skin condition with velvety dark plaques in the intertriginous areas (areas where opposing skin surfaces touch and rub). It is usu ally due to Type 2 diabetes and obesity, but it is also

Postgastrectomy syndromes include dumping syndrome, blind loop syndrome, and afferent loop syndrome. All are now infrequent because

5% of PUD cases

warrant surgery.

associated with various GT and lung malignancies. Of these malignancies, acanthosis nigricans is most often associated with gastric cancer.

Dumping Syndrome Dumping syndrome consists of postprandial vasomotor

Note that with H. pylori infection, some patients may

symptoms: palpitations, sweating, and lightheadedness .

develop MALT (extranodal marginal zone B-cell lym

There are 2 types. The early type occurs 30 minutes

phoma of mucosa-associated lymphoid tissue ... er, like

after eating and is of uncertain etiology (hyperosmo

I said, MALT). This is diagnosed by EGD with biopsy.

lality of food and fluid shifts in the small bowel). The

When the

H. pylori infection is treated, the MALT may

late type occurs 90 minutes or more after eating and is probably due to hypoglycemia. Treat both types iden

resolve. Close endoscopic follow-up is necessary.

tically: Restrict sweets and lactose-containing foods, separate liquid and solid intake by at least 30 minutes, and encourage frequent small meals that are high in pro tein and complex carbohydrates.

Blind Loop Syndrome Blind loop syndrome is bacterial overgrowth in a loop (generally in patients with prior gastrectomy or Billroth II gastrojejunostomy) manifested by fat and B12 malab

sorption, and a low D-xylose absorption test (bacterial overgrowth and with small bowel mucosa) problems).

Image 1-11: Gastric adenocarcinoma

MedStudy-Please Report Copyright Infringements to copyright@medstudy.com

INFLAMMATORY BOWEL DISEASE

which leads to a vicious cycle. Treat by maintaining tight glucose control.

Q�uiz •

Clinical presentation is nausea, vomiting, early satiety, and a predisposition for bezoars.

What are the clinical and environmental risk factors for gastric cancer?

•

Other Causes of Gastroparesis

Carcinoid may be associated with which

Aside from diabetic neuropathy, gastroparesis can be

skin condition? •

•

caused by:

What is the relationship of alcohol to gastric cancer?

•Autonomic dysfunction-amyloid ncuropathy

How do you rule out gastric cancer in a patient

•An infiltrative process of the smooth muscles scleroderma, amyloidosis

with a nonhealing gastric ulcer? •

•An antecedent viral infection (particularly norovirus

What is the best diagnostic test for suspected

•

G R V

and rotavirus)

gastroparesis?

•A CNS disorder (stress, MS, parkinsonism, tumor,

When are barium enemas contraindicated

cord injuries)

in 180?

•Post-vagotomy •Opioid analgesics

Afferent Loop Syndrome With a gastrojejunostomy, an anastomosis is formed between the stomach and the jejunum. The "afferent loop" is the portion that is bypassed and through which bile and pancreatic fluids still flow toward the jejunum. Occasionally these

patients

get

"afferent

Workup of suspected delayed gastric emptying requires

d e

that you rule out obstruction first. Then diagnosis is con firmed with a radiolabeled solid meal (gastric emptying study).

t i n

Treat with:

loop syndrome."

•good hydration;

Presentation is abdominal bloating and pain 20 minutes

•dietary modification (low-fat, low-residue; multiple

to I hour after eating; vomiting often relieves symptoms.

small meals);

U -

The emesis is often bile-colored. Many believe the cause

•tight control of blood glucose;

is an incompletely draining afferent loop, which fills with

•symptom management (anti-emetics);

the biliary and pancreatic secretions. Studies of anatomy

•metoclopramide (FDA warning, though, for long

(using barium)

and physiology (using radiolabeled

9 9

meals) may help further identify the specific pathophysi

ology involved in a patient with symptoms of dumping syndrome.

r i h

Gastroparesis

term use-extrapyramidal side effects may become

permanent!); and

•domperidone (widely used outside the U.S.).

IV erythromycin, which is very similar in structure to

motilin, stimulates gastric motility but is not very useful as a long-term therapy. It can, however, be used in the

Gastroparesis, strictly defined as delayed gastric emp

acute setting when oral intake is inhibited by severe

tying, is increasingly identified in patients who present

stasis.

with symptoms of nausea, vomiting, and abdominal pain among other complaints. Recent guidelines have better defined this syndrome and its characteristics, diagnosis, and therapies.

Gastroparesis in Diabetics Highly variable gastric emptying is seen in diabetics. Emptying may be slow, normal, or fast. However, long

Gastric electrical stimulation has been approved for drug refractory gastroparesis since 2000 in the U.S. and may be a therapeutic option for selected patients.

INFLAMMATORY BOWEL DISEASE COMMON FACTORS

term diabetics tend to develop gastroparesis. This occurs

Inflammatory bowel disease (IBD) comprises Crohn

much more commonly in Type I than in Type 2.

disease (CD) and ulcerative colitis (UC). In both,

Blood glucose

200 mg/dL has been shown to result

in decreased antral motility and delayed gastric empty ing. Hyperglycemia may also have a negative long-term direct efe f ct on gastric motility. Conversely, slowed gastric emptying itself tends to increase blood glucose because of the delay of insu linemic and glycemic responses to the carbohydrates,

MedStudy

family members are at increased risk of IBD, and the patient has an increased risk of GI cancer-but the risk of cancer is much higher in long-standing UC than in CD. Toxic megacolon is a complication in both, so a barium enema is contraindicated if the patient is having an acute exacerbation.

1-17

1-18

INFLAMMATORY BOWEL DISEASE

Infectious colitis, early CD, and UC can appear identical

was recently approved for the treatment of mild-to-mod

on sigmoidoscopy. Stool examination for blood, WBCs,

erate UC. As with other corticosteroids, bone mineral

C. difficile toxin assay are included in

density should be monitored yearly. At this point, it

O&P, C&S, and

the initial workup. Refer to Table 1-2 as you review the

is uncertain whether budesonide has less effect than

diagnosis of CD and UC. See Table 1-3 on page 1-22

prednisone on bone density.

for a comparison between treatments of CD and UC.

6-mercaptopurine (6-MP) and azathioprine (which

Smokers are more likely than the normal population to

metabolizes to 6-MP) are prednisone-sparing drugs

develop CD. UC, however, is uncommon in smokers

useful in both Crohn's and UC, but they usually take

only

10% of UC patients are smokers!

Colonoscopy is the usual method used to assess IBO. Barium enema is not used anymore, but CT enterogra phy can be helpful in diagnosis of small bowel as well as colonic disease.

CBC monthly. There is no report of increased malig nancy with long-term use of either drug. lnfliximab

(Remicade®),

certolizumab

G R

pegol

(Cimzia®), and adalimumab (Humira®) are monoclonal

The main drugs used to treat IBO include: •

3-4 months to show an effect. Also, because these 2 drugs have bone marrow suppressive effects, monitor

antibodies to TNF-a. They are given for moderate

Mesalamine (5-aminosalicylate or

to-severe Crohn disease, fistulous Crohn disease, and

5-ASA preparations)

refractory UC. Know that TB may reactivate with

•

Sulfasalazine

usage, but the most common side effect is actually URI.

•

Metronidazole

Patients should be assessed for latent TB and hepatitis B

•

Budesonide

V d ti e

and have all recommended age-appropriate vaccinations before initiation of therapy.

•

Azathioprine and its metabolite, 6-mercaptopurine

•

Inftiximab, adalimumab, and certolizumab

Note: Monoclonal antibodies (mAb) are immunomodula

(monoclonal antibody to TNF-a)

tors that are identical antibodies derived from clones of a

Prednisone

single parent cell. The standard recombinant DNA proce

•

dure produces mouse (murine) Ab. The human body reacts

n U -

Methotrexate and cyclosporine are also available.

against these foreign Ab with an inflammatory response.

To overcome this, a portion of mouse DNA that codes

COMMON DRUGS FOR 180

for the binding site is combined with human DNA. The result is a chimeric (human-murine) Ab or a humanized

Mesalamine (5-aminosalicylic acid, 5-ASA) is nor

(mostly human) Ab. The more human, the less reaction.

mally rapidly absorbed from the upper digestive tract,

Fully human antibodies have been developed using trans

but different oral formulations release mesalamine into

genic mice. Monoclonal Ab's generic names always end

the distal ileum and colon. For colonic disease, it is

in "mab" (mAb, get it?) with the preceding letters further

9 9

given either rectally-as an enema (proctosigmoiditis)

defining what type of antibody it is-chimeric (-ximab),

or suppository (for proctitis only}--or in a formulation

humanized (-zumab), or human (-umab).

designed to delay absorption of the drug.

Drugs proven to decrease the relapse rate in CD are aza

r i h

Sulfasalazine is split, by bacterial action in the colon,

thioprine, 6-mercaptopurine, MTX, and also inftiximab.

into mesalamine (active component) and sulfapyridine. Because this takes place in the colon, sulfasalazine

Table 1-2: Comparison of CD and UC

is ineffective for CD of the small bowel. The other breakdown product, sulfapyridine, is absorbed in the colon, acetylated in the liver, and excreted in the urine. Sulfapyridine is a highly reactive sulfa moiety, which is responsible for most of the side effects of sulfasala zine-such as reversible infertility in men, leukopenia, and headache.

Crohn

Ulcerative

Disease

Colitis

Lesions

Clinical Course

Indolent

More acute

Granulomas

Pathognomonic

None

Abscesses,

None

Metronidazole is beneficial for perianal abscesses and

fistulas in CD. Long-term use is hampered by the side effect of peripheral sensory neuropathy (particularly if the dose is >

10 mg/kg).

Budesonide is an enteric-coated corticosteroid that

is released mostly in the ileum and ascending colon. It

R'�ctal

Perianal Disease

fistulas

metabolizes in the liver to inactive products. It has a 90% first-pass effect-thus, much fewer systemic side effects than prednisone. It was previously used specifically for small bowel CD. A new preparation of extended-release budesonide, which targets the full length of the colon,

.Small Bowel Involvement

*Forflares. Not/or long-term maintenance therapy.

INFLAMMATORY BOWEL DISEASE

screen long-term (> 8 years) CD patients every other year for cancer. CD tends to be more indolent than UC and therefore also •

tends to be less responsive to treatment. It is harder to get

Sulfasalazine is ineffective in which types

these patients off steroids. Patients with CD are more likely

of CD?

to have perianal fistulae and abscesses. They are also more

•

What are the side effects of metronidazole?

•

When is budesonide used for CD? for UC?

•

What are the indications for monoclonal

likely to have strictures, inflammatory masses, and associ ated obstruction. One big problem with CD is the high rate of recurrence. It was once thought to be 50% at 10 years, but this is the symptomatic recurrence rate. Radiologic/

antibodies in patients with IBD? •

•

endoscopic recurr ence rate is 75% at 3 years!

What is the relationship of Crohn disease

Osteoporosis is common in patients with Crohn disease.

to cancer?

About 70% have abnormal bone density-due to chronic

What are the colonoscopy and biopsy findings

disease, vitamin D deficiency, and/or steroids.

G R

in Crohn's? •

Diagnosis

What is the significance of an "apple-core" lesion? How does it differ from the "string sign"?

CD is diagnosed by finding patchy, focal, and aph

V d ti e

thous ulcers and deep transmural ulcers with occasional (Infliximab reduces relapse only in infliximab-induced

strictures

remission.) Note that all of the standard drugs decrease

quently found on biopsy specimen of these ulcers, are

the relapse rate in UC! Mesalamine drugs and cortico

pathognomonic. See Image 1-12 through Image 1-14.

steroids are good for inducing remission in CD but not for maintaining it. Smoking cessation decreases relapse rate in CD and

A tetrad to remember for "Crohn colitis": 1) Rectal sparing

n U -

2) Skip lesions

increases it in UC.

3) Perianal disease

Use in pregnancy:

•FDA risk category B (no evidence of risk in humans): metronidazole (although, because of insufficient data, contraindicated in I st trimester), prednisone, sulfasalazine, and mesalamine.

9 9

olsalazine.

r i h

CROHN DISEASE Overview

Although most patients present with Crohn disease (regional enteritis) in their 20s or 30s, the disease can

present at any age. There is a second, smaller peak of incidence in 70-80-year-olds. The incidence of CD is rising. There is an increased risk of GI cancer with CD, especially with long-standing disease and Crohn colitis;

Image 1-12: Crohn colitis with "string sign" in RLQ

4) Ileocecal involvement

Patients with CD may present with fever, abdominal pain, and systemic symptoms. One classic but uncom

mon feature is the string sign, which may be seen in the

•FDA risk category C (risk cannot be ruled out):

and fistula formation. Granulomas, infre

Image 1-13: Crohn proctitis

terminal ileum during a small bowel follow-through.

The terminal ileum is so edematous and/or fibrotic that the lumen is compressed and can be visualized only as

a "string" of contrast. If you see this narrowing of the

lumen elsewhere in the colon, with or without CD, it is called an apple-core lesion, which suggests cancer. Bowel involvement in CD: 30% colon only, 30% small bowel only, and 30-50% both. Initially, a definitive diagnosis cannot be established in up to 15% of patients with IBD. Serologic tests (p-ANCA and ASCA, anti-saccharomyces antibody) can be useful in indeterminant cases. p-ANCA is associated

Image 1-14: Crohn disease with submucosal edema causing cobblestone appearance

1-19

1-20

INFLAMMATORY BOWEL DISEASE

with UC and ASCA with CD. Panels containing addi

•Metronidazole

tional serologic markers, which increase sensitivity/

• Ciprofloxacin

specificity, are commercially available.

•Azathioprine (and its metabolite, 6-mercaptopurine) [Know Table 1-3 on page 1-22. And know:]

Extraintestinal Manifestations of CD The extraintestinal manifestations occur primarily in CD involving the colon. These manifestations are identical to those ofUC (which involves only the colon). So, these are discussed later under Extraintestinal Manifestations ofUC on page 1-21.

•In general, treatment for mild disease is a slow release oral 5-ASA formulation with progression to other drugs if response is not adequate. 5-ASA analogs are more effective in CD with colon disease only vs. ilea! or ileocolic disease. •Prednisone is more effective in UC than CD-again, probably due to the indolent nature of CD. In CD,

Terminal Ileum Problems in CD

prednisone is more effective than sulfasalazine when

Problems related to disease/resection of the terminal ileum are found in CD-but ordinarily not in UC. These problems include:

CD affects only the small intestine. Prednisone is

G R

best used only for fl.ares; long-term use (> 3 months) should be discouraged because of side effects. • Budesonide is a 1st line drug for mild-to-moderate CD

•Calcium oxalate kidney stones

of the ileum or ileocecal disease.

•Steatorrhea

V d ti e

• Infliximab is helpful in patients with fistulas, and

• Gallstones

it also facilitates withdrawal from corticosteroids.

• B12 deficiency

Before starting this agent (or adalimumab, below),

• Hypocalcemia (from vitamin D malabsorption)

screen all patients for tuberculosis and hepatitis B. The most common adverse reactions are development

• Bile acid-induced diarrhea

of a positive ANA in 55% and URls in 32%. Severe

•Nutrient malabsorption What type of gallstones occurs? Pigment gallstones are

n U -

the usual type, and the risk appears to correlate with the amount of ilea) disease or resection.

fungal infections, in addition to tuberculosis, can be seen while on therapy. Additionally, lymphoma and multiple sclerosis have been described.

•Metronidazole is effective, especially for fistulas

Note that anytime> 60 cm of terminal ileum is resected,

and perianal CD (used for UC only when there is fulminant disease with peritonitis). Long-term use

patients have B12 malabsorption.

Bile acid-induced diarrhea is usually the cause of diar

rhea in Crohn patients when < I 00 cm of distal ileum is resected. Some of the bile acids escape absorption in the

9 9

is hampered by neuropathy.

•Ciprofloxacin is also occasionally used for fistulous or perianal Crohn disease.

terminal ileum and go on to stimulate colonic salt and

•6-mercaptopurine (6-MP) and azathioprine are used

H20 secretion by the colon. Treat with bile acid seques trants (e.g., cholestyramine, colestipol), which bind and

prednisone. Note: Long-term treatment with 6-MP

r i h

inactivate bile acids.

When > l 00 cm of distal ileum is resected, the patient gets steatorrhea from greatly decreased proximal gut

concentration of bile salts. (Synthesis does not keep up with GI losses with the loss of distal ileum resorption.)

with Crohn patients who cannot be weaned off

and azathioprine has been shown to decrease recurrence rates in CD. Like 6-MP and azathioprine, mesalamine may also decrease

the

relapse

rate

in CD. Prednisone

and

metronidazole do not affect relapse rate.

Treat these patients with a low-fat diet. Sometimes, the low-fat diet does not allow them to get enough calories. In this case, give them supplemental medium-chain triglycerides (MCT).

treatment

Surgery is only for intractable disease and specific serious

complications.

Previously,

60%

Crohn

patients required surgery in the first 5 years and then again after� 8 years. These numbers are decreasing with

Treatment Overview for CD Medical

Surgery and Recurrence in CD

includes

many

the

same drugs as that for UC. See more detail on these medications on page 1-2 l . Medical treatment of CD: •5-aminosalicylate (5-ASA, mesalamine-slowrelease formulations)

improved medical therapy options (especially 6-MP, infliximab). The incidence of recurrence after surgery depends on: •Site-ileocolic is highest. •Nature of the complication-obstruction, perforation, and abscesses have a higher rate of recurrence.

•Olsalazine

Essentially, the worse the disease is where you cut, the

•Corticosteroids (prednisone, budesonide)

more likely is the recurrence at that site. Colectomy and

•Infliximab, adalimumab, and certolizumab pegol

ileostomy provide the best results for Crohn colitis when there is no Heal inflammation (> 60% have no recurrence).

INFLAMMATORY BOWEL DISEASE

of involvement tends to remain the same from the time of diagnosis but does extend more proximally in I 0%.

Q�uiz •

70--80% of UC patients are p-ANCA-positive, although this test is of little use clinically (low sensitivity and specificity). ESR and C-reactive protein (CRP) are often elevated.

What GU complication can arise in a patient with Crohn's of the terminal ileum?

•

What is the usual etiology of diarrhea in CD patients with With

The main symptoms of UC are abdominal pain and bloody diarrhea. Clinical course and degree of involve ment are variable-from mild ulcerative proctitis (rectal area only) with minimal symptoms to severe colitis of the entire colon with bad cramps, liquid stools contain ing blood and pus, anemia, extraintestinal manifestations (below), and constitutional symptoms. Occasionally, tenesmus (painful anal sphincter spasm with no bowel movement) and constipation may be the major clinical presentation.

100 cm of distal ileum removed?

100 cm of distal ileum removed? What is

the treatment for each? •

What additional screening should be done in patients with Crohn's who have been treated with chronic steroids?

•

What are the findings of UC on colonoscopy?

•

What serological marker may be found in

•

70-80% of patients with UC?

•E.coli

of UC.

Treatment Scenarios for CD

Colon only: sulfasalazine or mesalamine tablets/enemas. Sulfasalazine is about $30/month vs. $300+/month for mesalamine and other drugs. Therefore, sulfasalazine is the 1st choice-then 5-ASA drugs, if required because of intolerance to the side effects of sulfasalazine.

Only ileum or small bowel involvement: slow-release mesalamine or budesonide.

Fistula or perianal: infliximab (or other immunomodula tors), metronidazole, or ciprofloxacin. 6-MP also used.

9 9

r i h

Corticosteroids are a I st line drug for incomplete acute small bowel obstruction. Otherwise, they are used for flares and only if there is inadequate response to the 5-ASA drugs.

Note: Be sure to screen CD patients for osteoporosis. About 70% have abnormal bone density due to chronic disease and/or steroids. ULCERATIVE COLITIS Overview

Ulcerative colitis (UC) consists of uniform, contiguous mucosa( inflammation with shallow ulcers. The inflam mation always starts in the rectum, extends proximally, and always is confined to the colon (Image 1-15). There is typically a sharp margin between the area of involvement the and normal mucosa. The area Image 1-15: Ulcerative colitis

0157:H7 (EHEC)

•Shigella •Salmonella • Yersinia •Campylobacter •C. difficile •E. histolytica (amebiasis) Especially Campylobacter-since it can have a chronic, relapsing course that mimics UC.

d e

t i n

U -

Any ileum or small bowel involvement: slow-release mesalamine.

Steroid-dependent: 6-MP, azathioprine, mAb.

G R V

You must rule out infectious causes of colitis:

Describe the extraintestinal manifestations

Consider C. difficile infection in a flare-up-it is generally thought of as an acute disease, but it can mani fest as diarrhea 1-3 months after antibiotic use! Don't forget that C. difficile can occur even without preceding antibiotic use. Diagnosis is made with colonoscopy or sigmoidoscopy. Extraintestinal Manifestations of UC

Extraintestinal manifestations of IBO are usually seen in IBO patients with colitis (so they are typically associated with UC, although they can be seen in CD involving the colon). These extraintestinal manifestations include: •RF-negative peripheral polyarthritis (types I and 2) • Ankylosing spondylitis (also HLA-B27+) •Skin lesions-Erythema nodosum and pyoderma gangrenosum-which correlate with disease activity • lritis/episcleritis/uveitis (HLA-B27+) •Venous thrombosis •Pericholangitis •Primary sclerosing cholangitis (PSC, HLA-B8+; see page 1-48) •Aphthous ulcers of the mouth The complications associated with HLA antigens tend not to improve with improvement of colitis, whereas the other problems mentioned here usually get better as colitis improves!

1-21

1-22

INFLAMMATORY BOWEL DISEASE

Type 2 peripheral arthritis (polyarticular)-predomi

Cancer in UC

nantly MCP; independent of disease activity.

Risk of cancer in patients with UC is high. Risk starts

Type 1 peripheral arthritis (pauciarticular)-parallels

increasing about 8 years after onset of symptoms in

disease activity.

patients with pancolitis. It is up to 5-10% at 20 years and up to 12-20% at 50 years. Risk increases with:

So, what disease do you think of if a patient with UC develops jaundice, itching, and cholestatic LFTs?

•Duration of UC

Note that the JSEM mnemonic leaves out primary

•Extent ofUC-pancolitis has the highest risk, whereas ulcerative proctitis has no increased risk

sclerosing cholangitis, the answer to this question! PSC occurs in 5% of UC patients. As with any newly

•Concurrent PSC

increased LFTs, do an ultrasound first, then do MRCP

•Persistent mucosa! inflammation (disease activity)

(shows "string of beads," multifocal strictures of intra

•Dysplasia

hepatic bile ducts) to confirm the diagnosis of PSC.

Any patient who has had pancolitis for 8 years or

Check LFTs, especially alkaline phosphatase, initially and periodically. If the alkaline phosphatase becomes

G R V

left-sided colitis for 15 years should have a colonoscopy with multiple biopsy samples to check for dysplasia.

2 x nl and persists, work up for sclerosing cholangitis .

Once started, routine colonoscopy screening for cancer every 1-2 years should be continued .

Table 1-3: Comparison ofTreatments Used for Ulcerative Colitis and Crohn Disease

d e

Ulcerative Colitis Severity: ... definition of severity

Mild Stools/d

Between mild

t i n

and severe

> 10

KUB

Normal

P hysical

Normal;

Fever, Abd tenderness,

Fever, Abd

exam

but h/o

freq fecal blood

tenderness, and

intermittent fecal blood

Treatment:

Distal disease:

U -

distention

Distal disease:

Oral or rectal corticosteroids

Rectal corticosteroids; oral

budesonide; inflix

or rectal aminosalicylates

9 9

Extensive colon involvement: Oral aminosalicylates

Severity: Definitions same as for UC Treatment:

r i h

Normal

imab (R_emicade�) and adalimumab (Humira�as

Extensive colon involvment: Oral corticosteroids

Crohn Disease

Mild

Oral amino

Oral

IV corticosteroids;

Metronidazole

Oral

salicylates;

corticosteroids

IV infiiximab;

(delays anas

aminosalicylate;

metronida

(short term

Elemental diet or TPN

tomotic recur

azathioprine or

zole

< 3 months);

transient benefit

budesonide,

rence--danger

6-MP especially if

of neuropathy)

steroid dependent or refractory;

azathioprine, 6-MP, or

6-MP or azathio

methotrex-

prine is standard

ate if steroid

maintenance

dependent or

therapy.

refractory Infliximab and adalimumab are frequently used to maintain remission

Note the differences and similarities in these treatments! Metronidazole and diet (bowel.rest) are ineffective inl';TC. .

Rectal preparations are used only in UC ofth�,distal colon.

DIARRHEA

For moderate-to-severe

UC,

initial therapy

a.�uiz

and treat with rv corticosteroids, infliximab, or cyclo sporine; the patient may need a colectomy if fulminant

•

What is the relationship of UC to cancer?

symptoms persist for > 48 hours.

•

What is the treatment for UC with high-grade

Maintenance therapy after remission:

dysplasia? •

•

Sulfasalazine or mesalamine daily for 2 or more years.

What is the treatment for moderate-to-severe UC?

•

Azathioprine and 6-mercaptopurine for frequent recurrences/steroid dependence; treatment may

Associate these "buzzwords" with UC or CD:

take 3-4 months to show an effect.

a) tenesmus, b) rectal bleeding, c) fecal soiling, d) pneumaturia.

•

Cyclosporine provides short-term remission in 40-50% of patients with severe colitis, but long-term

•

How is diarrhea classified?

•

What tests are done for the workup

G R

remission in only 20-30%. Long-term remission is improved when adjuvant azathioprine is used.

of acute diarrhea?

•

lmmunomodulators

A few buzzwords:

Treatment of UC

V d ti e

UC is cured with surgery! But it may be a difficult

•

Tenesmus (UC)

surgery, so reserve it for findings of cancer or dyspla

•

Rectal bleeding (UC)

sia! UC colectomy is recommended for patients with

•

Fecal soiling (think fistula= CD)

dysplasia in a mass lesion and for high-grade dysplasia

•

Hydronephrosis without stones (obstruction from inflammatory mass= CD)

in flat mucosa. Repeat colonoscopy in 6 months if there is low-grade dysplasia without inflammation. Some

•

Pneumaturia (think fistula to the bladder= CD)

n U -

authorities recommend colectomy if low-grade dys

plasia without inflammation is confirmed on 2 biopsies within 6 months. Repeat in 6-12 months for dysplasia with inflammation (usually not precancerous). Other indications for UC surgery besides cancer are: •

•

is oral

prednisone. Hospitalize patients with fulminant UC

Intractable disease

DIARRHEA

OVERVIEW

Diarrhea is defined variably as

200-250 g/day of stool.

Normal average daily output is 150-180 grams. Note:

Perforation

•

Growth retardation in children

•

Toxic megacolon

•

Stricture

•

Steroid dependence

•

Exsanguinating hemorrhage

•

Complication from therapy

9 9

r i h

Know all the treatments for UC! Therapy for UC is changing due to the advent of 5-ASA compounds without sulfa, newer immunomodulators, and short-term use of corticosteroids. UC, a more acute inflammatory process, responds to steroids much better than CD (Table 1-3). For mild disease, there are several options:

Small-volume, loose stools are not considered diarrhea.

Normal bowel frequency varies from 3 to 21 stools/week. Diarrhea

typically

symptoms. Acute is

categorized

duration

2 weeks, persistent is 2-4 weeks,

and chronic is > I month.

ACUTE DIARRHEA The infectious causes of acute diarrhea are covered in the Infectious Disease section, Book l , under Common ID Syndromes: Gastrointestinal.

Introduction Acute diarrhea commonly has an infectious etiology,

•

Oral sulfasalazine

•

Oral mesalamine

side effects. Infectious diarrhea may be invasive or

•

Rectal mesalamine (suppository for proctitis; enema

nonmvas1ve.

but it may also be caused by food poisoning or drug

for proctosigmoiditis) •

Hydrocortisone enemas

Diagnosis of Acute Diarrhea

All have similar efficacy-75% response and 30% remission

after

months.

The

enemas have

few side effects and lead to quicker symptom relief than mesalamine.

Do the simple things first! Check diet and travel history. Lab: First, check stool for blood (guaiac test) and fecal WBCs. The invasive types usually are positive for fecal WBCs.

1-23

1-24

DIARRHEA

In normal bowel contents, the cations are equal to the

Table 1-4: Osmotic vs. Secretory Diarrhea Osmotic

anions:

Secretory

,.Vo.lume/day

[Na+]+ [K+] =[CJ-] +[HC03-] +other anions (The "other anions" are mostly short-chained fatty acids

Effect of Fasting on Diarrhea

Decreases

>50%

< 20%

290

Example [Na+] Example [K+] So [Na+] +[K+]

Stool osmolalitycalc= 2[Na+ +K+]

105

145

For normal stool and for diarrhea of any cause: Stool osmolality=serum osmolality

120

Osmotic Gap

You can calculate stool osmolality using only the Na+ and

K+ concentrations:

that are usually absorbed early in bowel transit.)

G R

But! ... Depending on the cause of the diarrhea, the

< 25

>50

amount of unmeasured anions may vary from normal to high.

If these are elevated, do:

Note: Serum osmolality is typically 280--300 mOsm/L

V d ti e

•Culture +Sensitivity exam (C+S)

or, for the equations, 290 mOsm/L.

•Ova+ Parasite exam (O+P) (especially with positive

Because the fluid in secretory diarrhea is, in essence, an

travel history)

ultrafiltrate of the serum, secretory diarrhea is similar to normal stool in that 2[Na+ + K+] =290 mOsm/L.

•+/- Sigmoidoscopy with biopsy If you suspect E. coli 0157:H7 (enterohemorrhagic E.

coli; EHEC),

specifically ask for MacConkey

With osmotic diarrhea, part of the osmolality is due to unmeasured, nonabsorbable, osmotically active mole

sorbitol agar for the stool culture media. If you suspect

cules-so the 2[Na+ +K+] is much less than 290 mOsm/L.

Clostridium difficile, also add C. difficile toxin assay.

This difference is usually> 50 mOsm/L.

Rectal/colonic biopsies can be useful in differentiating

Summary: Here are the pertinent equations again. Learn

infectious colitis from inflammatory bowel disease. Crypt

them, and you should be able to handle this topic:

abscesses may be found in both, but crypt distortions are

Stool Osmca1c =2 x (stool [Na +] +stool

found only in inflammatory bowel disease.

9 9

Treatment of Acute Diarrhea

n U -

Stool Osmolar Gap=290 - Stool Osmcalc If SOG > 50, the gap is increased, and added osmoles

Generally, invasive diarrhea is treated with quino

r i h

lones (especially ciprofloxacin), but use macrolides for Campylobacter (high quinolone resistance) and metroni

dazole for amebiasis. Antibiotics may prolong Salmonella infections and, therefore, are typically not used.

which

treated

only

are present that are causing diarrhea. When the SOG < 25, the stool is either normal, or the

diarrhea is secretory.

These calculations are very academic and work in straightforward situations, but many causes of diarrhea

Another big exception is E. coli O l 57:H7 infection (EHEC),

[K+])

symptomatically;

antibiotics are contraindicated!

Before reading further, see Infectious Disease, Book

have both secretory and osmotic components. At the bedside, the calculations are less useful. For a Board exam, though, definitely know how to do this. Make sure this makes sense to you before you move on!

1, to review more detail on the specific organisms and

treatments.

Secretory Diarrhea In secretory diarrhea, 2[Na+ +

CHRONIC DIARRHEA

�

K+] of the stool is

290 mOsm/L; i.e., measured serum osmolality (SOG

is < 25). There is more stool volume in secretory diar

Mechanisms of Chronic Diarrhea

rhea than in osmotic diarrhea, often > 1 Lid, so there is

Overview

obviously an increased secretion of electrolytes; thus,

Again, chronic diarrhea is defined as loose stools

the patient is at risk for an electrolyte deficiency. There are many causes of secretory diarrhea:

> 200-250 g/day for> 1 month. Chronic diarrhea can be classified according to 3 mech

•Enterotoxins from E. coli, cholera, and S. aureus

anisms:

•Villous adenomas (rare cause)

osmotic,

secretory,

and

increased

motility.

First, let's compare and contrast osmotic and secretory mechanisms. In this section, when discussing ion concen trations, note that "[x]" means "concentration of x."

•Gastrinomas •Microscopic colitis

DIARRHEA

Causes of Chronic Diarrhea AIDS [Know!] With the advent of highly active antiretrovi •

ral therapy (HAART), infectious causes of diarrhea in

What are the treatments generally used

AIDS patients have reduced dramatically from> 50% to

for invasive diarrhea?

13%. Despite HAART, diarrhea still occurs frequently.

• Which cause of invasive diarrhea should not

If the patient with AIDS has diarrhea and weight loss

be treated with antibiotics? •

without fever but has a low CD4 count, suspect one of noninvasive organisms:

Cryptosporidia (usual

What is the osmolar gap in patients

these

with osmotic diarrhea?

cause), E. histolytica, Giardia, Jsospora, Strongyloides, or AIDS enteropathy.

• Will a 24-hour fast stop osmotic diarrhea?

With

• In an AIDS patient with fever and diarrhea,

fever,

Salmonella,

what organisms are on your differential list?

think

Mycobacterium,

Campylobacter,

Cryptococcus, Histoplasma, and CMV.

G R

(These are covered in Infectious Disease, Book 1, under Common ID Syndromes: Gastrointestinal.)

•Collagenous colitis

Volume is a big clue in AIDS-associated diarrhea;

•Bile acids

> I Lid suggests a small bowel cause.

•VIPomas that produce vasoactive intestinal peptide

V d ti e

A CD4 count

(VIP) A 24--48-hour fast does not decrease secretory diarrhea, except in fatty acid- and bile acid-related diarrheas. See Table 1-4.

200, especially if accompanied by

weight loss, points to an infectious etiology rather than AIDS enteropathy.

IBD

[Know!] Chronic inflammatory diseases of the colon

Osmotic Diarrhea

n U -

In osmotic diarrhea, ([290] - 2[Na+ + K']) is > 50. So,

there is at least a 50 mOsm/L osmotic gap that is due

to a nonabsorbable osmotic agent. A 24-hour fast does resolve or greatly improve the diarrhea. Lactase defi

ciency is one of the most common causes of osmotic

diarrhea. Other common causes are: Mg-containing laxatives and antacids, non- or poorly absorbable car

9 9

bohydrates (xylitol, lactulose, sorbitol, fructose), and

(UC and Crohn colitis) cause loose stools with many WBCs and histologic damage. Volume may be greater or less than 200 g/day. Chronic bloody stools suggest

UC. Chronic loose stools associated with chronic RLQ abdominal cramping, especially palpation of thickened

bowel in the RLQ, suggest CD.

Note: Fecal WBCs and blood are found in both invasive diarrhea and UC. See page 1-17 for more on IBD.

nutrient malabsorption; i.e., pancreatic insufficiency,

celiac disease, bacterial overgrowth. If an osmotic diar

rhea persists despite a 24-hour fast, suspect surreptitious ingestion of an Mg-containing antacid. Most laxatives,

h a

Diabetes

Diabetic diarrhea may be caused by:

including castor oil, cause an osmotic diarrhea.

•Use of dietetic foods rich in sorbitol (erroneously

Diarrhea 2° Increased Motility

• V isceral autonomic neuropathy (Especially suspect

labeled "sugarless")

The last mechanism of diarrhea is increased motility. The dysmotility syndromes include antibiotic-associ ated diarrhea, hyperthyroidism, carcinoid, and irritable bowel. Treatment for most antibiotic-associated diar rhea is simply to stop the drug. C. d ifficile diarrhea is a different animal (discussed later). Different mechanisms of diarrhea may occur together in certain diseases. In celiac disease ' for example osmotic and secretory mechanisms coexist becaus there

malabsorption

carbohydrates

�

(osmotic)

and fat (secretory). Exudative diarrhea (i.e., high fecal WBCs; includes invasive bacteria and IBD) contains all 3 mechanisms: Inflammation causes altered motility, and malabsorption can cause both osmotic and secretory components.

MedStudy

this in the incontinent diabetic patient.) • Malabsorption (less common) due to celiac disease (present in 5% of diabetics), pancreatic insufficiency, or bacterial overgrowth (treat with metronidazole and amoxicillin-clavulanate) •Pancreatic exocrine insufficiency (more common in DM due to pancreatic disease)

Carbohydrate Intolerance Consider carbohydrate intolerance in all patients with chronic diarrhea who excessively ingest beverages rich in sorbitol and fructose. Note: Coke/Pepsi has 40 g of fructose per 16 oz (480 mL ).

1-25

1-26

DIARRHEA

Carcinoid

Microscopic Colitis

There are several types of carcinoid tumors (GI, lungs,

Microscopic colitis consists of both collagenous colitis

kidneys, ovaries), and they can present with carcinoid

and lymphocytic colitis. These patients have grossly nor

syndrome or symptoms associated with tumor growth,

mal-looking mucosa but abnormal findings on mucosa

such as pain or obstruction.

biopsy (hence the name microscopic colitis). These patients have a chronic secretory, watery diarrhea.

Carcinoid syndrome is the neuroendocrine manifestation caused by release of vasoactive mediators, including

Colonoscopy is normal, but mucosa! biopsy of the

5-hydroxytryptophan, 5-hydroxytryptamine, histamine,

normal-looking mucosa shows a lymphocytic infiltrate

kallikrein, and prostaglandins.

or a collagenous band in the submucosa. [Know:] These entities do not progress to IBO. Budesonide is the 1st line

With GI tumors, carcinoid syndrome occurs only when

treatment.

the primary tumor has metastasized to the liver. In other tumors, the liver deactivates the vasoactive mediators,

Other

so symptoms don't occur. But, with liver mets, the vaso active mediators are released directly into the circulation

G R V

Other causes of chronic diarrhea include:

from the liver and, thus, are not deactivated. Some bron chial carcinoids can present with carcinoid syndrome,

•Steatorrhea (discussed further below)

but it's extremely rare!

• Endocrinopathies (hyper- and hypothyroidism, adrenal insufficiency)

So, when you see carcinoid syndrome, think GI primary

•Colon cancer

with hepatic metastases! Most carcinoids are asymptomatic, are found in the GI

• Fecal incontinence (radiation; diabetes; rectal

track outside of the midgut, and do not metastasize. Most

surgery; and childbirth injury to anal sphincter,

t i n

symptomatic carcinoids are associated with a primary

especially forceps delivery)

tumor in the midgut (ileum and proximal colon).

Patients may not want to mention that they have fecal

Carcinoid is an uncommon cause of chronic diarrhea.

incontinence. They frequently tiptoe around the issue

Gastric carcinoids are related to hypergastrinemic states (discussed on page 1-15).

U -

Carcinoid syndrome presents as paroxysmal flushing;

crampy, explosive diarrhea; and hypotensive tachycar dia. The flushing is often bright red to violaceous, with

well-defined borders, and can be on the whole body

9 9

including palms and soles.

Because tryptophan, a precursor of niacin, is used up in

carcinoid syndrome, niacin deficiency (pellagra) may

r i h

occur (scaly rash, thickened tongue, angular cheilitis, and mental status changes). Diagnosis

carcinoid:

Check

24-hour

urine

for

5-hydroxyindoleacetic acid (5-HIAA)-a breakdown

by asking "for medication to control the diarrhea." Ask

patients with diarrhea if they experience fecal inconti nence more than once a week. If so, the differential diagnosis includes the items listed previously.

Chronic Loose Stools The following may cause loose stools < 200 g/day, so they do not meet the criteria of diarrhea: •Lactase deficiency (lactose intolerance) is a common cause of loose stools, although the volume is

product of 5-hydroxytryptamine. Normal is< 10 mg/d; with carcinoid, patient has

d e

• Radiation-induced disease

25 mg/d. In patients with

generally< 200 g/day. • Irritable bowel syndrome (IBS) has loose stools with normal daily volume. See page 1-32 for more on JBS.

carcinoid syndrome from a primary GI tumor, CT of

Diagnosis of Chronic Diarrhea

liver should show metastatic lesions.

Know the following 3 stages of diagnosis:

Visceral Autonomic Neuropathy (Diabetes, Amyloidosis)

Stage 1 •Stool O&P

Visceral autonomic neuropathy is characterized by:

•Fecal leukocytes x 3

•Delayed gastric emptying (i.e., gastroparesis)

•Serum chemistry and thyroid profile

•Postural decrease in blood pressure

• C.

•Anhidrosis (inability to tolerate heat, lack of functioning

•Stool pH

sweat glands)-especially in lower extremities

difficile toxin assay

• Weight of stool/day

• Fecal incontinence

•3-day fecal fat (or if Sudan stain is positive, do

•Impotence (men)

the fecal fat)

• Urinary overflow incontinence

• Lactose-free diet if Iactase deficiency is at all suggested by history

Patients may exhibit any one or all of the above!

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DIARRHEA

MALABSORPTION Overview

uiz •

•

Malabsorption may be short-lived, but patients often

What tumor causes the majority of cases

present with chronic diarrhea.

of carcinoid syndrome?

The "Big 6" blood tests are those done in the routine

What is the clinical presentation of carcinoid

workup for malabsorption. These tests are albumin,

syndrome?

Ca++, cholesterol, carotene, serum iron (all low), and

•

How do you diagnose carcinoid?

•

Explain each of the 3 stages used in the workup

PT (prolonged). These are discussed later in this section, but first let's discuss the causes of malabsorption-which can be

of chronic diarrhea. •

divided into decreased mucosa! transport (something

What lab tests are done in the workup

wrong with intestinal uptake) or decreased digestion

of malabsorption? •

What are the extraintestinal manifestations of celiac disease?

Malabsorption Due to Decreased Mucosa! Transport

Stage 2

Decreased mucosal transport may be caused by celiac

•If steatorrhea is confirmed, order ultrasound or CT

disease, tropical sprue, common variable immune defi

scan for pancreatic calcification (further tests for

ciency with hypogammaglobulinemia, W hipple disease,

steatorrhea discussed in detail on page 1-30).

intestinal lymphoma, eosinophilic gastroenteritis, bacte

If diabetic has suggestive history: Do either a

rial overgrowth, and other small bowel disease. These

lactulose breath test for bacterial overgrowth or

are discussed below.

(more often) just treat empirically. •If> 1,000 cc/day of stool, check vasoactive intestinal polypeptide. Specific urine tests for bisacodyl, anthraquinones, and phenolphthalein 0

Stool osmotic gap> 100 mOsrn/L (magnesium-containing)

9 ri 9

Stool measurement of phosphate and sulfate

•If the stool osmolality is< 290, the patient could be adding water or urine to the stool. Stage 3

h ta

• EGO and colonoscopy

Celiac Disease

Celiac disease (gluten-sensitive enteropathy, previously

• Check for laxative abuse by: 0

V d ti e n U Introduction

•Immunoabsorbent assay for giardiasis.

•

G R

(not enough digestive enzymes).

A significant number of patients have no discernible cause

celiac sprue, nontropical sprue) is one of the most com monly undiagnosed disorders. It occurs in up to I% of

the population of most countries.

Celiac disease is an autoimmune intestinal disorder in which there is an altered gut mucosa! response to dietary gluten, which is in wheat, barley, malt, and rye, resulting in small bowel villous atrophy and crypt hypertrophy with resulting malabsorption. It can cause growth retar dation in children and is associated with HLA-DQ2 and HLA-DQ8. It may go into remission during ado lescence, and then recur. If detected early, the patient may have only mild symptoms such as bloating and

of the diarrhea and have no abdominal pain and normal

loose stools.

EGO and colonoscopy. These patients have idiopathic

Extraintestinal manifestations of celiac disease:

chronic diarrhea.

Often, a hospital stay is required after stage 3 to redo the previous tests with better controls. Suspect occult bile acid diarrhea if the patient has loose watery stool but no abdominal pain.

Loose Stools and Fecal Impaction

• Iron deficiency anemia (most common presentation; iron is absorbed mostly in the duodenum): low Hgb, MCV, and ferritin • Abnormal serum aminotransferases • Dem1atitis herpetiformis-discussed below • Osteoporosis • Osteomalacia

Watery stool may leak around a fecal impaction, caus

• Neuropsychiatric symptoms

ing small-volume watery effluent. See more on fecal

• Dental enamel defects

impaction on page 1-32.

Primary intestinal lymphoma is a rare, late complication of celiac disease.

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1-28

DIARRHEA

Deficiencies caused by celiac disease:

If there is a high suspicion for celiac disease, serology in conjunction with early EGD with small bowel biopsy is

•Iron

often utilized for diagnosis.

•Folic acid

Note: The small bowel biopsy results are characteristic

•Calcium

but not pathognomonic, since you may see similar

•Vitamin D

villous atrophy with hypogammaglobulinemia ("hypo

•Vitamin B12 (rarely) •Vitamin

gammaglobulinemic sprue"), small intestinal bacterial

overgrowth, lactose intolerance, giardiasis, peptic duo

There is a wide spectrum of presentations. Patients often

denitis, and tropical sprue! Many small bowel disease

have little or no GI symptoms and may present with

processes can cause villous atrophy.

only a psychiatric disorder, osteomalacia, or a purulent

Treat celiac disease with a gluten-free diet (GFD).

pustular rash. Dermatitis herpetiformis is a manifestation of celiac disease. It is characterized by intensely itchy vesiculo papular eruptions on the face, trunk, buttocks, sacrum, and extensor surfaces of elbows and knees (Image

1-16).

Most patients with dermatitis herpetiformis do not have abdominal symptoms, although 85% have the characteristic findings on intestinal wall biopsy. Diagnosis of celiac disease includes these

80% eventually respond. For those patients who do not, consider: •Dietary noncompliance (most common) •Intestinal lymphoma •Microscopic colitis •T-cell enteropathy •Lactose intolerance 2° to lactase deficiency (damaged mucosa)

4 criteria:

• Pancreatic insufficiency

I) Evidence of malabsorption (steatorrhea, weight loss, iron deficiency anemia)

•Collagenous sprue (see below) •Ulcerative jejunoileitis

2) Many patients with latent celiac disease may have only a positive tissue transglutaminase antibody test (90+% sensitivity) or positive antiendomysial antibody test 3) A positive response to a gluten-free diet (clinical, chemical, histological, and immunologic)

4) Abnormal small bowel biopsy to clinch the diagnosis The best antibody tests are:

Emphasize

the

patient

the

need

for

lifetime

gluten restriction. One can test for compliance by doing repeat tests for tissue transglutaminase antibody (tTg). Now that you know about celiac disease, what test will you remember to order in the following patients? A I 6-year-old presents with a diagnosis of bipolar

•Tissue transglutaminase (tTG) antibody

disorder.

•lgA antiendomysial Ab (but not good with lgA

A 33-year-old presents with bone pain in his spine

deficiency)

and legs.

Antigliadin antibodies (AGA) are sensitive but not specific and are superseded by tTG antibody or antien domysial Ab. Because IgA deficiency occurs in 1-2% of U.S. population, if lgA tTG antibody is negative in

A 28-year-old presents with a pruritic papulovesicular eruption on her extensor elbows and knees. A 30-year-old presents with heme-negative stool and

the setting of a strong suspicion of sprue, check serum

low Hgb, MCV, and fen-itin.

lgA levels. These antibody tests may also be useful for

Good! tTG or IgA antiendomysial Ab for celiac disease.

determining latent celiac disease or as a measure of compliance with the gluten-free diet.

Celiac disease is a commonly missed diagnosis. Collagenous Sprue

Collagenous sprue is an unusual, possible variant of celiac disease in which the small bowel biopsy shows flattened mucosa with large masses of subepithelial eosinophilic hyaline material in the lamina propria. Collagenous sprue is one cause of failure to respond to GFD treatment. Tropical Sprue

Tropical sprue causes malabsorption with partial villous atrophy and is probably caused by a still-unknown infectious organism. It is endemic in areas of the Caribbean, South Africa, Venezuela, India, and South East Asia (i.e., the equatorial areas). Patients often have megaloblastic anemia.

Image 1-16: Dermatitis herpetiformis

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DIARRHEA

Strongyloides can also cause a peripheral eosinophilia ( Giardia does not), so be sure to rule this out before you start the steroids!

•

How do you diagnose celiac disease?

Short Bowel Syndrome

What is the clinical presentation of Whipple disease?

the small bowel, generally due to:

Short bowel syndrome occurs after massive resection of

What must be ruled out in a patient older than 55 with pancreatic insufficiency?

Treatment: tetracycline or doxycycline for

•severe ischemic injury, • surgery for small bowel volvulus,

3-6 months.

Folic acid replacement can also be effective either alone

• jejunoileal bypass for morbid obesity, or •multiple surgeries for Crohn disease. Short bowel syndrome is likely when there is (roughly)

or as adjunctive treatment.

< 2 feet ( 60 cm) of remaining small bowel, especially when the proximal jejunum and/or distal ileum are

Whipple Disease

Whipple disease is a seemingly rare disease (< cases

total;

probably

under-reported)

1,000

caused

Tropheryma whipplei, a gram-positive actinomycete.

removed. Lifelong total parenteral nutrition (TPN) is likely to be required if the remaining small bowel is <

100 cm and there is loss of the ileocecal valve.

These patients are susceptible to calcium oxalate kidney

The cardinal tetrad of symptoms:

stones

I ) Arthralgias-the most common symptom preceding diagnosis! (Much more so than abdominal problems!)

(2° steatorrhea) and gastric acid hypersecretion.

Treat short bowel syndrome with a low-fat diet, small frequent meals, and vitamin supplements. TPN may be needed after large resection and/or while waiting for

2) Abdominal pain

bowel adaptation after surgery.

3) Weight loss

4) Diarrhea Patients may have severe malabsorption-often with marked hypoalbuminemia and neurologic symptoms (depression, paranoia, dementia). Some of these symp toms are the result of lymphatic obstruction.

Malabsorption Due to Decreased Digestion There are

2 main causes:

Pancreatic insufficiency: can be seen in chronic

pancreatitis, pancreatic cancer, and cystic fibrosis. Determine pancreatic insufficiency by qualitative stool

Upper endoscopy with small intestine biopsy is the diag

exam, revealing undigested muscle fibers, neural fat,

nostic procedure of choice. Small bowel biopsy shows specific foamy macrophages that are positive for PAS

split fat, and low levels of fecal elastase.

staining bacterial remnants. You can also check CSF for

•The undigested muscle fibers indicate impaired

digestion.

whipplei by PCR, which is diagnostic if found.

•Low fecal elastase is characteristic of pancreatic

Treat with ceftriaxone or IV PCN for treat with TMP/SMX for

14 days and then 1 year. Relapse often manifests

insufficiency steatorrhea. •Further confirm impaired digestion by a positive

with CNS symptoms. DDx:

Similar

symptoms

also

may

caused

response to treatment with pancreatic enzymes. The

d-xylose absorption test may also be done during the

lymphatic blockage from primary intestinal (or other)

workup (discussed below) and is normal.

lymphoma.

•You must rule out pancreatic cancer if there is evidence of pancreatic insufficiency in patients

Eosinophilic Gastroenteritis

Eosinophilic

gastroentent1s

> 55 years of age. CT scan frequently shows

can

m1m1c

NN,

diarrhea, abdominal pain, weight loss, albumin wasting, and iron deficiency anemia. They often have a peripheral eosinophilia; and even though it is thought to be due to an allergy to certain foods-which would be mediated by IgE-only

20% have specific food allergies with an

increased lgE. Treat with corticosteroids for

pancreatic abnormalities.

intestinal

lymphoma and regional enteritis. Patients have

Bile acid deficiency:

• Ileal resection

(> I 00 cm-see page 1-3 I) or disease

that decreases bile acid uptake •Severe liver disease, which decreases production of bile acids •Zollinger-Ellison syndrome (ZES), in which the patient has increased acidity in the small bowel that

2-6 weeks and avoidance

of the causative foods (commonly 7-food elimination diet-soy, milk, seafood, wheat, com, egg, and peanut).

causes precipitation of bile acids •Bacterial overgrowth resulting in the breakdown of bile acids, making them useless for fat digestion (discussed on next page)

1-29

1-30

DIARRHEA

Steatorrhea is the best

indicator of malabsorption

because it commonly is the most prominent problem:

An alcoholic who has an elevated prothrombin time easily corrected by vitamin K more likely has malab sorption as the cause of the high PT-not liver disease!

• The 3-day, quantitative fecal fat measurement is the "gold standard" for determining steatorrhea.

Summary

Steatorrhea is defined as> 14 g/d of fecal fat. •Sudan stain of the stool tests for fat, which is the best screening test. •Serum carotene levels are a less specific indicator for malabsorption (see next).

When malabsorption occurs with steatorrhea: • Low "anything" suggests small bowel mucosa) problem or bacterial overgrowth. • Normal xylose absorption test with nomrnl carotene,

Steatorrhea from pancreatic insufficiency causes the

calcium, and prothrombin suggests pancreatic insuf

most fecal fat (can be > 50 g/d). Any patient having

ficiency-especially if there is very high fecal fat.

40 g/d of fecal fat almost certainly has pancreatic

insufficiency-barring history of intestinal resection, which can also increase fecal fat to these levels.

Bacterial Overgrowth There can be combined causes of malabsorption, as in bacterial overgrowth, which results in bile acid

Diagnosing the Cause: Transport vs. Digestion

deconjugation and patchy destruction of intestinal villi.

First, determine whether it is a small bowel mucosa!

Patients

problem or a digestive problem by testing directly for celiac disease and chronic pancreatitis. Other common causes of malabsorption are Crohn disease and bacterial

with

bacterial

overgrowth

usually

have

moderate steatorrhea, but their presenting complaint is often abdominal distention. The overgrowth of bacteria makes more folate but decreases absorption of B12, so

overgrowth. A small bowel biopsy may be needed.

you can get the odd finding of macrocytosis with high

The xylose (D-xylose) absorption test is not used much.

folate and low B12 levels.

Still, it is frequently a quiz topic and is still useful for

Bacterial overgrowth occurs in a variety of conditions:

differentiating disorders in carbohydrate absorption. D-xylose requires normal transmucosal transport; but to be absorbed, it does not require digestion by pancreatic enzymes. Therefore, a normal test result in a patient with steatorrhea tells you that mucosa! transport is normal. Diffuse small bowel disease can be excluded (i.e., CD, short bowel syndrome) and pancreatic insufficiency is more likely. These patients are often empirically treated with pancreatic enzymes. Resolution of the symptoms with treatment confirms the diagnosis. On the other hand, low D-xylose absorption is not specific. It can be caused not only by small bowel dis ease, but also by many other conditions, including poor gastric emptying, bacterial overgrowth, ascites, renal insufficiency, and old age. But, if the patient definitely has steatorrhea, the diagnosis probably is small bowel

• Structural abnormalities-diverticula, fistulae, strictures, after ileocecal resection . • Motility disorders-peristalsis is a major mechanism for clearing the small intestine of bacteria. (Peristalsis may be defective in diabetes and scleroderma and a number of other conditions.) • Achlorhydria-acid in the stomach kills bacteria before it enters the small bowel. • Immune disorders-immunoglobulins secreted in the small bowel may decrease bacterial growth. There are data showing a direct causative relationship between bacterial overgrowth and rosacea! In this study, almost 50% of patients with rosacea had bacterial over growth and 100% of these patients had long-term resolu tion when their bacterial overgrowth was resolved with a

disease since most of the other causes of an abnormal

I 0-day course of rifaximin-a nonabsorbable antibiotic.

xylose test do not cause steatorrhea. So if the xylose test

Diagnose bacterial overgrowth with the lactulose hydro

is low, do a small bowel biopsy!

gen breath test (or simply, hydrogen breath test) and

Again, normal D-xylose = normal small bowel. In which case, pancreatic insufficiency is probably the cause of steatorrhea. The absorption of carotene, vitamin K, vitamin D, folate, and iron also are independent of pancreatic enzyme digestion. So low serum carotene, hypocalcemia, hypo prothrombinemia, and/or Fe deficiency anemia in the patient with steatorrhea suggests a small bowel mal absorption problem rather than a pancreatic disorder. This is true only if steatorrhea is chronic and the patient has a normal dietary intake. Conversely, chronic diar rhea and normal levels of the above indicate pancreatic insufficiency.

sometimes a C l4-glycocholate breath test. It can also be diagnosed by quantitative culture from small bowel aspirate during EGD. Also remember the high folate levels, low B12, and macrocytosis. CT or UGI may show any small bowel diverticula (usually from scleroderma) and dilated small bowel. The specific overgrowth tests are generally available only at large medical centers. Bacterial overgrowth is often treated empirically with antibiotics after suggestive history and lab findings with: • rifaximin (a nonabsorbable antibiotic that stays in the digestive tract), or • amoxicillin-clavulanate, or

CONSTIPATION

The large majority of cases are idiopathic! Lifestyle habits, such as a change to low-fiber diet; sudden, prolonged inactivity; and high stress may result in constipation. •

•

Steatorrhea is the best indicator of

habits (e.g., no changes to diet, no new medications) sug

What is the "gold standard" test?

gests an obstructing lesion (neoplasm, stricture, foreign

What is the significance of a normal D-xylose absorption test in a patient with steatorrhea? Low D-xylose?

•

What are some important causes of bacterial overgrowth?

•

Bacterial overgrowth is associated with which dermatologic condition?

•

How do you diagnose bacterial overgrowth as a cause of diarrhea?

•

Most cases of constipation are due to what? What common gynecologic surgery leads to constipation in

of patients?

•combination antibiotics (usually cephalexin +metro nidazole) that cover both anaerobes and aerobes, or •doxycycline.

overgrowth: on antibiotics for 2 weeks, off antibiotics for I week, and repeat indefinitely. If symptoms recur while on a given antibiotic, switch antibiotics.

Bowel Resection and Diarrhea Massive resection of small bowel can cause malabsorp tion (short bowel syndrome), especially if the terminal ileum and ileocecal valve are resected. The ileum absorbs specific nutrients, especially B12 and bile acids. Know the following:

60 cm of terminal ileum resected: B12 deficiency. 100 cm of terminal ileum resected: Bile acid uptake

capacity is decreased, causing bile acid to make it to the colon and cause a bile acid-induced diarrhea. >

body). Pelvic floor dysfunction acts like outlet obstruc tion. Hysterectomy leads to refractory constipation in

5% of patients. Neurologic causes affecting the parasympathetic inner vation of the distal colon and rectum cause acquired megacolon; MS,

e.g.,

Chagas

traumatic

disease,

sacral

nerve

aganglionic

damage,

megacolon

(Hirschsprung's). Chagas disease is found in Central and South America. It is caused by infection with Trypanosoma cruzi, resulting in achalasia, cardiomyopa

thy, and acquired megacolon. Aganglionic megacolon (Hirschsprung disease) is typically diagnosed within the first

6 months of life, but a milder variant may present

in adults. Drugs

with

anticholinergic

properties

are

common

causes of constipation. These include antipsychotics, antidepressants, I st generation antihistamines, anticho linergic cold medications, and especially most narcotics.

Appropriate antibiotic treatment regimens for bacterial

Recent onset of constipation without change in lifestyle

What is the best screening test for steatorrhea?

100 cm of terminal ileum resected: Bile acid uptake

capacity is lost. Synthesis cannot keep up with loss, resulting in bile acid deficiency and subsequent fat malabsorption. See Crohn Disease, Terminal Ileum Problems in CD on page 1-20.

Other causes include iron preparations, calcium sup plements,

calcium

channel

blockers,

and

antacids

containing aluminum or calcium. Dehydration is one of the most common causes of constipation, especially in the elderly. Endocrine disorders, such as diabetes mellitus (DM) and hypothyroidism, often cause mild constipation. Myxedema may result in acquired megacolon. The altered progesterone and estrogen levels are the probable cause of constipation in pregnancy. Collagen

vascular

diseases,

especially

progressive

systemic sclerosis, also cause constipation. Many of these causes of constipation can be determined with a careful history.

DIAGNOSIS Whom do you work up for constipation? Patients with constipation who additionally have weight loss, rectal bleeding, or anemia should get: • A colonoscopy (to exclude structural disease; e.g., cancer, strictures)

CONSTIPATION CAUSES Causes of chronic constipation are many, but they usu ally result in:

• Serum ca++ and TSH (to exclude hyper/hypocalcemia and hypothyroidism; DM is usually evident from the history) For intractable constipation, test for colonic transit function. 24 radio-opaque markers ("Sitz markers") are taken by capsule, and a flat plate of the abdomen is

5 days later. Normally, most markers are gone. It is 5 to be retained. If the markers are spread

•generalized or regional colonic inertia, and

done

•pelvic floor muscle dysfunction.

abnormal for�

throughout the colon, the cause is generalized colonic

1-31

1-32

IRRITABLE BOWEL SYNDROME

inertia. Clustering of markers in the rectosigmoid colon

anal tone and sacral nerve stimulation (InterStim®) to

indicates pelvic floor dysfunction.

improve function of the anal sphincter and pelvic floor

Other tests for chronic constipation include evaluation

muscles.

of pelvic floor function, often by anorectal manometry with or without anal EMG, and by defecograms, which look for underlying abnormalities such as intussus ception. These tests should be reserved for refractory constipation.

FECAL IMPACTION Fecal impaction is a large mass of dry, hard stool in the rectum causing constipation. Those at greatest risk are elderly persons with inadequate fluid intake who are also on narcotics or anticholinergics or who have decreased

TREATMENT

mobility.

Treatment of constipation consists of correcting any

Often,

reversible causes. If idiopathic or irreversible, treat by

the impaction causing a watery fecal incontinence.

> 20 g/day and encourage

Presentation is sudden onset of watery stools/inconti

increasing dietary fiber to

proximal

watery

stool

leaks

around

adequate fluid intake (to avoid dehydration).

nence in a person with chronic constipation.

Note: Fiber or bulking agents often help with colonic

Treatment is to remove the impaction. Initially, you can

inertia but not with pelvic floor dysfunction, which often

try a mineral oil enema, but often the impaction must be

responds to pelvic floor retraining (+/- biofeedback).

manually removed by breaking off small pieces until the

Fiber can also cause bloating and abdominal cramping

obstruction is cleared. Longer-term treatment focuses on

(especially in female patients).

remedying the constipation: docusate stool softeners and bulk-forming agents used along with a bowel-training

Increase exercise. Short-term use of an osmotic laxative and/or stool

program (daily/regular BMs).

softener is okay. Avoid stimulant laxatives.

IRRITABLE BOWEL SYNDROME

Pelvic floor retraining, using modified Kegel exercise, can be quite helpful in refractory cases of constipation. Difficult cases generally respond well to daily use of polyethylene glycol powder with water or the recently approved (Linzess®).

lubiprostone Surgical

(Amitiza®) treatment

linaclotide

indicated

for

Hirschsprung disease. In patients with constipation related to narcotic use, mu-opioid antagonists can be used to counteract peripheral effects of narcotics on the bowel without affecting pain-killing properties. Osmotic laxatives (polyethylene glycol, sorbitol, glyc erine, etc.) cause increased fluid movement into the lumen, increasing fecal bulk.

OVERVIEW A large part of a gastroenterologist's practice consists of functional complaints. Around

15% of the population

has signs/symptoms of irritable bowel syndrome (IBS), and women are diagnosed with it more often than men

(2: I). IBS has characteristic symptoms of abdominal pain or discomfort associated with disturbed defecation. Abdominal pain is improved with defecation. These symptoms may be either continuous or intermittent. There are no nocturnal or organic symptoms. Patients generally have an increased bowel motor response to emotional and physical stimuli, but these motor patterns

Stimulant laxatives (senna or bisacodyl) cause colonic

are not specific to IBS. Patients with IBS are more likely

muscles to

to have experienced psychological or physical trauma in

contract.

They are

indicated only

for

childhood.

short-term use. Prophylaxis: When you initiate narcotic treatment, also start a stool softener

fiber supplement "bowel

regimen" to reduce the risk of iatrogenic constipation.

DIAGNOSIS OF IBS Overview Establish diagnosis of IBS by:

FECAL INCONTINENCE Fecal incontinence is a major health problem, especially

•

in the elderly as well as women who have had childbirth

•

excluding other diseases, and looking for characteristic symptoms.

related pelvic floor injuries. The diagnostic evaluation is

Rarely,

similar to constipation using the same diagnostic tests:

sigmoidoscopy is required.

transit studies, defogram, and anorectal manometry +/- EMG. Most therapies have aimed to increase stool bulk and/or to decrease diarrhea, which can contribute to fecal incontinence. Several new therapies for refrac tory cases have become available, including injection of a submucosal bulking agent (Solesta®) to increase

invasive

evaluation

with

colonoscopy

These patients are more likely to have psychosocial dysfunction that doesn't meet criteria for major disor ders. They may have neuroses, anxiety, or depression. As mentioned, they are also more likely to have a history of physical or psychological trauma.

IRRITABLE BOWEL SYNDROME

TREATMENT OF 185 Know the following:

uiz

Reassurance is paramount, as evidenced by the very

•

What are common causes of fecal incontinence?

•

What is the clinical presentation of fecal

patients-although only 30% have adequate relief with placebo. It is critical to fonn a therapeutic physician

impaction? •

patient relationship.

What other diagnoses should be excluded prior to diagnosing a patient with irritable bowel

Diet: Take a diet history and advise against "sugar free"

or "sugarless" foods that contain sorbitol. Have the

syndrome?

Patients

impressive 60-70% (!) response to placebo by these

patient keep a diet log to identify putative foods causing

50 years of age with new-onset !BS-like

symptoms should prompt consideration and workup for

diarrhea. Behavioral and cognitive therapies help the psycho

an alternative, organic cause.

social issues.

Exclude Other Diseases

although it is more helpful in constipation-predominant

Fiber supplementation is a traditional standard of care,

Celiac disease: 2-4% of patients with a diagnosis of

IBS, especially those referred to a secondary center, actually have celiac disease (page 1-27). In this popu

IBS and can actually worsen bloating. Probiotics, such as Lactobacillus,

acidophilus, and

Bifidobacterium longum, can be tried.

lation, screening with tissue transglutaminase Ab or

Antispasmodic agents used for IBS are anticholin

antiendomysial Ab testing may be helpful.

ergics (dicyclomine, hyoscyamine). Long term, these

Lactose intolerance: Rule out lactose intolerance. Also,

consider that 33% of patients with lactose intolerance do not improve on a lactose-restricted diet because they have concurrent IBS !

have more side effects than benefits. They are, however, acceptable for short-term or intermittent use. Tricyclic antidepressants (TCA) in low doses work

well for IBS, especially if patients have loose stools,

Bacterial overgrowth has been implicated in some

cases. Sorbitol: Rule out excessive sorbitol intake from excess

ingestion of"sugarless" candies, mints, gums.

because TCAs slow bowel motility and may improve neuropathic pain. Motility

drugs:

Loperamide

decreases

motility,

increases sphincter tone, and is good for loose stools. Lubiprostone (Amitiza®) is effective for constipation

predominant IBS.

Look for Characteristic Symptoms The characteristic symptom pattern of abdominal pain and altered bowel habits has been formalized into the

International Classification

for

Irritable

Bowel

Syndrome-commonly called the Rome criteria. The Rome criteria are at least 3 months of continuous or recurrent (at least 3 days out of the month): •

Abdominal pain relieved by defecation or accompanied by a change in frequency or consistency of stool,

•

stimulates intestinal fluid secretion and transit. Low FODMAP diet: Limited data suggests symptomatic

benefit from avoiding fermentable oligo-, di-, and mono saccharides and polyols (FODMAPs). Both physicians and patients can obtain FODMAP diets from a number of online sources.

and

5-hydroxytryptamine-3 receptor antagonists cause com

Disturbed defecation at least 25% of the time,

plications such as ischemic colitis and severe constipa

consisting of2 or more: 0

Altered frequency

Altered consistency

Passage of mucus

Altered stool passage

Abdominal distention and ...

•

Linaclotide (Linzess®) is newly approved for constipa

tion-predominant IBS. It is a guanyl cyclase agonist that

tion. Alosetron was withdrawn from the market and now is back, but with an FDA boxed warning. Other agents include ondansetron and granisetron. 5-hydroxytryptamine-4 receptor agonists have had even more issues (cardiac side effects!), and the only agent in this class-tegaserod-was withdrawn by the FDA in March of2007. It is now back, under investigational use. Alternating diarrhea and constipation may be due to

No constitutional signs or symptoms, such as fever,

patients' use of "stoppers," such as loperamide (e.g.,

weight loss, anorexia, and anemia. Specifically, no

Imodium®), and "starters," such as laxatives.

nocturnal symptoms!

MedStudy

1-33

1-34

COLON CANCER

COLON CANCER OVERVIEW Colon cancer risk factors: •Age> 50 •Adenomatous polyps (current or past) • Ulcerative colitis • Crohn colitis

Image I-17: Colon cancer

• BRCAJ mutation

Image 1-18: Po�yps in the colon

•Acromegaly

Adenomas with "advanced" features are defined as any

•Obesity

of the following: •Presence of high-grade dysplasia

•Smoking

•Presence of villous histology

• Diets high in calories and animal fat

•Size> 10 mm

Hereditary risk factors:

"Advanced" means likely

• 1st degree relatives with colon cancer or

develop into

cancer.

Progression to cancer from an early adenoma takes

adenomatous polyps

5-10 years. Diet plays a role in GI cancer-possible

•Familial polyposis syndromes (see next page)

dietary factors include high animal protein and fats, low

• Hereditary, nonpolyposis colon cancer

fiber, and low calcium. Be sure and discuss these impor

(HNPCC-see below)

tant considerations with patients on a "low-carb" diet!

Lifetime risk of colon cancer is 6% in average-risk persons.

Again, large or villous adenomatous polyps are likely to harbor or progress to cancer (Table 1-5).

Diagnostic flags for colon cancer:

Perspective:� 30% of people> 40 years old have adeno

•Anorexia

matous polyps, but only 1% of adenomatous polyps ever

• Weight loss

become malignant.

•Anemia

Hyperplastic polyps have no malignant potential and

•Fever

contain no features of dysplasia. This makes sense

• Heme+ stools

because hyperplasia, by definition, is increased growth of normal tissue.

• Change in bowel habits, especially with nocturnal stools

After polyps are found, follow-up depends on the type of polyp, size, number, and family history. Only adeno

•Onset of symptoms after age 45 Remember: Endocarditis caused by either Streptococcus

bovis or Clostridium septicum is often associated with colon cancer, so perform a colonoscopy in these patients. Aspirin reduces the risk of both colonic adenomas and carcinoma. In some series, the protective effect did not become evident until after 10 years of use. Low dose aspirin has now been shown to reduce the risk of right-sided colon cancer. Aspirin also reduces the risk of development of recurrent colon cancer, and evolving

matous polyps require specific follow-up. Hyperplastic polyps, if< 1 cm (except for those with a hyperplastic polyposis syndrome), have the same follow-up as no polyp (10 years). The 2008 American Cancer Society (ACS) guidelines recommend the following: •Patients with I or 2 small tubular adenomas with low-grade dysplasia should have repeat colonoscopy

5-10 years after initial polypectomy.

data suggest a reduction in carcinomas and adenomas

•Patients with 3-10 adenomas, or 1 adenoma> I cm,

after resection. Protective effect of aspirin is thought to

or any adenoma with villous features or high-grade

be related to:

dysplasia should have repeat colonoscopy in 3 years.

• Dose of aspirin •Frequency of use per week

Table 1-5: Malignant Potential vs. Polyp Size

• Duration of use (years)

<1cm

•Ongoing investigation into the appropriate dose and potential benefit of aspirin continues.

Tubular

Most GI cancers arise from adenomas (Image 1-17, Image 1-18). 25% of colorectal cancers are located distal to the splenic flexure.

1-2cm

>2cm

10%

Mixed(TV)

Villous

10%

45%

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COLON CANCER

2) Gardner syndrome-a

variant of FAP with more

extraintestinal benign growths. The adenomas have the same risk of cancer as FAP (100%) . These patients often have bone lesions (osteomas) and soft tissue Endocarditis due to

•

warrants a colonoscopy to search for colon

Patient has multiple osteomas found incidentally on

cancer.

an x-ray. W hat do you do? Colonoscopy!

3) Peutz-Jeghers syndrome-multiple hamartomatous

What size and histologic features of colon

•

tumors. Treatment is the same as FAP. Question:

(organisms)

polyps throughout the small bowel, and occasionally

adenomas are considered "advanced features"

in the colorectum and stomach, plus melanotic pig

with increased malignant potential?

mentation (freckles) on the lips and buccal mucosa.

What is the relationship between hyperplastic

•

The most common presentation is with abdominal

polyps and colon cancer?

pain due to intussusception or bowel obstruction by

Know the 2008 ACS guidelines for

•

a large polyp. Even though these polyps are hamar

recommendations on follow-up intervals

tomas, which have no risk of cancer, these patients

based on type and number of polyps.

still have a higher than baseline risk of cancer because

Which 2 familial polyposis syndromes have the

they occasionally develop adenomas that can become carcinomas. Risk of cancer is

highest risk of carcinoma? Which has no risk

What is the risk of cancer in a patient with

•

To date, no specific guidelines for screening/surveillance

Peutz-Jeghers syndrome?

•

Patients with

colonoscopy

I 0 adenomas should have repeat

3 years. (Consider the possibility of an

underlying familial syndrome-see below.) •

have been established in the U.S. for juvenile polyposis.

At what age does screening begin for HNPCC?

•

Patients with sessile adenomas that are removed piecemeal require repeat colonoscopy in

2-6

50% by 60 years of age.

4) Juvenile polyposis also consists of hamartomas (> JO juvenile polyps -juvenile polyposis syndrome).

of carcinoma?

months

to verify complete removal. The American Gastroenterology Association (AGA) published similar guidelines in 2012.

Hereditary Nonpolyposis Colon Cancer As the name suggests, most patients with this form of cancer do not have a familial polyposis; rather, the cancer arises from normal-appearing epithelium. Hereditary nonpolyposis colon cancer (HNPCC, a.k.a. Lynch syndrome) can be defined as "the occurrence of a HNPCC-associated cancer ( colorectal, endome (one is a

1st

degree relative of the other two)

relatives over at least

INHERITED COLON CANCER Overview Inherited colon cancer can be categorized into either polyposis or non-polyposis syndromes.

3 1st degree

trial, small bowel, ureter or renal pelvis) in at least

person diagnosed

generations, and with at least

age

50."

These rather loose diag

nostic criteria suggest that Lynch syndrome is respon sible for cancer in as many as

in 20

(5%) patients with

colon cancer! Women in families with HNPCC have an increased incidence of ovarian and endometrial cancer as well as renal, ureteral, stomach, pancreatic, and

Familial Polyposis Syndromes The familial (or hereditary) polyposis syndromes are all

biliary tree cancers. Start screening those with HNPCC risk profile at age 25.

autosomal dominant (AD). The

4 types are listed here in order of decreasing cancer potential. The first 2 are adenomatous, the second 2 are hamartomatous: I)

SCREENING Review Current screening recommendations are also covered

Familial adenomatous polyposis (FAP)-hundreds

in General Internal Medicine, Book

of adenomas in the colon-I 00% risk of cancer if not

Tests. In general, do yearly fecal immunohistochemical

treated. These patients often require a prophylactic

testing (FIT) in average-risk patients.

proctocolectomy by age 20! They can also get some duodenal adenomas, which also have a high risk of cancer. After colectomy, patients with FAP tend to get duodenal cancer. They are also at increased risk of developing secondary tumors (ampullary adenomas and carcinomas). Giant stomach tumors are common in patients with FAP, but they are benign.

under Screening

Low-risk patients: The 2008 American Cancer Society guidelines for colorectal cancer screening for asymp tomatic adults

� 50 years of age with a negative family

history for colon cancer or adenomatous polyps have broken down the tests into the following 2 areas:

Tests that detect adenomatous polyps and cancer (preferred by the guideline-writing committee):

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1-35

1-36

COLON CANCER

FOBT

•Colonoscopy every 10 years, or •Flexible sigmoidoscopy every

5 years, and

time. This varies with age;

•CT colonography every 5 years

Of positive FOBTs,

2% have GI cancer. 66% of 6 Hemoccult® cards

Remember: The FOBT is negative in up to

2) Tests that primarily detect cancer:

patients with colon cancer. Using

•Annual fecal immunochemical test with high

(the full FOBT series) will detect advanced colonic

sensitivity for cancer, or

cancer in only about

•Annual guaiac-based fecal occult blood test

25% of patients. This makes it a

pretty poor screening test, but it is used (annually or

with high sensitivity for cancer, or

biennially) because it is quick and cheap.

•Stool DNA test with high sensitivity for cancer,

Even if one FOBT is positive, do a colonoscopy.

interval uncertain Each strategy has inherent strengths and weaknesses. FOBT is the most inexpensive and obviously least invasive, but it may miss

2% of the 5% after 60 years of age.

Fecal occult blood testing (FOBT) is positive

•FOBT yearly, or

�

1/3 of advanced cancers.

Colonoscopy has the highest yield of finding polyps and cancers, but is most costly and invasive. Guidelines

A flex-sig + ACBE (air-contrast barium enema) is also acceptable but clearly less desirable.

CEA

recommend that any positive test (other than colonos

Note:

copy) should be followed up by a full colonoscopy with

useful only for surveillance for recurrence of colon

Carcinoembryonic antigen

(CEA)

levels are

2008

cancer-and only if levels were elevated before surgery

USPSTF guidelines generally agree with the American

and reduced after surgery. CEA may also be mildly ele

biopsy of any identified abnormalities/polyps. The

Cancer Society guidelines except that the USPSTF rec

vated in patients who smoke or who have benign biliary

ommends against screening in those >

disease, sclerosing cholangitis, or IBO.

85 years of age.

Repeat colonoscopy timing based on polyp pathology (see page

1-34).

Increased-risk

STAGING OF COLON CANCER patients:

should begin at age

Surveillance (colonoscopy)

40 years or I 0 years before age at

which the index case is diagnosed-whichever is first.

40 if a 1st degree relative was 52; start at age 20 if several I st degree relatives had colon For example: Start at age

TNM Classification The

2 methods for staging colon cancer are TNM and

Duke's. They are similar, but TNM classification, which was updated in

2010, is the preferred method.

diagnosed with an adenoma or colon cancer at age

cancer at age 30. Colonoscopy is the screening procedure of choice in patients with any

1st degree relatives with either colon

cancer or an adenomatous polyp. It is also the screening method of choice in patients who have a history of an

Table 1-6: Indications for Colonoscopy Occult bleeding

adenomatous polyp. Time between surveillance colonos copies depends upon the cancer potential of the polyp- see previous discussion, under Colon Cancer Overview on page

1-34.

Gross lower GI bleeding except bright red blood in a younger person

Virtual colonoscopy or CT colonography is a CT scan with special software. It has high yield for detecting larger polyps and cancers. Areas of adherent stool can be

Adenomatous polyp--initially and for all follow-ups

mistaken for small polyps. However, it is an excellent test for a patient who cannot complete a standard colonoscopy to visualize the entirety of the colon. If abnormalities are

1st degree relative with colon cancer

found on CT colonography, the guidelines recommend proceeding to colonoscopy if possible (since the patient

IBD: Suspicion, follow-up, surveillance

has already been prepped). Sigmoid colon cancer can perforate the bowel wall and simulate diverticulitis. So, screen for colon cancer after

Ischemic colitis

an episode of diverticulitis in older patients. To avoid risk of perforation, wait for resolution of acute inflam mation

(6 weeks after episode of diverticulitis) before 1-6 for the

proceeding with colonoscopy. See Table

most common indications for colonoscopy.

4-8 weeks after new-onset, presumed diverticulitis to rule out colon cancer

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DIVERTICULAR DISEASE AND LOWER GI BLEED

•

DIVERTICULAR DISEASE

Under what circumstances should periodic colonoscopy be started at age 40?

•

Types of Diverticular Disease

What common colon proglem in older patients

There are 4 types of diverticular disease (see Image 1-19

is an indication for colonoscopy? •

and Image 1-20):

Are CEA levels useful for primary diagnosis,

I) Asymptomatic diverticulosis (most common)

recurrence, or both in colon carcinoma? Why? •

2) Painful diverticulosis (contraction of hypertrophied

Surgery for cure is the rule in colon cancer.

colonic muscle)

When is adjuvant chemotherapy used?

3) Diverticular bleeding

When is radiation used?

4) Diverticulitis In general, the cancer stage becomes more advanced as the tumor enlarges and invades the colonic wall: •

TNM stage I: extends into submucosa (T1) or muscu

laris (T2); no nodal involvement; no metastases •

TNM stage II (subclassifications A,

past muscularis into tissues around the colorectal area invasive (T4b); no nodal involvement; no metastases TNM stage Ill (subclassifications A,

8, and C): any

combination ofTl-T4b with nodal involvement and no metastases •

Diverticulosis is the presence of one or more diverticula in the colon. Incidence increases with age. About 80--85% are asymptomatic. It has been assumed that

8, C): extends

(T3) or into visceral peritoneum (T4a) or is directly

•

Asymptomatic Diverticulosis

TNM stage IV: any combination ofTl-T4b, any N, with distant metastases

diverticulosis is caused by a low-fiber diet and can be warded off by a high-fiber diet. A 2011 study casts doubt on this theory. Current guidelines still recommend high fiber diet for those with asymptomatic and symptomatic diverticulosis. Recent work on the pathophysiology of diverticular disease has focused on the inflammatory etiology of diverticular fomrntion and the possible role of antiinflammatory agents in retarding diverticular for

mation. However, no new guidelines have been issue(' in

Colon cancer virtually always metastasizes to the liver

this regard.

first (via portal circulation). However, if it involves only the rectum, the blood supply bypasses the portal circulation, so the patient may have lung, bone, and brain mets without liver mets.

Symptomatic Diverticulosis Painful diverticulosis is due to hypertrophy of both circular and longitudinal colonic musculature myo chosis, which leads to luminal narrowing, pencil-thin

TREATMEN T OF COLON CANCER

stools, and bouts of colicky pain often relieved by pass

Surgical resection is the 1st treatment option and is poten tially curative. Recurrences after surgery are probably due to micrometastases. Adjuvant chemotherapy consists of a 5FU-based therapy. Typically, 5FU plus leucovorin (LY) is used. Trials have shown benefit rrom oxaliplatin being added to this regi men. This protocol is called FOLFOX.

ing flatus or having a bowel movement. This occurs in about 10--15% of diverticulosis patients. Another helpful clue in establishing a diagnosis of colonic myochosis is a palpable and thickened sigmoid and left colon. Treat with bulking agents which typically contain psyllium

methylcellulose.

Probiotics

may

beneficial as well.

Adjuvant chemo is effective only for stage III or locally advanced II. Radiation therapy prior to surgery is helpful for rectal lesions only. Hepatic

resection increases survival

with

solitary liver mets. If you remove a cancerous polyp, you must do a bowel resection if the cancer extends to either a blood vessel or the cautery line. Image

1-19: Intestinal diverticulosis, x-ray

Image

1-20: Diverticular disease

1-37

1-38

DIVERTICULAR DISEASE AND LOWER GI BLEED

Treatment of diverticulitis should cover both aerobic and anaerobic gram-negative organisms.

Diverticular Bleeding Diverticular bleeding occurs in only a small percentage of patients with diverticulosis. Even so, diverticular bleeding is the most common cause of colonic bleeding in the elderly; angiodysplasia is next on the list and often results in more severe bleeds. Diverticular bleeding usu ally originates in the right colon, and typically stops spontaneously. Patients classically present with "painless, maroon stool," but color can actually vary from red to black. Treatment for diverticular bleeding: Stabilize patient with IV crystalloid and give packed red blood cell transfusion if needed. Rule out UGI bleed. Correct any coagulopathies and discontinue any medications that worsen bleeding. Colonoscopy is indicated only if bleeding does not stop. Note: UGI bleed is suggested by a BUN/Cr ratio> 30: 1, which indicates blood is being digested and breakdown products are being absorbed. Diagnose diverticular bleeding with colonoscopy or technetium-tagged RBC scan. Angiography with embolization can be performed if bleeding is severe or continuous. See Table I -7 for common indications for GI angiography.

Treat mild diverticulitis in a patient able to drink and without peritoneal signs with outpatient metronidazole (for gram-negative anaerobic coverage) plus either ciprofloxacin or TMP/SMX (for gram-negative aerobic coverage) and follow up closely. Treatment of moderate-to-severe diverticulitis: Inpatient parenteral treatment for those with peritoneal signs may consist of dual- or single-drug therapy: l ) Dual-drug therapy (best!), such as: •aminoglycoside or ciprofloxacin (gram-negative aerobic) plus •clindamycin or metronidazole (gram-negative anaerobic) 2) Single-drug therapy, such as: •Ticarcillin/clavulanic acid •Piperacillin/tazobactam •Imipenern/cilastatin •Ampicillin/sulbactam •Cefotetan Note that all of these single-drug therapies cover both aerobic and anaerobic gram-negative organisms.

Diverticulitis

Drain abscesses percutaneously.

Diverticulitis, as the word suggests, is caused by inflamed diverticula. It is typically due to microperfora tions. It occurs in < 5% of patients with diverticulosis. Signs and symptoms include:

Perforation from sigmoid colon cancer can present similarly to diverticulitis, so follow up patients > 50 years of age with a flex-sig/colonoscopy 4-8 weeks after the acute condition resolves.

• LLQ pain •Fever •High WBC • LLQ tenderness •No bleeding! The LLQ tenderness, and sometimes rebound tenderness, is usually localized. Look for a sigmoid mass (i.e., pal pable, tender sigmoid) on physical exam, on U/S, or on CT. CT is most useful in assessing diverticulitis: It may show areas of thickened sigmoid colon or pericolic fluid accumulation. Avoid colonoscopy on any patient with diverticulitis (due to risk of perforation).

Table 1-7: Angiography 1n GI Disease Chronic and acute mesenteric ischemia Severe lower GI bleed Rarely used for UGI bleed-some duodenal ulcers TIPS in variceal bleeding Therapeutic uses: embolization, vasopressin

Meckel diverticulum is the most common congenital GI anomaly. Although < 1/2 of these diverticula have gastric mucosa, only these ulcerate and bleed. Meckel diverticula cause 1 /2 of all GI bleeds in children; they can also cause obstruction and intussusception. They may be seen with the technetium scan ("Meckel's scan"). Technetium is taken up by gastric mucosa. ANGIODYSPLASIA AND LOWER GI BLEED Angiodysplasia ( vascular ectasia, AVM) is the 2"d most common cause of lower GI bleeding in the elderly (diverticular bleeding is 151). Think of these as spider nevi of the GI tract. =

Bleeding in angiodysplasia may be occult to severe. The usual bleeding site is the right colon (cecum, ascending). AVMs typically are not cauterized unless they are bleeding significantly. Hereditary hemorrhagic telangiectasias (HHT Osler Weber-Rendu) is a hereditary condition in which there are multiple AVMs affecting all the organs, includ ing brain, lung, skin, and mucous membranes and the GI tract-especially in the upper GI tract (AVM is usually lower). Patients with HHT often have a history of epistaxis. =

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BOWEL OBSTRUCTION

and upright abdominal film showing (typically) exces sive amounts of air in the small bowel with no air in the colon. The presence of air fluid levels is helpful when there are "J-loops," in which the air fluid levels •

What may be seen on abdominal

CT scan

of bowel. This signifies a dynamic obstruction.

in a patient with diverticulitis? •

What is the treatment of moderate-to-severe diverticulitis?

•

are at different heights on either side of the same loop

What is "thumbprinting," and when is it seen?

Angiography may be used in workup of severe disease (again, see Table I- 7).

If the

fluid levels are the same height on either side of the loop, paralytic ileus is the more likely diagnosis. Treat with IV fluids and NG suction. Further workup is indicated if the symptoms do not resolve in

1-2 days.

Gastrografin enema can be helpful if the obstruction is thought to be of colonic origin.

Endoscopic treatment can help, although there are often

INTESTINAL ISCHEMIA

many lesions and not all can be treated.

TYPES

ISCHEMIC COLITIS Ischemic colitis (CI; a.k.a. colonic ischemia) causes

There are

4 types of intestinal ischemia:

abdominal pain (from the ischemia) and maroon stools.

I) lschemic colitis (most common)

This is covered fully under Intestinal Ischemia.

2) Chronic mesenteric ischemia 3) Acute mesenteric ischemia (70% mortality!)

�DEO CAPSULE ENDOSCOPY

4) Mesenteric venous thrombosis

Okay, with EGO you can see the upper GI tract, and there is colonoscopy for the lower GI tract. We now have the wireless video capsule endoscopy (VCE), which is used to visualize the previously unvisualizable small bowel. It is especially useful in working up small bowel bleeds or occult blood loss without an obvious cause.

ISCHEMIC COLITIS lschemic colitis is the most common form of intestinal ischemia. It is due to a nonocclusive ischemia-mostly involving some portions of the splenic flexure, descend ing colon, and/or sigmoid colon; i.e., inferior mesenteric

[Know:] A patient presenting with recurrent melanotic

circulation. Most often, no specific cause for the isch

stools, with negative EGDs and colonoscopies, should

emia is found. It is a disease primarily of the elderly

undergo wireless video capsule endoscopy.

and may be seen post-op (colonic surgery and aortic

The VCE is also becoming useful for other small bowel problems; e.g., assessing tumors, Crohn disease, and celiac disease. A similar capsule to VCE is now available that measures pressure, temperature, and pH and may have a role in the evaluation of transit disorders.

aneurysmectomy); it is occasionally associated with low-flow

conditions

(CHF),

medications/cocaine,

and hypercoagulable states. Because this condition is virtually never embolic, patients are not likely to have valvular heart disease or cardiac arrhythmia. In many cases, an evaluation of underlying coagulation disorders may be indicated. Symptoms of ischemic colitis: typically a sudden LLQ

BALLOON-ASSISTED ENTEROSCOPY Single

and

double

balloon-assisted

enteroscopy

allows for evaluation and treatment of small bowel lesions which were previously out of reach of standard endoscopes.

pain with an urge to defecate, followed by passage of red-to-maroon stool within I day. Also think of this in extreme athletes; e.g., marathon runner with abdominal pain and hematochezia after a long race. Mildest injury: mucosa) and submucosal hemorrhage and edema-which severe injury ranges

BOWEL OBSTRUCTION

is completely reversible. More from replacement of mucosa

and submucosa with granulation tissue to transmural infarction and fulminant colitis.

The most common cause of small intestine obstruction is postoperative adhesions. The most common causes of colonic obstruction are (in decreasing frequency): carcinoma, diverticulitis, and volvulus. The diagnosis of obstruction is suggested in the setting of persistent vomiting, obstipation, and constipation. The diagnosis is confirmed radiographically with a flat

MedStudy

Submucosal hemorrhage and edema (mildest injury) are seen on abdominal x-ray (KUB) or barium enema

(BE)

as "thumbprinting." This thumbprinting lasts only a few days and is not specific for the type of ischemia, just for submucosal edema or hemorrhage. CT scan is gener ally the

I '1 diagnostic test. Portal venous gas on CT is

indicative of transmural necrosis/injury.

1-39

1-40

PANCREAS

If there are peritoneal signs, diagnose with colonoscopy

Bowel infarction leads to lactic acidosis. In the early

(which is usually done without bowel prep to reduce

stages, excruciating abdominal pain (from ischemia)

risk of decreasing blood flow due to use of dehydrating

may be disproportionate to the abdominal exam, which

agents). Sigmoidoscopy is also acceptable. Angiography

can be relatively benign.

is not usually done.

The usual treatment for colonic ischemia is bowel rest,

angiography

unless

there

evidence

perforation (e.g., rigid abdomen, lactic acidosis, intra

fluids, and antibiotics. Most cases resolve with conser

peritoneal air)-in which case the patient goes directly

vative measures. Rarely, strictures or acute abdomen

develop.

embolectomy.

CHRONIC MESENTERIC ISCHEMIA

MESENTERIC VENOUS THROMBOSIS

Chronic mesenteric ischemia is also called intestinal

Mesenteric venous thrombosis (MVT) is associated

surgery

for

dead-bowel

resection

and

possible

angina. Patients may require further evaluation if they

with hypercoagulable states, such as deficiencies of

have the classic triad:

antithrombin III, prothrombin 2021 OA (a gene variant), protein S, protein C, and Factor V Leiden defect.

1) Abdominal pain after meals

MVT is also linked to any of the following:

2) Abdominal bruit 3) Weight loss (from tolerating only smaller meals)

•

The pain is due to episodes of inadequate blood flow

•

brought on by digestion.

•

Suspect mesenteric vascular ischemia in the above setting, especially if abdominal pain is out of proportion

•

Pancreatitis Liver disease (cirrhosis) Intraabdominal sepsis Sickle cell disease Paroxysmal nocturnal hemoglobinuria (PNH)

MVT

to any physical findings. Symptoms are l -3 hours of dull, gnawing abdominal pain - 30 minutes after eating. The etiology is athero sclerosis of the mesenteric arteries, with the symptoms caused by gastric "steal" after eating. Patients often have signs of other types of peripheral vascular disease

may

acute,

subacute,

chronic.

mesenteric infarction, the pain of MVT is often out of proportion to the abdominal exam. If the portal or splenic veins are involved in chronic MVT, there may be bleeding from gastroesophageal varices. Cirrhosis patients with coagulopathy can still develop MVT.

(PVD) and often have a history of smoking (no clear

CT is the diagnostic procedure of choice-with CT,

association).

90% of MVT can be diagnosed.

Diagnosis is mainly based on symptoms. The next step

Treat acute MVT with thrombolytics and long-term

is commonly an MRA (magnetic resonance angiogram)

anticoagulants; patients may require surgery if peri

or CT angiogram. These have good sensitivity for proxi

toneal signs are present. Treatment of chronic MVT is

mal lesions, such as superior mesenteric or celiac arter

focused on minimizing bleeding from varices with

ies, but are much less sensitive as the involved lesion

sclerotherapy, portosystemic shunts, or similar devices.

becomes more distal. Splanchnic angiography is then done if these are abnonnal.

PANCREAS

Treatment is surgical bypass or angioplasty.

ACUTE PANCREATITIS ACUTE MESENTERIC ISCHEMIA

Overview

Acute mesenteric ischemia is the most severe and life-threatening form of intestinal ischemia, with a mortality rate of 70o/o-even with treatment!

It is

caused by the lodging of a thromboembolus in a mes enteric artery, leading to acute loss of blood flow to the corresponding small intestine and/or ascending colon.

Acute pancreatitis is frequently caused by either alcohol abuse or gallstones; these are the #1 and #2 etiologies in the U.S. In Europe, the reverse appears to be true. These are not firm conclusions; results from studies are influenced by where they are done. F or example, if the study is done in a VA hospital, the primary cause is prob

Acute mesenteric ischemia is seen in older patients with

ably alcohol abuse; whereas, if it is done in a community

a history of CHF, recent MI, cardiac arrhythmias, or

hospital, gallstones are more likely to cause the majority

hypotensive episodes.

of cases.

Patients often have symptoms of intestinal angina

Endoscopic

(above) for months before the acute event. Because this

(ERCP) causes acute pancreatitis (see page

condition is commonly due to emboli, patients are likely

2-5% of patients. Other causes of acute pancreatitis

retrograde

cholangiopancreatography

1-1) in

to have concomitant valvular heart disease or cardiac

are acidosis (as in DKA), hypertriglyceridemia, hyper

arrhythmia. These patients are acutely ill with vomiting,

calcemia, trauma, and other problems that result in

diarrhea, and rectal blood.

obstruction of the ampulla of Yater (e.g., pancreatic cancer).

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PANCREAS

Severity of Pancreatitis

Factors and Results The severity of acute pancreatitis is directly related to •

the degree of pancreatic necrosis (10-25% have necro

What is the clinical presentation of chronic

sis) and whether this necrotic tissue is infected(mortality

mesenteric ischemia? •

What is the clinical presentation of acute mesenteric ischemia?

•

methods of assessment for severity:

What happens to serum amylase and lipase

• Hemoconcentration

What 2 relationships do high triglyceride levels have with acute pancreatitis?

•

•Heart: systolic BP< 90 mmHg; tachycardia> 130 bpm • Lungs: P02< 60 mmHg •Renal: progressive azotemia or oliguria to< 50 mL/hr

Know the Atlanta classification of acute

•CNS: altered sensorium

pancreatitis. •

5-10%!

These multiorgan failure indicators are used in several

levels over time with acute pancreatitis? •

Severe pancreatitis causes shock and multiorgan failure.

What are the most common causes of pancreatitis in the U.S.?

•

30%) or not (mortality= 10%). Overall, mortality rate

for acute pancreatitis

•Metabolic: low calcium(<

What physical findings reflect severe pancreatic

8 mg/dL) and

albumin< 3.2 g/dL

necrosis with multiple organ failure? •

Assessing Severity

What is Cullen sign? What is Turner sign?

Skin Signs Always check medications. Quite a few drugs can cause acute pancreatitis:

Okay, so we know severity of pancreatitis is associated with the degree of necrosis and signs of multiple organ failure. How do we determine severity on admission?

• Diuretics: furosemide and thiazides •Estrogens

Good clues arc the skin signs that may be seen with

•Azathioprine

severe acute pancreatitis:

•5-ASA derivatives

•The most common skin finding is an erythema of the

•Antibiotics: tetracycline and sulfonamides •Anti-HIV drugs; e.g., pentamidine and didanosine •Oral hypoglycemics

flanks caused by extravasated pancreatic exudates. •Cullen sign and Turner sign, when seen(unusual), indicate a severe necrotizing pancreatitis:

• 6-mercaptopurine, L-asparaginase, and valproic acid

Many cases of "idiopathic" pancreatitis are actually secondary to biliary microlithiasis, cystic fibrosis, hered

flanks, results from tissue catabolism of

With acute pancreatitis, amylase and lipase are gener

hemoglobin from retroperitoneal blood

ally elevated. The serum amylase level is almost always elevated early on (> 3x N is almost always due to pan onset. Remember, amylase is less specific than lipase because there are other etiologies for hyperamylasemia (see below). The lipase level increases later and stays elevated longer than the amylase(beyond day

7).

Turner (or Grey-Turner) sign, a bluish-reddish purple or greenish-brown discoloration of the

itary pancreatitis, or hypertriglyceridemia.

creatitis) but decreases within 2-3 days after disease

Cullen sign, a faint blue discoloration around the umbilicus, indicates hemoperitoneum.

dissecting along tissue planes. °

Cullen and Turner signs are characteristic but not pathognomonic for acute pancreatitis. Cullen sign is also seen with intraperitoneal bleeding(especially ruptured ectopic pregnancy), and Turner sign is seen with other causes of retroperitoneal bleeding.

High triglyceride levels in the setting of acute pancreatitis may cause a spuriously normal amylase level!

Severity Scoring Systems

Additionally, triglyceride levels > 1,000 mg/dL can

Multiple systems have been developed over the years,

cause pancreatitis.

including Ranson and Glasgow. However, neither of

The 2012 revision of the Atlanta classification for acute

these scoring systems has been validated in larger trials.

pancreatitis identifies that 2 of the following must be

Newer systems are the Apache II and the BISAP score:

present:

I) Upper abdominal pain radiating through to the back 2) Serum amylase or lipase 3x the upper limit of normal 3) Cross

sectional

pancreatitis

imaging

consistent

with

acute

APACHE

II has been shown to have good sensitiv

ity and specificity, although adding body mass index (APACHE 0) has produced conflicting results. In addi tion, APACHE II scoring requires calculators to perform.

1-41

1-42

PANCREAS

BISAP (BUN > 25, impaired mental status, SIRS, age > 60 years, pleural effusion) has similar reliability for mortality (but not other indices) to the APACHE II with the added benefit that BISAP can be done at the

Fluid I Masses in Acute Pancreatitis Types of fluid collections and masses found in acute pancreatitis:

Acute fluid collections with high amylase levels appear

bedside.

SIRS (systemic inflammatory response syndrome score) has been validated in smaller studies, is also easily done at the bedside, and can be repeated daily. It is typically used for inpatient daily follow-up assessment.

in up to 50% of patients within 48 hours of pain onset. They usually resolve spontaneously. A sympathetic tran sudative left pleural effusion frequently occurs. Rarely, a diaphragmatic defect into the pleural space causes an effusion high in amylase(Figure 1-4).

SIRS is a measurement of the body's physiologic response to an undefined insult (infectious or not) and does not necessarily imply multiple organ failure. SIRS is part of a somewhat newer method of categorizing severe illnesses. For instance, sepsis is defined as SIRS plus a documented or presumed infection.

Necrotic tissue: Inflamed, edematous, necrotic pancreas occurs in the first 1-2 weeks and may simulate a pseu docyst (which typically occurs later; discussed below). Necrotic tissue can be differentiated from a pseudocyst with the aid of ultrasonography. Pancreatic necrosis is serious and may require drainage.

SIRS requires 2 or more of the following:

Infected

necrosis:

•Temperature< 36° C(96.8° F) or> 38° C (I 00.4° F)

generally

requires

•Tachycardia (HR> 90)

CT-guided) or surgery (infrequent nowadays) within

pancreatic

necrosis

drainage (endoscopic

2 weeks of the episode. You can diagnose by CT-guided

•Tachypnea(RR> 20 or pC02< 32) •WBC abnormal(> 12 Kor< 4 Kor> I 0% bands) Current

Infected either

AGA Recommendations

aspiration of necrotic pancreas with Gram stain and culture.

Pseudocyst: A pancreatic pseudocyst develops in less

Currently, the AG A recommends the following to assess severity:

than 10% of patients with acute pancreatitis. It requires a minimum of 4 weeks to develop after the acute attack. It is now recognized that walled-off necrosis can mimic

• Use the APACHE II score::=:: 8 as a cutoff for

a pseudocyst. Basically, it is a collection of pancreatic

severe disease. Patients with ::=:: 8 or those with

fluid, which, if small enough, resolves spontaneously. A

organ failure at 72 hours should undergo

size > 5 cm suggests it may not resolve on its own. If

CT to assess for necrosis.

the pseudocyst persists > 3--6 months and causes symp toms, it may require surgical, radiologic, or endoscopic

•Clinical judgment is still important.

drainage. Remove enlarging, symptomatic pseudocysts Independent risk factors include:

because they are associated with serious complica tions--especially fistula,

•Morbid obesity(BM! > 30) is associated with a 2x increase in mortality.

15%

and then suddenly gets worse. Most experts, consistent

are inconsistent regarding the significance of

with newly emerged data, recommend early intervening

this finding.

in symptomatic patients.

•Age> 75. •Organ failure. Pancreatic necrosis is best confirmed by dynamic CT scan or MRI (at some is considered severe if

ACUTE PANCREATITIS

When following after admission, do

Acute fluids

daily

and

48 hrs

look

for signs of multiple organ failure. Worsening indicators equal worsen ing severity. ICUs may also use the

Inflamed tissue; Infected necrosis

2 wks

4wks

APACHE system.

Abscess: A pancreatic abscess occurs 4--6 weeks after onset of acute severe pancreatitis-in which there is severe pancreatic necrosis. It may be seen

Pain onset

::=:: 30% of the pancreas is necrotic. evaluation

ity! Consider this in a patient who is recovering normally

despite fluid resuscitation; however, studies

a SIRS

rupture,

mortality, while rupture with hemorrhage= 60% mortal

•Hemoconcentration (> 44%) that is persistent

centers). It

pseudo-aneurysms,

and hemorrhage. Rupture without hemorrhage

as a "soap bubble sign" on upright abdominal x-ray. This is a very serious condition that may present with fever and septic shock. Diagnose

pancreatic

abscess

with

Gram stain of a CT-guided percutane Pseudocyst;

ous aspirate, which is 90% accurate.

Abscess

T his allows for immediate surgical or

6 wks

radiologic debridement and drainage.

Figure 1-4: T1mel1ne of Comphcat1ons

PANCREAS

Gastric varices, in the absence of esophageal varices, occur only in the setting of splenic vein thrombosis, which is a complication of both severe acute pancreatitis and chronic pancreatitis. •

What is the APACHE II score that indicates

ERCP is not done acutely unless a patient has biliary

severe pancreatitis?

sepsis. Use MRCP after the acute period to diag

•

How is pancreatic necrosis best confirmed?

•

What masses may develop due to acute

nose suspected common bile duct stones; e.g., the bilirubin is

pancreatitis? What is their timeline, and what

cholecystectomy

Symptomatic pseudocysts persisting for more

•

after

gallstone

pancreatitis

Criteria for resumption of oral feeds in acute pancreatitis:

intervention(s )?

•

ASAP

-after the inflammation has resolved.

than 3-6 months generally require what

•

2.5 and rising or the ultrasound shows

treat ductal obstructions found on MRCP. Perform

is their treatment? •

a dilated common duct. Do therapeutic ERCP to

What is the 1st test in the workup of the etiology

• Bowel sounds present and passing flatus/stools.

of acute pancreatitis?

•Not requiring narcotics. •Patient is hungry and wants to eat!

What is the clinical presentation of chronic pancreatitis?

Question: W hat conditions can cause abdominal pain

What is the classic diagnostic triad for chronic

with an elevated amylase? Answer: Acute pancreati tis, acute cholecystitis, intestinal infarction, diabetic

pancreatitis?

ketoacidosis, perforated ulcer, salpingitis, and ecto pic pregnancy. Other causes of hyperamylasemia are

Diagnosis of Pancreatitis

increased

In working up the cause of acute pancreatitis, the

1st and

often only test is gallbladder ultrasonography to rule out

salivary

amylase

and

macroamylasemia

(benign condition due to a low urinary excretion of amylase).

gallstones. Diagnosis is otherwise often based mainly on history.

CHRONIC PANCREATITIS Overview

Treatment of Acute Pancreatitis With supportive care,

�

90% resolve spontaneously

within a few days. Patients must be made NPO for a variable period of time, but NG suction is generally not required. Provide vigorous TV crystalloid fluid hydration plus colloids as needed. Early enteral feeds have been shown to be superior to TPN in maintaining nutritional status in patients with protracted acute pancreatitis. High-protein,

low-fat,

semi-elemental

formulas

via

nasojejunal tube are recommended. Give systemic antibiotics only if there is established infection. Give 20 mL/kg bolus of lactated Ringer fol lowed by continuous infusion at a rate of for the next

3 mL/kg/hr

6-8 hours. At 8 hours, if the patient is fluid 1.5 mg/kg/hr; if patient is fluid

responsive, continue

refractory, give another 20 mL/kg bolus followed by a continuous infusion at a rate of

3 mg/kg/hr. Recheck at

16 hours. Watch for antibiotic-associated fungal infections.

In developed countries, chronic pancreatitis is commonly

(60-70%) a result of chronic alcohol ingestion-typi > 10 years. Next in frequency is idiopathic (30% ). About 10% are rare hereditary disorders (lack of cationic

cally

trypsinogen activator inhibitor, SPINK abnormality) and other causes such as cystic fibrosis, pancreas divisum, tumor, and hyperparathyroidism. Autoimmune pancre atitis is a newly described, rare disorder that accounts for

1-5% of cases (see page 1-45). Chronic pancreatitis has disease, when

initial, asymptomatic phase,

80-90% of the endocrine and exocrine

pancreatic function is lost, patients develop steatorrhea and diabetes mellitus. The fecal fat in late-stage patients is elevated-it may be

100 g/day. More than 40 g/day

is highly suggestive of chronic pancreatitis. Ultimately,

40-80% of patients with chronic pancreatitis develop diabetes, and 50-80% develop exocrine insufficiency. Chronic pancreatitis also increases the risk of pancre atic cancer 2-fold

(4% lifetime risk}-but not enough to

support screening.

Pearls of Acute Pancreatitis If the amylase is still elevated after

followed by recurrent bouts of abdominal pain. Late in the

10 days, think of

something else going on, such as a leaking pseudocyst.

Diagnosis of Chronic Pancreatitis

With large fluid collections, consider a disrupted pancre

The classic diagnostic triad for chronic pancreatitis is:

atic duct leaking fluid. This can be treated by ERCP with stenting of the duct. Recurrent acute pancreatitis with no evidence of gallstones or alcohol abuse may be due to microlithiasis; so, consider an elective cholecystectomy.

I) Pancreatic calcification 2) Diabetes

3) Steatorrhea

1-43

1-44

PANCREAS

But this triad is present in

20% ofcases and usually is

chymotrypsin, all of which can be measured. An endo

found only during late-stage disease.

scopic secretin test is also now available. Fecal elastase,

Diagnosis can be difficult, so begin evaluation with

in addition to a fecal fat, can also be used to evaluate for

simple, noninvasive tests that detect advanced forms

malabsorption.

of chronic pancreatitis. First, get a CT of the abdomen -if the pancreas is calcified, or ifthe pancreatic duct is dilated, or ifthe pancreas is atrophic, you have made the diagnosis ofchronic pancreatitis! Initial tests used in the diagnosis ofchronic pancreatitis: •Abdominal CT has

80-85% sensitivity and specificity

and is the initial procedure ofchoice. •Endoscopic ultrasound (EU/S) is very sensitive and may be the best test yet, but it requires a very skilled gastroenterologist. It is the procedure ofchoice in

Complications of Chronic Pancreatitis A major complication is persistent and severe abdominal pain. In this setting: •Rule out continued EtOH use. •Rule out pseudocyst. •Do MRCP, EUS, or MRCP with secretin to define duct anatomy. Pancreatic cancer develops in 4% ofpatients with chronic pancreatitis >

some centers. •Abdominal U/S.

20 years.

Complications of chronic pancreatitis include gastric varices (from splenic vein thrombosis), B12 malabsorp

•Plain radiograph of the abdomen showing pancreatic calcification (only

30% sensitive, but

tion, jaundice, pleural effusion, and brittle diabetes mellitus.

very specific). •Secretin stimulation test (see below).

The only skin involvement is tender red nodules from fat

Follow-up tests. If results from the tests above are

necrosis; this is uncommon, but can simulate erythema

negative, and you still have suspicions, do either mag

nodosum.

netic

The diabetes associated with chronic pancreatitis is

resonance

cholangiopancreatography

(MRCP;

preferred) or ERCP:

different from the usual DM. It occurs when

•MRCP is accurate in diagnosing chronic pancreatitis

80%

of the pancreas is destroyed. There is a decrease in

without the risk ofcausing pancreatitis (unlike ERCP,

production ofinsulin and glucagon.

below). Additionally, MRCP allows for visualization

Because the pancreas is producing so little glucagon, the

ofthe biliary tree and can also be useful in cases of

patient is very prone to hypoglycemia. Therefore, less

suspected bile duct stones or other biliary diseases like PSC. MRCP is the preferred

stringent control of hyperglycemia is recommended to

211d level test, and

decrease the chance oflife-threatening hypoglycemia.

some centers advocate secretin-stimulated MRCP.

These patients do not commonly develop retinopathy

•ERCP may induce pancreatitis (2-5%). The only advantage ERCP has over MRCP is the potential for endoscopic removal ofcalcific stones, which may be located within the duct and, hence, can be reached with the endoscope. Both MRCP and ERCP can show large duct disease and small duct disease. With large duct disease, the pancre

and nephropathy associated with the usual DM. They commonly

have

neuropathy,

but

•Alcohol and tobacco cessation •Pancreatic enzymes (a minimum •Decreasing dietary fat

can compress the common bile duct as it passes through

•Antioxidants

exocrine function; however, it is complicated, so it is generally performed only in major medical centers, and only when there is still a high "index of suspicion" after negative follow-up tests. (This does vary-in some places with ready access, it is done before ERCP.) IV infusion ofsecretin (+/- cholecystokinin [CCK]) causes a direct stimulation of the pancreas. Duodenal pancre atic secretions are then measured via a duodenal cath eter. The bicarbonate concentration should be

60,000-80,000 units

oflipase per meal and snacks) supplementation

chronic pancreatitis but also by pancreatic cancer. Either

The secretin test is the most sensitive test for pancreatic

likely

Treatment includes:

an irregular "chain oflakes."

the head ofthe pancreas.

Treatment of Chronic Pancreatitis

atic duct has stenoses and dilations, which visualize as Dilation of the common bile duct can be caused by

this

secondary to alcoholism and/or malnutrition.

Pancreatic enzymes must either have an enteric coating or be given with antacids/H2 blockers because gastric acid destroys enzymes. Alcohol consumption must be avoided. Discontinuation of smoking is very impor tant because smoking accelerates the development of pancreatic calcification and makes pain management more difficult. Analgesia is sometimes required. Most try a short-term opioid with amitriptyline. There is no therapy proven to show benefit ifthe pain persists.

mEq/L. CCK stimulates lipase, amylase, trypsin, and

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PANCREAS

Patients frequently present with some combination of jaundice , unexplained upper abdominal pain, and/or weight loss. •

•

What is the preferred initial test used in the workup of chronic pancreatitis? When is ERCP considered over MRCP as a 2nd level test in the workup of chronic pancreatitis? What are the classic symptoms of pancreatic carcinoma? How is pancreatic cancer treated if there are metastases? Without metastases?

Tumor location affects presenting signs and stage: • Head: Painless jaundice tends to be the presenting sign with early-stage cancers of the head of the pancreas. • Body and tail: These patients are more likely to present with pain and weight loss Uaundice in only 30%) and with the cancer at a much more advanced stage. -

When is ERCP indicated in pancreatic cancer?

Pain and weight loss are indications of advanced dis ease. The pain typically has a gnawing quality, is not relieved by eating, and occasionally radiates to the back.

Other therapeutic options include: pancreatic sphincter otomy, pancreatic duct stenting, pancreatic duct stone extraction, nerve blocks, surgical duct drainage, and Whipple procedure.

Diagnosis is made with helical CT, CT angiography, endoscopic ultrasound (EUS)-guided FNA biopsy, and Iaparoscopy.

•

AUTOIMMUNE PANCREATITIS (AIP) You should know this entity, even though it occurs in < 5% of cases of chronic pancreatitis. It is interesting in that its presentation often simulates cancer of the pancreas. What to know: • 50% present with obstructive jaundice (simulating cancer of the pancreas). •CT can show a mass in the head of the pancreas (again simulating cancer) or diffuse enlargement (sausage-shaped pancreas). •There may be bile duct and pancreatic duct strictures. • Serum lgG4 level is usually 2: 2x normal. Histology shows a dense lymphoplasmacytic infiltrate. Treat with prednisone at an initial dose of 40 mg/day with a taper of 5 mg/week. In patients who relapse on corticosteroids, immunomodulators (azathioprine, ritux imab) are often added. AIP is now recognized as an IgG4 systemic disease which, in addition to autoimmune pancreatitis, can include any or all of the following: 1) Mediastinal fibrosis and adenopathy

The most-used serum marker is cancer-associated antigen 19-9 (CA I 9-9). Treatment of pancreatic cancer: Resection is the only hope for cure. Most common reasons for tumor unresectability: •Distant metastases • Local invasion of major vessel (portal vessel or superior mesenteric vein or artery) If the patient is a surgical candidate, the mass is in the head of the pancreas, and the cancer appears resectable, do a pancreaticoduodenectomy (Whipple resection). Evaluate lymph nodes for evidence of metastasis. There is a modest survival benefit (survival increased 3+ months) with specific chemoradiotherapy (especially with 5FU or gemcitabine). If noninvasive workup shows that the cancer has already metastasized, avoid surgery-provide supportive care or give experimental chemotherapy (especially gem citabine) only. Place a stent using ERCP to palliate biliary obstruction. This is the only time you use ERCP for pancreatic cancer. Post-surgical prognosis: 5-year survival is 30% if node-negative and 10% if node-positive.

2) Retroperitoneal fibrosis 3) Chronic periaortitis 4) Tubulointerstitial nephritis 5) IgG4 associated cholangitis

PANCREATIC NEOPLASMS Pancreatic Cancer Pancreatic cancer is astonishingly aggressive. 80% of patients present with advanced disease. Heavy smokers have 2x the baseline risk. Other risk factors include OM, pancreatic cancer in 2 first-degree relatives, hereditary pancreatitis, and chronic pancreatitis.

2014 MedStudy

Glucagonoma A glucagonoma is a glucagon-secreting, alpha-cell tumor of the pancreas that causes a unique set of clinical findings: •Scaly necrolytic erythema •Weight loss •Anemia •Diarrhea • Persistent hyperglycemia • Plasma glucagon (by RIA) usually > l ,000 pg/dL

1-45

1-46

BILIARY SYSTEM

lnsulinoma

common duct stones. If the ultrasound is technically

Insulinoma is a very rare, insulin-secreting beta-cell tumor of the pancreas. This is covered in Endocrinology, Book 4, under Hypoglycemia.

inadequate, consider MRCP or oral cholecystogram. The usual procedures used for diagnosing common duct obstruction are MRCP, ERCP, and transhepatic cholangiography. The HIDA scan (cholescintigraphy) is the best test for

Gastrinoma

confirming acute cystic duct obstruction (i.e., acute

Gastrinomas are discussed under ZES on page

1-15.

cholecystitis) by imaging of the bile duct but not the

Most (50%) are found in the duodenum, 24% in the pan

gallbladder. HIDA scan is rarely used because ultra

creas. This diagnosis is likely when the serum gastrin is

sound has characteristic findings for acute cholecystitis.

500 in a patient who is able to secrete gastric acid (not

on PPI, no prior peptic ulcer surgery).

Note: About half of pigment stones are radiopaque, whereas cholesterol stones are radiolucent.

VI Poma

Treatment of Cholelithiasis

VIPomas are tumors that secrete vasoactive intestinal peptide (VIP). 2/3 occur in the pancreas, and

112 of

these are malignant. They cause a profuse secretory diarrhea ("pancreatic cholera"). Diagnosis: increased

If the patient has gallstones and is symptomatic, do an elective cholecystectomy because 70% of these patients will have recurrent symptoms if not treated. Do not treat asymptomatic cholelithiasis because only

serum VIP level and hypokalemia.

20% of patients go on to develop symptoms within

I 0-20 years. Don't mistake symptoms of reflux for that BILIARY SYSTEM

of cholelithiasis, even if you incidentally find stones in the gallbladder.

CHOLELITHIASIS

Supplemental oral bile acid (ursodeoxycholic acid) may be used in the treatment of gallstones for those who are

Overview Cholelithiasis is widespread-20% of women and 8% of men-and typically asymptomatic. It is not associated with hypercholesterolemia. The pathophysiology of cholelithiasis involves I or more of the following 3 factors:

too ill to have surgery or refuse surgery. Lithotripsy can be effective, but few centers have the expertise necessary to perform this procedure. Acalculous cholecystitis occurs only in seriously ill patients; e.g., major trauma, bums, after major surgeries. Diagnosis may be assisted by ultrasound or CT showing

Abnormal bile secreted by the liver (lithogenic

no stones, but a large, tense, often thickened gallbladder with pericholecystic fluid (or no stones and a HIDA scan

-supersaturated with cholesterol) 2) Accelerated nucleation of microcrystals to macrocrystals 3) Defective gallbladder emptying

showing cystic duct obstruction). Treatment is cholecys tectomy, but cholecystostomy (percutaneous drainage) can be done if the patient is too sick for surgery.

Cholelithiasis has been associated with obesity, oral contraceptive use, clofibrate treatment, and ilea! dis ease or resection. 75% of gallstones are composed of radiolucent cholesterol (pure or mixed); the rest are bile

Common Duct Stones Alkaline phosphatase and bilirubin are generally not

pigment gallstones.

elevated in typical gallbladder cases because the gall

Profile for cholesterol stones: rapid weight loss in

levels of alkaline phosphatase and bilirubin (bilirubin

obese patient (these stones prevented by aspirin or ursodeoxycholic acid), Native American, octreotide use. Profile for pigment stones: ilea! resection (as in Crohn

stones block only the exit to the gallbladder. Increasing >

4 mg/dL) suggest the presence of a common duct

stone. Consider common duct stones in the gallbladder patient with increased alkaline phosphatase and bili or

disease), sickle cell disease, or anything else that causes

the post-cholecystectomy patient with persistent pain.

hemolysis; e.g., Clonorchis sinensis (biliary dwelling

Common duct blockage also can cause cholangitis (next

trematode).

page).

Symptoms: RUQ pain lasting 20-60 minutes-espe

Common duct stones are removed by ERCP with pm

cially after a fatty meal. But fatty food intolerance is a

endoscopic sphincterotomy.

very nonspecific finding.

CHOLESTASIS Diagnosis of Cholelithiasis

Cholestasis can be obstructive (as with common duct

To detect the presence of stones, do an ultrasound (90%

stones) or hepatocellular. In both cases, there is reten

sensitive). A normal ultrasound in the presence of normal

tion of the substances normally released into bile. In

bilirubin and liver enzymes is sensitive for excluding

both cases, there is a cholestatic pattern jaundice with

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BILIARY SYSTEM

•

What are the 3 causative factors of cholelithiasis? What should you investigate in the patient who persists in having RUQ pain after cholecystectomy or with symptoms of cholangitis? What is the "hallmark" test for primary biliary cirrhosis? How do you confirm the diagnosis?

increased alkaline phosphatase and conjugated bilirubin with bilirubinuria. More on bilirubin on page 1-61. CHOLANGITIS

Cholangitis is a complication of common bile duct blockage-usually from bile duct stone or cancer. Acute cholangitis is suggested by the triad of biliary colic, fever, and jaundice (Charcot's triad). Suppurative cholangitis additionally has mental confusion, bacteremia, and septic shock. Treatment is with parenteral antibiotics, IV hydration, and biliary drainage; antibiotics alone are not sufficient. When you suspect suppurative cholangitis, the best pro cedure for both diagnosis and treatment is ERCP with endoscopic sphincterotomy. If ERCP is unavailable, surgery or percutaneous transhepatic cholangiography with drain placement should be considered. Emphysematous cholecystitis requires emergent lapa rotomy with cholecystectomy and antibiotics. In both suppurative cholangitis and emphysematous chole cystitis, the antibiotics must be effective against both gram-negative and anaerobic organisms. Do not use ceftriaxone-it can cause biliary sludge and has no (zero!) anaerobic coverage.

The cause of PBC is unknown, but 70% have associ ated autoimmune diseases (e.g., Sjogren's, scleroderma, autoimmune thyroiditis, limited scleroderma). The dis ease does tend to run in families. 90% have a positive antimitochondrial antibody test (> 1 :40), but degree of elevation does not correlate with severity of disease. PBC patients who present with symptoms have advanced disease. Most patients present asymptomatically or with fatigue and are worked up because of a high alkaline phosphatase noted on a liver enzyme screening. If they have symptoms, patients initially complain of itching first in the palms and soles and later throughout the body. Later, patients develop jaundice, hyperpigmenta tion, inflammatory arthropathy, keratoconjunctivitis and/or xerostomia, and accelerated osteoporosis. Patients can develop xanthomas and xanthelasma from associated hypercholesterolemia, but this does not convey increased risk of CAD (not an atherosclerogenic lipid pattern). (See Image 1-21 and Image 1-22.) PBC is indolent, but relentlessly progressive. Symptomatic patients previously had a median sur vival of 7 years, and asymptomatic l 0-16 years. These numbers are increasing significantly as patients are diag nosed earlier and all patients are treated with ursodiol (ursodeoxycholate; see Treatment on next page). When the bilirubin increases to > 2, the disease acceler ates. Most die within 2 years after the bilirubin reaches I 0 unless the patient undergoes liver transplantation. Incidental discovery of a 2-5x increase in serum alkaline phosphatase has been the primary reason for the increase in PBC diagnoses. High levels of alkaline phosphatase occur in up to 95% of patients with PBC. Note: The antimitochondrial antibody test is the hall mark test for PBC. Even so, it is not a good indicator

PORCELAIN GALLBLADDER

X-ray showing a gallbladder with a calcified outline ("porcelain gallbladder") suggests the possibility of cancer, and an open cholecystectomy is indicated. PRIMARY BILIARY CIRRHOSIS

Image 1-21: Jaundice in the patient with bilimy cirrhosis

Overview

Primary biliary cirrhosis (PBC): slow onset. 95% are women-typically middle-aged. PBC is characterized by a nonsuppurative, progressive, destructive cholan giolitis. The florid duct lesion on liver biopsy is pathog nomonic. However, it is seen only in small numbers in early stages. The bile ducts become chronically inflamed and eventually cause obstructive jaundice and liver cirrhosis. Image 1-22: Xanthelasmata

1-47

1-48

BILIARY SYSTEM

of the severity of PBC. The antimitochondrial antibody test is occasionally positive in both autoimmune hepati tis and drug-induced chronic hepatitis; a high titer in a

PRIMARY SCLEROSING CHOLANGITIS Overview

patient with autoimmune hepatitis suggests an overlap

Primary sclerosing cholangitis (PSC): also indolent. It

syndrome (Table 1-8).

primarily occurs in males (70%) with average age of 45. PSC is strongly associated with colitis-so it is mainly

Diagnosis of Biliary Cirrhosis

seen in ulcerative colitis (up to 75% of PSC patients

Diagnosis is confirmed only with a liver biopsy, which may show granulomas (florid duct lesions); often find ings are nonspecific. PBC patients also have a high

have UC!), but it can occur in patients with Crohn coli tis as well. Incidence of PSC has no relationship to the severity of colitis.

hepatic copper level (as do patients with pnmary

PSC occurs in 5% of UC patients and perhaps 2% of

sclerosing cholangitis and Wilson disease).

Crohn patients. UC may precede the diagnosis of PSC, but not necessarily. So, all PSC patients should have a colonoscopy.

Treatment of Biliary Cirrhosis Ursodiol

(ursodeoxycholate-a

synthetic

bile

acid)

13-15 mg/kg/day is the best proven treatment available for PBC. It improves LFTs and decreases symptoms, and it significantly slows progression of the disease. Patients

Conversely,

PSC

UC; therefore,

may

precede

the

diagnosis

any UC patients with a persistent,

:::: 2x increase in alkaline phosphatase should be screened for PSC.

who have a biochemical response to ursodiol (defined as

Cause is unknown. Patients develop inflammation and

a decrease in alkaline phosphatase, AST, and/or bilirubin

sclerosis of the entire biliary tract (intra- and extrahe

to much lower level at 1 year) have dramatic slowing of

patic), leading to obstructive jaundice and eventually

the progression.

cirrhosis.

Additionally, symptomatic treatment includes:

Patients

are

initially

asymptomatic

but

eventually,

with advanced disease, develop weakness and fatigue,

•

Pruritus: cholestyramine

•

Osteomalacia: vitamin D and calcium

•

Malabsorption: decreased dietary fat

abdominal pain, itching, and jaundice. Bilirubin and alkaline phosphatase levels are elevated (cholestatic pattern). There is an elevated hepatic copper

Treatment has no effect on late disease. For late disease,

level (as in primary biliary cirrhosis and Wilson disease),

liver transplantation is recommended. It has been shown

but the antimitochondrial antibody is negative. The total

to significantly improve survival in late PBC. PBC is

protein level gives an idea of how much the disease has

one of the most common indications for liver transplan

affected liver function.

tation; hepatitis C is the most common indication. The "AAAABCs of PBC" are: Anti mitochondrial Antibody Attack increases Alk phos and causes obstructive Biliary lesions and liver Cirrhosis.

8-15% of PSC patients develop cholangiocarcinoma. One-third have cholangiocarcinoma when first diagnosed with PSC! Suspect cholangiocarcinoma if symptoms of PSC abruptly worsen. CA 19-9 is elevated in 80% of patients with cholangiocarcinoma .

Table 1-8:

Serologic Markers in PBC and CAH Drug-

Auto-

Biliary

induced

immune

Diagnosis of PSC is made with MRCP, ERCP, or

Cirrhosis

CAH*

transhepatic cholangiography. These reveal irregularly

Antimitocbondrial Ab

occ

Positive

narrowed bile ducts with small bile duct ballooning just prior to obstructions, producing the typical "beaded" appearance. With ERCP, if a dominant stricture exists, it

(low titers}think

Anti-Smooth

Diagnosis of Sclerosing Cholangitis

Primary

Negative

muscle Ab Antinuclear Ab

Negative

can be dilated. Liver biopsy shows "onion skin" fibrosis in portal triads.

overlap

In small duct PSC, the extrahepatic and intrahepatic

syndrome

biliary system may be nondiagnostic, but liver biopsy

Positive

abnormalities establish the diagnosis. Secondary causes of sclerosing cholangitis must be ruled out. T hese include: bacterial cholangitis (stones or bile duct stricture), atypical anatomy (congenital or previ ous surgery), bile duct neoplasms, and AIDS-associated

chronic active hepatitis

cholangiopathy.

LIVER

To help remember the differences, drop the abbrevia tions and think:

Q�uiz •

•Biliary cirrhosis: 55-year-old woman named Hillary C. Roses with fatigue and pruritus. Antimitochondrial Ab+.

PBC: What is the best, proven treatment for

• Sclerosing cholangitis: 45-year-old man with UC.

early disease? For late disease? •

Also review Table 1-9.

List the similarities and differences between PBC and PSC. These are commonly confused diseases. [Know!] What are the alk phos,

LIVER

bilirubin, hepatic copper, and antimitochondrial antibody tests in PBC and PSC? •

HEPATITIS NOTES

A patient presents with cholestatic jaundice

Regarding ALT (SGPT) and AST (SGOT), know:

and a history of 180 (or a history of chronic diarrhea). Which of the following do you include in your differential-PBC or PSC? Why?

• To remember that ALT is more liver-specific than AST, think of"L-L" (ALT-Liver): •With alcoholic hepatitis, the AST:ALT is about 3:1

Treatment of Sclerosing Cholangitis

because the alcohol damages mitochondria, which

The only sure treatment for PSC is liver transplantation. Colectomy cures ulcerative colitis, but does not alter the course of PSC. [Know:]

High-dose

ursodeoxycholic

acid

(UDCA,

20-25 mg/kg) was recommended in the past, but a 2010 guideline from the American Association for the Study of L iver Diseases now recommends against UDCA because of lack of efficacy and increased risk of adverse effects! If patients are already on UDCA because of past recommendations, some authorities now recommend discontinuing it. Remember: When a patient presents with jaundice and increased alkaline phosphatase and has a history of chronic diarrhea or IBD, especially UC, rule out PSC with MRCP or ERCP! Again,

PSC:

sclerosing

then release the AST. Mitochondrial damage is less liver-specific. •With viral hepatitis, the ALT is generally greater than the AST because its toxicity is more liver-specific. Table 1-10 is a review of serologic testing for viral hepatitis. •Nonalcoholic fatty liver disease (NAFLD) is also more liver-specific and has an ALT:AST ratio> 2:1. • Acute viral hepatitis has histologic characteristics of diffuse liver cell injury and swelling, increased macrophages, accelerated apoptosis (the normal programmed cell death is accelerated by viral hepatitis), and inflammatory periportal infiltrates (mostly lymphocytic). Chronic viral hepatitis has histologic characteristics of interface hepatitis (formerly known as piecemeal

cholangitis,

col itis,

high

necrosis) and fibrosis.

cholestatic bili, and alkaline phosphatase levels; nega tive antimitochondrial antibody, cirrhosis, and liver failure. Abnormal magnetic or endoscopic retrograde cholangiopancreatography (MRCP, ERCP).

EVALUATION OF A BNORMAL LIVER BIOCHEMICAL TESTS Increased Transaminases

PBC vs. PSC

An abnormal laboratory value should be confirmed

These two conditions are often confused because they have similar abbreviations and both affect the bile tracts and have high alkaline phosphatase and elevated hepatic copper level. Both eventually cause obstructive jaundice and cirrhosis. (Hmm. Why the confusion?)

IBD

Cancer

set of liver biochemical tests, including alkaline phos phatase, total and direct bilirubin, albumin, PT, and CBC. If the transaminases are still elevated, order more specific tests for hepatitis A, B, and C-and tests for hemochromatosis with iron studies and ferritin level.

Table 1-9: PBC vs. PSC Sex

before ordering follow-up tests. To confirm, order a full

Increased Alkaline Phosphatase UDCA effective?

Remember that alkaline phosphatase comes from liver and bones. Gamma glutamyl transpeptidase (GGT) typi cally rises in parallel with alkaline phosphatase from the liver and should be checked in cases of increased alkaline

�t"':!"

No PSC

Male

Yes

(UC) 8-15% risk of cholangiocarcinoma

phosphatase with normal bilirubin and transaminases.

'Rare

Generally, the next test is abdominal ultrasound to look for dilated biliary ducts or metastatic liver lesions. In appropri ate patients, also order antimitochondrial antibody test (to screen for PBC).

1-49

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LIVER

Table 1-10: Hepatitis - Serological Tests AntiHAV lgG

AntiHAV lgM

HBsAg

Acute hepatitis A

AntiHBs lgG

AntiHBc lgG

AntiHBc lgM

HBeAg

AntiHOV

iill +

Previous HAV

+early

Acute HBV

Acute HBV-window Chronic active HBV +

Remote HBV (immune)

+early

Acute hepatitis D

(w/ acute HB) +

Acute hepatitis D

(w/CAH)

HEPATITIS A

The incidence of hepatitis A has fallen dramatically due to immunization.

Hepatitis A is an RNA virus. It is easily transmitted by

Hepatitis A vaccine (Havrix® and Vaqta®) is for use in

the fecal-oral route-commonly via food or water. It can also be sexually transmitted. There is no transplacental

patients> I year of age and is given as 2 doses, 6+months

transmission! There are no carrier or persistent states,

apart. Virtually all of those completing the series develop

although, occasionally, these patients get prolonged cho

protective antibodies (anti-HAY IgG). Trends, based on

lestasis (with increased bili and alkaline phosphatase)

what is now known about antibody levels, suggest protec

for up to 4 months. Incubation period is 15-50 days. See

tion for up to 20 years in those who complete the series.

Figure 1-5.

If completion of the 2-dose series is delayed, there is no need to start the series over again.

Symptoms are unusual in children and very common in adults (70%). Complications are rare; there is

�

Indications for use of HAY vaccine:

chance of fulminant hepatitis. Immune globulin (IG)

•High-risk sexual behavior (see hepatitis C section).

is good prophylaxis only against HAY (use HBIG for

•IV drug use.

hepatitis B).

•Universally recommended for all> 1 year of age. •Chronic liver disease.

Diagnosis of acute infection: high titers of anti-HAY IgM in serum. (lgG indicates only a previous infection.)

Table 1-11: I nterpretation of Hepatitis B Tests HBsAg

Anti-HBc

Anti-HBs

+ +

Interpretation Acute infection

3 possibilities: 1) Acute infection (IgM anti-HBc) 2) Chronic Hep B (high ALT, IgG anti-HBc) 3) Inactive carrier (normal enzymes, IgG anti-HBc)

Remote infection

More than I infection; e.g., IV drug user or renal dialysis patient with

both acute and chronic hepatitis B (infected with different strains of hepatitis B)

MedStudy-Please Report Copyright Infringements to copyright@medstudy.com

LIVER

excess viral coat protein. Having HBsAg means you are producing hepatitis B virus. HBsAb: Finding HBsAb in the serum indicates past •

exposure to either hepatitis B virion or to the vaccine.

With what coinfections can hepatitis A become

Usually it indicates immunity.

fulminant?

HBcAg is the inner shell protein of the above 42 nm virion.

• How do you confirm that a hepatitis B vaccine

This protein is retained in the hepatocyte until it is covered

was immunogenic?

with HBsAg+ nucleocapsid outer shell, which then incorpo

• Regarding HBsAg, HBcAg, and HBeAg: Which

rates the DNA. Free HBcAg does not circulate in the serum.

is the best marker for infectivity? Which is the

Antibody to HBcAg appears early in the disease (initially

best marker for past infection?

IgM, then IgG) and persists for life, so HBcAb IgG is the . best marker for previous exposure to HBV However, it does

•

What is the "window" period for hepatitis B

not distinguish between active or "cured" infection.

infection? •

HBeAg is a soluble protein made from the same gene

Polyarteritis nodosa is associated with which

as HBcAg, but, unlike HBcAg, HBeAg is secreted from

hepatitis virus?

the hepatocytes and circulated in the serum. HBeAg correlates with the quantity of intact virus and, there

•Travel to high-risk countries. •HAY vaccine is also given to all patients with chronic hepatitis B and hepatitis C; if these patients get

fore, with infectivity and liver inflammation. The HBe antibody (HBeAb) appears several weeks after the ill ness. Detecting HBsAg and HBeAg indicates active

hepatitis A, it can be fulminant.

virions and high infectivity (more so than HBsAg+ and

•Also now (since 2007) recommended for post-exposure

HBeAg-). The tests for HBeAg and HBeAb are often

prophylaxis instead of immunoglobulins.

not available locally.

Note: Onset of jaundice is 3 weeks with hepatitis A and 3 months with hepatitis B-an important diagnostic clue!

Confused? Reread the highlighted text and remember: • HBsAg+ means a patient is making hepatitis B virus. Levels may be low or very high. It can be acute or chronic.

HEPATITIS B

• HBsAb+ almost always means the patient is "cured" of previous hepatitis B infection or, if this is the only

Overview The

HBsAg,

main serological markers in hepatitis B are HBsAb,

HBcAb,

HBeAg,

and

HBeAb

(Table 1-10 and Table 1-11 ). HBsAg: There are

marker (specifically no IgG HBcAb), then the patient was vaccinated. • HBeAg+ means the patient is highly infectious and actively making hepatitis B virus.

3 HBsAg+ proteins seen in the

serum in patients with hepatitis B: one large, double

42 nm particle that is the intact virion and two smaller 22 nm spherical or rod-shaped protein particles that outnumber the large particle by up to 1,000 to 1 ! These 22 nm HBsAg+ particles are thought to be just shelled

Hepatitis B is the only hepatitis virus composed of DNA. Incubation period is

1--6

months. It is transmit

ted by contaminated blood products. Once infected, the I st marker detectable in the serum is the antigen HBsAg.

This is followed by the appearance of antibody to the core antigen (HBcAb lgM). After HBsAg becomes undetectable, there is a period of weeks to months before the HBsAb antibody becomes detectable. This is called

HEPATITIS A SEROLOGY

the "window," and you must perform an HBcAb IgM test JAUNDICE

during this period to confirm acute hepatitis B (Figure 1-6

C=:::J

and Table

lncr'd ALT ,_______...,

A�tiiHAV lgM . �/ ..... ' : 1:

(

Anti-HAV lgG

�

I :

precipitates an autoimmune reaction resulting in PAN.

Clinical: '

' 12

Figure 1-5: Hepat1t1s A Serology vs Time after Exposure

MedStudy

First,

there

are

prodromal

constitutional

symptoms, which typically resolve at the time jaundice

WEEKS AFTER EXPOSURE

20-30%

of these patients. It appears that the hepatitis B infection

/ /

:,...

nodosa (PAN). The surface antigen is found in

\( /

Hepatitis B is strongly associated with polyarteritis

- - .

1-1 O).

becomes apparent. Occasionally ( 10-15%), the pro dromal symptoms are serum sickness-like with fever, arthritis, urticaria, and angioedema. This seems to be caused by circulating immune complexes (especially "HBsAg-HBsAb" immune complex) which activate

1-51

1-52

LIVER

the complement system. With the onset of jaundice, the

•

If an asymptomatic patient has HBsAg in the serum,

patient generally feels much better but may have liver

it means either the patient is a carrier or the patient

swelling and tenderness and cholestatic symptoms.

has early hepatitis B-so initial action is only to follow closely. (Once the patient is infected, neither

Removal of HBV is T-cell-mediated, and the only

vaccine nor HBIG helps.)

purpose of HBsAb is to prevent reinfection. Hepatitis B immune globulin (HBIG; HBsAb) provides

•

Sexual contacts and infants cared for by a patient with acute HBV infection should be given HBIG followed

some protection against hepatitis B, although it appears

by a complete course of HBV vaccinations. Pregnant

to only decrease the severity of illness rather than protect

women are treated the same.

the patient from disease. HBIG is effective both as short-term prophylaxis and when given in early infection.

ensure that it has not become a chronic infection.

Hepatitis B Vaccines The

Chronic Hepatitis B

hepatitis B vaccines are composed of HBsAg.

They are equally effective and are safe for pregnant patients. It is best if the hepatitis B vaccine is given _ before the patient is exposed to HBV. 95% of 1mmu nocompetent patients develop antibodies, whereas only about

50%

Note: Several months after an episode of hepatitis B infection, check for loss of HBsAg and HBV-DNA to

of dialysis patients do (even though dialy

sis patients also are given a much higher dose of the vaccine).

The likelihood of developing chronic HBV is inversely related to age. Chronic HBV occurs in infected at birth,

90%

in children age

of infants

1-5

years,

and 5% in older children and adults. Note that comor bid conditions (hemochromatosis, AIDS/HIV, alcohol) worsen course and response to treatment. Less than

1% of

patients with hepatitis B develop fulminant hepatitis, but

5-7% develop chronic carrier states.

To ensure effectiveness after the course of vaccine has been given, check for HBsAb, which is produced in response to the vaccine. There is no HBcAb.

There are

persons engaging in high-risk sexual behavior, those with chronic liver disease, persons with HIV infection, healthcare personnel, and dialysis patients. There is universal preschool vaccination in the U.S.

2 types of

hepatitis B carrier states:

Inactive carrier state (asymptomatic with normal

Chronic active hepatitis B (abnormal enzymes)

liver enzymes)

Indications for hepatitis B vaccine in adults include

A liver biopsy is usually required to confirm the diagnosis of chronic hepatitis B. Patients with inactive carrier states can develop severe exacerbations of hepatitis B if they become immuno

Hepatitis B Treatment Scenarios

compromised. For example, a woman with breast cancer who also has an inactive carrier state with hepatitis B

Scenarios: •

25-50%

is to be started on chemotherapy. What other drug is

Give a newborn of a mother with hepatitis B both

given? Lamivudine (or lamivudine

hepatitis B immune globulin (HBIG) and hepati tis B vaccination. There is a

5-10% transplacental

adefovir) is given

with her chemotherapy to blunt viral replication. Chronic hepatitis B is a serious illness. It often progresses

transmission of HBV.

to cirrhosis and is strongly associated with hepatocellular carcinoma (HCC;

conversion per year). Lifetime risk

for HCC is 20%.

HEPATITIS B SEROLOGY

Screen for HCC every 6 months with abdominal ultra sound irrespective of cirrhosis. Helical C T or MRI can

JAUNOIC.;:_E..tl===---.,

also be used (more sensitive but much more expensive). Note: Previously, an alpha-fetoprotein test was also used for screening, but the

2010

AASLD HCC guide

line notes that alpha-fetoprotein does not have adequate '>

flt if'

'rt /

sensitivity or specificity to support its use for every-6months HCC surveillance. This new guideline supports an ultrasound-alone strategy.

MONTHS AFTER EXPOSURE

Treatment of Chronic Active Hepatitis B Who Should Be Treated Use HBV DNA, ALT, HBeAg, and degree of cirrhosis to determine when to treat.

LIVER

Increased risk for hepatitis C: •IV drug abuse; common in prisons

a.�uiz •

•High-risk sexual behavior: with STD, sex with

Are hepatitis B vaccines safe for pregnant patients?

> 5 sexual partners per year

•Blood transfusion/transplant recipients before 1992 • Tattoos, body piercing

Treatment is recommended for those with HBV DNA > 20,000 and ALT> 2 x ULN: •Treatment is started immediately for HBeAg-. •Treatment is delayed

3-6 months for newly diagnosed

HBeAg+ patients to see if seroconversion takes place. The presence of cirrhosis requires less HBV DNA to initiate treatment. Treat:

• Shared razors and toothbrushes • Snorting cocaine •Needle stick injuries • Renal dialysis personnel •Children born to HCV infected mothers The hepatitis C "rule of 2s": •2% of U.S. population

•Compensated cirrhosis when HBV DNA> 2,000 •Decompensated cirrhosis when HBV DNA> 200 See Table

prostitutes,

1-12 for treatment options for chronic active

hepatitis B. Lamuvidine used to be a main treatment option, but it is less desirable now because the drugs shown in the table develop resistance at a lower rate. Liver transplantation is the only treatment for end-stage liver disease. The HBV recurs in the transplanted liver, but an antiviral treatment program can help.

•2% risk of needlestick transmission (though some say 5%+) •2% risk of neonatal transmission •2% risk of spousal transmission •2% cirrhotics with hepatitis C develop hepatoma each year

HIV and Hepatitis C In the U.S., 25% of patients with HIV are coinfected with HCV. These patients progress faster to cirrhosis than those with HCV alone. Best treatment of HCV for

HEPATITIS C

HIV-infected patients is combination therapy: pegylated

Overview

interferon and ribavirin (with the addition of HCV

Hepatitis C: single-strand RNA virus. It is one of the

specialist for treatment.

most common liver diseases in the U.S. [Know this section well!] It is second only to NAFLD (nonalco holic fatty liver disease, see page

1-57). Hepatitis C has

blood-borne transmission and was the cause of 90% of transfusion-associated hepatitis prior to the early 1990s. Since then, especially with the

2"d generation HCV Ab

assays, the incidence of transfusion-related hepatitis has become very rare. Hepatitis C genotypes are

I a, 1 b, 2, 3, 4, 5, and 6.

Genotypes influence response to treatment. Most HCV infections in the U.S.

(> 70%) are genotype 1, which

happens to be less responsive to treatment than the other

specific protease inhibitors in genotype

I). Refer to a

Extrahepatic Disease with Hepatitis C Extrahepatic disease includes: • Small vessel vasculitis with glomerulonephritis and neuropathy •Mixed cryoglobulinemia (discussed under Chronic Hepatitis C, next page) • Porphyria cutanea tarda (PCT) PCT is associated only with hepatitis

C (and not B).

So, skin blisters? Think C!

genotypes. Table 1-12: Treatment of Chronic Active Hepat1t1s B

Treatment Tenofovir

Entecavir

Benefits

Disadvantages

Resistance is rare. Drug of choice for'li;�

Limited experience on using

lamivudine-resistant HBV

in adefovir�,resistant disease

Low drug resistance; Potent antiviral

Not for lamivudine

Used for

Primary treatment

resistant HBV Telbivudine

Slightly more potent than

Same resistance profile as

adefovir and entecavir

lamivudine

Adefovir

Active against lamivudine-resistant HBV

Low viral suppression

Lamivudine-resistant HBV

Interferon

Limited duration of therapy;

Side effects may be severe;

·�pmary treatment for yollllg

35% complete remission;

Contraindica�ed in

patiep.ts and women

No resistance; Potent

decompensaied liver disease

contemplating pregnancy

Not used much

1-53

1-54

LIVER

Serology and Hepatitis C

Vaccinate all patients with chronic hepatitis C against

Within 2--4 months after an exposure or episode of hepa titis C, recheck for loss of HCV RNA(PCR) to ensure that the disease has not become chronic. Note: This HCV RNA test is not quantitative-but it is sensitive

hepatitis A and B. Giving the combination HAV+HBV vaccine is the simplest method, and either the routine or accelerated immunization schedule is reasonable. Mixed cryoglobulinemia is strongly associated with chronic

and can determine if there are more than 200 IU/mL of

HCV infection (55% of those with chronic HCV). It pres

HCV RNA present.

ents as a small vessel (leukocytoclastic) vasculitis with a

In a person positive for HCV Ab, check for active virus with HCV RNA. This is necessary because the HCV Ab does not confer immunity (as does the HBV antibody to HB).

papules." Mixed cryoglobulinemia is far less common in patients with chronic hepatitis B(15%), other chronic liver diseases(30%), HIV, and connective tissue diseases.

Treatment of Chronic Hepatitis C

Chronic Hepatitis C Whereas

rash consisting of "palpable purpura" or "crops of purple

5% of adults with hepatitis B develop chronic

disease, 70-80% of acute HCV infections become chronic! Hepatitis B has high virus counts, whereas hep atitis C has lower virus counts, as evidenced by hepatitis

If the patient has chronic hepatitis C and elevated liver enzymes, the current standard treatment is the combina tion of the following: •

C viral RNA(units/mL).

Pegylated INF-a(weekly injections-see hepatitis B), which also decreases risk of HCC

These low virus counts are consistent with the more

•

Oral ribavirin

insidious nature of hepatitis C:

•

Protease inhibitors telaprevir/boceprevir(genotype 1)

•

Only 25% of acute infections are symptomatic.

Prior to the use of protease inhibitors, 40-50% of patients

HCV infection has an increased likelihood to

with hepatitis C cleared the virus after 6-12 months of

become chronic.

dual therapy. With the addition of a protease inhibitor to

The chronic form is relatively benign. (25% are

interferon and ribavirin, 65-75% of patients with hepati tis C cleared the virus after 6-12 months of therapy. The

only carriers; 50% have no symptoms but have

newer direct antivirals have been shown to result in viral

abnormal LFTs; 25% have chronic active disease

clearance in over 90% of hepatitis C patients.

with symptoms.) •

•

Low rates of sexual transmission are seen in

Measure response to treatment by following HCV RNA;

monogamous couples-2% after 10-20 years!

if no response is noted at 12 weeks-seen as a decrease

This is low, but it does occur-so safe sex is

in HCV RNA by 2 log units-discontinue therapy. For

required! Sexual transmission increases with

those who respond, if the HCV is genotype 1, treat for

multiple sexual partners.

1 year; if it is genotype 2 or 3, treat for 6 months.

Needlestick transmission from a known infected

Notes on treatment:

patient is 2-6%. •

Transplacental infection can occur(� 2%), although

Medications have no role in end-stage cirrhosis. Ribavirin therapy can cause hemolytic anemia, but if

this is less of a risk than for hepatitis B (5-10%). 70-80% of patients infected with HCV develop chronic hepatitis, and about 25% of these get end-stage cirrhosis after 20-25 years! And 1--4% of patients with cirrhosis

mild, this is not an indication to stop treatment; rather, give epoetin(erythropoietin, recombinant). However,

ribavirin

relatively

contraindicated

develop hepatocellular cancer (HCC) each year (similar

cardiac patients with borderline hematocrit levels.

to chronic active HBV).

Caution when using INF-a in patients with a history of

Screen for HCC every 6 months with abdominal ultra

depression, as depression can worsen while on treatment.

sound (as with hepatitis B and alcoholic cirrhosis).

A number of newer agents for hepatitis C are under

Helical CT or MRI can also be used (more sensitive but much more expensive).

development, so the area of hepatitis C therapy is evolving rapidly.

Note again: Previously, alpha-fetoprotein test was also included, but the 2010 AASLD HCC guideline notes that alpha-fetoprotein does not have adequate sensitivity or specificity to support its use for every-6-months HCC surveillance. This new guideline supports an ultrasound alone strategy. Chronic HCV infection has become the #1 reason for liver transplantation in the U.S.

HEPATITIS D Hepatitis D is an RNA virus that requires a coexistent hepatitis B virus infection for the hepatitis D to become pathogenic. It is typically found in IV drug abus ers and high-risk HBsAg carriers (HBV DNA levels >

10 million).

LIVER

Autoimmune Chronic Hepatitis Type I autoimmune hepatitis generally has an insidious onset and is most often found in young women. Type 2 is a childhood disease and is not discussed here. All the

1-10 through Table 1-13.

•

Know Table

•

What test confirms that a previous hepatitis C

following concern Type I only.

50% of adult patients with autoimmune chronic hepati

infection did not become chronic? •

tis also have other disorders of altered immunity; e.g., thyroiditis, Coombs+ anemia, and ITP.

With which chronic hepatitis infection is mixed cryoglobulinemia strongly associated? How

Autoantibodies are common; affected patients may have

does it present? •

a positive ANA(+/- anti-dsDNA), anti-smooth muscle

What is the treatment of hepatitis C genotype

Genotype 2-3? •

antibodies (anti-SMA), anti-actin antibodies (AAA), p-ANCA, and anti-soluble liver antigen(anti-SLA).

Which virus does hepatitis D require to

ANA

replicate?

serological marker.

•

Hepatitis E is associated with which risk factor?

•

What test has an

80% rate of specificity for

autoimmune hepatitis?

is the

most

sensitive

but

the

least

specific

Anti-smooth muscle antibody (anti-SMA) is more

specific than ANA, and it is positive in� 80% of patients with Type I autoimmune hepatitis. It is occasionally seen as an overlap syndrome with P8C or PSC. Refer

Hepatitis D usually does not worsen an acute HBV infection but, if acquired as a superinfection in an HBV carrier, the infection is frequently very severe. If acquired acutely, HDV does not increase risk of chronic hepatitis B. Immunity to hepatitis B implies immunity to hepatitis D. Suspect hepatitis D if sudden decompensation in patient with chronic hepatitis 8. Diagnosis: anti-HDV IgM.

to Table 1-8. Anti-actin antibody (AAA) test is now commonly

available and has, in some labs, replaced the anti-SMA test because it is even more specific and sensitive. Anti-SLA is the most specific but not sensitive.

You can also check for antimitochondrial antibody it is only occasionally slightly positive, but high titer occurs in primary biliary cirrhosis (P8C) and indicates an overlap syndrome. Remember, as a rule of thumb,

HEPATITIS E Hepatitis E: single-strand RNA virus. Fecal/oral spread (like HAY). Found in the Far East, Africa, and Central America, commonly due to contamination of water supplies after monsoon flooding. Like hepatitis A, no chronic form is known. Unlike hepatitis A, hepatitis E carries a very high risk for fulminant hepatitis in the yct trimester of pregnancy

P8C

occurs

middle-aged

women,

autoimmune

hepatitis occurs in young women, and PSC occurs in middle-aged men. Diagnosis: Early diagnosis is essential because this form of chronic hepatitis responds well to treatment. Other forms of hepatitis must be excluded, and the antibody tests covered above are done.

with a 20% fatality rate. T hink of hepatitis E in a traveler Table 1-13: DDx Chronic Hepatitis

with acute hepatitis and negative standard serology(hep A, 8).

Autoimmune may have -ANA+/- anti-dsDNA

HEPATITIS G

-Anti-SMA

Hepatitis G is bloodbome, like hepatitis 8 and C. Mode

-Anti-SLA antibody - Anti-actin antibody

of transmission is not well defined but likely is simi

-p-ANCA

lar to HCV. There is evidence of infection in 1.5% of blood donors. It causes

0.5% of community-acquired

hepatitis. There is no evidence that HGV causes chronic liver disease.

1Hepatitis B �&:

Hepatitis C

_; , Hepatitis D (only with Hep B) ""

CHRONIC HEPATITIS Overview

Diseases: ,,

There are quite a few causes of chronic hepatitis as

-Wilson disease

;;, . - u1-antitrypsin

shown in Table 1-13. We have already discussed chronic

-Hemochromatosis

hepatitis 8 and C. We' II cover the other causes here. F

�

Drugs (see text)

NAFLD

1-55

1-56

LIVER

Scoring system for autoimmune hepatitis (AIH): •ANA or SMA

> 1:40

1 point

•ANA or SMA

> 1 :80

2 points

•IgG

>Upper limit Normal

I point

> 1: 1 Upper limit Normal 2 points •Liver histology Compatible with AIH Typical AIH

1 point

2 points

•Absence of viral hepatitis • Diagnosis 2: 6 2: 7

probable AIH definite AIH

Confirm diagnosis by characteristic changes (piecemeal necrosis with plasma cell infiltrate) found on histologic examination of a liver biopsy. These changes are charac teristic but not specific, so drug history and serologic tests are required to rule out other types of hepatitis. Treatment: Unlike other types of hepatitis, patients with autoimmune chronic hepatitis typically have a rapid reversal of symptoms and increased survival with prednisone/budesonide +/- azathioprine.

Birth control pills, anabolic steroids, chlorpromazine, amoxicillin-clavulanate, and erythromycin are associ ated with cholestasis but not hepatitis. Now let's talk a little more about acetaminophen, alcohol, methotrexate, INH, oral contraceptives, and aspirin. Acetaminophen

Acetaminophen poisoning is discussed under Poisoning in General Internal Medicine, Book 5. Briefly, when acetaminophen is ingested, 90% of it is processed via the glucuronidation pathway, 5% is excreted unchanged in the urine, and 5% is oxidized by the cytochrome P-450 system. The P-450 system produces a toxic, intermedi ate compound (N-acetyl-p-benzoquinoneimine, NAPQI), which is quickly reduced by glutathione. W hen there is an acetaminophen overdose, glutathione is rapidly depleted, and the resulting unreduced toxin causes direct liver damage.

Azathioprine (AZA) is used as a steroid-sparing drug. Initially, AZA has no effect as a sole agent; although, over years, some patients can be tapered off steroids and remain on AZA.

Alcohol-acetaminophen syndrome: Chronic, moderate to-heavy use of alcohol has a 2-fold effect: the cyto chrome P-450 system is cranked up (i.e., more NAPQI is produced) and the amount of glutathione is decreased (so less is available for detoxifying the NAPQI). Therefore, long-term users of moderate-to-heavy amounts of alco hol who take acetaminophen in nonnal or higher doses are at risk for severe hepatic toxicity or liver failure.

Alpha-interferon (IFN-a) exacerbates autoimmune hepatitis and is therefore contraindicated (although effective in chronic hepatitis B and C). So, it is vital to make the correct diagnosis.

Glutathione levels are depressed in malnutrition. Acetaminophen liver toxicity also may develop by not eating for 3-4 days (e.g., with an acute viral illness) and taking therapeutic doses of acetaminophen; i.e.,< 4 g/d!

Despite the usual response to treatment (above), there is no cure for autoimmune hepatitis, and it frequently progresses to cirrhosis and sometimes hepatocellular carcinoma (less often than with chronic viral hepatitis).

30% of healthy people taking the maximum recom mended dosage (4 grams per day) for 2 weeks develop an ALT> 100 IU/L.

Liver transplant is indicated for end-stage disease, although the disease process slowly recurs. Drug-Related Chronic Hepatitis Overview

Drug-related chronic hepatitis is associated with methyldopa, nitrofurantoin, acetaminophen, trazodone, phenytoin, methotrexate, oral contraceptives, and iso niazid (INH) (although INH far more commonly causes acute hepatitis). Histologic changes are similar to those seen in autoimmune hepatitis, and the patients are often ANA+. Hypergammaglobulinemia is also often present. Best treatment is to stop the offending drug. Drug-related liver disease (acute) can be caused by the direct toxic, allergic, and/or idiosyncratic effects of drugs. Acetaminophen causes a direct toxic effect. Drugs causing an idiosyncratic effect are: halothane, phenytoin, chlorpromazine, and erythromycin. Drugs causing both toxic and idiosyncratic effects: methyldopa, INH, and sodium valproate.

[Again, know:] Acetaminophen liver damage is potenti ated with chronic alcohol use, one-time heavy alcohol use, malnutrition, chronic use, and even dieting. Acetaminophen toxicity is the most common cause of fulminant hepatitis in the U.S. If suspected, draw acetaminophen blood levels; and treat early with intra venous or oral n-acetylcysteine (NAC; Mucomyst®, Mucosil®).The specifics of treatment are discussed under toxicities in General Internal Medicine, Book 5. There is also potential value to NAC treatment even with late diagnosis (more than 48 hours after inges tion and/or toxicity). Liver failure in this setting may be fatal or may require lifesaving liver transplant. Alcohol

Alcoholic liver disease results in a macrovesicular fat accumulation. There is also PMN infiltration in the liver. Women are more susceptible than men to alcoholic liver disease. Alcohol induces GGT, so this enzyme is dispropor tionately high in alcoholic liver disease. Also, there is

LIVER

Aspirin and Reye Syndrome

Reye

Q�uiz

•

What is the treatment for autoimmune hepatitis?

•

What drugs are commonly associated with

(microvesicular-as in acute fatty liver of pregnancy)

How does alcohol intake affect liver toxicity

NH3, and prothrombin time. Hypoglycemia, as a result of severe liver failure, is common. Mortality is 50%.

What is nonalcoholic fatty liver disease

Other Diseases that Cause Chronic Hepatitis

What are the treatment recommendations

The main diseases besides hepatitis that cause chronic

G R

hepatitis are the following hereditary liver diseases. See

discordance between AST (SGOT) and ALT (SGP T) with an AST:ALT ratio of 2: 1. The AST is virtually always 300-even with severe alcoholic liver injury.

Direct toxic effect is modified by other factors-including very susceptible to acetaminophen liver damage because alcohol induces the cytochrome P-450 system. The combination may cause fulminant hepatitis. Know that acetaminophen may not be given in the patient's history. Patients may know only that they have been taking a "non-prescription pain reliever." and

pentoxifylline

are

Hereditary Liver Disease on page 1-61. • Wilson disease •a1-antitrypsin deficiency

nutrition. Toxic effects may be additive. Alcoholics are

Corticosteroids

children

and progressive encephalopathy. Elevated are ALT, AST,

for NAFLD?

cella (chicken pox}-and especially when there has

(NAFLD), and who tends to get it? •

exclusively

been concurrent ASA use. These patients get a fatty liver

from acetaminophen? •

occurs

recent viral illness--especially influenza A or B or vari

drug-induced hepatitis? •

syndrome

15 years old. Although rare, it tends to occur after a

of transient

V d ti e n U • Hemochromatosis

NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) Also

called

nonalcoholic

steatohepatitis

or NASH,

NAFLD is an increasingly important cause of liver dis ease. NAFLD looks just like alcoholic liver disease, but there is no history of alcohol abuse. NAFLD is the inclu sive tenn, which, like alcoholic liver disease, covers the

benefit in severe alcoholic hepatitis.

spectrum of steatosis (fatty degeneration), steatohepa

Nonalcoholic fatty liver disease (NAFLD) is very simi

titis, fibrosis, and cirrhosis. 75-80% of "cryptogenic"

lar to alcoholic liver disease; see next column. Methotrexate

Methotrexate

(MTX)

can

9 ri 9

cause

indolent,

asymptomatic liver disease that progresses to cirrhosis.

Liver enzyme monitoring is recommended routinely in patients taking even intermittent doses of M TX. Liver

h ta

injury is believed to be related to cumulative lifetime dose. lsoniazid (INH)

INH causes an occasional, mild, transient increase in liver enzymes. I% of these develop a more severe hepatitis -the frequency and severity of which correlate with age. Oral Contraceptives

Oral contraceptives (OCPs) are associated with benign, hepatic adenoma; peliosis hepatis (blood-filled sinu soids); and focal nodular hyperplasia of the liver. So, a young woman on OCPs who has a mass in her liver? Probably an adenoma. Hepatocellular cancer generally occurs in the setting of cirrhosis.

cirrhosis is due to NAFLD.

The pattern of liver enzyme elevation is opposite that of alcoholic liver disease, with ALT> AST. NAFLD is associated with the following: •Obesity • Type 2 OM •Protein malnutrition • Hyperlipidemia • Amiodarone • Corticosteroids •"DROP" •Prolonged IV hyperalimentation DROP is a metabolic syndrome with: Dyslipidemia,

insulin

Resistance,

Obesity,

and

increased

blood

Pressure. These patients with NAFLD and DROP have a higher incidence of fibrosis. Treatment of NAFLD is not standardized. In general, treat with weight loss and control of any OM or hyper lipidemia. For patients with NAFLD and none of the common signs, recommend a low-fat diet. A GA and AASLD recommend vitamin E 800 IU/day as 151 line therapy for biopsy-proven NASH in nondiabetics. All patients with NAFLD should avoid alcohol and be immunized against hepatitis NB.

1-57

1-58

LIVER

HEPATOCELLULAR CARCINOMA

CIRRHOSIS

Hepatocellular carcinoma (HCC, "hepatoma"):

75%

have antecedent cirrhosis. HCC is associated with chronic liver disease of any type: chronic hepatitis B and C, hemochromatosis, a1-antitrypsin deficiency, alcoholic

Causes: •Alcohol (most common cause in the United States) •Hepatitis (B or C)

liver disease, and autoimmune hepatitis. In addition,

•NAFLD

hepatocellular carcinoma is associated with aflatoxin

•Post-necrotic (drugs and toxins)

exposure (can be found in raw peanuts or raw peanut

•Biliary disease

butter, especially in Asia).

•a1-antitrypsin deficiency

Alcoholic liver disease, frequently

(75%)

with concur

•Hemochromatosis

rent hepatitis C, is the most common cause of HCC in

• Wilson disease

the U.S. Chronic hepatitis B infection, acquired at birth,

• Schistosomiasis

is the most common cause in developing countries.

•Cardiac causes (primarily severe, prolonged

in RUQ, phatase.

G R

right-sided CHF-which is rare)

HCC is associated with tender hepatomegaly, a bruit bloody ascites, and high alkaline phos

70-80%

of patients have a very elevated

alpha-fetoprotein (AFP) level.

Stigmata of Cirrhosis

The physical exam findings of cirrhosis may include any

I-ICC-associated paraneoplastic syndromes are common and are clues to the diagnosis:

V d ti e

of the following alone or in combination: •Hepatosplenomegaly

•I-Iypercalcemia (due to parathyroid-like hormone

•Jaundice

produced by the tumor)

•Ascites

•Hypoglycemia (due to tumor's high metabolic needs or, more rarely, insulin-like growth factor II) •Watery diarrhea

•Caput medusae

•Spider angiomas (Image

n U -

1-23)

•Gynecomastia and testicular atrophy

•FUO

•Palmar erythema

Consider HCC in any cirrhotic patient who decompen

•Fetor hepaticus

sates without an obvious reason. IFN-a treatment in

•Asterixis (in hepatic encephalopathy)

chronic hepatitis C reduces the risk of HCC.

•Clubbing (usually in biliary causes)

Screen all cirrhotics for HCC with abdominal ultrasound

every 6 months. Alternately, some centers use helical CT

Complications of Cirrhosis

or MRI, which are more expensive, but either has better

Esophageal Variceal Hemorrhage

9 9

sensitivity than ultrasound.

Overview

Note yet again: Previously, alpha-fetoprotein test was also included as part of HCC screening, but the

2010

AASLD HCC guideline noted that alpha-fetoprotein

h a

does not have adequate sensitivity or specificity to sup port its use for every-6-months HCC surveillance. This guideline supported an ultrasound-alone strategy.

Know some basics about the treatment of liver cancer:

Resect a solitary tumor without vascular invasion (best

::; 5 cm 2)

in diameter).

If unresectable or underlying liver disease is so bad (commonly due to cirrhosis), can consider for liver transplant (single lesion< 5 cm, smaller than

S 3 lesions all

3 cm, no extrahepatic disease or vascular

invasion).

Even with advanced disease, there are lots of treatment options, including radiofrequency ablation, transarte rial chemoembolization, and oral-targeted therapies.

One-third of patients with esophageal varices bleed, and bleeding has a

30%

mortality rate. With a bleed, the

ratio of wedged:free portal pressure gradient is usually >

1 2 mmHg (normal

S 6). Size of varices also correlates

with risk of bleeding (Image

1-24).

Prophylaxis Nonselective beta-blockers, such as propranolol and nadolol, decrease rebleeds and may delay or prevent the occurrence of the 1st variceal bleed. Therefore, these agents should be prescribed to all patients with medium to large varices-whether or not they have had bleeding. Endoscopic ligation can be used for primary prophylaxis in patients with large varices or in those who cannot tolerate beta-blockers. Beta-blockers have been shown to have deleterious effects (increased mortality) in patients with refractory ascites. Sclerotherapy does not prevent a 1st hemorrhage-it actually appears to make things worse. What do you do for the patient with cirrhosis and small esophageal varices? Do nothing-only big varices bleed!

LIVER

TIPS (transjugular intrahepatic portosystemic shunt) is used only for cases that rebleed. TIPS allows for decom

Q�uiz •

pression of the portal vein-effectively a portocaval shunt without the major surgery. The other main use for TIPS is for intractable ascites due to cirrhosis.

What is the most likely diagnosis in a patient with tender hepatomegaly, an RUQ bruit, bloody

Summary of treatment for esophageal varices:

ascites, a high alkaline phosphatase, and a very

• Nothing for small varices

elevated alpha-fetoprotein level?

• Propranolol or nadolol for all medium-large varices

•

Name the causes of cirrhosis.

•

Bleeding risk of esophageal varices is best

or any history of bleeding varices • Banding or sclerotherapy for active bleeds or to

correlated with what aspects of the varices? •

prevent rebleeds-preferably with somatostatin

What drug class is used for prophylaxis against

• TIPS for rebleeds

bleeding with large esophageal varices? What

•

Hepatic Encephalopathy

Which drugs and which endoscopic therapies

Hepatic encephalopathy may be precipitated by:

are used for active variceal hemorrhages? •

•GI bleed

Why are antibiotics given to cirrhotics with GI

•Hypoxia

What drug is given to a cirrhotic patient with a

•Hypokalemia

history of variceal hemorrhage to decrease the

•Sedatives

chance of rebleeds?

•Tranquilizers

•Portal venous obstruction

Active Bleeds

Primary

therapy

V d ti e n U •Hypovolemia

bleed? Which antibiotics are used? •

G R

do you do with small esophageal varices?

• Infections (pneumonia, bacteremia, urosepsis, and

actively

bleeding

varices

endoscopic banding or sclerotherapy. Somatostatin and its analog, octreotide, are splanchnic vasoconstrictors. These are frequently given paren

terally in conjunction with endoscopic therapy and have a proven benefit over endoscopic therapy alone. Endoscopic injection of sclerosants (sodium morrhuate

9 9

or ethanolamine) into bleeding varices will stop bleed ing but cause necrosis of the esophageal tissue, which

can lead to esophageal ulcers and eventual stricture formation.

Balloon tamponade is rarely used because it has a high

h a

rate of complications.

Any cirrhotic patient with GI bleeding should be

spontaneous bacterial peritonitis [SBP])

•Alkalosis, which increases ammonia/ammonium

carefully managed in the ICU. Consider elective endo tracheal intubation if there is active hematemesis because aspiration pneumonia is common. Always do endoscopy. Remember: Cirrhotics can bleed from sources other than varices; e.g., PUD. If the bleeding is due to varices, do endoscopic therapy with either banding or sclerotherapy.

ratio (NHiNH/)-because only the non-ionized form, NH3 (ammonia), crosses the blood-brain

barrier. (Acidosis has the opposite effect.)

Signs of hepatic encephalopathy include fetor hepaticus (unique musty odor to breath and urine), hyperreflexia, asterixis, and altered mental status. Treat with lactulose with goal of

3 bowel movements/

day. This disaccharide, more commonly used as an osmotic laxative, passes through the upper GI tract and is broken down by colonic bacteria into organic acids. The excess H+ in the proximal colon: •inhibits coliform bacterial growth and thereby decreases NH3 production, and •traps NH3 as inactive NH/. Supplemental/alternative treatments: Oral antibiotics (also to decrease NH3 production) may be given if the patient doesn't respond to lactulose.

Give all cirrhotic patients with bleeding or ascites prophylactic oral or IV antibiotics to prevent spontane ous bacterial peritonitis (SBP), AKI, and to decrease mortality. 3rd generation cephalosporin or quinolones (if

PCN/cephalosporin

allergic)

are

the

preferred

antibiotics.

Preventing Rebleeds

Propranolol or nadolol should be prescribed to all patients who have had bleeding varices to decrease the chance of rebleeds.

Image 1-23: Spider te/angiectasia

Image 1-24: faophagea/ varices

1-59

1-60

LIVER

Neomycin was previously used but has nephro/oto toxic

•Constrictive pericarditis

ity. Rifaximin, metronidazole, rifampin, and vancomycin

•Peritoneal diseases

are now used.

•Myxcdema

Acarbose (used for diabetes mellitus) inhibits breakdown

•Nephrogenic ascites

of carbohydrates into monosaccharides. Monosaccharides

•Chylous ascites

promote the growth of bacteria that produce ammo nia. Probiotics alter gut flora and similarly decrease ammonia levels.

•Malignancy •Pseudochylous ascites •Fulminant and subfulminant hepatitis •Hepatic veno-occlusive disease (including

Hepatorenal Syndrome

Budd-Chiari)

Hepatorenal syndrome is also called "oliguric hepatic failure." It is a diagnosis of exclusion so other causes of renal failure such as prerenal azotemia, obstruc tion, and drugs must be excluded before a diagnosis of hepatorenal syndrome can be made. [Know:] Urine sodium is very low (commonly< IO) in

•Hypoalbuminemia (nephritic syndrome, protein-losing enteropathy, severe malnutrition) •Pancreatogenous (pseudocyst, disrupted duct)

G R

Cirrhosis-induced ascites: Ascitic fluid is resorbed via the peritoneal surface. Maximum capacity is

- 900 cc/d. So,

if you try to diurese off> I liter/day, it is at the expense

hepatorenal syndrome.

of intravascular volume. This disease causes the most

Current treatment: Careful volume management (IV

avid sodium retention state known.

albumin infusions) and midodrine (an

Note: A chylous ascites is due to lymphatic blockage

agonist) +

octreotide (stimulates fluid absorption from GI tract).

V d ti e

(trauma, tumors-especially I 0 lymphoma, TB, and filariasis), not cirrhosis or CHF.

PT in an Alcoholic Again note: Alcohol causes malabsorption of some vita in an alcoholic is prolonged, it is often easily corrected

by IM vitamin K. Also, if a I: I mix corrects the PT, the

disorder is due to decreased coagulation factors; if it does not correct, there is likely a circulating inhibitor.

ASCITES

9 9

Causes Causes of ascites: •Cirrhosis •Alcoholic hepatitis •CHF

r i h

Cirrhosis, liver failure,

to-ascites albumin gradient (SAAG) > 1.1 g/dL. This (where the albumin level in the ascites is low, generally < 1.0 g/dL): •Cirrhosis (most common) •RHF •F ulminant liver failure •Budd-Chiari syndrome Ascites T. protein

> 1.1

<2.5

Budd-Chiari syndrome,

TB peritonitis,

Cell count: If the cell count is elevated (> 250 PMNs),

do a C&S and start antibiotics.

occurs in ascites due to any of the following conditions

•Myxedema SAAG < I. I g/dL (i.e., high level of albumin in the ascites and no portal HTN) is seen with ascites due to tuberculosis peritonitis, nephrotic syndrome, pancre atitis, and peritoneal carcinomatosis. Note: SAAG is a

myxedema, and SBP Right heart failure

Know all of the following:

Chemistry: Portal hypertension is indicated by a serum

Protein and Albumin in Ascites SAAG

of a peritoneal fluid specimen for appearance, cell count

with differential, cytology, total protein, and albumin.

infection; milky, lymphatic obstruction.

Table 1-14: Causes of Asc1tes and Associated Findings

Causes

Determining the cause of ascites often requires analysis

Appearance: Bloody fluid suggests a tumor; cloudy, an

Ascites is defined as the accumulation of fluid in the peritoneal cavity.

Diagnosis of Ascites

n U

mins, including vitamin K. If the prothrombin time (PT)

difference, not a ratio! It is defined by: > 1.1 < 1.1

_ _. .. _

> 2.5 > 2.5

bacterial/fungal

SAAG

Albuminserum -Albumin Ascitcs

An elevated ascites protein level

(� 2.5

g/dL ) is seen in

all cases that cause increased levels of albumin. It is also

peritonitis,

seen in cardiac ascites! See Table 1-14.

nephrotic syndrome,

TIPS (transjugular intrahepatic portosystemic shunt) is

pancreatitis, and

used to treat refractory ascites caused by cirrhosis. As

peritoneal carcinomatosis

MedStudy-Please Report Copyright Infringements to copyright@medstudy.com

LIVER

• WBC very elevated, often> 5,000 • Ascites fluid LOH> serum LOH Treatment: Active SBP is typically treated with cefo •

taxime (Claforan®) or similar spectrum

If the PT is prolonged in an alcoholic and is easily corrected with vitamin K, what does this

antibiotics.

indicate? •

IV albumin is also given in the treatment of SBP

What is chylous ascites due to?

•

How does SBP differ from neutrocytic ascites?

•

How does SBP differ from PBP?

•

Why is albumin given in the treatment of SBP?

•

What hereditary liver disease has increased

( 1.5 g/kg on day I and I g/kg on day

3). Albumin main

tains blood volume and thereby decreases the incidence of irreversible renal impairment and mortality.

Treatment of Ascites

G R V

Treatment: mainly dietary sodium and water restriction

unconjugated bilirubin? •

3rct generation

cephalosporin. Milder cases can be treated with oral

(needed only if the Na+ < 125). Then, if needed, start

When does jaundice in Gilbert syndrome

spironolactone, then a loop diuretic. Stop all anti-prosta

typically occur?

glandin medications (e.g., ASA) because these decrease

stated before, TIPS allows for decompression of the portal vein. Effectively, it is a portocaval shunt without the major surgery. A common complication of TIPS is encephalopathy; therefore, it is generally not recom mended for elderly patients-who are most susceptible. As previously discussed, TIPS is also used in the treatment of rebleeding esophageal and gastric varices.

urinary Na+ excretion! Also, do not give aminoglycosides in this setting because they may precipitate renal failure.

ascites or with severe refractory ascites if the patient's

t i n

renal function is normal and there is: •No GI bleeding •No sepsis

Spontaneous Bacterial Peritonitis

d e

Again, do not diurese > I Lid. It is okay to do daily paracenteses during the initial treatment of recent-onset

•

No portosystemic encephalopathy (PSE)

U -

Spontaneous bacterial peritonitis (SBP) is indicated by

With large-volume paracentesis(2:5 L), replace6-8 grams

a peritoneal fluid with > 250 PMN/mL in a patient with

albumin for each liter of fluid removed. Also, give albu

ascites. Usual causes are £. coli, then S. pneumoniae, then Klebsiella.

min IV in life-threatening ascites, although it has only a

short-term effect.

9 9

Because SBP patients may not have abdominal pain or tenderness, you must consider SBP if there is deteriora

tion in the status of any patient with ascites; e.g., new

HEREDITARY LIVER DISEASE

onset confusion, fever, signs of hepatic encephalopathy,

Review of Bilirubin

or renal failure.

Hyperbilirubinemia is the main finding in hereditary

Risk factors for SBP:

•History ofvariceal bleed

•Prior episode of SBP

h a

• Ascites protein< I g/dL

liver diseases. In general, only conjugated bilirubin passes the glom eruli and is excreted in the urine. The unconjugated bilirubin is tightly bound to albumin, and this complex is too large to pass through the glomerulus. Conjugated

Patients with these risk factors should receive either

bilirubin is less tightly bound to albumin, and the 5%

intermittent (preferred) or continuous prophylactic oral

unbound portion easily passes into the urine.

antibiotic therapy. Typically, use oral therapy with a quinolone (norfloxacin 400 mg daily). You must rule out 2 other possible causes of high WBC

So, bilirubinuria results only from conjugated hyperbili rubinemia. Because bilirubin is conjugated in the liver, bilirubinuria is an indication of cholestasis.

in ascitic fluid before you can assume it is SBP:

I) Neutrocytic ascites: Basically, this is PMNs > 250/ ml with no evidence of SBP and negative cultures. 2) Primary bacterial peritonitis (PBP) is due to perforated viscus. In cirrhotics, it can be confused with SBP. Note that PBP has markedly different ascitic fluid lab findings than SBP: •Protein> I g/dL, frequently> •

Glucose< 50 g/dL

3 g/dL

Unconjugated Bilirubin Gilbert syndrome is a very common, benign, chronic disorder resulting in a mild, unconjugated hyperbiliru binemia. Remember: unconjugated

indirect

without

bilirubinuria. Jaundice may come and go and is typically brought on by physical stress (especially surgery, exertion, and infection), fasting, and alcohol ingestion. Around 7% of the population has Gilbert syndrome. It appears to be an autosomal dominant syndrome with variable penetrance.

1-61

1-62

LIVER

Gilbert syndrome is due to decreased or absent glucuro nyl transferase in the liver cells or decreased liver cell uptake of unconjugated bilirubin. 1/2 of patients have a very low-grade, chronic hemolysis. This probably reflects 2 separate syndromes, but, for now, they are still grouped together. Phenobarbital stimulates glucuronyl transferase and decreases the bilirubin level. Diagnosis:

Increased

unconjugated

bilirubin

after

prolonged fasting. No treatment is needed.

Clinical findings: •Hepatomegaly (95%) •Gray hyperpigmentation (90%) •Secondary diabetes, "bronze diabetes" (65%), so suspect this in a thin 50-year-old with new onset DM •Arthropathy (40%--especially 2nd and 3rd MCP joints of the wrist!) •Cardiac involvement (15%) Secondary hypogonadism also occurs and is caused by depression of the hypothalamic-pituitary axis. There is

Conjugated Bilirubin If a patient is noted to have increased conjugated bilirubin after a major surgery, it is not Gilbert syndrome (which is unconjugated). It is most likely an entity called benign postoperative cholestasis. This is most often seen if the patient became hypotensive or required many transfusions during the operation.

a 25-30% risk for hepatocellular carcinoma in patients with cirrhosis caused by hemochromatosis-higher than

G R

any other cause!

Diagnosis of hemochromatosis is suggested by high levels of serum Fe, ferritin, and transferrin levels. The most helpful screening test is transferrin saturation >

45%. (You can read up on these lab tests at the begin

V d ti e

ning of Hematology, Book 4.) Liver biopsy confirms the

a1-Antitrypsin Deficiency

diagnosis and allows for staging of fibrosis.

a1-antitrypsin deficiency (autosomal recessive) mainly affects the liver and lungs and causes a chronic hepa titis and eventually leads to cirrhosis and emphysema. For diagnosis, check a serum a1-antitrypsin level. Liver disease is caused by accumulation of intrahepatocytic AAT molecules.

Liver >

biopsy is indicated

1,000 ng/mL.

when

serum

ferritin

Confirm the diagnosis for the hereditary type with an assay for the HFE gene.

n U

If this disease is successfully treated early enough

Treatment: Other than liver transplant or liver + lung transplant, the only other minimally effective treat

ment is augmentation therapy with weekly infusions

of pooled human AAT (a1-antiprotease). Augmentation

therapy has no effect on liver disease associated with a1-antitrypsin deficiency.

Hemochromatosis

9 9

especially if prior to development of cirrhosis-patients

have a normal life span with negligible risk of cancer. Initial treatment is weekly phlebotomy. Ultimately, the

patient has phlebotomy 4x/year with the goal of a fer ritin level between 50 and 100 ng/mL. This treatment results in decreased skin pigmentation, improved cardiac

function, and prolonged life expectancy. But, if already

lost, the secondary sex characteristics do not return; the damage is done!

Know this topic very well. Consider all the following highlighted!

h ta

Wilson Disease

Two types of hemochromatosis: genetic and acquired. The genetic form involves the HFE gene and is autosomal recessive (AR).

The acquired form is generally secondary to blood transfusions used to treat underlying anemia, such as sickle cell disease. Less frequently acquired hemo chromatosis can occur secondary to an iron-related chronic anemia with secondary erythropoiesis, such as sideroblastic anemia or thalassemia. This form usually develops in men between ages 40 and 60 years. In both genetic and acquired types, there is abnormally increased intestinal iron absorption, which leads to iron deposition in the tissues. This iron deposition causes fibrosis and damage to organs-especially the liver, heart, pancreas, and pituitary gland. Note:

Symptomatic

hemochromatosis

Wilson disease is an AR genetic disorder that typically presents as liver disease or neurologic/psychiatric dys function in adolescents. It usually presents between ages 15 and 25. Other symptoms include arthritis from chondrocalcinosis. Wilson disease is caused by impaired excretion of copper into bile, which results in an excess copper in body tissues-especially the liver. Hemolysis is common. Serum ceruloplasmin is low (in most liver diseases, it is high) and urinary copper level is high. Kayser-Fleischer rings are pathognomonic; if suspected, a slit-lamp exam is required: Look for a single brownish corneal ring in each eye, formed by copper deposition along the outer edge of the cornea (Image 1-25). Liver biopsy confirms the diagnosis; it shows a high liver copper level-but remember, so do PBC and PSC!

lOx

frequent in men-this is probably because of the effect menses has on iron stores in women.

LIVER

uiz •

What is the risk of hepatocellular cancer in a patient with cirrhosis caused by hemochromatosis?

•

What lab findings are common in Wilson disease?

•

What is a pathognomonic finding in Wilson disease?

•

Image

Which patients should be considered for a liver transplant?

1-2 5:

Kayser-Fleischer ring on rim of iris of the eye

G R

3rd Trimester

Screen with the following tests for Wilson disease in all

Remember that hepatitis E can cause fulminant hepati

adults with chronic liver disease without obvious cause,

tis in the 3rd trimester of pregnancy-with a 20% fatality

especially if younger than 40 years of age:

rate.

which there is microvesicular fat deposition in the liver

2) Slit-lamp exam

(as in Reye syndrome), with only modest elevation of

3) Urine copper

AST/ALT/Bili. It occurs in the 3rd trimester and is asso

All 3 of the above are positive in< 50% of patients with Wilson disease. Treatment of Wilson disease is a 2-phase process. First, decrease copper levels, generally with chelation. Then, order maintenance therapy to prevent reaccumulation of copper. Phase I: Chelation with penicillamine (must give sup

plemental pyridoxine with this drug). If the patient

cannot tolerate penicillamine or has progressive neurologic

9 9

manifestations, use trientine. Zinc is a 3rd option. Phase

V d ti e n U

Fatty liver of pregnancy is a very serious condition in

I) Serum ceruloplasmin

Maintenance

therapy

with

low-dose

penicillamine or trientine, or with zinc. Oral zinc blocks

the absorption of copper. Low-copper diet is required

ciated with encephalopathy, hypoglycemia (again like

Reye syndrome), preeclampsia, pancreatitis, DIC, and renal failure. Early delivery is required. HELLP syndrome: Hemolysis, Elevated Liver Enzymes,

Low Platelets. Most patients also have hypertension and

proteinuria. This is thought by most to be a severe vari

ant of preeclampsia. It tends to occur before 36 weeks of

pregnancy. Delivery of the infant is the only consistently beneficial treatment.

lntrahepatic

cholestasis

itching

increased

and

AST, and ALT.

The

alkaline

condition

pregnancy

causes

phosphatase, tends to

bili,

recur

subsequent pregnancies.

(avoid nuts, peas, chocolate, mushrooms, shellfish, liver).

h a

A liver transplant cures Wilson disease!

In fulminant Wilson disease, there is severe hemolytic anemia and a high serum copper level due to the release

of copper from the liver. Penicillamine therapy is not effective; the only treatment is liver transplant.

LIVER DISEASE DURING PREGNANCY 1st Trimester

Hyperemesis gravidarum can cause N/V, volume deple tion, and mild increase in AST and ALT.

LIVER TRANSPLANT [Know!] Consider liver transplant for almost all patients with irreversible end-stage acute and chronic liver dis ease. The selection process excludes many of these patients. The selection is commonly made by a liver transplant committee at the liver transplant center. The process is inexact, and the waiting period for a liver is often more than a year. Evaluate patients with chronic, progressive liver disease early in the course of the disease. The Model for End-stage Liver Disease (MELD) scale gives a fairly accurate short-term (3-6 month) predic tion of mortality risk, and it is used to determine organ

2"d Trimester

allocation for liver transplant. It uses bilirubin, creati

2"d trimester is the best time for surgery for severely

nine levels, and INR (normalized prothrombin time).

symptomatic gallstone patients.

The MELD score: 3.78 log0(bilirubin [mg/dL]) +I 1.2 log0(INR) +

9.57 loge (creatinine) [mg/dL]) + 6.43

1-63

1-64

JAUNDICE

Be sure and know this formula for the exam! And know

JAUNDICE

the quick way to do logs without a calculator. (Just kidding ... on both counts.) Actually, all you might need to know about the MELD score is:

review ofthe workup ofa patient with jaundice.

•< 10 =won't be on the transplant list unless patient has a liver tumor • >

We've discussed many of the causes of jaundice in this section, and now we'll summarize these with a quick

Jaundice (also known as icterus) is a yellowish pig

20 = candidate for transplant

mentation of the skin, the conjunctiva! membranes

Common indications for liver transplant: Most types of chronic end-stage liver disease, metabolic liver disease,

over the sclerae (whites of the eyes), and other mucous membranes caused by hyperbilirubinemia (increased

primary and secondary biliary cirrhosis, primary scle

levels ofbilirubin in the blood).

rosing cholangitis, and fulminant hepatitis. Cirrhosis

The differential diagnosis of jaundice includes:

with a small, early-stage hepatocellular cancer (HCC) is another indication. Associated biochemical indications seen in end-stage chronic liver disease: bilirubin I 0-15 mg/dL, albumin <

2.5, and a PT> 3-5 sec above normal (10-12 sec).

Other signs/symptoms suggesting it is time to transplant:

•Viral hepatitis •Alcoholic liver disease •Chronic hepatitis

• Gallstones and complications

V d ti e n U

intractable pruritus, hepatic encephalopathy, bacterial

•Pancreatic cancer

peritonitis, intractable ascites, and the development of

•Sickle cell disease

hepatocellular carcinoma.

•Gilbert syndrome

Controversial: liver transplant to treat alcoholic cirrhosis. Absolute contraindications: preexisting advanced or uncontrolled

nonhepatic

disease,

active alcohol

drug abuse, life-threatening systemic disease, and meta

static cancer. There are many relative contraindications, including advanced age. A prior TIPS (see page

1-58 under Complications of

Cirrhosis) is not a contraindication to transplant. In fact, it is often a lifesaving "bridge" to transplantation.

9 9

Table 1-15: Workup of Jaundice Acute Viral Hepatitis Bilirubin

ALT/AST AllcPhos

AIG

Chronic Cirrhosis

h a

<20

>400

NL/NL

PT/PTT

<20 unless

•Ascariasis

•Primary sclerosing cholangitis but the majority falls into the following

1) Acute viral hepatitis

2) Chronic cirrhosis

3) Obstructive problem (common duct stone or pancreatic cancer)

3 causes are strongly associated with certain

Obstructive: CD Stone or Pancreatic Cancer

<20

1) Acute viral hepatitis is the most common cause (85-90%) in those< 30 years old. 2) Chronic cirrhosis is the usual cause (50-70%) in those 40-60 years old. 3) Obstructive jaundice (common duct stone or pan creatic cancer) is the usual cause (80%) in those 60-80 years old without other risk factors.

renal

<400 usually

If the patient recently arrived from outside the United States, consider ascariasis-especially in a patient with eosinophilia.

4-lOxULN

Jaundice workup consists of:

Low/High

UsuallyNL/NL

High/High

UsuallyNL/NL

• a careful history, • ultrasound, and •LFTs (Table

Cholesterol

3 causes:

age groups:

function

NL-4xULN

•Primary biliary cirrhosis (PBC)

And these

impaired

<400

G R

•Drug-induced jaundice

NL to Low

NL to High

1-15).

Ultrasound results determine the next test to be done:

Serologies

Excludes

Excludes acute

•Dilated common bile duct and stones: ERCP

A,B,C

acute viral

viral etio if

•Dilated common bile duct and no stones:

EBY

etio if

needed

CMV

needed

Abd U/S

CT (think pancreatic cancer) or EUS •Dilated intrahepatic ducts: CT

Maybe

93/95 sens&spec

•Dilated ducts and testing to exclude PSC: MRCP

helpful

ifbili > 10 x 10 d

•Ifno dilated ducts: liver biopsy

NUTRITION

patients on chronic hemodialysis. There are 2 major manifestations of thiamine deficiency: wet beriberi and

a.�uiz •

•Wet beriberi: Symptoms of wet beriberi are heart

What is the usual cause of jaundice in persons <

•

dry beriberi. failure, ascites, and often an accompanying

30 years old? 40-60? 60-80?

peripheral edema.

• Dry beriberi is confined to the nervous system:

What is the timeframe for development of vitamin deficiency for each of these:

a) water-soluble vitamins, b) vitamin A and D, c) iron and cobalt, d) 812? •

Wemicke encephalopathy (vomiting and nystagmus, ophthalmoplegia, ataxia, and mental deterioration); and

What are the symptoms of wet beriberi? Dry beriberi?

•

peripheral neuropathy (symmetrical sensory, motor, and reflex loss);

Korsakoff syndrome (confabulation, poor recent memory and learning).

What is the classic presentation of a patient with Wernicke encephalopathy?

Thiamine

replacement

G R

usually

cures

Wemicke

encephalopathy, but it reverses symptoms in only 1/2 of patients with Korsakoff syndrome-and fully cures

NUTRITION

only 25%.

VITAMIN DEFICIENCIES

V d ti e

Glucose infusions may precipitate Wemicke encepha lopathy, so a classic presentation is a closet drinker who

Time Until Onset of Symptoms

develops ophthalmoplegia or nystagmus post-surgery.

[Know!] The time until onset of symptoms of vitamin or

Always give thiamine to an alcoholic before starting an

mineral deficiency-as when on TPN without vitamin

IV dextrose solution.

supplementation (and barring other problems):

Wemicke encephalopathy is a medical

•Weeks: water-soluble vitamins, magnesium (muscle stiffness and cramps-often causes tetany in patients with Crohn disease), zinc (acroderrnatitis and poor wound healing), and essential fatty acids

• Months: copper (hypochromic, microcytic anemia) and vitamin K (bleeding, high PT/INR)

9 9

(glucose intolerance and peripheral neuropathy)

• Several years: iron, cobalt (anemia) • Many years: B,2

r i h

n U

daily for 3-5 days, then transition to oral dosing.

Vitamin 82 Deficiency

• Year: vitamins A and D, selenium (myalgias, cardio myopathy, and hemolytic anemia), and chromium

emergency.

Immediately give thiamine 500 mg IM or JV. Repeat

VitaminB2 is riboflavin.B2 deficiency almost invariably

occurs in association with other vitamin deficiencies. Phenothiazines and tricyclic antidepressants increase

the tendency to develop riboflavin deficiency. Patients

present with a norrnochromic norrnocytic anemia, sore throat with hyperemic mucosa and glossitis, cheilosis, angular stomatitis, and a seborrheic dermatitis, espe

These deficiencies are important. [Know them cold!] A

cially involving the perineal/scrotal area. Symptoms are

good way to review this section is to fill in the following

reversed with riboflavin.

sentence, using the appropriate times, symptoms, and

mineral deficiencies from above.

If, after 1-2 L_), a patient on TPN develops L_), you would suspect L_).

Vitamin 86 Deficiency Vitamin B6 is

pyridoxine.

Deficiency

is rare and

frequently caused by drugs but may also be seen with

More on vitamin deficiencies: Vitamins B and C are

general malabsorption syndromes and chronic alco

water-soluble, while vitamins A, D, E, and K are lipid

holism. The main drug culprits are isoniazid (INH),

soluble. We'll discuss these in this order.

cycloserine, and penicillamine. Presenting symptoms

[Know all this info about vitamins and minerals!]

Vitamin A Deficiency Vitamin A deficiency is a major cause of blindness in developing countries; night blindness is the earliest symptom.

include glossitis, cheilosis, vomiting, and seizures.

Vitamin 812 Deficiency Vitamin 812 deficiency is discussed in Hematology, Book 4, under Nuclear Maturation Defects, and in Neurology, Book 5, under Myelopathies. It results in macrocytic anemia, smooth tongue, and peripheral neu ropathy. Subacute combined degeneration of the spinal

Vitamin 81 Deficiency Vitamin 81 is thiamine. Thiamine deficiency causes beriberi. It commonly develops in alcoholics or in

MedStudy

cord is rather specific forB12 deficiency; patients initially experience pins-and-needles sensation, followed by loss vibration and proprioception (position). Dementia is a rare symptom ofB12 deficiency.

1-65

1-66

NUTRITION

Niacin Deficiency

•

insufficient dietary intake

Niacin deficiency causes pellagra. Niacin (nicotinic acid) is made from tryptophan in the body (so it is not actually a "vitamin"). Niacin deficiency is rare in the U.S. because niacin is now added to grains. It is still seen in carcinoid syndrome, in which tryptophan is depleted, and when isoniazid (INH) is used in treat ing TB. Presenting signs of niacin deficiency are a dermatitis-especially on sun-exposed surfaces, glos sitis ("bald tongue"), stomatitis, proctitis, diarrhea, and

Decreased intestinal absorption: steatorrhea,

•

Kidney disease

Consider vitamin D deficiency especially in any older patient who has musculoskeletal pain/weakness and especially if there is a history of fat malabsorption or vegetarianism. If osteopenia is diagnosed, check 25-(0H)-D levels.

changing mental status-ranging from depression to

Vitamin E Deficiency

dementia to psychosis. (Remember these by the 3 Ds:

Vitamin E is an antioxidant. Deficiency is rare and is

mucosa! Dermatitis, Diarrhea, and Dementia.) Patients

usually seen in the setting of concomitant malabsorp

may be hyperpigmented.

tion and codeficiency of the other fat-soluble vitamins.

Vitamin C Deficiency

decreased vibration and position sense.

G R

Vitamin E deficient patients can have areflexia and

Vitamin C (ascorbic acid) deficiency causes scurvy. Ascorbic acid is vital in connective tissue formation.

VITAMIN OVERDOSE

Scurvy

Vitamin A

generally occurs

in poverty-stricken urban

areas. First symptoms are petechial hemorrhages and ecchymoses; then the patient develops hyperkeratotic papules around hair follicles, hemorrhage into muscles and joints, purpura, and splinter hemorrhages in the nail beds. Perifollicular hemorrhage is a rather specific find ing. In children, it affects bone formation and can cause intraeerebral

hemorrhage.

Symptoms

improve

of vitamin supplements. Symptoms include headache and flaky skin. A single massive overdose causes abdominal pain, sluggishness, papilledema, and a bulg

n U

only

when the normal pool is replenished (1.5-3 grams).

Vitamin D Deficiency

V d ti e

Hypervitaminosis A can be caused by eating polar bear liver, but it is more commonly a result of over-ingestion

ing fontanel in infants. This is followed in a few days with desquamation of the skin and recovery. Chronic

over-ingestion (25,000 IU/d) is associated with arthral gias, anorexia, dry skin, hair loss, low-grade fever, and

hepatosplenomegaly.

Vitamin D deficiency causes rickets in children and osteomalacia in adults. Most vitamin D is synthesized in

9 9

the skin (from a protovitamin D + sunlight), but some is absorbed from the gut. This vitamin D is then converted

to 25-0H-D in the liver and further to 1,25-(0H)rD, the

r i h

active form of vitamin D in the kidney.

25-(0H)-D is what is typically measured on blood tests. 1,25-(0H)rD levels are quite labile and are not routinely

Vitamin 86

Vitamin 86 excess can cause a peripheral neuropathy

with normal motor and sensory function, but absent positional and vibratory sensation.

Vitamin D

measured due to poor reproducibility.

Hypervitaminosis D results in increased calcium absorp

Vitamin D deficiency causes decreased absorption of

tion from the bowel, hypercalcemia, and hypercalciuria.

calcium from the gut and decreased calcium resorption from the kidney. Vitamin D deficiency also stimulates the release of PTH. Early in the course of the disease, the hypocalcemia is blunted by the increase in PTH, which increases absorption of calcium from the gut and

It probably increases the tendency for calcium renal stones. The hypercalcemia and hypercalciuria seen in chronic granulomatous diseases (such as sarcoidosis and lymphomas) are due to an equivalent hypervitaminosis D state, in which there is increased 1,25-(0H)i-D.

also leaches calcium from the bones. Therefore, despite a normal or slightly low serum calcium level, patients still develop bone problems! Symptoms in adults are often solely musculoskeletal pain and weakness.

Vitamin E Vitamin E is relatively nontoxic acutely. The main trouble with vitamin E is that large doses can cause a marked potentiation of oral anticoagulants. Long-term vitamin E supplementation has been associated with

Main causes of decreased 1,25-(0H)rD:

increased all-cause mortality.

•

Decreased production in skin

•

Elderly: decreased skin synthesis at age

•

Winter: decreased sun exposure (Roughly 40% in

northern climes are deficient by end of winter.)

Vitamin C Vitamin C megadoses increase the incidence of oxalate renal stones and can interfere with the absorption of vitamin 812.

FOR FURTHER READING

Indirect calorimetry units that measure oxygen con sumption and C02 production are more precise and usually better for determining needed calories for in-hospital, critically ill patients. •

Petechiae are associated with which vitamin

Refeeding syndrome: Chronically malnourished patients

deficiency? •

•

(e.g., anorexia nervosa, cancer, short gut)-especially

Explain how vitamin D is produced and altered

those with resting bradycardia, hypotension, or body

in the body.

weight

What does vitamin D deficiency cause

80% ideal weight-are at risk for cardiac

sium replacement, frequent monitoring of electrolytes,

in the adult? •

failure with rapid refeeding. Phosphate and potas and telemetry should be used during the initial days of

What are the findings associated with excessive

refeeding to minimize the risk for cardiac failure.

continuous ingestion of vitamin 86?

G R V

FOR FURTHER READING

Niacin High doses of niacin can cause acanthosis nigricans and cholestatic jaundice. The flushing and pruritus often occurring at the start of treatment can be prevented by taking aspirin 30 minutes before the niacin and/or by taking niacin in divided doses or after meals.

[Guidelines in blue]

ESOPHAGUS

Ajani JA, Barthel JS, et al. Esophageal and esophagogastric junction cancers. J Natl Compr Cane Netw.

d e

2011 Aug I ;9(8):830-887.

Ament PW , Dicola BD, et al. Reducing adverse effects of

ENTERIC FEEDING vs. TPN

t i n

proton pump inhibitors. Am Fam Physician.

If the choice is between enteric feeding and TPN, enteric

2012 Jul I ;86(1):66-70.

feeding is the better option. The short-chained fatty acid

Beck WC, Sharp KW. Achalasia. Surg C/in North Am.

substrates (fatty acids are synthesized in the small intes tine) in the enteric feedings help maintain the integrity of the small intestinal wall-the loss of which is associ

2011 Oct;91(5):1031-1037. Cecconi E, Di Piero V. Dysphagia-pathophysiology, diagnosis

U -

ated with the onset of multisystem failure. Percutaneous

endoscopic gastrostomy is often used in patients who

cannot swallow. It is a better alternative to the NG tube, and general anesthesia is not required. Contraindications

and treatment. Front Neurol Neurosci. 2012;30:86-89.

Chubineh S, Birk J. Proton pump inhibitors: the good, the bad, and the unwanted. South Med J. 2012 Nov;I 05(11):613-618. Constantin A, Mates JN, et al. Principles of surgical treatment

to percutaneous endoscopic gastrostomy are delayed

of Zenker diverticulum. J Med life. 2012 Feb 22;5(1):92-97.

gastric emptying and gastric outlet obstruction.

Dzeletovic I, Ekbom DC, ct al. Flexible endoscopic and

9 9

these instances, various types of jejunostomy tubes can

be used.

MALNUTRITION

h a

Simple clues to malnutrition:

• Weight/ideal weight< 70%

•Lymphocyte count< l ,OOO/mm3

Gastroentero/ Hepatol. 2012 Aug;6(4):449-465; quiz 466.

Geeganage C, Beavan J, ct al. Interventions for dysphagia and nutritional support in acute and subacute stroke. Cochrane Database Syst Rel( 2012 Oct 17;I O:CD000323. Kumar S. Swallowing and dysphagia in neurological disorders. Rev Neural Dis. 2010;7(1):19-27. Masri 0, Sharara A. Plummer-Vinson syndrome.

•Low albumin or prealbumin

C/in Gastroentero/ Hepato!. 2013 Dec;11(I 2):e85.

•Low triceps skin-fold thickness

•Low urine creatinine-to-height ratio

surgical management ofZenker's divcrticulum. Expert Rev

(24-hr

urine excretion of creatinine in µg) -o- (height in centimeters);< 10 in men;< 6 in women.

Patti MG, 1-lerbella FA. Achalasia and other esophageal motil ity disorders. J Gastrointest Surg. 2011 May;15(5):703-707. Saghafi 0, et al. Images Dx. Plummer-Vinson (Paterson-Kelly) syndrome. J Hosp Med. 2010 May-Jun;5(5):3 I l-312.

Greater than 10% weight loss over 6 months indicates

Smith MS. Diagnosis and management of esophageal rings

a possibility of malnutrition. Albumin is an indicator of

and webs. Gastroenterol Hepatol (N Y). 20I0Nov;6(11):

nutritional status, but it may also be lower after major

701-704.

trauma or during an infection (due to vascular leakage)

Spechler, Sharma SJ, et al. American Gastroenterological

or secondary to liver disease (low production) or the

Association medical position statement on the management of

nephrotic syndrome (secondary to "spillage" into the

Barrett's esophagus. Gastroenterology. 2011;140:I 084-1091.

urine). Malnourished patients may be anergic. Triceps

W hite GN, O'Rourke F, et al. Dysphagia: causes, assessment,

skin-fold measurement is good only for long-term assessment of nutritional status. Short-term changes may not be meaningful because of fluctuations in hydration and edema.

treatment, and management. Geriatrics. 2008 May;63(5): 15-20.

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de Wijkerslooth LR V leggaar FB, et al. Endoscopic manage

Lau JY, Barkun A, et al. Challenges in the management

ment of difficult or recurrent esophageal strictures. Am J

of acute peptic ulcer bleeding. lancet.

Gastroe/1/erol. 2011 Dec; I06(12):2080-2091; quiz 2092.

2013 Jun 8;381(9882):2033-2043.

Zografos GN, Georgiadou D, et al. Drug-induced esophagitis. Dis Esophagus. 2009;22(8):633-637.

Najm WI. Peptic ulcer disease. Prim Care. 2011 Sep;38(3):383-394, vii.

ASGE Standards of Practice Committee, Evans .JA, Early DS, ct al .. The role of endoscopy in Barrett's esophagus and other premalignant conditions ofthe esophagus. Gas1roinles1

Laine L, et al. Management ofpatients with ulcer bleeding. Am J Gaslroenlerol. 2012 Mar; I 07(3):345-360.

Endosc. 2012 Dec;76(6):1087-1094.

Lanza FL, et al. Practice Parameters Committee ofthe Ameri

Dellon ES, Gonsalves N, et al; ACG clinical guideline: Evi

can College ofGastroentcrology. Guidelines for prevention of

denced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic csophagitis (EoE). Am J Gas1roen1ero/. 2013 May; I 08(5):679-692;quiz 693.

NSAID-relatcd ulcer complications. Am J Gas/roentero/. 2009 Mar; I 04(3):728-738.

GASTRIC CARCINOID

Katz PO, Gerson, LB, et al. Guidelines for the diagnosis and

Zhang L, Ozao J, et al. Review of the pathogenesis, diagnosis,

management of gastroesophageal reflux disease.

and management of type i gastric carcinoid tumor.

Am J Gaslroenlerol. 2013 Mar; I 08(3):308-328. Erratum

World J Surg. 2011 Aug;35(8): 1879-1886.

in: Am J Gastroen/erol. 2013 Oct; I08( I 0): 1672.

GASTRIC CANCER

Shaheen NJ, Weinberg, DS, et al. Upper endoscopy for

Ajani JA, Barthel JS, Bekaii-Saab T, et al. NCCN Gastric

gastroesophageal reflux disease: best practice advice from

Cancer Panel. Gastric cancer. J Natl Compr Cane Ne!w.

the clinical guidelines committee ofthe American College of

2010 Apr:8(4):378 -409.

Physicians. Ann Intern Med. 2012 Dec 4; 157(11):808-816. Sharma P, Kozarek R. Practice Parameters Committee of American College ofGastroenterology. Role ofesophageal stents in benign and malignant diseases. Am J Gas1roenterol.

OTHER GASTRIC SYNDROMES Bolton JS, Conway WC. Postgastrectomy syndromes. Surg Clin Norlh Am. 2011 Oct;91(5):1105-1122. Tack J, Arts J, et al. Pathophysiology, diagnosis and

20 I 0 Feb; I 05(2):258-273. Stefanidis D, et.al. Guidelines for surgica l treatment ofgas troesophageal reflux disease (GERO). SAGES. 2010. http://

management of postoperative dumping syndrome. Na! Rev Gas/roenterol Hepa to/. 2009 Oct;6(I 0):583-590.

www.sages.org/publ ications/guide Iin es/guidelines-for-surgical

Camilleri M, Bharucha AE, et al. Epidemiology, mechanisms,

lreatment-o f-gastroesophageal-refl ux-disease-gerd/

and management ofdiabetic gastroparesis. Clin Gaslmenterol

Stefanidis D, Richardson W, et al. Society ofAmerican Gastro

Hepa!ol. 2011 Jan;9(1):5-12; quiz e7.

intestinal and Endoscopic Surgeons. SAGES guidelines for the

Hasler WL. Gastroparesis: pathogenesis, diagnosis and

surgical treatment ofesophageal achalasia. Surg Endosc.

management. Na! Rev Gastroenterol Hepatol.

2012 Feb;26(2):296-3 I I.

20 II Jul 19;8(8):438-453.

Wang, KK, Sampliner RE. Updated guidelines 2008 for the

Camilleri M, Parkman HP, et al. Clinical guideline:

diagnosis, surveillance and therapy ofBarrett's esophagus.

management of gastroparesis. Am J Gastroenterol.

Am J Gasfro. 2008; I 03:788-797.

2013 Jan; I08( I):18-38.

INFLAMMATORY BOWEL DISEASE

STOMACH den Hollander WJ, Kuipers EJ. Current pharmacotherapy

Blonski W, Buchner AM, et al. Inflammatory bowel disease

options for gastritis. Expert Opin Pharmacothe1:

therapy: current state-of-the-art. Curr Opin Gastroentero/.

2012 Dec;13(18):2625-2636.

2011 Jul;27(4):346-57.

Moayyedi P. Dyspepsia. Curr Opin Gastroentero/.

Kulaylat MN, et al. Ulcerative colitis and cancer.

2012 Nov;28(6):602-607.

J Surg Oneal. 2010 Jun 15;101(8):706-712.

Chey. et.al. American College ofGastroentcrology Guideline

Trikudanathan G, V. Diagnosis and therapeutic management of

on the management of Helicobacterpylori infection.

extra-intestinal manifestations of inflammatory bowel disease.

Am J Castro. 2007; I 02: I 808-1825.

Drugs. 2012 Dec 24;72(18):2333-2349.

Talley, Vakil N. et al. Guidelines for the management of

Wilkins T, Jarvis K, et al. Diagnosis and management of

dyspepsia. Am J Gas1ro. 2005; I 00:2324-233 7.

Crohn's disease. Am Fam Physician. 2011 Dec 15;84(12):1365-1375.

PEPTIC ULCER DISEASE (PUD) Drugs for peptic ulcer disease and GERO. Treat Guide/ Med let!. 2011 Sep;9(I 09):55-60; quiz 2 p following 60.

Kornbluth , Sachar DB, et al. Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gaslro.

Ellison EC, Johnson JA. The Zollinger-Ellison syndrome: a comprehensive review ofhistorical, scientific, and clinical considerations. Curr Prob/ Surg. 2009 Jan;46( I): 13-106.

2010; I 05:500-523. Lichtenstein GR, Hanauer SB, et al; Practice Parameters Committee of American College ofGastroenterology.

Jairath V, et al. The overall approach to the management of up

Management ofCrohn 's disease in adults. Am J Gaslroen/ero/.

per gastrointestinal bleeding. Gastroinlesl Endosc C/in N Am.

2009 Feb; I 04(2):465-483; quiz 464, 484.

2011 Oct;2 I (4):657-670.

FOR FURTHER READING

DIARRHEA Afshar P, Redfield DC. W hipple's disease: a rare disease revisited. Curr Gastroenterol Rep. 20I0 Aug;12(4):263-269. Bures J, Cyrany J, et al. Small intestinal bacterial overgrowth syndrome. World J Gastroentero/. 2010 Jun 28;16(24): 2978-2990. Jain A, Sebastian K, et al. Collagenous sprue, an enigma amongst the spectrum of celiac disease. Clin Gastroenterol Hepatol. 2013 Jun 8. Juckett G, Trivedi R. Evaluation of chronic diarrhea. Am Fam Physician. 2011 Nov 15;84( I 0):1119-1126. Lucendo AJ, Arias, A. Eosinophilic gastroenteritis: an update. Expert Rev Gas/roenterol Hepatol. 2012 Sep;6(5):59 l-60 I. McClarren RL, Lynch B, et al. Acute infectious diarrhea. Prim Care. 2011 Sep;38(3):539-564. Obokhare I. Fecal impaction: a cause for concern? Clin Colon Rectal Surg. 2012 Mar;25( I ):53-58. Rossit AR, Gon�alves AC, ct al. Etiological agents of diarrhea in patients infected by the human immunodeficiency virus- I: a review. Rev Inst Med Trap Sao Paulo. 2009 Mar-Apr;51 (2):59-65. Sandhu DK, Surawicz C. Update on chronic diarrhea: a run-through for the clinician. Curr Gastroentero/ Rep. 2012Oct; l 4(5):421-427. Siddiqui Z,Osayande AS. Selected disorders of malabsorption. Prim Care. 2011 Sep;38(3):395-4I4.

Lieberman DA, Rex DK, et al. Guidelines for colonoscopy surveillance alicr screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroent erology. 2012 Sep;143(3):844-857. Rex DK. Johnson DA. et.al. American College of Gastroenterology Guidelines for Colorectal Cancer Screening 2008. Am.! Gas1ro. 2009 Mar; 104(3): 739-750. U.S. Preventive Services Task Force. Screening for colorcctal cancer: U . S. Preventive Services Task Force recommendation statement. An11 Intern Med. 2008 Nov 4; 149(9):627-637.

DIVERTICULAR DISEASE AND LOWER GI BLEED Biondo S, Lopez B, et al. Current status of the treatment of acute colonic diverticulitis: a systematic review. Colorectal Dis. 2012 Jan;14(l):el-e l I. Debus ES, Miiller-Hiilsbeck S, et al. Intestinal ischemia. Int J Colorectal Dis. 2011 Sep;26(9): I 087-1097. Feucrstadt I', Brandt LJ. Colon ischemia: recent insights and advances. Curr Gastroenlero/ Rep. 20I0Oct;12(5):383-390. Hemming J, Floch M. Features and management of colonic diverticular disease. Curr Gastroenterol Rep. 2010 Oct;12(5):399-407. Barncrt J, et al. Diagnosis and management of lower gastrointestinal bleeding. Nat Rev Gastroentero/ Hepatol. 2009Nov;6(11):637-646. The role of endoscopy in the management of patients with peptic ulcer disease (PUD). Castro Endoscopy 20 I 0;71 (4):663-668. The role of endoscopy in the

Rubio-Tapia A, Hill. ID, et al; American College of

management of obscure GI bleeding. Gas/ro Endoscopy .

Gastroenterology. ACG clinical guidelines: diagnosis and

2010; 72(3):471-479.

management of celiac disease. Am.! Gas1roe111erol. 2013 May;I 08(5):656-676. Surawicz CM, Brandt LJ, ct al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gas1roe111ero/. 2013 Apr; I 08(4):478-498.

IRRITABLE BOWEL SYNDROME

AASLD Liver Biopsy 2009: http://www.aasld.org/practice guidelines/Documents/Bookmarked Practice Guidelines/Liver Biopsy.pdf American Society of Gastrointestinal Endoscopy: http://www. asge.org/publications/publications.aspx' 1 id-352 AASLD TIPS 2009: http://www.aasld.org/practiceguidelines/

Chang JY, Talley NJ, et al. An update on irritable bowel

Documents/Bookmarked Practice GuidelincsfflPS Update

syndrome: from diagnosis to emerging therapies.

Nov 2009.pdf

Curr Opin Gastroenlerol. 2011 Jan;27( I ):72-78.

COLON CANCER

Stoll man

1-1, Raskin JB. Diagnosis and management of diver

ticular disease of the colon in adults. Ad Hoc Practice Param

Benson AB 3rd, Arnoletti JP, ct al. National Comprehensive

eters Committee of the American College ofGastroenterology.

Cancer Network. Colon cancer. J Nall Compr Cane Netw.

A 111 J Gastroemerol. 1999 Nov;94( 11):3110-3121.

2011 Nov;9(11):1238-1290. Qaseem A, Denberg TD, et al. Screening for colorectal cancer: a guidance statement from the American College of Physi cians. Ann Intern Med. 2012 Viar 6;156(5):378-386. Burt RW, Barthel JS, et al. NCCN. NCCN clinical practice guidelines in oncology. Colorectal cancer screening. J Natl Compr Cane Nef\I'. 20 I 0 Jan;8(I ):8-61. Levin, Lieberman DA. et.al. Screening and Surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society. the US Multi-Society Task Force on colorcctal cancer. and the American College of Radiology. Gastroentero/. 2008 May;134(5):1570-1595.

BOWEL OBSTRUCTION Dayton MT, Dempsey DT, et al. New paradigms in the treatment of small bowel obstruction. Curr Prob/ Surg. 2012Nov;49(11 ):642-717. Maung AA, Johnson DC, et al. Evaluation and management of

small- )owel obstruction: an Eastern association for the surgery of trauma practice management guideline. .J 7i'auma Acute Care Surg. 2012 Nov;73(5 Suppl 4):S362-9. Diaz JJ Jr. Bokhari F, et al. Guidelines for management of small bowel obstruction. J hauma. 2008 Jun;64(6): 1651-1664.

INTESTINAL ISCHEMIA Debus ES, Miillcr-Hiilsbeck S, ct al. Intestinal ischemia. Int .J Colorectal Dis. 2011 Sep;26(9):I087-1097.

MedStudy

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FOR FURTHER READING

Feuerstadt P, ct al. Colon ischemia: recent insights and ad

Bhandari BM, et al. Primary biliary cirrhosis. Gastroenterol

vances. Curr Gastroenterol Rep. 2010 Oct;l 2(5):383-390.

C/in North Am. 2011 Jun;40(2):373-386.

Herbert GS, Steele SR. Acute and chronic mesenteric isch

Frossard JL, Morel P. Detection and management of bile duct

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Matin A, Sass DA. Liver disease in pregnancy. Gastroenterol Clin North Am. 2011 Jun;40(2):335-353.

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Reshetnyak VI, Karlovich Tl, et al. Hepatitis G virus.

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Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gaslroen/erol f-lepa10/. 2010 Jan;7( I ):31-40.

Wedemeyer H, Pischke S, et al. Pathogenesis and treatment of hepatitis E virus infection. Gastroen/erology. 2012 May;l 42(6):1388-1397. Wiest R, Krag, A, et al. Spontaneous bacterial peritonitis: recent guidelines and beyond. Gut. 2012 Feb;61(2):297-310.

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Ghany, Strader DB, et al. Diagnosis, management, and treatment of hepatitis C: an update. [AASLD Guidelines]. f-lepa10/ogy. 2009 Apr; 49(4):1335-1347.

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AASLD practice guidelines. Management of adult patients with ascitcs due to cirrhosis: update 2012. http://www. aasld. org/practiceguidelines/Documents/ascitesupdate2013.pdf. AASLD practice guidelines. Prevention and management of gastroesophagcal variccs and variceal hemorrhage in cirrhosis 2009. http://\\'\\ '\\ ·.aasld.org/practiceguidelines/Documents/ Bookmarked%20Practicc%20Guidelines/Prevcntion%20 and%20Management%20o l %20Gastro%20Varices%20 and%20Hemorrhage. pelf Advisory Committee on Immunization Prac tices (ACIP) Centers for Disease Control and Prevention (CDC). Update: prevention of hepatitis A a Iler exposure to hepatitis A virus and in international travelers. Updated recommendations of the Ad

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Diagnosis and management ofhemochromatosis: 2011 practice

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treatment, and prevention of vitamin D deficiency: an

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Infectious Disease HOST DEFENSE CYTOKINES

2-1

.................... . . . . . .. . . . . .. ............... ........................ . . . . . . .

2-1

.... ................... . . ..... . . . . . . . ....... . . . . . ....... .................. .. . . . . .

NEUTROPENIA

. . . .................. . . ......... . . . . . . . . . . ...................... ...........

Epidemiology and Risk Factors Febrile Neutropenia

. . ..............................................

............ . . ........... . . . ..... ..................................

HUMORAL DEFICIENCIES

.. ........ . . . . . ................... . . . . . ................

Inherited Deficiencies

......... . . . . ....... . . . ................... . . . . . . ...............

Acquired Deficiencies

.. . . . .............. .............. . . . . . . .................. . . . . . .

COMPLEMENT DEFICIENCY

. . . ............ . . . . . . ................. . . . .........

Classical Pathway Deficiencies

........... . . . . . . . . . ............................

Acquired Classical Deficiencies T-CELL DEFICIENCY

...... . . . ...................... ..................................

Solid Organ Transplantation HIGHLIGHTS

...... . . .......... ............ . . . . . . . . . . .......

. . . . . ........... .. . . . . . . . ............................

........... .. ........ . . . ...... . . . . . . . . . . ................ . . . . . . . ................

ANTIBIOTIC THERAPY

................... . . ....................... . . . . .................

HOW ANTIBIOTICS W ORK Review: Protein Synthesis

.... . . . . . . . . ........ . . . . ....... . . . . . . ......... . . . . . ...

.... . . . ............ . . . . . . . . . . . . . ................. . . . . . ..

Antibiotics that Block Protein Synthesis Review: Cell Wall Synthesis

...... . . . . . .................. . . . . .

...................... . . . . . . . ............ . . . . ........

Antibiotics that Affect the Cell Wall

. . . ..... .................... . . . . . . .......

Antibiotic that Affects the Cell Membrane IMPORTANT PI-IARMACODYNAMICS Important Basic Microbiology

....... . . . . . . .................. . . . . . . . ............

General Rules of Antibiotic Use

............. ..................................

Concentration-Dependent Killing Time-Dependent Killing

Overview of the Penicillins

. . . . . . . ..... . . . . . . ........... . . . . . . ... . . . . . . . ......... . . . .

. . ......... . . . . ........ . . . . . ......... . . . .. . . . . . . . . . .....................

Overview of Cephalosporins Monobactams Carbapenems

.................................................................... . . . ....

Tigccyclinc

..................................... . . . . ........................ .. . . . . .

. . . . . . . ......... . . . ......................... . . . . . . .. ..................... . . . .

.... . . ............ . . . ......... . . . ............ . . . . . . . . ........... . . . . . . . .......

Aminoglycosides

......... . . . . . ....... .. . . . . . ...... . . . . . . ......... .................. ..

Fluoroquinolones Macrolides

. . . . . . . . ....... . . . . . . ........ . . . . . . . . ..................... . . . .

. . ......... . . . . . . ....... . . . . . ........ . . . . . . . . . . . . .. ............ . . . . . . . . ......

Oxazolidinones Daptomycin

.... ............. . . ........ . . . . . . . . .......... .....

. ......... . . . . . . . ...... . . . . . . ........ .. . . . . . . .. . . . . . . . ....... . . . . . . . ......

OTHER ANTIBIOTICS Vancomycin

....... . . . . . .................... . . . . . . . . ...... . . .

................................... . ...................

.... . . .................................... . . . . . .......... . . . . .

Penicillin Allergy Again Desensitization

........................ . . . . . . .......... . . . . .

..... . . . . . . . . ............................. . . . . . . . . . . .......

BETA-LACTAM ANTIBIOTICS Development of PCNs

... . . . . .. ....... . . . . .......... . . . . ..................................

............... ....... ....................................... . . . . ............ . .

ANTIVIRAL AGENTS

. . . . . . . ........ . . . . . ........ . . . . . . . . . . . ............ . . . . . .......

ANTIFUNGAL AGENTS

....... . . . . .......... . . . . ..................................

Polyenes (Amphotericin and Nystatin) Imidazoles Triazoles

. . . . . .............................

....... . .......................................................................

....... . . . ............ . . . ......... . . . . ........... . . . . ............... . . . . . . . . ......

Echinocandins

. . .......... . . . . . . ................... . . . .................................

Other Anti fungals

.... . . . . . . . . ....... . . . . . . ........ . . . . . . . .. .............. . . . . . .......

ANTIPARASITIC DRUGS BACTERIA

...... . . . ....... . . . . . . . . . . . . ..

............. . . . ..................

... . . . . . . . ...... . . . . . . . . . . . . ...... . . . . . . . . . . ............

. . . . . . ..................................................................... ...... . . ...

GRAM-POSITIVE ORGANISMS Staphylococci

....... . . . . . . . ...............................

............................... . . . . . ................. .. . . . . ...............

Streptococcus pneumoniae

................ . . . . . . ................................

Streptococcus pyogenes (Group A)

. . . . . . . . . . ............... . . . . . . .........

Streptococcus agalactiae (Group B) Group D Streptococci Enterococci

.. . . . . . . ............. . . . ..............

. . . . . . ..................... ..................................

..... ............ . . . . . .................. . . . . . .. ...............................

listeria

.......... . . . .......... . . . . . . . ............ . . ......... . . . .................. . . . ........

... . . . . . . . . . . . ............................

Bacillus anthracis and Bacillus cereus Clostridium

. . . . . . . . ................ . . . . . ......

... ........... . . . ............................... ............ . . . . . . ............

Neisseria

2-1

Moraxella

Pseudomonas

.................... . . . ..... . . . . . .............. . . . . . . ...........................

....................... . . . . . ................ . . . . . . . . . . . . ..................

2-2

Enlerobacteriaceae

2-3

legionella

2-3

Bruce/la

Francise//a Bar/one/la

2-4

...... . . . . .... . . . . .......................................... . . ...

Rocky Mountain Spotted Fever Q Fever

2-5

Ehrlichia and Anaplasma

..................................... . . . ......

GRAM-VARJABLE BACTERIA ACID-FAST BACTERIA Mycobactcria

2-6

Nocardia

OTHER ORGANISMS Aclinomyces

SYPI-IILIS

2-7

LEPTOSPIROSIS

2-8

LYME DISEASE Overview

Diagnosis of Lyme Disease

2-8

Treatment of Lyme Disease

........... . ......... . . . . . . . . . . . . . . . ................

. . . . ............. ..................................

. . .................... . . . ........ . . . . .............. .................................. .........

OVERVIEW

2-11

CANDIDA

........................ . . . . ............ . . . .....................................

............ . . . . . . . . . . . . . . . . . . ................ . . . . . . .................... . . . . . . . . . . . .

2-11

Candidemia

2-12

Chronic Disseminated Candidiasis

2-12

Ocular Candidiasis

................................................................... . . . .......

CRYPTOCOCCUS.

2-13

ASPERGILLOSIS

2-13

ENDEMIC FUNGI

............................................................. . . . . . .....

....... . . . . .................................................. . . . . . . . . .

Coccidioidomycosis

2-13

Histoplasmosis

2-14

Blastomycosis

2-14

SPOROTRICHOSIS

........................................................................

........................................... ......... . . . . ...........

2-14

MUCORMYCOS!S

DERMATOPHY TES

............................................... ..... ........... . . ....

PARASITES

.. . . . . . . . . ............................................ . . . ..........

........................................................ ...... . . . . . . . . . . . . . ..........

PROTOZOA

2-15

Overview

2-15

Sporozoa

2-16

Malaria

2-16

Ameba

2-16

........................................ ...... . . . . . . . . ..........

........ . . . . . ......................................... ..... . . . . . . . . . . . . . .

2-14

2-17

................. ...................................................... . . . ......

........ . . . . ....................................................................

......................... . . . . . . . . . . . . . . ........... . . . . . . . . ......... ...............

. . .................. ............................................... ........ ... . . . ....

......................................... . . . . . . ......................................

Flagellates

......................... . . . . . . . .......... . . . . . . . . . . . . . . . ....... ................

1-!ELMINTHIC ORGANISMS

2-17

Overview

2-18

Nematodes

2-18

Tapeworms

2-18

Flukes ("Flatworms")

2-18

..................... . . . . . . . . . . . ............ . . . . . . . . . .

. . . . ..................................................... . . . ..........

2-13

2-14

VIRUSES

. . . . ......................... . . . . . . . . . . . . . . . . . . ....

..................... . . . . . . . . . ..... . . . . . . . . ........ . . . . . . . .......................

................................... ............... . . ...........................

........................ . . . . .............. . . . . ......... . . . . . . . . ...............

..... . . . . . . ........ . . . . . .... ..................................

............... ........... ............ . . . ........................................ . . . . ....

HERPES SIMPLEX VIRUS (HSV) 2-18

....... . . . . . . . . .. ................ . . . . . . . .

..................................................................

Genitourinary Candidiasis

2-12

VARICELLA-ZOSTER VIRUS

2-19

Chicken Pox

2-19

Herpes Zoster (Shingles)

2-27

...............................

. . . . . . . . . . ...... . . . . . . ...............................

Prevention of Lyme Disease

. . . . . . . . . . . ..... . . . . . . ....... . . . . ..........

... ......... . . . . . . ......... . . . . ..................

.. . . . . . . . . . . ..................................................... ... . . . .....

.. . . . . .. . . . . . . . . . . . . . ..... . . . . . . . . . ......................

CYTOMEGALOVIRUS (CMV)

...... . . . . . ............ . . . . . ....................

2-27 2-27

.............................................................. . . . . . . .............

Clinical Manifestations of Lyme Disease

2-10

2-27

. . . . . . . . . . .......................................... . . . .................

2-8

2-15

2-24 2-24

........................... .......... . . . . . . ........ . . ....................

2-8

2-12

2-24

........... . . . ............................ . . . . . .. . .

. . . . . . . . . . .....................................................................

...... . . ....... . . . . . ................................................................

2-8

FUNGI

2-24

. . . . . . . ...... . . . . . ........................................... . . . . . ...........

2-7

2-24 2-24

................... . . . . . . . ............................ . . . . . ....

Chlamydia I Chlamydophila

2-23 2-23

.......... . . . . .......... . . . . ...............................................

SPIROCHETES

2-10

2-23

........................ . . . . . ..................

................................. ... . . . . . . . . . . . . . . . . . . ...... . . ....................

2-7

2-10

2-23

.................. . . . . . ....... . . . . . . .. . . . . . .................

2-5

2-22 2-23

...................... ..................................

2-5

2-22 2-22

................ . . . . . . . . . . . . .. ...................................... . . . . . . . . . . .. . . . .

2-5

2-7

2-22

........................ . . . . ............................................... . . . . .

2-4

2-6

2-22

........................ . . . . . . . . ......... . . . . . ................................

2-5

2-6

2-21

............... . . . . . ..................... .......................................

Helicobac/er pylori RJCKEITS!A

2-20 2-20

2-22

......... . . . . . . .. . . . . . .............................................................

2-4

2-20 2-20

2-21

....... . . . . . ...................................... . . . . . ... . . . ....

. . . . . . .. . . ..... ............................ . . . . . . . ..............................

2-4

. . . . . . . . .. . . . . . ............ .......... . . ........

. . ....... . . . .......................... . . . . . . . . . . . . ........ . . . . ....................

2-1

Conmebacterium diphtheriae, JK, and Arcanobacterium haemolyticum

GRAM-NEGATIVE BACTERIA

2-27 2-28 2-28 2-28 2-28 2-28 2-28 2-29 2-29 2-29 2-29 2-30 2-30 2-30 2-31 2-31

2-31 2-31 2-32 2-32 2-32 2-32 2-32 2-33 2-35 2-35 2-36 2-36 2-36 2-38 2-39 2-39 2-39 2-40 2-40 2-40 2-41

EBV

2-41

......... ......... . . . .............. . . . . ............ . . . . . . .. ...................................

RUBELLA (GERMAN MEASLES) RUBEOLA (MEASLES) RETROVIRUS

....................... .....................................

. . . . . . ............. . . . . . . . . . ....... . . . ................. . . . . . . . . .............

RESPIRATORY VIRUSES Rhinoviruses

.....................................................

RABIES MUMPS

HAJ\TAVIRUS DENGUE

Brain Abscess

.... . . . . . . ..................... .....

.................... . . . . . . . . . . . . ........... . . . . . . . . . . . . . . . . . . . . . . . . . ........

...... . . . ........ . . . . . . . . . ......... . . . . . . .......... . . . . . . . . ........... . . . . . ..........

....... . . . . . ............................................................

Papillomavirus

......... . . . . . . ........................................................ . .

PRION DISEASE HIV AND AIDS OVERVIEW

.......... ...........................................................

......... . . . . . . . ....

......... . . ........................................

............ . . . . . . ......... . . . . . . . . . . . . ............................. ....... ....

............... . . . . . . . . ..................................................... . . . .

HIV STRUCTURE

......................................................................

HOW HIV INFECTS EPIDEMIOLOGY DIAGNOSIS

. . . . . . . . . .........................................................

........ . . . . . .............. . . . . . ................................. . . . . . .

.................................................

TREATMENT OF HIV INFECTION Antiretroviral Drugs

..............................

........................................

.............................................................. . .

Key Words and Side Effects State of Current Treatment

...

PRIMARY HIV INFECTION

...................................................

......... . . . . . . . . . . . . .............................

..... . . . . . . . . . .....................

I IIV I AIDS OPPORTUNISTIC l:-JFECTIONS Introduction

.......... . . . . . . .

.................... . . . . .

............. . . . . ............................................................

PULMONARY INFECTIONS Pneumocystis Pneumonia Tuberculosis

. . . . . . . . ........................

......... . . . . .....

................................................ .......

. . . . .......... . . . . . . . . . .....................................................

SYSTEMIC INFECTIONS

.................... ....................................

2-43 2-43

.................................

. . . . . . . . . ...... . . . . . . . . . . . ................ . . . . . . . ....................

................. .............................................................

................................... ............................................ . . . . .

GI IJ\FECTIONS Esophagitis Diarrhea

....... . . . . . .......... ...................................................

.......... . . . . . . ............ . . . . . . . . . . ............. ................... . . . . . . . .

.................. . . . ........ . . . . ........................................... . . . . . . .

MISCELLANEOUS INFECTIONS HCV

............... . . . . . . . . ....................

. . . ................ . . . . . . ................ ............... ..... ........... . . . . . . . . . . . ......

CMV

..................... . . ............... . . . . . .................... ... .............. . . .. . . . .

Kaposi Sarcoma

................................ ... . . . . . . . . . . . . . . .......... ...........

And Again: PJP and MAC Prophylaxis COMMON ID SYNDROMES

INFECTIVE ENDOCARDITIS (IE) N ative Valve Endocarditis

History and Physical Exam

............. . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . .

................ . . . . . . . . . . . . . . .......................

..... . . . . .................. . . . . . . . ......... . . . . . . ...........

Culture-:-Jegative Endocarditis Echocardiography Diagnosis

. . . ........... . . . . . . . . ....................

. . . . . . . . . . ....... .......... . . . . . . . . ....................

Prosthetic Valve Endocarditis Laboratory Evaluation

. . . . . . . . . . . . ......................

.................... ............. . . . . . . . ................

........... . . . . . . . . . . .......... . . . . . . . . . . ......

....... . . . . .......... . . . . . . . . ......................................

. . . . . . . . . . . . . ........ . . . . . . . . .................. . . . .......... ........... ..........

Preferred Treatment of B acterial Endocarditis Complications of E ndocarditis

....

. . .. . . . . . . . . ......

...... . . . . ................. ....................

...................... ..................................

Dia1Thea due to Shigella, Salmonella, or Campylobacler Diarrhea due to£. coli

2-44

Diarrhea due to C. difficile

2-44

Diarrhea due to Clyptosporidium Viral Gastroenteritis

......

. . . . . . . . . . . . . . . . . . . . . . ........... . . . . . . . . . . . . ........... . . . .

........... . . . . .................................. . . . . . .......

. . . . . . . . . . ................ . . . . . . ............... .......

................. . . . ...•................ . . .

.......... . . . . . . . ....... . . . . . . ..........

SEXUALLY TRANSMilTED DISEASES

2-45

Overview and Screening

2-45

GU Infections with Genital Ulcerations

2-45

Treatment.

2-45

PID

2-46

Cervicitis

......... . . . . . . ...... . .

...............................

. . . . ............. .......................................

.................................

................... . . . . . . . . . . . . . . . . . ............ . . . . . . . .................. . . . . . . .

............................... . . . ......... . . . . . . . ......

............ . . . . . . ............ . . . .

................................ . . . . . . .. . . .......................... . . . . . . . . . . . . .

2-46

Urethritis

2-46

Gonococcemia

2-46

Epididymitis

..................................................................................

. . . . . . . ............. ................................................ . . . . .

............... . .. . . . . . . . . . . . ....................... . . . . . ...................

2-46

Vaginitis

2-46

Urinary Tract Infection

2-47

OT!TlS AND SINUSITIS

.......... . . . . . . ........................... ............................... . . . . . . . . .

...........................................................

. . . . . . ....... .................................... . . . .......

2-58 2-58 2-60 2-60 2-60 2-60 2-60 2-60 2-61 2-61 2-61 2-61 2-62 2-62 2-62 2-62 2-62 2-63 2-63 2-64 2-64 2-64 2-65 2-65 2-65 2-66 2-67

2-47

Otitis Media

2-49

Otitis Extema

2-67

2-50

Sinusitis

2-68

2-51 2-52 2-52 2-52 2-52 2-53 2-53

...... . . . . . .................. . . . . .............. . . ............................

. . . . . . . . ......... . . . . . .....................................................

. . . ......................... .......................................................

SKIN I SOFT TISSUE, BONES, JOINTS Classic Soft Tissue Infections Osteomyelitis VACCINES

.. .

Adult Vaccinations PROPIIYLAXIS

2-54 2-54 2-54 2-54 2-55 2-55 2-55 2-55 2-55 2-55 2-55 2-55 2-56 2-56 2-56 2-56 2-57 2-58

. . . . . . . .................... . . . . .

.............................................. . . . . . . . . . . ..........

............................................................... . . . .

Malaria

2-54

. . . . . . . . ...... . . . . ............................................................

Travelers' Diarrhea

2-54

. . . . . . . . . . . . . . . . . . . . . . . . . . . .............. . . . . . . . . .

................................. ..... . . . . . ........

2-53

2-54

. . . . . . .................. ........

. . . . .................. . . . . . . . . . . . . ........... . . . .

. .............. . . . . . . . . ....................................................

NOSOCOMIAL INFECTIONS

2-54

Ciyptococcus ........................................................................... 2-54 Toxoplasma

INFECTIOUS DIARRHEA

Diarrhea due to Vibrio

2-44

......... . . . . . . . .

.......... . . . . . . ......... . . . . . . . . . ........................................

2-44

2-45

...

. . .............. . . . . ............. ............. . . . . ........

......................................... . . . ..............................

Meningococcemia

Mycobaclerium Avium-intracel/ulare

Syphilis

....... . . . . . . . . . . . . . . . . . . . . . ................ . . . . .

2-43

Mycobacterium Avium Complex I CNS INFECTIONS

. . . . . . . . . . . . . . . . . . . . . . ............. . . . . . . . . . . . . ............. . . . . . . . . . . . . .

Ncurosyphilis

.........................................................................

Polyomavirus JC

TIJ Meningitis

2-42

............ ........................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

SLOW VIRUSES

2-42

................................... ...............................

2-42

.................................... ....................... . . . . . . . .....................

ARBOVIRUSES

Aseptic Meningitis Lyme Meningitis

........ . . . . ............................................. . . . . ..................... . . . . .

PARVOVIRUS

2-42

................................................ . . . .............

Spinal Epidural Abscess

. . . . . . . ............. . . . . . . .................. . . . . . . . . . . . . . ........ . . . . ........

........... ..................................................... . . . . . . . .......

Bacterial Meningitis

2-42

.................. . . . . . . . . ..........................

. . . . . . . . . . . . . . . ... . . . . . . . . . . . . ......... . . . . . . . . ....

MENINGITIS

2-42

...

............................ . . . ...................................................

Coronavirus POLI0

..................... . . . ............... ..................... . . . . ............

Respiratory Syncytial Virus Influenza

............... . . .........................

........... .......................................................

............. . . . . . .................. . . . . . . . ............. . . . . ......... . . . . . . . . . . ......

FOR FURTHER READING

. . . . . . . .....................................................

2-67

2-68 2-68 2-69 2-69 2-70 2-70 2-72 2-72 2-72 2-73 2-73

HOST DEFENSE

Table 2-1: Cytokines

HOST DEFENSE Type

CYTOKINES See Allergy & Immunology, Book 4, for a description of

Interleukins

the basic functions of the immune system. Cytokines are signaling molecules produced by immune system cells. These molecules help different branches of the immune system talk to each other and respond to

IL-I

Fever, stimulates T cells

IL-2

Proliferates T cells, activates B cells

IL-4

tors on other cells to alter cell function. The molecules

IL-6

can ramp up the immune system or tone it down.

IL-12

Examples of cytokine types include colony-stimulating factors (CSFs), interferons (IFNs), interleukins (IL s),

IL-15

Covered here are the most clinically relevant cytokines

IL-17

and their functions.

Increases IFN-gamma, induces Thl

Induces TNF-alpha release Important in autoimmune chronic inflammatory reactions and anti-fungal immunity.

Cytokines are released in response to an interaction between T cells, an antigen-presenting cell (e.g., a mac rophage or dendritic cell), and an antigen that stimulates an immune response.The cytokines produced depend on

TNF-alpha IFN-gamma

TGF-beta

Activates T cells, NK cells,

Inhibits T-cell proliferation and pro-inflammatory cytokines

Major subsets includeT-helperThO, Th I, Th2, and Th 17: Platelet-derived

ThO cells are unrestricted. They are na"ive T cells

Cachexia, stimulates T cell

macrophages

the type ofT cell involved (termed a ''T-cell subset") and the cytokine profile of that subset.

Proliferates fibroblasts

growth factor

that can respond to novel antigens that the immune system has not yet encountered.

Th1 cells produce IFN-gamma, IL-2; are important in cell-mediated immune response (e.g., delayed-type hypersensitivity reaction); and are stimulated by the IL-12 superfamily.

•

Cell proliferator, acute-phase reactant

differentiation

and growth factors (Table 2-1 ).

•

Immunoglobulin switch signal, suppresses Th I

threats. After cells release them, they bind target recep

•

Functions

the condition is called sepsis. Tumor necrosis factor (T

F)-a may be the most important mediator. TNF-a is

a cytokine released by neutrnphils, monocytes, and mac rophages in response to endotoxin (lipopolysaccharide; LPS). Once released, TNF-a amplifies the signal LPS

Th2 cells produce IL -4 , IL- IO; are important in

and transmits it to other cells.

humoral immune response (antibody development and allergic responses); and are stimulated by IL-4,

•

IL-I 8, and IL-33, working together.

NEUTROPENIA

Th17 cells produce IL-17A, IL-l 7F, IL-22; are

Epidemiology and Risk Factors

important in antifungal immunity and also auto

Neutrophils help to fight disease by disrupting or con

immune-related chronic inflammatory diseases (e.g., rheumatoid arthritis, inflammatory myopathies); and are stimulated by IL-I, -6, -21, -23.

suming disease-producing cells and microorganisms. Neutropenia (granulocytopenia) occurs in leukemia, bone marrow transplant, ablative chemotherapy, expo

Cytokines that mediate cellular migration into tissue are

sure to drugs or toxins, bone marrow metastases, and

called chemokines. IL-8 is an example.

overwhelming sepsis. Most often, sepsis is caused by

Some cytokines that inhibit the immune system are

bloodstream across disrupted gut mucosa, via an intrave

prostaglandins, transforming growth factor (TGF)-beta, and IL-10.

nous catheter, or through the oropharynx into the lungs and/or sinuses. Neutropenic infections can be caused by

Unregulated cytokine systemic

flora that are colonizing the patient and that enter the

inflammatory

activation contributes response

syndrome

the

(SIRS),

which is a severe condition with systemic inflammation and organ dysfunction and failure. SIRS is diagnosed if any 2 of the following parameters are present: tem perature > 38 or

36; heart rate > 90; respiratory rate

> 20; WBC > 12.0 or> I 0% bands on peripheral smear. SIRS may have an infectious or a noninfectious etiol ogy. When infection is suspected or demonstrated,

both gram-negative and gram-positive bacteria. Of

the

gram

positives,

the

most

common

are

Staphylococcus aureus, S. epidermidis, and streptococcal species. But we are also seeing more infections associ ated with the less common gram-positive organisms such as Co1Jmebacterium species, Propionibacterium acnes, Bacillus species, and Leuconostoc. These are important to remember because some are not effectively treated with vancomycin.

2-1

2-2

HOST DEFENSE

Common gram-negative infections include Pseudomonas species

and

Enterobacteriaceae including Klebsiella species, and Enterobacter. Anaerobic

infections

are

not

seen

coli,

A thorough physical exam must be repeated every day. If you are giving treatment to increase the ANC, you may see localizing signs of infection become apparent

commonly

neutropenia.

as the ANC rises. Initial lab evaluations of febrile neutropenia include:

Fungi, including yeasts such as Candida and molds

•Complete blood count with differential

such as Aspergillus species, are important pathogens

• Basic chemistries

in patients with prolonged neutropenia. Infections with

•Liver transaminases and bilirubin

Fusarium species and agents of mucormycosis are espe cially deadly and are being seen more frequently. Not all fungi are equally susceptible to all antifungal drugs. When a patient with neutropenia develops fever and/or an infection while receiving an empiric antifungal drug, it

•::::

2 blood cultures, including a set from each lumen of

central venous catheters •Urine cultures if symptomatic and/or catheter in place and/or abnormal UA

is very important to know which organisms are resistant

•Cultures from other sites if symptoms (e.g., sputum)

to that antifungal. (See discussion of antifungal drugs on

•Chest x-ray (CXR) if there are respiratory signs or

page

2-14).

The risk for infection in the patient with neutropenia is directly proportional to the degree and duration of

symptoms Consider these tests in the appropriate circumstances:

neutropenia.

•If diarrhea present, stool for C. difficile toxin

Other factors that increase risk are:

•Lumbar puncture if the patient is confused without identifiable cause or has other signs of meningitis

•Comorbid diseases

•Fungal markers such as galactomannan (Aspergillus)

•Presence of catheters •Concomitant use of immunosuppressive drugs such as monoclonal antibodies and corticosteroids (risk of

Pneumocystis and tuberculosis) The absolute number of important. A patient with <

granulocytes

is definitely

500 neutrophils (severe neu

tropenia) is at much higher risk than a patient with just <

1,500 (mild neutropenia); however, patients can

actually have an adequate number of cells yet still get infected if the present granulocytes do not function properly. Suspect granulocyte dysfunction (e.g., chronic granulomatous disease) if the patient has an adequate absolute neutrophil count (ANC) but has a history of recurrent staphylococcal skin infections, lung infections, and/or lymphadenitis. The duration of neutropenia is also key: An ANC <

500 for > 7 days greatly increases

the risk of infection.

and beta-D-glucan (Candida and other fungi) •CT chest if respiratory symptoms and unrevealing CXR •Bronchoscopy or open lung biopsy for pathology, Gram stains, and bacterial/viral/fungal cultures in patients with pulmonary infiltrates •Skin biopsies for pathology and bacterial + fungal smears and cultures Empiric Treatment

When a neutropenic patient presents with fever, you must initially cover for gram-negative aerobic bacilli and streptococci. Oral empiric treatment in less severely ill patients includes the combination of ampicillin/sulbac tam with ciprofloxacin or moxifloxacin. Treat patients with signs and symptoms of sepsis with intravenous drugs such as: •Piperacillin-tazobactam •Carbapenem (imipenem or meropenem)

Febrile Neutropenia

•Cefepime

Evaluation

It is important to recognize febrile neutropenia and begin emergent evaluation and empiric antibiotics. The definition of febrile neutropenia is a temperature of

Vancomycin is added to the above empiric regimens if any of the following are present:

> l 01° F (38.3° C) x 1 or 100.4° F (38.2° C) on 2 occasions

• Hypotension or other evidence of severe sepsis

> I hour apart and severe neutropenia (defined as an ANC< 500 or expected to be< 500 in the next 48 hours).

• Positive blood culture for gram-positive bacteria

An important part of the evaluation is the physical exam

•Pneumonia documented radiographically

with concentration on the upper airway mucosa (look

• Persistent fever while on empiric antibiotics

for mucositis), teeth and periodontal tissues, eyes, and

•Obvious skin infection or erythema at the site of an

rectum. Neutropenic patients, however, may lack local izing signs of inflammation. Any rash or skin ulceration/ swelling is potentially significant. Portals that allow infections to enter may include catheters and implants.

(before organism/susceptibility is discerned)

indwelling catheter •History ofMRSA infection or known colonization •Severe mucositis if quinolone prophylaxis has been given or ceftazidime is employed as empiric therapy

HOST DEFENSE

•Some unusual Candida species (C. parapsilosis,

uiz •

What are some differences between Th1, Th2, and ThO T-cell subsets?

•

Name some factors that affect whether a patient with neutropenia develops an infection.

•

What are your options for empiric treatment of the febrile neutropenic? When is vancomycin included?

•

What fungi are not covered by echinocandins?

•

In the empiric treatment of febrile neutropenia,

•

C. guilliermondii. Usually these have higher MICs with unclear clinical significance.) Worry about these organisms if the patient has persistent fever and neutropenia while on an empiric echinocandin. Know that fluconazole should not be used as an empiric antifungal because: •clinical trials show it doesn't work, and •it is ineffective against Aspergillus and some resistant yeasts (C. glabrata, C. krusei). Regarding which specific antifungal to choose, usually it doesn't matter, except in the following circumstance: Definitely choose voriconazole or liposomal amphoteri

when would you want to choose voriconazole or

cin B in the patient with a pulmonary presentation con

liposomal ampho B over an echinocandin?

sistent with invasive pulmonary aspergillosis.

What is the most common inherited

Empiric antifungal coverage resolves the fever in about

immunodeficiency?

1/2 of patients. It is problematic, however, because reso lution offever on an antifungal drug does not necessarily

Know which gram-positive organisms are not covered by vancomycin: •Vancomycin-resistant Enterococcus (VRE) •Leuconostoc •Lactobacillus •Pediococcus Worry about these organisms if the patient has persistent fever and neutropenia while on empiric vancomycin; however, the last 3 are fairly uncommon. VRE is much more relevant clinically. If vancomycin is included in the initial regimen, dis continue after 2 days if there is no evidence of a gram positive infection.

mean the patient has a fungal infection. Duration of treatment is often a problem. Note: Patients with acute myeloid leukemia (AML) have a markedly increased risk of developing Aspergillus infection.

Prophylaxis and Adjuvant Treatment According to the 20 I 0 IDSA guidelines, prophylactic antibiotics (e.g., ciprofloxacin and levofloxacin) should be considered for those at high risk of infection, particu larly those with expected neutropenia duration > 7 days and an A C :S 100 during this time period. In these same guidelines, colony-stimulating factors that stimulate the bone marrow to produce more neutro phils (e.g., G-CSF) are recommended in patients who

If the fever and neutropenia persists after 4--7 days on

arc at risk (:'.:'. 20% chance) of developing fever (e.g.,

empiric antibiotics (including vancomycin), empirically

expected long duration of neutropenia with low ANCs).

treat for a fungal infection by adding: •an echinocandin (caspofungin is the only one FDA

However, these agents are not recommended in treatment of established fever and neutropenia.

approved for this indication but other echinocandins are equally effective), •liposomal amphotericin B, or •voriconazole. Fluconazole is less effective as an empiric antifungal and should not be used. Know the organisms that are not covered (or probably not covered) by the echinocandins: •Cryptococcus •Fusarium •Filamentous molds (Mucor) •Endemic fungi (histo, blasto, cocci) Relative resistance to echinocandins occurs in: •Aspergillus species (Echinocandins can be used for salvage and/or combination therapy.)

HUMORAL DEFICIENCIES Humoral deficiencies can be inherited (e.g., X-linked agammaglobulinemia, common variable immunodefi ciency, lgA deficiency) or acquired (multiple myeloma [MM], acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], HIV /AIDS, asplenia).

Inherited Deficiencies The inherited disorders usually present in childhood and are typically cared for by pediatricians. Diseases are diag nosed by measuring total levels of immunoglobulins A, G, and M. (IgA is typically low; lgG and IgM should be normal.) Know that selective lgA deficiency is the most common inherited immunologic defect. Most patients have no symptoms. Symptomatic patients present with recurrent sinopulmonary disease from encapsulated organisms,

2-3

2-4

HOST DEFENSE

recurrent

giardiasis,

and

food/respiratory

allergies.

These patients often form autoantibodies and may have autoimmune diseases such as chronic autoimmune thyroiditis (previously Hashimoto's), celiac disease (glu ten-sensitive enteropathy), pernicious anemia, systemic lupus erythematosus (SLE), and rheumatoid arthritis. Know these 3 important facts about selective lgA deficiency:

Classical Pathway Deficiencies Cl, C2, and C4 deficiencies: recurrent sinopulmonary infections +/- otitis media with encapsulated bacteria, specifically pneumococcus, H. influenzae, and N. men ingitidis.These deficiencies are associated with develop ment of systemic lupus at an early age.

C3 deficiency: severe infections with pneumococcus and H. influenzae from infancy.

I) Women can have false-positive serum pregnancy tests. (Urine pregnancy test is nonnal.)

C5-C9 deficiencies ("terminal complement deficiency"): recurrent

2) Blood transfusion is associated with a higher-than

Neisseria

infections

(meningococcus

and

gonococcus). Thus, these patients often have recurrent

nonnal risk of anaphylaxis and should be avoided if

meningo - and gonococcemia. Usually the presentation

possible.These patients have anti-IgA antibodies, and

is mild or moderate-mortality from these infections in

transfused blood contains small amounts of IgA.

this group of patients is low.

3) IVIG and plasma infusions are contraindicated for the same reason as blood transfusion.

Screen patients for classical complement deficiencies if they have had recurrent bacterial infections and nonnal CBC and immunoglobulins or if they have repeat neis

Acquired Deficiencies

serial infections (or a family history). The screening

Acquired deficiencies are common clinical scenarios for the general internist. Infections arise because either effective antibodies are not produced or B and T lym phocytes are not communicating effectively with one another. Most of these diseases are associated with hypogammaglobulinemia (reduction in levels of specific lgA, M, and G) but with a relative polyclonal increase

test of choice is the CH50, sometimes also called "total hemolytic complement" or THC. Deficiency causes an undetectable CH50 titer. Once the CH50 is established as abnonnal, measure each individual complement com ponent to detennine the specific deficiency. C2 deficiency is the most common, and tenninal deficiencies are least common; so start with measurement of C2.

in the gamma globulin fraction (i.e., patients produce an excess of fairly useless antibodies that are not specific for an antigen, are usually ineffective, and may cross react with nonnal body components such as red cells and platelet surface receptors). Patients

with

acquired

humoral

deficiencies

are

predisposed to infections with encapsulated organisms, gram-negative rods (GNRs), and giardiasis. Recurrent giardiasis should trigger a workup for this. The spleen clears out bacteria and is the site for fonnation of opsonizing antibodies. Opsonizing antibod

Acquired Classical Deficiencies Certain systemic diseases that activate complement are associated with an increased risk for infection as a result: •Systemic lupus erythematosus •Mixed cryoglobulinemia due to chronic hepatitis B (HBV) or hepatitis C (HCV) •Some vasculitic diseases (polyarteritis nodosa) •Some primary renal glomerulonephritides, even when systemic complement levels are not that low

ies are important in defending the host from infection

End-stage liver disease is also associated with clinically

with encapsulated organisms, especially pneumococcus.

significant

Splenectomy and functional asplenia increase the risk

cannot synthesize these proteins.

hypocomplementemia

because

the

liver

of overwhelming pneumococcal, malarial, and babe sial infections. The latter 2 are intra-RBC protozoan parasites. IgA blocks viral attachment to mucosa! surfaces, and

T-CELL DEFICIENCY Overview T-cell-deficient patients are said to have decreased "cel

lgG blocks viral attachment to host cells.

lular" immunity.T-cell defects occur in the following: •HIV/AIDS

COMPLEMENT DEFICIENCY The complement cascade and complement deficiencies are discussed in Allergy & Immunology, Book 4.

•Hodgkin lymphoma ifT-cell-derived •T-cell variant of ALL

Deficiencies result in an increased risk of infection and

• Prolonged corticosteroid use

autoimmune disease.

•Solid organ transplantation (because of immuno

Let's review a summary of the complement deficiencies and the types of infections that tend to occur in each.

suppressant Rx) Patients withT-cell defects are more susceptible to routine community-acquired bacteria and viruses (pneumococ cus,

Mycoplasma,

Legionella, Listeria,

Salmonella,

ANTIBIOTIC THERAPY

HIGHLIGHTS

uiz •

Splenectomy predisposes a patient to worse infection from what organisms?

•

Patients with which complement deficiencies are at risk for Neisseria infections?

•

What test is used to screen for complement deficiencies?

•

Review the infections associated with solid organ transplants and when each is likely to occur.

influenza, respiratory syncytial virus [RSV]), and oppor tunistic infection (OT) with the following pathogens: •Bacteria (Nocardia, Rhodococcus equi, mycobacteria) •Viruses (especially new infections with cytomegalo virus [CMV], herpes simplex [HSY], varicella zoster [VZV]) •Fungi (Pneumocystis, Cryptococcus, Aspergillus, endemic fungi) •Parasites (Strongyloides) Patients also frequently reactivate protozoa! and viral diseases that they have previously held in check: • Toxoplasma gondii •CMV, HBV, HCV, VZV, H SY, papillomavirus, and BK polyomavirus Solid Organ Transplantation Patients who have received a solid organ transplant are also at risk for infections carried by the donor organ as well as nosocomial infections. Additionally, they can reactivate infections that had been previously controlled by their immune system. Some of these infections are mentioned above but also include endemic fungi and mycobacteria. Infections caused by immunosuppressive drugs tend to arise predictably, based on the length of treatment. Know the following classic 3 post-transplantation time periods and their associated infection risks: I) Month I : infections from the donor; nosocomial infec tion (specific to the type of surgery performed). 2) Months 2-6: Immunosuppressant medication is starting to take effect, and patients are at risk for the Ois described above. CMV can occur in a donor+/recipient- situation. 3)

6 months: community-acquired infections.

However, the use of routine prophylaxis with TMP/ SMX and valganciclovir has shifted the time of onset of some Ols. For instance, CMV may not occur until after valganciclovir is stopped in these patients.

[Know.] Inherited humoral deficiency of IgA: •Sinopulmonary infections with encapsulated organisms • Giardiasis •Food and inhalant allergies •False-positive serum pregnancy tests • Anaphylaxis with blood transfusion and IVIG •Association with autoimmune diseases Acquired humoral deficiencies: splenectomy, leukemias, lymphomas, myeloma, HIV IAIDS, encapsulated organisms. Classical complement deficiencies: sinopulmonary infections with encapsulated organisms, C2 deficiency that is associated with SLE. Terminal complement deficiencies: encapsulated organ isms, meningococcemia. T-cell defects: HIV /AIDS, post-transplant, corticosteroids, fungi, acid-fast bacteria, viruses, parasites.

ANTIBIOTIC THERAPY HOW ANTIBIOTICS WORK Most antibiotics work by subverting bacterial protein synthesis (Figure 2-1 ), folate metabolism, or the bacte rial cell wall or cell membrane. First, let's review protein synthesis; then we'll tackle how specific antibiotics block it. Review: Protein Synthesis The DNA molecule must be unwound from its supercoiled arrangement before it can be "read" by RNA polymerase. This involves cutting the strand, holding onto the cut ends to prevent them from being damaged, allowing the double helix to uncoil and the DNA to be copied, and then precisely gluing the cut ends back together again. The key enzyme that carries out this process in bacteria is DNA gyrase.

Transcription:

RNA polymerase moves along a section of DNA (a gene), uncoiled by the DNA gyrase and, following the coded messages on the deoxyribonucleotides, forms a string of complementary-paired ribonucleotides; i. e., a piece of RNA-more specifically, pre-mRNA. With the removal of an intron, the pre-rnRNA becomes rnRNA (messenger RNA). This is called transcription because the DNA code is transcribed into a complementary RNA code. Translation: Ribosomes are the translation units that convert the coded message in the mRNA to a specific sequence of amino acids. A 30S ribosomal subunit attaches to the mRNA at the "ribosome binding site," then moves along the RNA until the RNA reaches the start codon (AUG). Here, a tRNA (with anticodon

2-5

2-6

ANTIBIOTIC THERAPY

..:i!D

RNA polymerase 0NA

c;.� � ···· AUG

AAG

� �

mRNA

lniliation complex

···

� ..· �

quinolones and metronidazole. Rifampin binds to RNA polymerase. Tetracyclines bind reversibly and aminoglycosides bind irreversibly to form the ?OS ribosome. Oxazolidinones and macrolides bind to the 50S subunit.

A represents transcription. DNA gyrase is targeted by B to

C shows attachment of the 30S subunit to

to D shows attachment of the 50S subunit to

the mRNA.

Figure

2-1: Ant1b1ot1c Effects on Protein Synthesis

UAC), carrying an altered methionine (f-Met), binds with this subunit and mRNA to form the "initiation com plex." A

SOS ribosomal subunit then comes along and 70S ribosome.

binds to this complex to form the

Amino acid-specific transfer RNAs (tRNA) attach to

20 amino acids used in making protein. The bottom loop of these "inverted cloverleaf-shaped" tRNAs has 3 the

unpaired bases called anticodons. As the

the 30S subunit.

Tetracyclines (e.g., doxycycline) bind reversibly to 30S subunit, distorting it so that the anticodons of

the

the tRNAs cannot align properly with the codons on the mRNA.

Macrolides (erythromycin, clarithromycin, azithromycin) bind reversibly to the SOS subunit. They prevent peptide bond formation between the amino acids and, hence, keep the

70S ribosome moves along the mRNA, tRNAs

attach one at a time, bringing these amino acids with them. These amino acids are bound together, forming a

70S ribosome from translocating down the mRNA.

Clindamycin works very similarly to macrolides. Oxazolidinones (e.g., linezolid) and streptogramins SOS ribosomal subunit, thereby preventing

gradually lengthening protein chain.

bind to the

When the ribosome reaches the end of the coded message,

attachment to the initiation complex.

translation stops. The ribosomal subunits then separate and detach from the mRNA, and the completed protein is released.

Trimethoprim and the sulfonamides block the produc tion of folic acid from para-aminobenzoic acid (PABA). Folic acid is required to replicate DNA.

Antibiotics that Block Protein Synthesis Rifampin binds to RNA polymerase and blocks initiation of the transcription of DNA to mRNA.

Review: Cell Wall Synthesis Peptidoglycan

component

bacterial

cell

walls. It is composed of alternating polysaccharides:

Quinolone antibiotics (e.g., ciproftoxacin, levoftoxacin, moxiftoxacin) specifically target the DNA gyrase of bac teria. This allows the DNA gyrase to cut the double helix but then prevents the cut ends from being rejoined.

N-acetylglucosamine

(NAG)

and

N-acetylmuramic

acid (NAM). Cross-links form between the alternating strands that make the wall solid. NAG and NAM (and their cross-links) vary slightly between gram-positive and gram-negative organisms.

Metronidazole, a very important antianaerobic and antiprotozoal agent, probably has a primary mode of action similar to the quinolones, although it also affects

Gram-negative organisms have an

outer membrane

(OM) outside of the cell wall.

cell membrane function.

Antibiotics that Affect the Cell Wall Aminoglycosides (e.g., gentam1cm, amikacin) bind irreversibly to the 30S ribosomal subunit and prevent the SOS subunit from attaching.

A variety of antibiotics act at one or more stages of peptidoglycan synthesis. In order for an antibiotic to affect the cell wall of gram-negative organisms, the drug has to pass through the OM-passage is affected by

ANTIBIOTIC THERAPY

done to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the drug for those bacteria (see next).

•

Which antibiotics target DNA gyrase to interrupt protein synthesis?

•

usually by a microtiter method.

Which antibiotics antagonize folic acid?

Disk diffusion (Kirby-Bauer) testing is now used for

How are gram-negative organisms inherently

specific, difficult-to-treat bacteria that do not grow well

more resistant to antibiotics, compared to gram

in the automated media or for testing with antibiotics

positives?

that are not included in the standard panels.

Which class of antibiotics affects the developing bacterial cell wall?

•

Most hospitals currently use an automated system that performs identification and sensitivity simultaneously,

MIC and MBC

What information does the disk diffusion test

[Know.] The MIC is the concentration of antibiotic that

give you?

inhibits visible growth (visible turbidity) in vitro after

What is the specific definition of MIC and MBC?

drug size and charge. Thus, some gram-negative organ isms have inherent resistance to certain cell wall agents that are less able to pass through the OM.

24 hours of incubation. At the 24-hour assessment, some of the broth dilutions that have a higher concentration of drug than the MIC still have organisms growing in them-just not in sufficient numbers to cause turbid ity. But, if you subculture the non-turbid cultures that contain

higher concentrations

drug for

another

Beta-lactams are a class of antibiotics that interrupt

48 hours and then reassess growth, you can determine

formation of the bacterial cell wall. Because there is

the minimum bactericidal concentration (MBC). The

no analogous structure in human cells, relatively high

MBC is the concentration of drug that kills 2: 99.9% of

doses can be administered. However, idiosyncratic reac

the initial inoculum.

tions may occur with beta-lactams. Especially remem ber penicillin allergy, anaphylaxis, and acute interstitial nephritis.

Vancomycin works by inhibiting cell wall synthesis of gram-positive organisms. Telavancin (a synthetic derivative of vancomycin) works on inhibiting cell wall synthesis and also disrupting the cell membrane.

alternative

way

testing

MIC

with

the

Epsilometer test (Etest) strip, which uses a gradient of multiple concentrations of an antibiotic on a strip placed on the lawn of the bacteria growing on the agar. If your patient has a critical bacterial infection, which concentration of antibiotic do you aim to deliver to the site of infection-the MIC or the MBC? Of course, you would prefer the MBC-because you want 99.9% of

Antibiotic that Affects the Cell Membrane

Daptomycin inserts into the cell membrane of gram positive bacteria, creating a channel that allows for efflux of ions and disruption of membrane polarization.

the infection eradicated. The problem is that the MBC is costly, time-consuming, and less standardized so most microbiology labs do not perform them. However, as a general guideline, the MBC is - 8-lOx the MIC. Usually-prescribed

IMPORTANT PHARMACODYNAMICS Overview What happens to those blood, urine, and goop samples in the lab?

Important Basic Microbiology Bacteria can be directly visualized with a Gram stain and then grown in media. Some specimens are placed

drug

dosages

typically

achieve

therapeutic blood and tissue levels resulting in a concen tration that is around 8-1 Ox the MIC (i.e., the probable MBC) at the patient's site of infection. This dose may not be achievable because of toxicity, and of course you almost never know the concentration of an antibiotic at the actual site of infection.

General Rules of Antibiotic Use Know these important points:

directly in liquid (without a Gram stain first) if they are

•Source control is key to treating serious infections. If

not known to be certainly infected (e.g., blood). The

pus can be drained, do it. Lines, catheters, and devices

liquid medium is incubated for 24 hours and observed for development of turbidity, which would indicate bacterial growth. Once bacterial growth is established, identification and sensitivity testing are done. Traditionally, the culture would then be plated on various agar plates to identify the bacteria, and disk diffusion susceptibility would be

may need to be removed. • Pick the drug with the proper spectrum for the suspected or proven pathogen(s) and the site of infection. • Adjust dosage for body size and clearance when appropriate.

2-7

2-8

ANTIBIOTIC THERAPY

•If the patient does not respond, consider 3 things: 0

Development of PCNs

Is the patient getting/taking the drug? Is there

This topic area covers the penicillin-based antibiotics

resistance? 0

using the above development timeline.

ls there an undrained focus of infection? Know the difference between concentration

Penicillin

dependent killing and time-dependent killing.

The drug was first mass-produced and used effectively during World War II to treat war wounds. Today, PCN

Concentration-Dependent Killing Concentration-dependent

killing

means

that

killing

increases as you increase the concentration of drug above the MIC for the bugs you are treating. This is sometimes

referred

"dose-dependent"

killing

because killing is based on concentration above MIC, not on time. Aminoglycosides and quinolones are drugs that exhibit concentration-dependent killing. Quinolones

and

aminoglycosides

also

exhibit

post-antibiotic effect (PAE). A PAE is persistent kill ing of bacteria even after the concentration of drug has fallen below the MIC at the site of infection. The dose dependent killing and PAE allow these drugs to be dosed once daily, achieving a high peak concentration.

is appropriate mainly for streptococci, sensitive entero cocci, Listeria, Pasteurella, and syphilis. It has decent activity against gram-positive skin flora and some mouth anaerobes, but poor activity against gram negatives and gut anaerobes. Staphylococci rapidly developed resistance by producing penicillinase, a beta-lactamase enzyme that destroys the drng. These resistant staphylococci are referred to as "methicillin-sensitive" because they were sensitive to the next major drng class to come along which was ... Semisynthetic (Penicillinase-Resistant) Penicillins Methicillin (and later, oxacillin, nafcillin, and dicloxa cillin): These drugs are called "semisynthetic penicil

lins" and are stable against penicillinase. Semisynthetic

Time-Dependent Killing

penicillins, like nafcillin, are the drugs of choice for

In time-dependent killing, the concentration of drug above

S. aureus (MSSA), S. epidermidis (MSSE), and other

the MIC does not really matter. Instead, killing is related

coagulase-negative staphylococci.

to how long the concentration of antibiotic remains greater than the organism's MIC at the site of infection (termed "time over MIC"). Beta-lactams, macrolides, and glycopeptides (vancomycin) are such drugs. Aim for serum concentrations above the MIC for

50% of the

Today you only rarely encounter a penicillin-sensitive

Staphylococcus, but if you do, penicillin remains the drug of choice. The semisynthetic penicillins are good for skin flora but still lack activity against gram negatives. So, the next

dosing interval. Because beta-lactams are time-dependent, it is not as

major drug class to be developed was the ...

important to aim for 8-1 Ox the MIC with each dose. Instead, patients need repeated, reliable dosing intervals

Aminopenicillins

so they don't have prolonged periods during the dosing

Ampicillin (and its oral formulation, amoxicillin): These

interval when their serum levels fall below the MIC. The clinical relevance is that, with time-dependent killing, patients who miss doses risk treatment failure.

drugs are called "aminopenicillins." They retain the effi cacy of prior penicillins but also kill some susceptible gram-negative organisms, such as E. coli and Proteus

mirabilis. Therefore, this new class added activity against urogenital and colonic bacteria.

BETA-LACTAM ANTIBIOTICS

Unfortunately, resistance developed quickly; bacteria

Overview of the Penicillins The first of the beta-lactam antibiotics was penicillin (PCN). Its derivatives were created either to increase its spectrum of activity or to address developing bacterial resistance.

started producing other beta-lactamases. Another standing issue was that the aminopenicillins did not kill the more resistant gram-negative rods (GNRs) such as Klebsiella and Pseudomonas. So, the next major drug class to be developed was the ...

The development timeline of these drugs is: PCN - semisynthetic PCNs - aminoPCNs - extended

Extended-spectrum Penicillins

spectrum PCNs - aminoPCN/extended-spectrum PCNs

Piperacillin and ticarcillin: These

+ beta-lactamase inhibitors (BLls).

"extended-spectrum PCNs" (ES-PCNs) because they

drugs are called

take the spectrum of ampicillin and extend it to cover the more resistant GNRs, including Pseudomonas. The only problem with these PCNs was the rapid development of resistance via more beta-lactamases. So, the next addition to come along was the ...

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ANTIBIOTIC THERAPY

for the organisms' cell walls-except for the newest cephalosporin, ceftaroline. The staph that express this

Q�uiz •

•

gene

are

called

methicillin-resistant

(methicillin-resistant

What is the difference between concentration

resistant

dependent and time-dependent killing?

resistant coagulase-negative staph).

S. epidermidis [MRSE], and other methicillin

Vancomycin,

What is a post-antibiotic effect?

staphylococci

S. aureus [MRSA], methicillin

daptomycin,

and

linezolid

effectively

treat serious MRSA infections. Newer drugs with anti

In time-dependent killing, how long should a

MRSA activity include ceftaroline,

patient's serum concentration of a drug be

telavancin, and

tigecycline. Their exact clinical roles remain to be

higher than the infecting organism's MIC?

determined. Mild skin and soft tissue MRSA infections

•

What is the spectrum of activity of penicillin?

often retain susceptibility to clindamycin, trimethoprim/

•

Nafcillin is the drug of choice for which

sulfamethoxazole, or doxycycline.

•

organisms?

Next, we will discuss each type of PCN again, but in

What coverage does ampicillin add over

slightly more detail.

penicillin? Which important organisms does ampicillin not cover? •

Penicillin Again

Which organisms do extended-spectrum

Penicillin (PCN), as noted above, has the beta-lactam

penicillins cover? •

•

ring. It is very active against most streptococci (groups A

B l ls are combined with which drugs?

and

What is meant by "extended-spectrum

also active against some anaerobes usually found above

penicillins"? Which bacteria do they cover? •

B, viridans group, and S. pneumoniae), Pasteurella

(animal bites), Listeria, and many Neisseria species. It is the diaphragm (e.g., in the mouth; Prevotella) but not

What is a potential complication of nafcillin?

those found below (e.g., B. fragilis). Even though PCN is indicated for meningococcal infections, rifampin or quinolones are better for eradication of the carrier state.

Addition of Beta-lactamase Inhibitors

Addition of a beta-lactamase inhibitor (BU): Sulbactam,

Rifampin concentrates in the upper respiratory mucosa.

tazobactam, or clavulanic acid-in combination with an

PCN is still the drug of choice for many infections,

aminoPCN or an ES-PCN-protects the PCN from beta

including:

lactamase hydrolysis.

• Erysipelas due to Streptococcus pyogenes (group A)

PCN + BLI combinations: • IV ampicillin + sulbactam

• Streptococcus agalactiae (group =

• Viridans streptococci (some are now resistant to PCN

Unasyn®

•Oral amoxicillin + clavulanic acid= Augmentin® • IV ticarcillin + clavulanic acid= Timentin®

and ampicillin) • PCN-sensitive

S. pneumoniae

• Treponema pallidum (syphilis)

• IV piperacillin + tazobactam = Zosyni& The drugs retain the activity of the parent PCN, but

• Leptospirosis

they are also effective against bacteria that make beta

• Actinomycosis

lactamase. For example, Augmentin does not treat

• Neisseria meningitidis (bacteremia and meningitis)

Pseudomonas because ampicillin is intrinsically resistant

but can treat MSSA.

Nafcillin and Dicloxacillin Again

Penicillinase-resistant, semisynthetic penicillins (nafcillin, Extended-spectrum PCNs

Blls

oxacillin, and dicloxacillin) are used to treat methicillin

(Aka Anti-Pseudomonal PCNs)

sensitive

The

this penicillinase. Clinically, nafcillin and oral dicloxa

ES-PCNs

with

BLis

(Timentin

and

Zosyn)

can be used to treat gram-negative rods (including Pseudomonas), gram-positive cocci (including entero

cocci and MSSA), and both mouth and gut anaerobes. Organisms that are resistant to these drugs can be very difficult to treat.

S. aureus because 85% of the S. aureus have

cillin are used only to treat MSSA and MSSE. An important potential complication of these drugs is an immediate (on exposure) IgE-driven anaphylaxis. A less serious complication is a drug rash (which usually occurs several days after exposure). Serious late drug reactions include acute interstitial nephritis. Remember

Evolution of MRSA

Staphylococci eventually acquired the mecA gene, which encodes a change in the penicillin-binding proteins that the beta-lactams use to bind the bacteria. MecA tran scription results in reduced affinity of all beta-lactams

MedStudy

that manifestations of interstitial nephritis are fever, eosinophilia, and rash. Eosinophils may also be found in the urine. Allergic drug reactions are much less common with nafcillin or oxacillin than with methicillin.

2-9

2-10

ANTIBIOTIC THERAPY

Ampicillin Again

Overview of Cephalosporins

Ampicillin has a spectrum similar to PCN, but its

Cephalosporins also contain the beta-lactam ring but

spectrum

are inherently penicillinase-resistant because of their

extends

include

certain

gram-nega

coli, H. irifluenzae, Salmonella, Shigella, and Proteus mirabilis. However, it does not cover Klebsiella and resistant isolates of H. infiuenzae, E. coli, and P mirabilis. tive rods-especially

some E.

than the PCNs-probably the easiest way is to consider them based on their generation category. It is useful to remember that the spectrum of these drugs generally tends to widen and include more GNRs as the genera

Ampicillin is the drug of choice for: • Listeria

structure. They are slightly more difficult to remember

tions increase in number. Cephalosporins have no activity

monocytogenes

against enterococci and

Listeria. With the exception of

•Salmonellosis-if sensitive

ceftaroline, all methicillin-resistant staphylococci are

•UTis due to susceptible organisms

resistant to all cephalosporins.

•Susceptible enterococcal infections 1s1 Generation Cephalosporins

Ticarcillin and Piperacillin Again Piperacillin (the most commonly used extended-spec trum PCN) is more effective against the gram-negative organisms

(including

(including B.

Pseudomonas) and anaerobes fragilis). Similar to ampicillin-only

more "extended." Remember: A beta-lactamase inhibi tor can be added to ticarcillin (Timentin) and piperacillin (Zosyn) to protect the beta-lactam from beta-lactamase hydrolysis. They are the only PCN drugs effective against P

aeniginosa and Acinetobacter.

such as

E. coli, Klebsiella, and Proteus. (In fact, the

GNR coverage is superior to ampicillin.)

151 generation cephalosporins are commonly given for: •Skin and soft tissue infections from sensitive organisms •Oral treatment of mild urinary tract infections

Penicillin allergy is often claimed by patients. Know that you can test for this by performing skin test ing; a negative skin test has a negative predictive >

Cefazolin and cephalexin are unlike PCN in that they have some coverage against community-acquired GNRs

•Some surgical prophylaxis

Penicillin Allergy Again

value of

151 generation cephalosporins (e.g., IV cefazolin and PO cephalexin) are active against MSSA and most strep.

95% and thus makes a future anaphylactic

reaction to penicillin very unlikely. As an alternative, patients can also be desensitized.

2nd Generation Cephalosporins Gram-negative coverage increases for most of these drugs with coverage of H.

infiuenzae (cefuroxime ), Enterobacter and Neisseria gonorrhoeae. Pneumococcal coverage is retained. Two drugs in this group, cefoxitin and cefotetan, are noteworthy for their anaerobic cover age. These drugs are used to treat:

Desensitization

•Pelvic inflammatory disease (PID)

Desensitization is a procedure that can be done for any

•Postoperative abdominal infections

patient with an IgE-mediated immediate hypersensitivity reaction to a medication. Common antibiotics that can cause this reaction are the beta-lactams, quinolones, and clindamycin. Vancomycin can also cause an IgE-mediated immedi ate hypersensitivity reaction. However, the "red man syndrome" that may occur with vancomycin is a dis tinctly separate reaction that is approached differently (page 2-12). A typical desensitization procedure starts with very tiny oral or IV doses

(1/1,000 to 1/10,000 x normal) with

increased dosage every 15 minutes. After 4-8 hours, a full dose is reached, and a temporary tolerance to the drug is achieved. The patient can then be given the full course of the antibiotic. This tolerance is lost rapidly once the drug is stopped, so the procedure has to be

The 3rd generation cephalosporins have largely replaced the 2nd generation except for anaerobic infections (usually due to gut flora).

3rd Generation Cephalosporins 3rd

generation

against

most

cephalosporins

are

beta-lactamases

and

generally have

stable

enhanced

against pneumococci, H. irifluenzae, and gonorrhoeae. The GNR coverage is also enhanced

activity N.

over previous generations, so these drugs are better for the

Enterobacteriaceae (E. coli, Klebsiella, Proteus, Enterobacter, and Serratia). Remember the following facts about 3'd generation cephalosporins: •They are great pneumococcus drugs, so they are rec

repeated if the drug is ever given again.

ommended as

Note: Generally, oral doses are the preferred method,

pneumonia and PCN-resistant pneumococcal men

but even with oral doses, the patient must be in a moni tored setting where treatment for anaphylaxis (injectable

1st line agents for community-acquired

ingitis in combination with vancomycin for empiric treatment.

epinephrine and other drugs) is available at the bedside.

ANTIBIOTIC THERAPY

Monobactams Aztreonam is the only monobactam beta-lactam. It covers

uiz

only gram-negative bacteria, including Pseudomonas. Its

•

Which cephalosporins have anaerobic activity?

•

3rd

•

spectrum is similar to aminoglycosides and

3rd genera

tion cephalosporins. It is not active against gram-positive

generation cephalosporins are known for their activity against which organisms?

cocci or anaerobes. This drug can be used in patients with beta-lactam allergy, which is its niche. It is available for

Which beta-lactam drug can be given to patients with a penicillin allergy?

intravenous or inhaled use only.

Carbapenems •None of the drugs are I st line agents for MSSA;

Overview

I st generation cephalosporins or nafcillin/oxacillin

lmipenem, meropenem, ertapenem, and doripenem

are preferred for MSSA. •None of the drugs cover anaerobes.

are broad-spectrum beta-lactams recommended only for

2"d generation

use in complicated infections involving multiple organ

cephalosporins or PCNs are better. • Ceftazidime is the only

3rd generation drug that has

antipseudomonal activity. •Three of the

3rd generation cephalosporins can cross

an inflamed blood-brain barrier; therefore, they are indicated as the primary therapy for meningitis

isms (such as in the abdomen or the diabetic extremity with possible bacteremia) and for empiric treatment of the very sick. Carbapenemases

caused by Enterobacteriaceae. These are ceftri

Carbapenemases

axone (Rocephin®), cefotaxime (Claforan®), and

lactamases that confer carbapenem resistance. Various

difficile diarrhea than early generations.

aware

that

very

resistant

GNR

isolates

with

beta-lactams, including the carbapenems. These very

est in spectrum and the most stable against resistance. Cefepime has the gram-negative activity of

3rd genera

tions and gram-positive activity of I st generations, with enhanced stability against cephalosporinases. It has limited anaerobic coverage. highly

years. Be

The 4th generation drugs could be considered the broad

of the

beta

carbapenemases are emerging-with resistance to all

4th Generation Cephalosporins

aware

carbapenem-hydrolyzing

forms of these have been identified over the last several

ceftazidime.

•Their use has been associated with more C/ostridium

are

resistant organisms sometimes colonize the GI tract. Generally, we rely on the carbapenems to provide cover age for the most resistant organisms, so this discovery is very discouraging. The most critical characteristic of these very resistant organisms is their predilection for spreading--causing

resistant

organisms

that

produce extended-spectrum beta-lactamases (ESBLs)

community-acquired infections (especially E. coli) and nosocomial infections (especially

K. pneumoniae).

and cause significant infections in hospitalized patients and patients who have been repeatedly exposed to beta lactams. ESBL production is not always present when a patient first gets the infection. It is often induced by empiric antibiotic treatment with a beta-lactam. These patients may get better initially and then get worse again as their isolate begins to tum on the resistance genes and make ESBLs. However, a clue to the presence of an ESBL isolate is the selective in vitro susceptibility to cefepime, when the isolate is resistant to all other beta lactams. Currently, a carbapenem (imipenem or merope nem) is the drug of choice for empiric ESBL therapy. 5th Generation Cephalosporins

The only

5'11 generation cephalosporin currently FDA

approved is ceftaroline. Its main advantage is that it is the only cephalosporin that covers MRSA skin infec tions. It cannot be used to treat Pseudomonas infections.

Individual Carbapenems lmipenem covers most bacterial classes: gram-positive

cocci (GPC); GNRs, including Pseudomonas and other resistant GNRs; mouth and gut anaerobes (B. fragi/is). It also is effective against ESBL-producing organisms. The few organisms resistant to it include: • Enterococcus faecium • Burkho/deria cepacia • Corynebacteriumjeikeium

(JK)

•Stenotrophomonas ma/tophi/ia •Acinetobacter species • MRSA Also, remember that although E. coli and K. pnewnoniae are typically sensitive to imipenem; the carbapenemase producing variety can spread easily and cause major problems. Resistance is increasingly common in Pseudomonas isolates especially in those patients with recurrent infec tions such as patients with cystic fibrosis.

2-11

2-12

ANTIBIOTIC THERAPY

[Know:] Imipenem can lower the seizure threshold,

Vancomycin sometimes (when it is rapidly infused)

so it should not be used in patients with seizures and

causes the "red man syndrome," consisting of tachy

advanced-stage chronic kidney disease.

cardia, flushing, occasional angioedema, and generalized

Imipenem is always fonnulated with equal amounts of cilastatin (combo= Primaxin®). Cilastatin is an enzyme inhibitor that impairs the metabolism of imipenem in the renal tubule, thereby increasing its half-life to I hour. Cilastatin is not a beta-lactamase inhibitor. Meropenem is a similar carbapenem with a longer

pruritus. It is an infusion-rate-related phenomenon that is usually associated with mast cell degranulation and release of histamine. The red man syndrome is not a true allergy. Patients who experience this reaction can be retreated with the drug if it is infused more slowly. Pretreat these patients with

blockers.

formulations of vancomycin had significant renal and

half-life, so there is no need for an enzyme inhibitor.

ototoxicity; current fonnulations rarely cause toxicity at

Doripenem is the newest carbapenem and has similar

nonnal doses(< 4 g/day).

activity and phannacokinetics to meropenem.

The sole indication for oral vancomycin is C.

Ertapenem is a carbapenem with once-daily dosing but

(pseudomembranous) colitis. IV

no activity against

Pseudomonas. Otherwise its spectrum

effective for C.

difficile

vancomycin is not

difficile.

is similar to the other carbapenems. Because it is available as once-daily dosing, it is useful

Oxazolidinones

for outpatient parenteral treatment, especially of diabetic

Linezolid is the only oxazolidinone on the U.S. market.

feet, and for abdominal, pelvic, and skin and soft tissue infections. Understand that once-daily dosing is a big deal for a beta-lactam because these drugs usually exhibit time dependent killing; hence, most have frequent-dosing schedules.

bacteriostatic

agent

active

against

VRE (vancomycin-resistant enterococci). Linezolid has no indication for bacteremia. Linezolid is available in oral (with 100% bioavailability) and IV preparations. to vancomycin for MRSA; however, due to concerns about side-effect profile (below), this drug is a

Vancomycin is a glycopeptide antibiotic that is effective

MRSA, MRSE,

cost and developing resistance, as well as an unfavorable

Vaneomycin most

The oral fonn of linezolid makes it a desirable alternative

OTHER ANTIBIOTICS

against

Linezolid

gram-positive organisms, including MRSA, MRSE, and

gram-positive

organisms,

including

Clostridium, and Corynebacterium. It is

a large molecule that diffuses poorly into most tissues with only about 1/8 of the blood concentration reaching the site of infection. It exhibits time-dependent killing, so pre-dose("trough") levels are measured to assure that they are about 8 times the usual cutoff for susceptibility

(2 µg/mL), as well as to limit toxicity. For most serious infections, pre-dose levels between 15 and 20 µg/mL are

2°ct line

agent for MRSA. Vancomycin remains the current drug of choice for MRSA treatment when the MIC is <

1 µg/mL. For staphylococcal isolates with a vancomy

cin MIC :'.:'. I µg/mL, the antibiotic is usually switched to linezolid or daptomycin. For a MIC :'.:'.

2 µg/mL, the

antibiotic is always switched to linezolid or daptomycin. Linezolid

can

cause

reversible

thrombocytopenia,

anemia, and leukopenia, especially if the patient has been taking it

2 weeks. It is also associated with

development of a sensory neuropathy. Know that linezolid can cause very serious CNS effects

recommended. Clearance of vancomycin in patients undergoing hemo dialysis may vary widely depending on the membranes used, so levels are needed to guide dosing. Some strains of enterococci are vancomycin-resistant. MICs are increasing in staphylococci but vancomycin

(serotonin syndrome) when used concurrently with selective serotonin reuptake inhibitors (SSRis) and serotonin-norepinephrine reuptake inhibitors (SNRis).

Daptomycin

resistant staphylococci (MIC :'.:'. 16 µg/mL) are exceed

Daptomycin is a cyclic lipopeptide active against gram

ingly rare. However, increases in the MIC that are still

positive organisms. It is indicated for treatment of skin

within the susceptible range

(1-2 µg/mL) are associated

with vancomycin treatment failure. Some experts sug gest using an alternative drug to treat the infection; e.g., linezolid or daptomycin. (Remember that daptomycin is inactive in the lungs, so linezolid should be used for vancomycin-resistant staph pneumonia.) It remains con troversial whether to start an alternative agent as soon as the MIC is available or wait for clinical outcome. Staphylococci with an MIC between

2 and 8 µg/mL for

vancomycin are considered to have intennediate suscep tibility, and alternative drugs should be used if possible.

and soft tissue infections, bacteremia, and right-sided endocarditis caused by MSSA or MRSA(see above). It is a parenteral drug with a long half-life that allows once-daily dosing. Generally, it is reserved for resistant organisms such as MRSA and V RE. Know that dapto mycin is inactivated by pulmonary surfactant and thus is not effective in treating pneumonia. A potential com plication of use is myopathy, so be careful with patients who are also taking a statin drug. Monitor CK levels at least weekly during use.

ANTIBIOTIC THERAPY

Fluoroquinolones Ciprofloxacin, levofloxacin, moxifloxacin, and gemi

Q�uiz •

floxacin

Which carbapenem should be avoided in those with seizures?

•

3 have both IV and oral forms. The oral bioavailability

with fairly good >

2 µg/ml?

Pseudomonas activity. Ciprofloxacin pneumoniae coverage.

On the other hand, levofloxacin and moxifloxacin are

What are potential complications of linezolid

approved for S.

use?

Moxifloxacin is less active than the others against GNRs,

pneumoniae; i.e., respiratory infections.

but it is the most active quinolone for M

Aminoglycosides exhibit what type of killing?

•

What can happen to a ciprofloxacin if it is dosed with a multivitamin?

tuberculosis and

is active against most anaerobes. Know the following side effects, complications, and contraindications of fluoroquinolones:

The use of which class of antibiotics is

•They are chelated by cations (Mg+2, ca+2), so certain

associated with tendon rupture? •

fluoroquinolones.

should not be used for empiric S.

•

FDA-approved

Think of ciprofloxacin as a gram-negative only agent,

What are the drugs of choice for staph pneumonia with a vancomycin MIC

the

is-100%.

Ertapenem is useful for treating diabetic infections in what type of setting?

•

are

Gemifloxacin is available only in oral form; the other

vitamins and laxatives may reduce their absorption.

What happens to the concentration of

•They can increase theophylline levels.

theophylline if a patient is also prescribed

•Do not give to pregnant/lactating patients or children.

erythromycin?

(FDA says no one

18 years of age; except cipro

floxacin is now approved for 2"d line therapy in children

Tigecycline Tigecycline is the first of the new class of antibiotics

called glycylcyclines, which are derivatives of tetracy cline. It is broad-spectrum with activity against gram positive organisms (including VRE, MRSA), anaerobes, and gram-negative rods. It has some coverage against ESBL-producing GNRs; however, it is not active against

Pseudomonas and has reduced activity against Proteus and Providencia. Tigecycline is indicated for complicated skin and soft tissue infections and intraabdominal infections. Give IV. Nausea and vomiting are its main side effects, occurring in > 20% of patients.

with UTis and patients with cystic fibrosis.) •Do not use them to treat MRSA, even if susceptibility testing shows that the isolate is sensitive-because of the possibility of development of resistance. •Quinolones predispose to tendonitis and tendon rupture (especially the Achilles tendon in older adults). •Peripheral neuropathy that may be irreversible has been reported.

Macrolides Three macrolides are currently available: erythromycin, clarithromycin, and azithromycin.

Erythromycin is effective against:

Aminoglycosides

• Mycoplasma

Aminoglycosides (AGs; gentamicin, tobramycin, ami kacin, streptomycin) are effective against the following:

•Aerobic GNRs (but not anaerobic GNRs such as

fragilis) • Yersinia pestis (plague) Francisella tularensis (tularemia) • Bruce/la species (brucellosis) • M tuberculosis • M avium-intracellulare •

AGs are also used to treat patients with febrile neutrope nia, in combination with a 3rd generation cephalosporin or an ES-PCN + BLI when local beta-lactam resistance rates are too high to trust beta-lactam monotherapy. These drugs exhibit concentration-dependent killing and a considerable post-antibiotic effect. Hence, they are best dosed once daily after a loading dose. Potential complications of use include oto- and nephrotoxicity more likely if amphotericin B is also used.

pneumoniae • Chlamydophila pneumoniae • Campylobacter •Diphtheria •Pertussis It is less effective against H. against Q fever

injluenzae and is not effective (Coxiella burnetii), which you would

treat with tetracycline. It increases intestinal motility; GI side effects may be poorly tolerated by patients. Erythromycin increases the concentrations of theophyl line, cyclosporine, and warfarin. Clarithromycin and azithromycin have better S.

moniae and

pneu influenzae coverage than erythromycin

and have better GI tolerance. Clarithromycin is available only orally, but azithromycin comes in both IV and oral formulations and has a very long half-life that allows for once-daily dosing.

2-13

2-14

ANTIBIOTIC THERAPY

ANTIVIRAL AGENTS

Infusion-related chills and fevers ("shake and bake")

Acyclovir is a nucleoside analog used for the treatment of

herpes simplex and varicella-zoster viruses. Treatment of zoster infections requires higher doses. High doses

may be severe. Some recommend giving a test dose first. Hypotension with the 1st dose may occur (decrease in peripheral vascular tone). Liposomal amphotericin B preparations are less nephro

can cause renal failure. Valacyclovir and famciclovir are oral antivirals that

also treat herpes simplex and varicella-zoster infections. Only acyclovir is available intravenously and is used to treat severe infections. Valacyclovir and famciclo vir drugs are used primarily for less-frequent dosing of outpatients. They are considerably more expensive than acyclovir.

toxic and have less infusion-related side effects, but are much more expensive. They are used primarily when toxicity has become a problem with the amphotericin deoxycholate preparation. However, lipid preparations may be better for some fungal infections, especially those that enter the reticuloendothelial system, such as cryptococcal meningitis

and disseminated histoplas

mosis. Lipid ampho B is also used to treat zygomycosis

Ganciclovir is used to treat cytomegalovirus (CMV )

(Mucor and Rhizopus) because you can give higher

infections in post-transplant patients and those with HIV/

doses of the preparation without nephrotoxicity.

AIDS. Typical CMV infections are retinitis, encephali tis, pneumonitis, colitis, and, occasionally, severe bone marrow suppression (neutropenia and thrombocytopenia). This drug is preferred over foscarnet and cidofovir.

Topical polyene macrolides are nystatin and amphoter icin B. These are effective only against mucocutaneous

candidiasis (not ringworm). Both are also available in liquid form for oral and esophageal candidiasis.

Valganciclovir is an oral preparation similar to ganciclovir

but with better absorption, leading to blood levels com parable to IV ganciclovir. Foscarnet is used in patients with ganciclovir-resistant

herpes infection or as an alternative to ganciclovir for CMV. Foscarnet toxicity includes decreases in serum potassium, calcium, magnesium, and phosphorus along with renal failure.

lmidazoles Ketoconazole is an oral and topical preparation that is

rarely used because there are better drugs now. Increased gastric pH (low acid) decreases oral absorption, so do not prescribe to patients taking H 2 blockers or proton pump inhibitors (PPis). Ketoconazole does not penetrate CSF well and increases levels of indinavir and digoxin,

Ribavirin is used as part of combination therapy for

with potentiation of benzodiazepines. Side effects of oral

hepatitis C. It may cause significant hemolytic anemias,

medication include nausea and hepatitis. It also causes

requiring downward dose adjustments.

a decrease in androgen production; hence, patients may

Amantadine and rimantadine ("adamantanes") were

have decreased libido, and males may get gynecomastia.

used to treat influenza A in the past but are no longer rec

Ketoconazole has many, sometimes dangerous, interac

ommended because of resistance (unless you are certain

tions with common drugs. For serious fungal infections,

your strain is susceptible). They are ineffective against

it has largely been replaced by fluconazole or itraconazole.

influenza B. Occasionally, these drugs are useful against

It is used rarely to treat refractory tinea infections.

oseltamivir-resistant influenza A. One side effect is CNS/ psychiatric toxicity, especially with amantadine.

Clotrimazole and miconazole are available in both

cutaneous and vaginal preparations (e.g., for vaginal

Oseltamivir and zanamivir are neuraminidase inhibitors

candidiasis). Many other preparations are also avail

that treat both influenza A and B. Resistance to oselta

able. They are used to treat cutaneous candidiasis, tinea

mivir is more common than resistance to zanamivir;

versicolor, and ringworm.

however, overall, these drugs are preferred to the ada mantanes--depending on local resistance patterns.

Triazoles

See page 2-47 for the antiretroviral medications.

ltraconazole is a triazole analog of ketoconazole and is

generally more effective and safer. Capsules should be

ANTIFUNGAL AGENTS

taken with food; a cola drink (acidity) helps with absorp

There are 4 major classes of antifungal medicines: poly enes, imidazoles, triazoles, and echinocandins.

tion. Always check levels when using itraconazole. The liquid formulation has much better bioavailability; but food decreases absorption, so take liquid on an empty stomach. Indications include endemic fungi (histo

Polyenes (Amphotericin and Nystatin)

plasmosis [including chronic suppressive therapy for

Amphotericin B deoxycholate used to be the standard

treatment for most systemic mycoses. Currently, it has been mostly replaced by lipid polyene formulations,

disseminated disease], blastomycosis, coccidioidomyco sis, and cryptococcosis), oral and esophageal candidiasis (especially if fluconazole-resistant), and sporotrichosis.

echinocandins, and azoles. It is given IV only and has

Fluconazole is indicated for oral and esophageal candi

many side effects: fever, renal failure, anemia, phle bitis, renal tubular acidosis, and low K+ and Mg2+.

diasis, candidemia (for susceptible isolates), disseminated

candidiasis, cryptococcosis, and vulvovaginal candidiasis.

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ANTIBIOTIC THERAPY

Caspofungin acetate is approved for:

Q�uiz •

•

peritoneum, pleural space, and fluconazole-resistant esophagitis

What class of drugs should no longer be used to treat influenza A?

•

Candidemia and Candida infections of the abdomen,

•

Liposomal amphotericin B preparations are used in what circumstances? Against which fungi?

Invasive aspergillosis in severely immunocompromised patients who are intolerant of lipid amphotericin B or voriconazole

Micafungin (Mycamine®) is similar to caspofungin but

Which candidal species are resistant to

does not require a loading dose and seems to have fewer

fluconazole?

drug interactions.

•

What are the indications for voriconazole?

Anidulafungin (Eraxis"'), the newest echinocandin, has

•

What are the indications for caspofungin?

•

similar activity to the other agents. Most experts use an echinocandin as their drug of choice

It has excellent penetration into the CSF. It should never be used as empiric antifungal treatment in febrile neutropenic

for empiric antifungal therapy in febrile neutropenic patients.

patients. Know the candidal species that are either entirely resistant (C. krusei) or have some degree of resistance (C. glabrata).

Other Antifungals

Be aware that fluconazole has many interactions.

and penetrates well into the CSF. Upon entering a fungal

Voriconazole is a triazole with an extended antifungal

spectrum,

including

Aspergillus,

Fusarium,

glabrata

and

krusei,

Scedosporium

(Pseudallescheria). The drug can be given orally or IV. Voriconazole is I st line therapy for invasive aspergil losis. Major toxicity is transient, reversible alterations in visual acuity and color vision. It happens in about 30% of patients 30 minutes after administration and lasts 30 minutes (30-30-30 rule). Check voriconazole serum levels whenever you are treating a serious infec tion because significant variations in levels occur from

Flucytosine (5-fluorocytosine; 5-FC) is highly soluble

cell, it is metabolized to the antimetabolite 5-fluorouracil. If used alone, drug resistance develops quickly. Amphotericin B used in combination with 5-FC both

decreases drug resistance development and has a syner gistic antifungal effect. This combination is used to treat cryptococcosis and serious forms of candidiasis. Note that 5-FC can cause serious GI, hepatic, renal, and bone marrow toxicities-the latter usually presents as neutropenia and thrombocytopenia. Slight decreases in renal function can increase 5-FC to toxic levels.

person to person. Posaconazole is the newest triazole with the extended

antifungal spectrum of voriconazole, and it has additional activity against the zygomycetes (e.g., Rhizopus, Mucor). It is FDA-approved for prophylaxis of Aspergillus and Candida infections in those with severe immunocompro mised states, including prolonged neutropenia or stem cell transplant recipients with graft-versus-host disease. It may be used for treatment of oropharyngeal candidiasis (partic ularly organisms refractory to itraconazole or fluconazole), invasive Aspergillus, and zygomycetes. It is an oral agent

ANTIPARASITIC DRUGS Praziquantel (Biltricide®) is the only drug effective

against all species of Schistosoma. It is effective against flukes and tapeworms. It is a T solium. Albendazole

for

intestinal

round

worms

be used only in non-pregnant patients.

that requires tid or qid dosing. Check posaconazole levels,

Niclosamide is a

tapeworm. Pentamidine

Terconazole is the only vaginal triazole fomrnlation

used

(Ascaris), cysticercosis, and schistosomiasis. It should

and make sure that patients take it consistently with a high fat meal.

2"d line drug to treat neuro

cysticercosis (brain cysts) caused by the pork tapeworm,

2"d line drug used for the treatment of effective

against

trypanosomiasis

(e.g., African sleeping sickness). F or Pneumocystis jir

for vulvovaginal candidiasis. Oral fluconazole is very

oveci, which is a fungus and not a parasite, it is given

effective as a single dose and is usually used instead of

via IV for treatment or via inhalation for prophylaxis.

topical agents.

It is not recommended as a I st line drug for treatment because of the many side effects, including azotemia, leukopenia, pancreatitis, and hypo- or hyperglycemia.

Echinocandins Echinocandins

inhibit

beta-1,3-glucan,

essential

component of the cell walls of several fungi, including Aspergillus.

Nitazoxanide is approved for treatment of Giardia lamblia and Oyptosporidium parvum. Other antifun gals for giardiasis include tinidazole, albendazole, and metronidazole with paromomycin. Antimalarial drugs: See Malaria, page 2-33.

2-15

2-16

BACTERIA

and fever along with 3 or more signs of organ system involvement:

GI (vomiting, diarrhea), muscle (myalgia or

elevated CPK), acute kidney injury, liver (transaminase or bilirubin elevation), thrombocytopenia, or altered consciousness. Hypocalcemia may also occur. The classic association is with tampon use during menses; however, currently about half of staphylococcal TSS cases are not menstrual. Supportive care; source control, including Image 2-1: Carbuncle on buttock

Image 2-2: Staphylococcal scalded skin synd.

removal of infected devices; and antibiotics are indicated. Streptococcal TSS is the other classic form of TSS. It is a complication seen in about 1/3 of invasive infections with Streptococcus

BACTERIA

pyogenes (group A strep). Risk factors

include trauma, surgery, and viral infections. Note: In staph TSS, blood cultures are usually negative,

GRAM-POSITIVE ORGANISMS

whereas in strep TSS, blood cultures are usually positive.

Staphylococci Overview

MRSA Treatment

S. aureus is the most common cause of soft tissue infec tions. Staphylococcus is the usual cause of folliculitis,

MRSA bacteremia and other serious MRSA infections

furuncles, and carbuncles (aka skin abscesses or boils;

remains the drug of choice for skin and moderate

Image

2-1 ), and impetigo. Patients often inaccurately

report a "spider bite" when in fact they have a staphylo coccal boil. The primary treatment for boils is to incise and drain the infection. Purulent drainage associated with surrounding cellulitis may also need to be treated with

trimethoprim/sulfamethoxazole,

tetracycline,

are

initially

treated

with

vancomycin. Vancomycin

to-severe soft tissue infections and invasive MRSA. Organisms with an MIC :::;

2 µg/mL are considered "sus

ceptible," but treatment failures are more common as the MIC climbs over

I µg/mL. Because of this, many

ID experts now recommend alternative drugs (linezolid or daptomycin) to treat isolates with MIC > 1 µg/mL in

linezolid, or clindamycin, given orally.

invasive disease. Tigecycline and linezolid are not indi

S. aureus is also an important cause of bacteremia,

cated in MRSA bacteremia; so, for now, do not use them

especially among those exposed to needles such as

to treat endocarditis/bacteremia.

IV drug abusers, insulin-using diabetics, hospitalized patients, and dialysis patients. In addition, it is a lead ing cause of hospital-acquired (line-related) bacteremia. Infection with

S. aureus may also result in toxic shock

syndrome (TSS) and scalded skin syndrome (SSS; Image

2-2). The latter does not occur in adults unless

they have chronic kidney disease, because the toxin is Pathogenicity is associated with production of entero- and exotoxins, coagulase, and leukocidin. In chronic carriers,

S. aureus resides on the nasal mucosa. The percentage of MRSA infections has grown substan tially due to indiscriminate beta-lactam use. In almost

S. aureus isolates are

MRSA. Unfortunately, MRSA is now the most common community-acquired

2nd line agents and

in vancomycin-resistant isolates.

Treatment for Other Staphylococcus aureus Infections In nonbacteremic, mild-to-moderate MRSA skin and soft

otherwise easily renally excreted.

all hospitals, the majority of

Linezolid and daptomycin are very expensive, and in general are not considered except as

S. aureus as well, presenting pri

tissue infections, other antibiotics are effective, includ ing TMP/SMX, clindamycin, or doxycycline. There is increasing resistance to quinolones.

Staphylococcus epidermidis and Staphylococcus saprophyticus S. epidermidis and S. saprophyticus are examples of coagulase-negative staph. S. epidermidis is almost

marily as skin and soft tissue infections, but occasionally

always methicillin-resistant. It is the most common

pneumoma.

cause of both catheter-related bacteremia and bacteremia

Nasal mucosa! colonization is difficult to eradicate; eliminating nasal carriage is of uncertain benefit in non outbreak situations. The typical regimen is intranasal topical mupirocin and washing with chlorhexidine scrub.

including heart valves and joints, pacemakers, shunts) is placed. Treatment is with vancomycin. Add rifampin

S. sap rophyticus causes cystitis in young women and, unlike

and gentamicin for prosthetic valve endocarditis.

other coagulase-negative staph, is usually susceptible to

Toxic Shock An important complication of

occurring post-op when a foreign body (e.g., prosthetics,

anti-staphylococcal penicillins and ampicillin.

S. aureus infection is

staphylococcal toxic shock syndrome (TSS). TSS pres ents with red skin (sunburn-like rash), hypotension,

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BACTERIA

those with sickle cell [SS] disease), very young and old patients, and in CLL, MM, and agammaglobulinemia.

uiz •

Alcoholics also are more susceptible, but not because of antibody problems.

What is the clinical presentation of toxic shock

Post-splenectomy

syndrome? •

•

state, are often seen on peripheral smear.

What is the drug of choice for initial treatment

Streptococcus pyogenes (Group A) S. pyogenes is the only group A beta-hemolytic strep

MRSA treatment failure is associated with

species. It causes pharyngitis

organisms with what MIC?

rapidly progressive cellulitis that spreads through lym phatics (erysipelas;

What antibiotics are useful to treat skin and soft

Image 2-4)

TSS, and

or along fascia! planes

tion to a cell surface protein, called the "M protein,"

What are the drugs of choice for treatment of

can

lead

rheumatic

fever

post-streptococcal

glomerulonephritis.

What are the treatments of choice for empiric

Strep pharyngitis (usually

treatment of bacterial meningitis in adults? •

(Image 2-3),

(necrotizing fasciitis), or scarlet fever. Immune reac

PCN-susceptible pneumococci? •

fatal. Howell-Jolly bodies, indicative of the asplenic

tissue staph infections? •

presents

staphylococcal and streptococcal toxic shock?

available)?

•

sepsis

How do blood culture results differ between

of MRSA bacteremia (until MIC results are

•

pneumococcal

nonspecific sepsis, purpura, and DIC. It can be rapidly

S. pyogenes) is cumulatively 4 findings (the Centor

more likely with each of these

What clinical findings are associated with group

criteria):

A beta-hemolytic streptococcal pharyngitis?

Temp>

100° F

2) Tender anterior cervical lymphadenopathy

Streptococcus pneumoniae

3) Exudative tonsils

Pneumococcal Pneumonia

S. pneumoniae remains the most common cause of

4) Absence of cough

community-acquired pneumonia. Resistance to penicil

If none of these is present, the chance that pharyngitis is

2: 8 µg/mL [:S 2 5% of S. pneumoniae isolates.

lin (PCN MIC

Penicillin-susceptible

(or

susceptible]) occurs in

intermediately

strains are treated with penicillins or a

susceptible)

3rd generation

cephalosporin. PCN-resistant

due to S. pyogenes is< 3%; 1 =

7%; 2 21 %; 3 38%; and 57%. Adults with 3 or 4 of the Centor criteria should =

have rapid antigen testing and, if negative, should not receive antibiotics and should not be cultured. The rapid antigen testing is very specific for

S. pyogenes (2: 95%),

so all patients with positive results should be treated. In pneumonia

can

treated

with

3'd generation cephalosporin, respiratory quinolonc (levo-, or moxifloxacin), vancomycin, or linezolid. See specifics under Community-Acquired Pneumonia Pulmonary Medicine, Book

adults, if you suspect streptococcal pharyngitis just do a rapid strep test; do not do a strep culture. According to the IDSA suggestive

2012 recommendations, findings

of viral pharyngitis

include:

rhinorrhea,

cough, hoarseness, and oral ulcers. Adults with more

I of these should not be tested or treated for S. pyo genes pharyngitis. Viral causes of acute pharyngitis (other

than Pneumococcal Meningitis

S. pneumoniae is also the most common cause of bacterial meningitis in adults. Empiric treatment for

community-acquired meningitis should include a 3rd generation cephalosporin (generally ceftriaxone) and vancomycin in case there is any beta-lactam resistance. Focused treatment for susceptible pneumococcal isolates should be with high doses of ceftriaxone or cefotaxime.

than acute HIV infection) rarely have effective treatment and rarely warrant treatment. Suspect acute HIV infec tion as a cause of pharyngitis in sexually active adults, men who have sex with men, sex workers, or injec tion drug users. More often, however, viral pharyngitis is due to a benign upper respiratory infection or EBY (see

page 2-41 ).

Cephalosporin-resistant isolates should be treated with vancomycm. Splenectomy and S. pneumoniae

Remember: You need a functioning spleen and an ability to make antibodies to defend against encapsulated

S. pneumoniae and

influenzae-so

both infections

MedStudy

Image 2-4: E1:vsipelas

2-17

2-18

BACTERIA

All

patients

with

pyogenes

pharyngitis

should

be treated with a penicillin; there is no resistance. Treatment shortens the duration of illness, decreases transm1ss10n,

decreases

suppurative

complications

(e.g., peritonsillar abscess), and prevents rheumatic fever (discussed later). There is no convincing evidence that

not bactericidal. In these cases, check the isolate for gen tamicin susceptibility, and if susceptible, add low-dose gentamicin. Review treatment of enterococcal infections: •

tis. PCN-allergic patients can be treated with clindamycin or azithromycin.

Simple enterococcal infections= PCN G, ampicillin, or vancomycin (depending on resistance testing).

treatment prevents post-streptococcal glomerulonephri •

Bacteremia (sepsis or endocarditis)

PCN G or

ampicillin or vancomycin + low-dose gentamicin (if susceptible).

Streptococcus agalactiae (Group B) S. agalactiae (group B) is more common in the elderly, especially if they are alcoholic or diabetic. It is a common cause of neonatal pneumonia and the most common cause of neonatal meningitis. In pregnant women, S. agalactiae causes UTis and is also a cause of postpartum endometritis and bacteremia. It originates from a GU reservoir. Treat with PCN or ampicillin; in PCN-allergic patients, treat with clinda- or vancomycin.

Listeria Listeria

monocytogenes,

anaerobic

gram-positive

rod, causes listeriosis, which is seen in patients with decreased cellular immunity such as AIDS, lymphoma, and leukemia. Also, these infections are associated with drugs that depress cellular immunity (glucocorticoids, transplant drugs). Listeriosis is also seen in neonates, the elderly, and pregnant women. Listeria is one of the most virulent food borne pathogens, and the mortality rate is

Group D Streptococci Group

streptococci

(S.

bovis/S.

equinus

com

plex) includes 4 species that are inhabitants of the GI

tract

and

cause

bacteremia

and

endocarditis.

Group D streptococcus bacteremia is associated with colon cancer in

20-30% of cases, so positive blood cul

tures from this organism warrant a colonoscopy.

�

15%. It may be found in deli

meats, hot dogs, milk, soft cheeses, poultry, and even fruit. In

2011, an outbreak of Listeria in cantaloupe from 30 deaths.

a fann in Colorado resulted in

Listeria can cause neonatal meningitis via transvaginal inoculation and also can affect the fetus. For this reason, pregnant women are

cautioned against eating soft

cheeses, unpasteurized milk, etc. Like Enterococcus, Listeria is resistant to all cephalo

Enterococci Enterococci are gram-positive cocci that are difficult to distinguish from streptococci under the microscope. Similar to streptococci, they occur in pairs and short chains. Two species normally inhabit the intestines with a higher amount of Enterococcus faecalis

(95%)

(5%). Similarly, E. faeca

than Enterococcus faecium

lis causes the vast majority of enterococcal infections (e.g., UTis, bacteremia, endocarditis, meningitis, and intra-abdominal). All enterococci are resistant to cephalosporins and penicillinase-resistant penicillins. They are moderately

sporins, which is why you always include ampicillin in the empiric treatment for meningitis in the elderly, immunosuppressed, or neonates. Treat mild-to-moderate cases of listeriosis with PCN or ampicillin. PCN-allergic patients should receive TMP/SMX. Vancomycin and chloramphenicol are 3rd line drugs. Although no ran domized trials have been conducted, addition of an aminoglycoside to treat meningitis is often done.

Corynebacterium diphtheriae, JK, and Arcanobacterium haemo/yticum

2-5) causes diph

resistant to the aminoglycosides such as gentamicin, but

Corynebacterium diphtheriae (Image

these drugs are commonly used for synergy in the treat

theria. Diphtheria is an upper respiratory infection with

ment of endocarditis. E. faecium is one of the few organisms resistant to imipenem and commonly exhibits high-level resistance to

vancomycin

(vancomycin-resistant

Enterococcus

[VRE]). The incidence of VRE is dependent on the local setting and the use of other antibiotics in the population

a gray-white pharyngeal pseudomembrane (Image

2-6),

hoarseness, sore throat, and a low fever ( < I 0 I ° F).

Toxin production causes myocarditis with heart failure and polyneuritis. Treatinent is erythromycin.

2nd choice

is penicillin. Diphtheria antitoxin is always given with the antibiotic.

being treated. VRE is more common in patients with

Corynebacterium jeikeium (JK) is seen in neutropenic

liquid tumors and stem cell recipients.

patients and in bone marrow transplant patients, where

Single antibiotics are used to treat mild-to-moderate infections

(urinary

tract

infections

and

uncompli

cated bacteremia) and include PCN G, ampicillin, or vancomycin, depending on sensitivities. Combination

treatment

used

for

complicated

bacteremia and endocarditis because single drugs are

it causes IV catheter-related infections. It is resistant to most drugs. Vancomycin is the drug of choice. Arcanobacterium haemolyticum causes pharyngitis in adolescents, similar to that of S. pyogenes, with a des quamative scarlatiniform rash and lymphadenitis. Treat with PCN, erythromycin, or tetracycline.

MedStudy-Please Report Copyright Infringements to copyright@medstudy.com

BACTERIA

Emetic

Q�uiz •

(cereulide)

and enterotoxin-producing

1) A short incubation (1-6 hr) emetic type in which the

When should you use 2 antibiotics to treat enterococcal infections? Which drugs would you

emetic toxin is preformed in the food ingested 2) A longer incubation (8-16 hr) diarrheal type in which the cnterotoxins are produced in vivo in the small

choose? •

Which patient populations are at risk for Listeria?

•

Treatment of serious Listeria infections includes which drug?

intestine The emetic form is associated with fried rice not cooked at a high enough temperature to kill the organism and then left too long at room temperature, which allows

•

What are the clinical manifestations of anthrax?

•

Inhalation anthrax is associated with what important x-ray finding?

•

toxin

strains cause gastroenteritis of 2 varieties:

What is the time of onset of vomiting due to 8. cereus toxin ingestion?

the organism to make the emetic toxin, which cannot be destroyed by reheating. Similar to S. aureus, the emetic

toxin is produced outside the host, is preformed in foods, and therefore provokes a rapid onset of symptoms (1-6 hr). Vomiting is universal with diarrhea occurring

in only 1/3 of cases. Symptoms generally resolve in

12-24 hours. No specific therapy is necessary.

Bacillus anthracis and Bacillus cereus

The diarrheal form is caused by toxin produced in vivo

Bacillus anthracis is a large, gram-positive rod that

watery, non-bloody diarrhea accompanied by abdominal

causes anthrax, a potential agent ofbioterrorism.

pain and cramps, nausea, and vomiting (less common).

There are 3 main clinical manifestations:

Cutaneous

(95%)

after ingestion of the bacilli. It results in a profuse,

The incubation period is 8-16 hours, and it resembles

C. perfringens food poisoning. Symptoms usually

resolve in 12-24 hours. No specific therapy is necessary.

2) Inhalation ("woolsorters' disease")

3) Pharyngeal + gastrointestinal

B. cereus is rarely an invasive organism. It occasionally causes infection in contact lens wearers, after a traumatic

Inoculation occurs from handling naturally contaminated hides/wool or, more recently, maliciously contaminated sources (e.g., mail or food). Unlike plague (discussed later), anthrax is not transmitted person to person.

Cutaneous anthrax starts as a painless papule that

vesiculates and forms a painless papule, then ulcer

eye injury, and in patients with IV catheters. Treatment for serious disease is vancomycin.

C/ostridium Clostridium species are anaerobic gram-positive rods that cause a wide variety ofhuman illness: •

(Image 2- 7), then a painless black eschar, often with nonpitting, painless induration (Image 2-8).

Inhalation anthrax presents similarly to influenza with

•

choline release causing weakness and parasympathetic cranial nerve dysfunction.

dramatic worsening of symptoms with hypoxia, hypo •

Gastrointestinal anthrax is acquired by eating under

(or less) diarrheal illness similar to the enteric form of B. cereus. It is associated with contaminated

cooked, contaminated meat. Patients get pharyngeal

meat or gravy.

eschars and/or gastrointestinal ulcerations. •

and quinolones (given with or without rifampin). Bacillus cereus is a close relative of Bacillus anthracis.

\..... . ..

C. perfringens is one of the most common causes of

food poisoning in the U.S. and presents as a 24-hour

inhalation anthrax is mediastinal widening.

Anthrax is usually sensitive to clindamycin, tetracycline,

C. botulinum causes botulism-it releases a powerful

paralytic toxin. The toxin blocks presynaptic acetyl

malaise, fever, and myalgias. After 2-3 days, there is a tension, and death. An important diagnostic finding with

C. difficile causes antibiotic-associated colitis. (See page 2-62.)

C. septicum is a gut organism that causes bacteremia,

and the majority of patients with C. septicum sepsis have an associated GI malignancy.

•

C. tetani is the cause of tetanus.

,.-

._ r � -Ii * _. , r

.._

, Y\, -

Image ]-5: C. diph!heriae

Image 2-6: Pha1yngeal pse11domembrane

Image 2-7: Anthrax ulcer (painless)

Image 2-8: Culaneous anthrax lesion

2-19

2-20

BACTERIA

Rapidly progressive cellulitis and gas gangrene can be

Neisseria

caused by several species, including C. septicum,perfrin

infections (gonorrhea) as well as disseminated gonococ

gonorrhoeae

(NG)

causes

localized

gens, tetani, or novyi. The main toxin in all Clostridia is

cal disease (DGI). NG is a gram-negative diplococcus.

the alpha toxin.

The penicillinase-producing strains of N. gonorrhoeae

For acute treatment of C. tetani cellulitis or tetanus

(page

2- 71 ), use metronidazole (now the antibiotic of

choice instead of PCN, which is still an alternative) and

now account for the vast majority of cases in many areas in Asia and Africa and are also common in the U.S. See the discussion on STDs

(page 2-62).

tetanus immune globulin.

Moraxella GRAM-NEGATIVE BACTERIA

Moraxella catarrhalis is a gram-negative coccobacillus

that causes respiratory infections, especially in immuno

Neisseria

deficient patients and those with COPD. It is a common

Neisseria meningitidis (meningococcus) is a gram

cause of sinusitis in adults and otitis media in chil

negative diplococcus that is carried in the human naso

dren. Treat adults with amoxicillin-clavulanate, a

pharynx in 5-10% of healthy persons. It usually does not

d 3r

G R

generation cephalosporin, or a quinolone. In the U.S.,

cause disease because specific antibodies and comple

almost all are susceptible to erythromycin, tetracycline,

ment lyse the organisms as they enter the bloodstream.

and TMP/SMX.

V d ti e

Patients with complement deficiency are especially prone

meningococcemia,

which

presents

with

fever, hypotension, and skin signs that vary from pete chiae (early disease) to diffuse purpuric lesions and DIC (later). Bloodstream infection may or may not be associated with meningococcal meningitis. d 3r

Pseudomonas aeruginosa is a gram-negative rod that

is a ubiquitous water organism and a common cause of hospital-acquired infections. There are several clinical presentations that are highly specific for infection with

Treat patients with suspected infection empirically with a

Pseudomonas

this organism:

n U

generation cephalosporin until susceptibilities are

known. Once known, treat meningococcemia and men

•

in the moisture absorbing middle layer of tennis shoes

ingitis due to PCN-susceptible isolates with penicillin or

and can be innoculated into soft tissue or bone after

ceftriaxone. Use chloramphenicol or fluoroquinolones in

stepping on nails.

patients with severe PCN allergy. With prompt treatment, the mortality rate of meningococcemia is 10%.

•

9 9

otitis extema with extensive soft tissue +/- bone

of patients with meningococcal bacteremia and menin

gitis to eradicate colonization of the nasopharynx, which invasive disease.

r i h

Close contacts are defined as: •

Persons who have spent> 8 hours within

destruction in patients with diabetes.

•

Ecthyma gangrenosum-a round, indurated black

lesion with central ulceration-may accompany Pseudomonas bacteremia in neutropenic patients. •

Folliculitis, which people get from improperly chlori

•

Endocarditis from P aen1ginosa is rarely seen on

nated hot tubs ("hot tub rash"), is usually self-limited.

feet of the

index case from I day prior to 1 day after presentation

Otitis extema presents as swimmers itch in nonimmunocompromised hosts and as malignant

[Know:] Prophylaxis should be given to close contacts

has been associated with subsequent development of

Cellulitis and/or osteomyelitis: P aeruginosa survives

native valves, except in injection-drug users.

(e.g., people who live in the patient's household or contacts at day care centers) •

People exposed to the patient's oral secretions (e.g., a health care worker who has intubated the patient)

Know that the traditional clinical encounter does not merit prophylaxis for health care workers because tradi tional encounters usually do not involve contact with the patient's oral secretions. To eradicate the carrier state, use: •

fluoroquinolones (non-pregnant adults), or

•

rifampin (children and non-pregnant adults), or

•

ceftriaxone (pregnancy and children

15 years of

age).

Treat invasive infections with

antipseudomonal drugs

until you know the susceptibility of the isolate because these GNRs are not predictably susceptible to any single antibiotic. The most active drugs include: •

Carbapenems (except ertapenem)

•

Aztreonam

•

Fluoroquinolones

•

Aminoglycosides

•

Ceftazidime

•

Cefepime

•

Piperacillin/tazobactam

•

Ticarcillin/clavulanate

[Know:] Patients with meningococcal disease who are treated with penicillin still need to be given one of these "prophylaxis" drugs, because penicillin does not eradicate the carrier state.

BACTERIA

and

chloramphenicol,

depending on sensitivities. Carriers without gallblad der disease or stones can •

•

What is the clinical presentation of

usually

meningococcemia? Empiric treatment?

6 weeks of ampicillin + probenecid.

Prophylaxis for meningococcemia should be

decreases

given to which contacts? •

causes

When should you suspect Pseudomonas as a

Salmonella infection is spread by which

•

higher

and

blood

Image 2-9: Typhoidfever with classic "rose spots"

Yersinia

animals? •

Probenecid

clearance

level of the ampicillin.

cause of infection? •

be cleared with

Yersinia pestis is a gram-negative coccobacillus that

Which form of plague is transmitted

G R

causes plague. Reservoir is wild rodents. It is transmit

person-to-person?

ted by fleas or direct contact (skinning animals) and has

What associated symptoms are often observed

a high mortality.

with Legionella pneumonia?

The bubonic type causes large, localized lymphadenopa thy ("buboes") that suppurates. If not treated, it can lead

Enterobacteriaceae

V d ti e n U

to sepsis and death. The pneumonic form occurs after

Enterobacteriaceae is a family of aerobic GNRs that includes: Salmonella, Yersinia, Shigella, Citrobacter, E. coli, Klebsiella, Proteus, Serratia, Enterobacter, and Edwardsiella. We'll discuss Salmonella and Yersinia here. Also see Infectious Diarrhea on page 2-61.

inhalation of the organism via aerosols from infected animals or from other humans with pneumonic plague.

Only a small inoculum is required, making it prone to

epidemics and a potential agent of bioterrorism. Plague and tularemia present similarly (adenopathy

after hunting), except that the geographic locations are dife f rent-Desert Southwest for plague vs. Arkansas,

Salmonella

Missouri, and Oklahoma for tularemia. More on tularemia

Salmonella are GNBs that are usually motile.

below.

Non-typhoidal Salmonella are a fairly common cause

of diarrhea. Because the bacteria are not host-specific to humans, like S. typhi, they can be found in many differ

ent, non-human host animals. Salmonella may be spread

9 ri 9

by frozen foods (especially chicken), milk, and eggs.

Peanut butter and alfalfa sprouts were recent sources of outbreaks. Baby chicks, iguanas, turtles, and other exotic pets also may be sources of infections.

Treatment is typically symptomatic because antibiotic

h ta

Diagnose plague by aspirating lymph nodes or sputum

specimens that reveal bipolar staining GNRs ("safety pin") and growth of Yersinia pestis.

Plague is I of2 infectious diseases in which aminoglycosides (specifically streptomycin) are the drugs of choice; the other

is tularemia. 2"d line choices are tetracycline or quinolones. Other Enterobacteriaceae are covered under Diarrhea in Gastroenterology, Book I.

therapy does not shorten the course of disease, increases the risk of developing a carrier state, and increases resis tance in the organism. However, treat patients > 50 years of age with significant comorbid illness, immuno suppression, and inflammatory bowel disease with a fluoroquinolone orally or ceftriaxone intravenously. Salmonella typhi causes typhoid fever, usually after ingestion from contaminated food, milk,

or water.

Adults are more likely to be carriers because S. typhi tends

colonize

gallstones.

commonly

begins

with initial constipation followed by diarrhea, leukope nia, and the appearance of classic rose spots (Image 2-9) on the trunk, which begin about a week after the fever starts. These look like little 2-3-mm diameter angiomas. Recommend typhoid vaccine to travelers (> 2 years old) who go outside of the usual tourist areas of Latin America, Asia, and Africa. Treatment

typhoid

fever

with

quinolones,

3rd generation cephalosporins, ampicillin, TMP/SMX,

Legionella Legionella are aerobic GNRs that require special media for culture (charcoal yeast extract). The Legionellaceae family is made up of 50 species. Legionella pneumophila causes 80-90% of human infections. Legionella easily colonize standing water, and entry into the lungs is via inhalation. Legionella pneumophila infection (legionellosis) causes legions of problems. Multisystem disease is the rule. Patients often present with diarrhea, hyponatremia, and CNS symptoms (headache, delirium, and confusion), in addition to the pneumonia. Treatment for moderate infections is azithromycin or quinolones. Treating patients for community-acquired pneumonia using generally accepted guidelines effectively treats legionellosis.

2-21

2-22

BACTERIA

Bruce/la

Often the site of inocula

Bruce/la is an aerobic gram-negative bacillus, and B. melitensis causes brucellosis in goats, sheep, and camels. Other strains: Brucel/a abortus (cattle), B. suis (pigs), and B. canis (dogs). These are often transmitted to humans via unpasteurized milk or cheese or by inhalation (work-related). Bruce/la affects the:

tion is no longer visil: when the patient preser with

lymphadenopatt

Treatment

with

azithr

mycin is associated wi decreased duration of i ness and is recommende

• heart (especially suspect in culture-negative

although most cases a1c

endocarditis),

self-limited.

• lungs (pneumonia),

Bartone/la

•GI tract (diarrhea),

bacilliformis

pleomorphic

bacterium

that

tiny,

gram-negative

causes

bartonellosis.

•GU area ( orchitis, abortion), and

Bartonella is transmitted by sand flies only in Peru,

• endocrine glands (thyroiditis, adrenal insufficiency,

Columbia, and Ecuador and only in certain areas of the

SIADH).

G R

Andes Mountains-called the "verruga (wart) zone." Rare outbreaks where there are no sand flies indi

Confirming the diagnosis is difficult because cultures may take up to

6 weeks to grow. Diagnosis can also be made

via acute and convalescent serum titers. Treatment requires

2) Verruga peruana (chronic)

gentamicin) x 4 weeks.

Oroya fever consists of a rapid, febrile hemolytic

6-8 weeks.

anemia with a high mortality if untreated

• Pregnant women should avoid doxy; treat with

900 mg daily for 8 weeks.

(

�

50%).

Superinfection is a common problem-usually with

n U

Salmonella, staph, or Enterobacter. Suspect this disease in acutely ill travelers to the "verruga zone."

Francisella Francisella

2 manifestations:

I) Oroya fever ([Carrion disease]; acute/severe)

• Doxycycline + aminoglycoside (streptomycin or

rifampin

V d ti e

Bartonellosis has

I of the following regimens:

• Doxycycline + rifampin x

cate other vectors can exist. The only known reservoir is humans.

tularensis

small,

gram-negative

pleomorphic bacillus that causes tularemia ("rabbit fever"). It is found in many animals. Francisella is transmitted by ticks and bloodsucking flies, but the organ

9 9

ism may also be ingested or inhaled. Especially seen in Arkansas, Missouri, and Oklahoma.

Typically, patients with tularemia present with a history

of sudden onset of fever, chills, myalgias, and arthralgias, followed by an irregular ulcer at the site of inoculation

h ta

that may persist for months. Regional lymphadenopathy

2-8 weeks after Oroya fever 50% of patients have no memory

Verruga peruana presents

or inoculation. Up to

of a febrile illness. It presents with warty growths of

hemangioma-like

tissue progressing

from pinpoints

(miliary), to nodules, to larger (mular) lesions. All stages

can exist in the same person. The drugs of choice for Oroya fever are chloramphenicol plus penicillin. Rifampin is the drug of choice for

vermga peruana.

develops, and these nodes may necrose and suppurate. If

Helicobacter pylori

pneumonia occurs, it may have hilar adenopathy similar

Helicobacter pylori is a gram-negative, spiral, flagellated

to plague.

bacillus. It causes gastritis and PUD and is a risk factor

The diagnosis is based on a typical clinical and epidemiological presentation. Serologic testing for Francisella tularensis is confirmatory as it usually takes

for adenocarcinoma of the stomach and gastrointesti nal lymphoma. Further discussion about H. pylori is in Gaslrnenterology, Book l.

2 weeks to tum positive. Cultures of apparently

infected tissue have a very low yield.

RICKETTS/A

Treat with streptomycin or gentamicin. Tetracycline can be used if the patient is not severely ill.

Rocky Mountain Spotted Fever Rickettsia rickettsii is a gram-negative coccobacillus that causes Rocky Mountain spotted fever (RMSF).

Bartone/la

This disease has a

Bartone/la henselae causes cat-scratch disease or, in the

5-10% mortality rate. Classic signs

and symptoms include a rash, fever, severe headache,

immunocompromised patient, bacillary angiomatosis.

arthralgias (but not overt arthritis), and a history of

The skin lesions of bacillary angiomatosis are identi

recent exposure to ticks. The rash occurs on the distal

(Image 2-11). It progresses from maculo

cal to verruga peruana (next). Cat-scratch fever has a

extremities

macule

papular to petechial. Patients may also present with

-->

papule

-->

pustule at the site of the infection

(Image 2-10) with painful regional lymphadenopathy.

diarrhea and abdominal pain.

BACTERIA

"spotless" Rocky Mountain fever. Like RMSF, ticks are the transmission vectors.

uiz •

There are 2 forms of ehrlichiosis:

Which geographic locations have the most

•

cases of tularemia? •

and Arkansas.

What are the manifestations of bartonellosis? •

•

Name the clinical signs and symptoms of

RMSF.

•

What is

Anaplasma phagocytophilum causes human granulo cytic anaplasmosis (HGA), mainly in the Northeast

What drugs are used for treatment? •

Ehrlichia chajfeensis and E. ewingii cause human monocytic ehrlichiosis (HME), mainly in Missouri

and upper Midwest U.S.

fever? How is it treated?

Rash occurs in only 1/3 of patients with HME and

with HGA. The organism infects either monocytes or

What are the forms of ehrlichiosis? How does it

neutrophils, and patients typically present with the triad

present?

of fever, headache, and leukopenia-they may also

Labs may show leukopenia or leukocytosis, thrombo cytopenia, hyponatremia, and increased transaminases.

G R

have thrombocytopenia. Think of this in the patient who presents with pancytopenia and a history of tick bite.

PT, PTT, and fibrin split products are often increased,

Diagnosis is definitively made by finding intracytoplas

although the condition is not often associated with true

mic inclusions in white cells. Serologies are available but

DIC. The increase in these parameters is thought to be due to organism-induced local injury in the blood vessels.

V d ti e n U

require a 4-fold change in titer and thus are not useful at presentation.

Treat all patients suspected or proven to have ehrlichiosis

It is important to diagnose this infection on clinical grounds to allow emergent treatment. The quickest confirmation of the diagnosis is via immunofluorescent staining of a biopsy of a petechial lesion. Serology even tually turns positive but is often negative on presentation. Treatment is doxycycline or chloramphenicol. Other rickettsial infections include R. typhi (endemic typhus), R. prowazekii (epidemic typhus), R. conorii

(Mediterranean spotted fever), and Coxiella burnetii (Q fever).

9 9

Q Fever

r i h

or anaplasmosis with doxycycline just like with RMSF.

Note: There are reports of dual infection with Ehrlichia + Babesia microti (an intra RBC protozoan parasite) and

Ehrlichia + Borrelia burgdorferi (Lyme) in the endemic Northeast areas.

GRAM-VARIABLE BACTERIA Gardnerella vagina/is is a gram-variable rod. It is one of the bacteria associated with bacterial vaginosis, the most common cause of vaginal discharge in women

of childbearing age (see Vaginitis on page 2-65). Treat

with metronidazole or tinidazole.

Q fever (Coxiella burnetii infection) is a zoonosis that is

transmitted mainly by inhalation of the aerosol released from the infected animal.

Q fever is seen in abattoir

Image 2-11: Rocky Mounlain �polledfever

(slaughterhouse) workers

ACID-FAST BACTERIA Mycobacteria All mycobacteria are acid-fast bacteria-they don't lose

and people exposed to an

their stained color when exposed to acids (red on a green

infected

background). As a rule, the treatment of mycobacterial

animal's

prod

ucts of conception during

birthing.

It usually presents as a flu-like

infections consists of a prolonged multidrug regimen.

febrile

illness,

with or without pneumo

nia and/or hepatitis. 5% of infections become chronic and manifest as a fever of unknown origin or culture negative endocarditis.

tuberculosis

prominent

global

cause

pulmonary infection. In addition, it can cause myriad extrapulmonary infections in any organ. More on TB in Pulmonary Medicine, Book 2.

M avium-intracellulare (MAI) or M avium complex (MAC) is a chronic pulmonary infection caused by either M. avium or

M intracellulare. Immunocompromised

Diagnosis is made with serology. Treat symptomatic

(especially

Q fever with doxycycline.

nated disease. Elderly, thin women and patients with

HIV )

patients are at risk

for dissemi

severe COPD may also present with an indolent MAI

Ehrlichia and Anap/asma Ehrlichia and Anaplasma are small, obligately intra cellular gram-negative organisms that cause ehrlichio sis and anaplasmosis. Ehrlichiosis has been called

2014 MedStudy

pulmonary infection.

M scrofitlaceum and MAC cause lymphadenitis in children; treat by excising the nodes.

2-23

2-24

SPIROCHETES

M leprae causes leprosy. Transmission is via respiratory droplets from person-to-person, but only a very small percent of the population is genetically susceptible. Diagnose with Fite stains of skin or nerve. Armadillos may also carry M leprae and are a reservoir in the southern U.S. M marinum is the "fish-tank bacillus." It causes nonhealing skin ulceration in people working around fish tanks (especially if any immunodeficiency is pres ent, such as diabetes). It often causes strings of lesions along the lymphatic channels. (Similar lymphatic channel lesions occur with Nocardia brasiliensis, Sporothrix schenckii, and cat-scratch disease). Treat M marinum with clarithromycin + either rifampin or ethambutol until 1-2 months after symptoms resolve.

Other non-tuberculous mycobacteria (NTM) include M kansasii (lung disease clinically similar to TB), and M abscessus (chronic pulmonary infections in patients with underlying lung disease). Nocardia

Usual treatment is high-dose sulfonamides or TMP/ SMX. In severely ill patients, add combinations of drugs including amikacin + imipenem. Minocycline is another alternate choice for those sulfa-allergic. Treat for 3 or more months!

9 9

Nocardia brasiliensis is in the soil. Like M marinum and Sporothrix schenckii, it can cause inflammation with associated surface lesions along lymphatic chan nels. Treat with sulfonamides or TMP/SMX. Nocardia brasiliensis is resistant to imipenem, but N. asteroides is usually sensitive.

h a

OTHER ORGANISMS

Image 2-12: Actinomycosis

Chlamydia I Chlamydophila Chlamydia and Chlamydophila are obligate, intracellular parasites. C. psittaci, C. trachomatis, and C. pneumoniae (formerly TWAR) are pathogenic in humans. Treat with doxycycline, macrolides, or quinolones. Chlamydia psittaci is found in psittacine and other birds and causes psittacosis: pneumonia and splenomegaly. Any pneumonia associated with poultry, especially with splenomegaly, strongly suggests C. psittaci. (DDx: Histoplasma also causes pneumonia and splenomegaly; it is associated with bird and bat droppings.) Onset of psittacosis is associated with myalgias, rigors, headache, and high fever-to I 05° F.

G R

V d ti e n U

is only weakly acid fast (easily missed). It is a beaded, branching, filamentous gram positive rod. It usually starts as a lung infection occasionally causing a thin-walled cavitary lesion. It can cause focal brain abscesses and chronic neutrophilic meningitis-most chronic meningitides are lympho cytic. Nodular skin lesions are common. It is hard to isolate. It can spread systemically. Nocardia asteroides

is an IUD in place. Also, in the abdomen, be aware of associated with appendicitis. Treatment is PCN or ampicillin; 2"d choice is tetracycline.

Actinomyces

(formerly Chlamydia but found to have different DNA and antigen) causes com munity-acquired pneumonia in adults who typically have not been exposed to birds; i.e., person-to-person spread. Bronchospasm is particularly prominent in respiratory infection caused by C. pneumoniae, as is an association with early pharyngitis and hoarseness. Chlamydophila pneumoniae

Chlamydia trachomatis causes GU infections and trachoma (chronic, anterior eye infection causing cata racts but not glaucoma; found especially in Asia and Africa). Approximately 5% of pregnant women have C. trachomatis in their genital tracts. The same C. trachomatis is also associated with neonatal pneumo nia. Lymphogranuloma venereum is an STD caused by the same C. trachomatis, but a different immunotype. (See STDs on page 2-62.)

SPIROCHETES SYPHILIS Treponema

causes syphilis. Sequence of

syphilis presents with a painless chancre (genital, anal, or oral ulcer) within 3--40 days, depending on the number of inoculated organisms, and painless regional lymphadenopathy. In women, if the infection is cervical, it is often asymptomatic. Chancre contains flexible, mobile, worm-shaped bacteria; it lasts 2-6 weeks, then resolves.

Secondary

Actinomyces

is an anaerobic organism that causes an infection in which yellow "sulfur" granules can be visual ized, which are actually clusters of organisms. The usual presentation of actinomycosis is cer vicofacial involvement ("lumpy jaw" Image 2-12). Actinomyces is a cause of PID when there

pallidum

infection:

Actinomyces

Primary

syphilis occurs 2 months later as spirochetes travel to other organs throughout the body. Symptoms include generalized lymphadenopathy, fever, malaise, and mucosa! and/or cutaneous lesions that can mimic many other lesions ("the great imita tor"). The skin lesions may be macular or papular but are never vesicular. They can occur on the palms and soles and are described as "nickel and dime" lesions (Image 2-13). Condyloma lata are cauliflower-like wet �

SPIROCHETES

UIZ •

•

General paresis is the name given to diffuse cortical disease seen in neurosyphilis. Its numer

•

ous manifestations can be remembered with the following mnemonic:

M. marinum causes what type of infection?

P =defects in personality

If a pathology report describes beaded,

reduced affect

abnormal reflexes

branching, mildly acid-fast, filamentous

E =eyes (Argyll-Robertson pupil, which is

organisms, what organism is likely?

miotic and irregular; constricts normally to

What organism is associated with pelvic

•

accommodation but not to light)

inflammatory disease in women with an

S = defects in sensorium

intrauterine device?

What associated symptoms are often seen in

•

respiratory infections due to C. pneumoniae?

defects in intellect defects in speech

Latent syphilis is the most commonly diagnosed stage

G R

•

Stroke may occur in which stage of syphilis?

of syphilis. It is defined as serology diagnostic of syphi

•

What does PARESIS stand for, when referring to

lis

neurosyphilis?

whether the last manifestations of syphilis or serocon

When will an MHA-TP revert to negative after a

•

with no active manifestations of infection. It is

divided into early latent and late latent depending on

V d ti e n U

version to syphilis occurred within I year or after 1 year,

patient has syphilis?

respectively. This distinction arose from observational studies that showed that

lesions in genital areas or the mouth that are teeming with treponemes. Meningovascular disease also can occur in secondary syphilis and present as strokes in a young person. Non-neurologic signs and symptoms resolve in

3-12

weeks, and the disease goes into a

latency period. Untreated,

1/3 of secondary

syphilis

cases eventually proceed to tertiary syphilis.

Tertiary syphilis occurs

1-20 years or more after the

initial untreated infection. There are 3 forms:

•

Gummatous syphilis presents with

I or more

gummas, which are noncaseating granulomatous

9 ri 9

lesions that are locally destructive. •

Cardiovascular syphilis is from obliterative endar

teritis of aortic vaso vasorum resulting in ascending aortic aneurysms and aortic insufficiency. •

Neurosyphilis has °

3 manifestations:

Chronic meningovascular can present with brain

h ta

90%

the I st year of infection.

of relapses occur within

Diagnosis of syphilis is based on direct visualization

of the organism via dark field microscopy of chancre exudate or cutaneous lesions of secondary syphilis; how ever, this is unavailable in most laboratories. Otherwise, serology is required to confirm the diagnosis of syphilis.

There are 2 types of serologic tests:

Treponemal (MHA-TP and FTA-ABS [or simply FTA]) that detect antibodies that directly react with

Tpallidum.

2) Nontreponemal tests (VDRL and RPR) detect antibodies directed against the cardiolipin-cholesterol-lecithin

antigen (a.k.a. "reagin"). Traditionally, the diagnostic sequence has consisted of

151 an inexpensive nontreponemal test, then if that's posi tive, a more specific and more expensive treponemal test

and/or spinal cord strokes similar to meningo

for confirmation. This confirmation is necessary because

vascular disease in secondary syphilis.

false-positive nontreponemal test results are common. If

Tabes dorsalis is due to destruction of the

posterior spinal cord columns leading to loss of

this sequence is followed, patients with a positive RPR and a confirmatory positive FTA are considered to have

position sense, abnormal foot-slapping gait, and

past or present syphilis.

Romberg sign.

More recently, high-volume laboratories have started to use a reversed approach: screening with a treponemal test and confirmation with a nontreponemal test. Using this sequence, if patients have a positive treponemal test,

2nd trepo 2nd treponemal test, treat the patient for late latent syphilis. If the 2nd treponemal test is negative; i.e., I positive and I negative trepo but a negative nontreponcmal test, perform a

nemal test. If also positive by a

nemal test and a negative nontreponemal test, then no treatment is indicated. Once positive, the specific treponemal tests (like the MHA-TP) usually stay positive for life. The nontrepone mal tests become negative after treatment unless treatment has been delayed for many years, in which case they

Image ]-13: Secondarv syphilis "nickel and dime" lesions

may stay positive (the "sero-fast" state). See Table 2-2.

2-25

2-26

SPIROCHETES

Table 2-2: Testing Scenarios for Syphilis

Testing Sequence

Result

Interpretation

Approach

Traditional: Nontrepo-

A. Negative non-

No syphilis or treatetl syphilis

In most cases, no further testing or

nemal followed by

treponemal

or prozone effect or'very early

treatment is needed. If suspicion for

treponemal

syphilis

syphilis is high, rule out pro:zone• �ffect (secondary syphilis) or perform dark field microscopy on lesion (primary syphilis) and/or repeat test in21 days.

Active syphilis or treated syphilis

Treat, unless treatment docu-

treponemal and

mented.

positive treponemal C. Positive non-

No syphilis (false-positive non-

treponemal and

trepo11emal test) er·early syphilis

negative treponemal

G R

Tr�at if chancre, repeat in 6 weeks.

V d ti e

Reverse: Treponemal

A. Negative trepo-

No syphilis or treated syphilis or

In most cases, no further testing or

followed by nontrepo-

nemal

very early syphilis

treatment is needed. If suspicion

nemal

for syphilis is high, perform dark field microscopy on lesion (primary syphilis) and/or repeat test in 21

days.

B. Positive trepo-

n U

nemal and positive nontreponemal C. Positive trepo-

No syphilis (false-positive

Check a different type of trepo-

nemal and negative

nontreponemal test) or late latent

nemal test; if that is negative, no

nontreponemal

syphilis

treatment indicated. If positive, then treat.

Note: In most treated patients, treponemal tests remain positive, put 15-25% of patients treated in primary stage will

9 9

revert to seronegative in 2-3 years.

• The prozone effect is one cause of false-negative nontreponemal �e�ting. It is caused by high levels of antibOO.ie � (mostly seen in secondary syphilis). If suspected, ask the lab to dilute the sample and test again. }·

According to the

20 10 CDC recommendations, perform

h ta

•

lumbar puncture in all patients who have neurologic

Late latent, latent of unknown duration, and non neurologic tertiary syphilis:

or ophthalmic manifestations consistent with neuro

syphilis, have other signs of tertiary syphilis, or have failed prior appropriate therapy for syphilis. In addition, patients with RPR titers 2:

1 :32 have a much higher risk

of neurosyphilis, and this warrants a lumbar puncture as well. RPR and

•

1 year after treatment of primary disease, 2 years after treatment of secondary disease, and 5 years or not at all

G 2.4 MU IM q wk x 3 (doxy JOO mg PO bid x 4 weeks)

Benzathine PCN cycline

Neurosyphilis: 0

G 18-24 MU IV divided q 4 hours or I 0-14 days. (If compliance is good: procaine PCN 2.4 MU IM qd with pro benecid 500 mg qid x 10- 14 days.) Follow with benzathine PCN 2.4 MU IM q wk x 3. PCN

continuous infusion for

VDRL titers should decrease with treatment.

They should be positive only in the undiluted specimen

(If PCN-allergic, the best course is to desensitize

2 g/day 10-14 days is an alternative for PCN-allergic

the patient and give the PCN. Ceftriaxone

after treatment of latent disease.

All pregnant women should get a nontreponemal test in

patients, but cross-reactive allergies may occur.

1st trimester. If at high risk, repeat in the 3rd trimester

the

and at delivery.

Treat pregnant women and newborns for syphilis only with PCN. If the pregnant woman is PCN-allergic,

Treatment of syphilis (alternatives in parentheses): •

desensitize her (see page

Primary, secondary, and early latent syphilis: 0

Oral doxycycline is not effective for neurosyphilis.)

G 2.4 MU IM x 1 (doxycycline 100 mg bid x 14 days)

Benzathine PCN

2-1 O); then treat with PCN.

After treatment, do a quantitative nontreponemal/reagin test monthly during pregnancy.

MedStudy-Please Report Copyright Infringements to copyright@medstudy.com

SPIROCHETES

Jxodes ticks have

uiz •

•

during the nymphal stage, because nymphs are more likely to feed on a person and are rarely noticed because

Can a patient have a negative RPR and have

of their small size(< 2 mm). Ticks require at least 2 days

neurosyphilis?

of attachment before transmission of infection occurs. A tick found walking on the skin is not transmitting

List the treatment regimens for the various

infection.

stages of syphilis. •

What drug is used to treat syphilis in pregnancy?

Clinical Manifestations of Lyme Disease

What if the woman has an anaphylactic PCN allergy? •

•

Stages of Lyme disease:

What spirochetal disease that causes jaundice

•Stage I; early localized: Erythema migrans (EM) is

and meningitis is most often found in veterinary

the pathognomonic skin lesion of stage I disease; it

workers and people who engage in outdoor

starts at the site of the bite and is a slowly spreading,

G R

water sports?

irregular erythematous lesion usually with a clear

What are the clinical presentations of

center(Image

•Stage 2; early disseminated: Weeks to months later, stage 2 disease occurs with neurologic symptoms

LEPTOSPIROSIS a

V d ti e n U lesions.

stages of Lyme disease?

I symptoms include

nopathy. About 50% of patients have secondary skin

What symptoms are associated with the various

Leptospirosis

2- I 4). Other stage

myalgias, arthralgias, fever, headache, and lymphade

leptospirosis? •

3 stages of development: larva, nymph,

and adult. Ticks transmit Lyme disease most efficiently

(lymphocytic meningitis, cranial or peripheral neuritis),

spirochetal

disease

caused

Leptospira interrogans and transferred by contact with

infected animals or contaminated water. L eptospirosis is considered to be the most widespread zoonosis in the world. It is common in Hawaii( 50% of all U.S. cases) -

and may be seen after recreational water exposures; e.g., in cross-country runners, white water rafters, adven

ture racers, and triathletcs-usually after contamination has been spread by heavy rains and flooding.

9 ri 9

Leptospirosis has a wide range of signs and symptoms,

from myalgias; fever; and headache, with or without

and/or heart problems (myocarditis, with transient Pt,

2"d, or 3rd degree heart block). A peripheral 71" nerve

palsy(Bell's palsy) is not uncommon. Bilateral Bell's

palsy, which is essentially unheard of in Bell's palsy that is idiopathic or due to herpes simplex, can occur with Lyme disease (or occasionally sarcoid).

•Stage 3; late: Months to years later, stage 3 occurs, most commonly, with arthritis (oligo- or migratory usually large joints), but there can also be chronic neurologic syndromes.

aseptic meningitis, to Weil syndrome (severe hepatitis

Diagnosis of Lyme Disease

with renal failure, pneumonitis, and hemorrhagic com

According to the latest diagnostic criteria from the CDC

plications). Subconjunctival suffusion is highly specific

in 2011, a diagnosis can be made in 2 ways:

since it is only rarely seen in other illnesses like systemic

h ta

lupus erythematosus and juvenile rheumatoid arthri

I) Presence of erythema migrans, or

tis. The hepatitis is characterized by the bilirubin being

2) One or more stage 2 or 3 manifestations and positive

disproportionately elevated compared to the liver trans

serology (an EIA test, followed by a Western blot

aminases. The variety of presenting symptoms makes

only if the EIA is positive).

for a high incidence of initial misdiagnoses.

There are a few important

Diagnose with blood and/or CSF cultures on special

caveats about testing for

media within the first 10 days of illness. After that, cul

Lyme disease:

ture the urine and send serum for anti-leptospiral IgM. Treat with PCN or doxycycline.

not

perform

symptoms. Patients seropositivity

LYME DISEASE

burgdoiferi

and

with no

symptoms have had prior

Overview Borrelia

serol

ogy if there are no Lyme

asymptomatic causes

Lyme

disease.

exposure;

they do not warrant and

transmitted by the Ixodes scapularis tick in the Mid

would

Atlantic, Midwest, and Northeast U.S. and the Jxodes

treatment.

not

benefit

from

pacificus tick in California. The protozoan Babesia is

also transmitted by Ixodes scapularis-see page 2-35. B. burgdoiferi crosses the placenta and may cause fetal

infection and death.

Image 2-14: E1ythema migrans

2-27

2-28

FUNGI

Do not perform serology in patients with erythema

likely to cause systemic disease in the nonhospital

migrans. Nothing else looks like it, and most patients are

ized, immunocompetent host. The dimorphic fungi are

seronegative in stage I . Just treat.

transmitted by a spore that converts to yeast at body

Reserve serology for persons from endemic areas with symptoms consistent with Lyme disease and no other obvious explanation.

depends

• Candida species

the

• Aspergillus species stage

and

type

manifestation.

•Endemic fungi (Histoplasma, Blastomyces, and Coccidioides: These are each found in specific regions of the U.S.)

I, Bell's palsy, and asymptomatic 2nd degree heart block with oral doxycycline or amoxicillin x I 0-21 days.

•Treat stage

• Dermatophytes (cause tinea capitis, tinea corporis,

I 51 or

tinea pedis, and tinea cruris)

G R

• Sporothrix schenckii

•Treat symptomatic heart block and neurologic disease with ceftriaxone 2 gm or PCN G 20 MU IV in divided doses x

Some of the clinically relevant fungi include:

• Oyptococcus species

Treatment of Lyme Disease Treatment

temperature.

14-21 days.

• Zygomycetes (Mucor, Rhizopus, and Cunninghamella)

•Treat arthritis with oral doxycycline or amoxicillin x

V d ti e n U CANDIDA

30--60 days.

Candida infections are usually caused by Candida

Although patients previously treated for Lyme disease

albicans. Infections with this organism are more likely

may more commonly have

to occur in patients who:

chronic

neuromuscular

symptoms (such as muscle and joint pain, fatigue, trou

ble with memory and formulating ideas) than patients never infected with B. burgdorferi, several studies have confirmed that there is no benefit in giving additional courses of antibiotics to these individuals.

• are immunosuppressed, • are on antibacterials,

• have indwelling catheters, • are receiving intravenous hyperalimentation, or

• have uncontrolled diabetes.

Prevention of Lyme Disease

Mucocutaneous candidiasis is occasionally the presenting

Because transmission does not occur until at least

2 days

of attachment, the best prevention is to keep ticks off

9 9

the body with clothing treated with insect repellents or to find and remove the Ixodes tick from the skin. When ticks are embedded in the skin, remove them by grasp

r i h

ing them with tweezers placed on their mouthparts and pulling them straight up from the skin.

200 mg PO if an embedded tick is found on the

skin and any of the following are true:

•Patient presents within

•Mucosa (thrush [oropharyngeal], esophagitis, or genitourinary infection)

•Bloodstream (candidemia) However, Candida can also cause invasive disease such tion, and renal fungus ball. Usually, candidemia, either from an infected vascular catheter or from overgrowth of Candida in the gut, is the source of dissemination to these other organ systems.

•Tick is found and it is in the nymph or adult stage •Tick was attached at least

Presentations vary. Disease can be localized to:

as endocarditis, ocular disease, hepatosplenic infec

Post-exposure prophylaxis: Give a single dose of doxy cycline

symptom of diabetes or HIV infection.

36 hours and is engorged

72 hours of tick removal

•Local rate of tick infection with B. burgdorferi is:::: 20% (New England, mid-Atlantic, parts of MN and WI)

Physical exam findings: Limited mucosa! Candida, such as thrush, is visible as whitish plaques with an under lying erythematous base. Patients who have esophageal symptoms and thrush can be assumed to have esopha geal candidiasis--endoscopy is not required to make the diagnosis. Vulvovaginal candidiasis presents as a thick,

There is no contraindication to doxycycline.

whitish discharge in the setting of intense vaginal itching (see Vaginal Candidiasis on page

2-66).

FUNGI Candidemia

OVERVIEW Fungi are roughly divided into

2 morphologic types:

yeasts and molds. There is also a dimorphic type that changes from a yeast to a mold, and vice versa, depend ing on temperature. The dimorphs are the type most

Fever; rash or painless, erythematous papules/pustules; visual complaints; and multiorgan involvement are signs and symptoms of disseminated disease. Candida species grow readily in routine blood culture bottles. Candida in a blood culture is never a contaminant; it represents real

FUNGI

Ocular Candidiasis Ocular candidiasis can be either endophthalmitis or

•

UIZ •

chorioretinitis. Disease can occur as a result of fungemia and seeding of the eye, or post-cataract surgery. Early

What is the treatment for Lyme disease with

disease (especially with chorioretinitis) may be relatively

symptomatic heart block? •

•

asymptomatic. Any patient who develops candidemia

In a febrile patient who is receiving intravenous

should have a dilated eye exam by an ophthalmologist.

hyperalimentation, what blood stream infections

Postoperative patients with eye pain should have cultures

might you suspect?

of the vitreous fluid that includes evaluation for fungus.

When can you disregard

Candida

as a blood

Treatment of chorioretinitis is with systemic antifungals,

culture contaminant? •

but endophthalmitis necessitates antifungals plus intra

What is the treatment of candidemia when a line is present?

•

therapeutic

What patient population develops hepatosplenic

G R

resistant species of

Candida.

Patients with candidemia should have what kind of referral?

•

concentrations

Genitourinary Candidiasis

Why are lipid amphotericin preparations not

Consider any localizing signs, such as rash, for biopsy sometimes a skin biopsy is the only way to make the diag It may take days to grow

sometimes appropriate to initiate empiric antifungal treat ment; e.g., in a neutropenic patient with a prolonged fever.

Treatment of candidemia includes removal of any infected catheters and giving a systemic antifungal. Fluconazole or

an echinocandin (caspofungin, micafungin, anidulafungin)

9 9

Echinocandins are the I st line for candidemia in the following settings: •Neutropenia •Moderate-to-severe disease

h a

• Recent azole exposure

• Azole-resistant species

V d ti e

especially in the

if the patient has had a urinary catheter.

Be concerned about repeatedly positive urine cultures for

Candida

in diabetics, in patients with recent uri

nary manipulation, and in patients with systemic signs

n U -

the organisms out of the blood. If your patient is ill, it is

are the 1st line agents in non-neutropenics.

humor.

hospital, and it often represents colonization-especially

disease, even if the patient is relatively asymptomatic.

Candida.

vitreous

Candida in the urine is fairly common,

recommended in patients with funguria?

nosis of disseminated

the

Voriconazole or amphotericin B + flucytosine is used for

candidiasis? •

vitreal amphotericin B +/- vitrectomy. Fluconazole is usually the initial treatment of choice because it achieves

of infection. Urinalysis showing pyuria is not very sen

sitive or specific for true infection. Evaluation should include renal imaging with either ultasound or CT of both the bladder and the kidneys.

Asymptomatic candiduria with negative imaging studies can be managed with a catheter change. If the patient is undergoing genitourinary procedures, give ampho

B deoxycholate or fluconazole for a few days pre- and

post-procedure.

Treat symptomatic candiduria with a systemic antifungal based on culture results. Fluconazole is preferred if the isolate is susceptible. Know that lipid amphotericins are not excreted in high enough concentrations in the urine to be useful in treat ing

Chronic Disseminated Candidiasis

Candida urinary

tract infections. Echinocandins are

also not recommended for the same reason. Bladder irri

Also called hepatosplenic candidiasis, this entity is virtually always seen in leukemic patients as they

gation also is not recommended for cystitis, although it has some use in treating upper tract disease complicated

recover from a period of neutropenia. Symptoms include

by fungus balls.

fever and pain in the right upper quadrant.

Any fungus ball should be surgically removed if it is not

Labs show increased alkaline phosphatase+/- increased

improved after ampho B upper tract irrigation.

transaminases and bilirubin. A contrast CT of the abdo men will show multiple small abscesses in the liver and spleen. Severely ill patients require amphotericin induction therapy

followed

fluconazole

for

maintenance.

Clinically stable patients do not require induction. Use echinocandins if infection with azole-resistant is suspected or proven.

Candida

CRYPTOCOCCUS In immunocompetent patients, Cryptococcus

neoformans

usually causes minimally symptomatic, self-limited infec tion after entering via the respiratory route. Patients may have a low-grade fever, cough, and a pulmonary infil trate-all of which resolve. Although it is found in pigeon droppings, most patients have no recollection of being in contact with birds. Cryptococcal pneumonia may form cavitary lesions and peripheral "cannon ball" lesions.

2014

MedStudy

2-29

2-30

FUNGI

Dissemination is more likely with Cryptococcus gattii,

since the organism is so common in the environment.

a related species, or in immunodeficient patients (AIDS,

Alternatively, Aspergillus galactomannan antigen can be

corticosteroid therapy, Hodgkin disease, ALL, diabetes,

measured in the blood or the BAL fluid. This test is most

and those who are post-organ transplant). These patients

useful in immunocompromised hosts.

are especially likely to get cryptococcal meningitis the most common presentation of severe cryptococcal infection. Suspect

Treatment of ABPA consists of itraconazole and steroids. Aspergillomas can be observed, but if symptomatic, (hemoptysis) should be resected. pt line treatment for

cryptococcal

meningitis

any

immuno

the invasive forms of aspergillosis is voriconazole.

suppressed patient who has headache +/- skin lesions and/or pulmonary lesions +/- fever. Lumbar puncture (LP) commonly shows increased CSF opening pres sure, usually > 200 mmH20. The rest of the spinal fluid analysis may be remarkably benign with minimal leukocytosis and protein elevation, although an India ink test may reveal the organisms surrounded by haloes. Patients with very high opening pressures are at risk for blindness if the pressure is not handled properly (repeat

ENDEMIC FUNGI Overview The

American

Histoplasma,

endemic

fungi

are

G R

Coccidioides,

Cryptococcus gattii, and Blastomyces.

They have the following characteristics in common: •They are found in specific areas of the U.S., and a patient becomes infected only after visiting or living

LP to drain CSF).

V d ti e n U

Confirm presence of the organism with a serum and/or CSF cryptococcal antigen test.

Initially treat cryptococcal meningitis with amphotericin B and flucytosine. Once the patient is clinically improved,

these 2 agents can be stopped and the patient can be

switched to fluconazole. Additionally, daily repeated lumbar punctures are recommended in those

with

increased intracranial pressure (> 200 mmH20) or with associated headache, clouded sensorium, visual/hear

ing loss, or cranial nerve palsies. Sometimes shunts are required.

Patients with AIDS require secondary prophylaxis with chronic fluconazole.

9 9

ASPERGILLOSIS

in the area where the organism is endemic and par ticipating in activities that encounter the organism.

• They are acquired by inhalation.

•They most commonly cause asymptomatic or mild, self-limited pulmonary disease.

• Less commonly, they cause significant pulmonary disease requiring medical treatment.

• Even less commonly, they cause disseminated disease.

• Significant pulmonary disease and dissemination are much more common in immunodeficient patients.

•Mild disease is treated with azoles. Severe or CNS disease is treated with amphotericin B.

Cryptococcus gattii is found in Northern California, Oregon, and Washington. The other endemic fungi are

also discussed in Pulmonary Medicine, Book 2.

Aspergillus species are ubiquitous in the environment.

r i h

A.fi1migatus is the most commonly isolated as a pathogen, and can cause severe infections, mostly in immuno compromised hosts.

Organism:

Coccidioides

and

immttzs

Coccidioides

posadasii cause coccidioidomycosis. The spores (arthro

Aspergillosis can present with a spectrum of disorders ranging from:

Coccidioidomycosis

conidia) are highly infectious at a very low inoculum.

Geography: C. immitis is found in the soil of the arid

• allergic bronchopulmonary aspergillosis ( ABPA),

Southwest U.S. and northern Mexico. This disease is

an allergic reaction to colonization with Aspergillus

often called "valley fever" because it is often identified

(clinical presentation similar to asthma), to

in the San Joaquin Valley and Death Valley.

• aspergilloma (a fungus ball in a previously formed cavity), to

•invasive aspergillosis, which may be an acute destruc tive pulmonary process in immunocompromised

Presentation: When inhaled, the arthroconidia convert to their yeast form that, days to weeks later, causes a self-limited, flu-like illness with arthralgias, erythema multiforme,

patients (acute invasive pulmonary aspergillosis), or chronic in those who are immunocompromised (chronic necrotizing aspergillosis) or immunocompe tent (chronic cavitary aspergillosis leading to chronic fibrosing aspergillosis).

and/or

erythema

nodosum.

Disease

may result in a pulmonary "coin lesion." People at highest risk for

severe infection include Filipino

and African-Americans, pregnant

women,

and

the

immunesuppressed. Extrapulmonary coccidioidomycosis can involve bone,

Invasive aspergillosis can be rapidly fatal and requires

skin, or the CNS. Coccidioidomycosis and ABPA are the

prompt diagnosis and treatment. The diagnosis can be

only 2 fungal diseases that cause peripheral eosinophilia.

made by lung biopsy and demonstration of the organ ism invading the lung and on culture. Use caution in interpreting expectorated sputum and BAL specimens

Diagnosis: Demonstration of spherules in body fluids or tissue is diagnostic. Culture is also diagnostic and

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FUNGI

Treatment: Acute pulmonary disease generally requires no therapy. More severe but localized disease can be treated with itraconazole. Disseminated disease requires amphotericin B (either deoxycholate or liposomal for •

Cryptococcal meningitis is associated with what

mulations), followed by itraconazole.

LP abnormality? •

Empiric treatment for cryptococcal meningitis

Blastomycosis

includes what drugs?

Organism: Blastomyces dennatitidis causes blasto

•

Where is Coccidioides immitis found?

•

What are the clinical presentations of

mycosis, a flu-like illness similar to that caused by Coccidioides and Histoplasma above. It may also cause

an acute illness that looks like bacterial pneumonia.

histoplasmosis? •

Geography: Blastomycosis is seen in states bordering

What tests are best for diagnosing various

the Mississippi and Ohio River basins and those near the

presentations of histoplasmosis? •

Great Lakes and along the St. Lawrence River.

Severe histoplasmosis is treated with what

Presentation: If it disseminates, it commonly does so to

antifungal? •

the skin, usually causing vem1cous (warty) lesions with

Think about blastomycosis in which patient

central ulceration. Bone lesions are common and may

populations? •

cause bone and joint pain.

Which patient groups are at risk for

Diagnosis: Demonstration of the yeast fonn with its

zygomycosis?

broad-based buds in secretions or tissue is diagnostic.

the organism grows well on almost all media in about I week. IgM serology is available but takes

1-3 weeks

Cultures require fungal media and tum positive in

1-4 weeks. Urinary antigen and serum antigen are usu ally positive in disseminated disease with the urine being

to tum positive.

a more sensitive test.

Treatment: Most patients have self-limited disease and

Treatment: Mild-to-moderate disease should be treated

do not require treatment. If needed, nonmeningeal, less severe infections can be treated with either itraconazole or fluconazole. Treat severe cases with amphotericin B. When treatment is indicated, continue for a prolonged duration

(6-12 months).

with itraconazole. Severe or CNS disease requires amphotcricin B.

SPOROTRICHOSIS Sporotrichosis is caused by Sporothrix schenckii a dimorphic fungus associated with soil and plants.

Histoplasmosis Organism: Histoplasma capsulatum causes histoplas mosis. Conidia or mycelial fragments are the infectious form.

Gardeners tend to get it, often after being pricked by a thorn.

Of the 4 clinical presentations, the cutaneous and

the lymphangitic (nodules form on the skin over lymph channels) types are treated with itraconazole, while the

Geography:

H. capsulatum is found predominantly in

severe pulmonary and disseminated types are treated

the Mississippi and Ohio River valleys and is especially

initially with lipid amphotericin B. Sporotrichosis can be a chronic problem. The disseminated type is more

prevalent in bat and bird droppings.

Presentation:

Immunocompetent

patients

typically

have a self-limited, flu-like illness with or without mild pulmonary infiltrates. It may present with inter

common in immunodeficient gardeners. Mycobacterium marinum, Nocardia brasiliensis, and cat-scratch disease

cause similar lesions over lymphatic channels.

stitial pneumonia, palate ulcers, and splenomegaly. Histoplasma occasionally causes upper-lobe cavitary

pneumonia similar to that seen in TB. In

immunocompromised

patients

(especially

HIVI

AIDS), H. capsulatum can disseminate, causing a rap idly progressive sepsis

picture

and/or

multisystem

involvement.

Diagnosis: Demonstration of characteristic yeast forms

MUCORMYCOSIS Mucormycosis (also known as zygomycosis) is caused by fungi in the order Mucorales. Mucor, Rhizopus, or Rhizomucor are the most common causes of human

disease. Rhizopus has special physiology that allows it to live in

acidic and high-glucose conditions. It has also adapted to

with narrow-based budding is diagnostic. Culture yields

grow well in patients with iron overload on deferoxamine

arc the highest in patients with chronic pulmonary dis

chelation. So, Rhizopus is especially adapted to thrive in

ease. Serum and urine antigen detection is diagnostic

the diabetic and in those with primary or secondary hemo

and has the highest yield in immunocompromised hosts

chromatosis. The severely immunosuppressed are also at

and/or disseminated disease. These tests cross-react with Blastomyces dermatitidis.

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risk.

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2-32

PARASITES

Table 2-3: C lassificatio n of Parasites Group

Subgroup

PROTOZOA

Organism

Sporozoa

Toxoplasma, Cryptosporidium, Cystoisospora belli (formerly

(Do replicate within the body)

Isoporii belli), Plasmodium, Bqbesia ·

(no eosinophilia, except with ' Cystoisospora)

Ameba Flagellates

Giantia-:--GI;

Trichomonas,,2-GU;

Le1Shmania, Trypanosoma HELMINTHS

Nemathelminthes

(Do not replicate within the body)

(

nematodes)

(+ eosinophilia)

(

roundworms)

____...___....� . ��--

Entamoeba histolytica

blood

Pinworms, Hookworms, Whipworms (Trichuris trichiura), Trichinella, Strongyloides, Ascaris

Platyhelminthes

Disease

can

rhinocerebral

present

infection.

invasive

pulmonary

Rhinocerebral

mucormyco

sis starts as a black necrotic spot on the nasal mucosa or paranasal sinuses, and extends intracranially. It has a

to cause infection. With the exception of Cystoisospora, protozoa do not cause eosinophilia. The 3 types of protozoa are: 1) Sporozoa (Toxoplasma, Oyptosporidia, Cystoisospora

poor prognosis. Mucormycosis may also cause a necrotizing, cavitating

[the new name for lsospora], Plasmodium, Babesia)

pneumonia similar to aspergillosis. Rule out mucormy

2) Ameba (Entamoeba histolytica)

cosis in a patient on voriconazole treatment or prophylaxis

3) Flagellates (Giardia, T richomonas, Trypanosoma,

with new or worsening pulmonary disease.

Leishmania)

Diagnosis is made by biopsy showing broad non-septate hyphae. The organism is quite fragile and may not grow

Sporozoa

in culture.

Toxoplasma gondii

Treat with correction of predisposing factors (e.g., diabetic ketoacidosis), aggressive

surgical

management, and

lipid amphotericin B. Posaconazole can be used as an option in those who cannot tolerate amphotericin B or for salvage therapy.

Toxoplasma

gondii

the

protozoan

that

causes

toxoplasmosis. Cats are the definitive host and excrete oocysts, which are consumed by other animals in which the organism encysts in their muscles. When under cooked meat from these animals (pigs, lambs, and cattle) is ingested by humans, the organism ex cysts and tachyzoites are released that circulate through the blood

DERMATOPHYTES Dermatophytes are the skin and hair fungi. These organisms are found in the soil, and they infect keratin ized material (e.g., human nails and hair).

stream and infect any nucleated cells, with a predilection for neural tissue. Approximately 20% of pork and lamb, and 10% of beef contain T gondii cysts. Thus, con sumption of undercooked meat, as well as cat contact or

The names of the diseases caused by dermatophytes

ownership, are the modes of acquisition, and infection

begin with "tin ea" (e.g., tinea capitis, tinea corporis,

is common in the U.S. with l/3 of adults demonstrating

tinea pedis, and tinea cruris).

seropositivity to the organism.

Treat ringworm (tinea corporis) with topical clotrimazole

There are 4 clinical presentations of toxoplasmosis:

or undecylenic acid. Then, if no success, itraconazole or terbinafine are the preferred oral agents. Infection of hair follicles (tinea capitis) requires treatment with an oral agent, usually griseofulvin.

1) Toxoplasmosis in the immunocompetent host is most often asymptomatic, but may cause fever, lymph adenopathy, and atypical lymphocytosis similar to mononucleosis; yet pharyngitis is conspicuously absent. Diagnosis is made by demonstrating the pres ence oflgM antibody. It is self -limited and requires

PARASITES

no treatment. 2) Congenital toxoplasmosis: The only time Toxo

PROTOZOA

plasma is of real concern in immunocompetent people

Overview

is if it is acquired during pregnancy, when it can infect

There are 2 main types of parasites: protozoa and

the fetus and cause congenital toxoplasmosis-<:ausing

helminthic organisms. See Table 2-3. The protozoa are single-celled and can replicate within the body, so it takes only a small number of organisms

intellectual disabilities and necrotizing chorioretinitis. The fetus is more likely to have a congenital infection if the disease is acquired later in pregnancy (15% risk

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PARASITES

It may also cause acalculous cholecystitis and is the only protozoan that causes eosinophilia. Diagnosis is by wet

Q�uiz •

•

antibody staining. On the acid-fast stain, it is large and oval, whereas Cryptosporidium is small and round. Treat

Tinea capitis requires treatment with what drug?

with TMP/SMX and quinolones in the sulfa-allergic

How is serology useful in making a diagnosis of

CNS •

mount or acid-fast staining with or without monoclonal

patient.

toxoplasmosis?

In a patient with diarrhea who has recently

Cyclospora

ingested imported fruits or vegetables, are

Cyclospora

protozoan parasites a likely cause of infection?

cayetanensis

acid-fast

intestinal

protozoan parasite that causes diarrhea in both immu in I st trimester; 70% risk in 3rct trimester), but those infected later in pregnancy are usually asymptomatic. Diagnosis is made by demonstrating the presence of lgM antibody in blood. 3)

CNS toxoplasmosis occurs in immunocompromised patients from reactivation of previous infection. These patients present with new onset of seizures, neuro logic deficit, and/or altered consciousness. Diagnosis

nocompromised and immunocompetent patients similar to Cryptosporidium and Cystoisospora. It is often the cause of outbreaks related to imported fruits or veg etables. Systemic symptoms such as malaise, myalgia, low-grade fever, and fatigue are commonly seen with Cyclospora infection. It is diagnosed by acid-fast stain ing of the stool. Treat with TMP/SMX and quinolones in the sulfa-allergic patient.

is made by head imaging revealing multiple bilat eral lesions with a predilection for the basal ganglia.

Malaria

Because this is reactivation disease, lgM antibody

Overview

will not be present but IgG will be. A negative lgG also does not necessarily exclude infection because sometimes AlDS patients have difficulty making antibod ies. Treatment is with pyrimethamine, sulfadiazine, and leucovorin. AIDS patients remain on therapy for life unless CD4 counts climb above 200 for several months.

Plasmodium is the protozoan that causes malaria. There are

5 disease-causing Plasmodium species:

I) P falciparum 2) P vivax 3) P ovale

4) Ocular toxoplasmosis causes retinal lesions that look

4) P malariae

like yellow-white cotton patches and also irregular

5) P knowlesi

scarring and pigmentation. (Disseminated candidiasis produces white cotton wool patches.) Treatment con sists of pyrimethamine and a sulfonamide (sulfadiazine or trisulfapyrimidine) for 3 weeks.

commonly associated with nephrotic syndrome.

Oyptosporidium parvum and

C. hominis are protozoa

that cause infection, especially in the immunocom promised but also in the immunocompetent, and are second only to Giardia as the most common human GI parasite. The oocytes are passed in animal (includ ing human) feces. In the immunocompetent it causes secretory

infections. Any type of malaria can cause nephritis from immune complex deposition, but P malariae is most

Cryptosporidium

Plasmodiwn is transmitted via the Anopheles mosquito and infects RBCs. Asplenic patients have more severe

diarrhea,

which is

self-limited,

lasting

Malaria should be considered in any fever in the returning traveler, especially if it is cyclical. The incubation period is

30 days. Geographic hot spots include sub-Saharan

Africa and tropical regions of South America, Asia, and Indonesia. As we go through the

following,

see Table 2-4:

Treatment and Prophylaxis of Malaria.

1-2 weeks. In the immunosuppressed, it is chronic and requires immune reconstitution and/or specific therapy to resolve. Diagnosis is by acid-fast stains of stools and can be enhanced via monoclonal antibody staining. lmmunocompromised patients improve if antiretroviral therapy can raise the CD4 count. Nitazoxanide has vari able efficacy.

P. falciparum

P falciparum causes the most severe malaria; it is the cause of virtually all fatal infections. It also has wide spread chloroquine resistance. Most cases of Pfalciparum are acquired in central Africa. Differentiating this species from the others is critical because of its capacity to be resistant to chloroquine,

Cystoisospora (/. be/11)

Cystoisospora

belli

(previously

fsospora

belli)

another acid-fast protozoan that causes a secretory diar rhea in patients with AIDS, similar to Cryptosporidium.

its ability to infect RBCs of all ages (thus causing overwhelming parasitemia with end-organ damage), and the need to hospitalize infected patients and docu ment a decline in parasitemia with therapy. Fortunately, P falciparum has several unique findings on blood

2-33

2-34

PARASITES

Table 2-4: Treatment and Prophylaxis of Malaria Type of Malaria Non-falciparum

Treatment

Prophylaxis

Chloroquine, and primaquine

Chloroquine 500 mg (300 mg base)

malaria

w�y. Give daily in en�mic areas.

P. falciparum

Chloroquine

Choose any one of the following:

Chloroquine sensitive

Atovaquone/proguanil

Chloroquine Atovaquone/proguanil Mefloquine Doxycycline

Atovaquone/proguanil

P. falciparum

Atovaquone/proguanil: one dose

Chloroquine resistant

daiJy,focluding 1-2 days before

Not very ill

and 7 days after

P. falciparum

IV quinidine gluco�ate with either doxycycline, or tetracy

Chloroquine resistant

cline, or clindamycin

Very ill

Alternative: Artemjsinin derivative.

or I>oxycycline: 100 mg 1-2 days i?,efore travel and continued 4 weeks after return

smears that facilitate this speciat1on: banana-shaped

Patients with severe disease should receive IV quinidine

gametocytes; double chromatin knobs (giving the para

gluconate with either doxycycline or tetracycline or

> 1 parasite per cell; and the number of infected RBCs being > 5% (Image 2-15).

clindamycin. Artesunate may be used as an alternative.

This contrasts with the other forms of malaria in which

P vivax from Papua New Guinea and Indonesia should

site the appearance of headphones);

the parasitized RBCs are often hard to find. Even though

P falciparum causes the highest levels of parasitemia, the schizonts are not seen on peripheral smear. If you see schizonts, the patient has one of the other types. Treatment of

P falciparum malaria depends on the

likelihood of chloroquine sensitivity, which depends on the country of acquisition. As of 2012, chloroquine susceptible regions remain in

4 parts of the world.

Malaria acquired from these areas can safely be treated with chloroquine:

Non-falciparum Malaria

be assumed to be chloroquine-resistant; otherwise all

non-jalciparum species are chloroquine-sensitive and should receive chloroquine. Primaquine is adjunctive medication for infections with

P vivax and P ovale to eradicate hypnozoites in the liver. Hypnozoites are the malarial forms responsible for relapse. Some

P vivax isolates in Southeast Asia are

resistant to chloroquine and can be treated with meflo quine, atovaquone-proguanil, or quinine + doxycycline. Remember that primaquine induces hemolytic anemia in

I) Central America west of Panama

G6PD-deficient persons, so you must screen for G6PD

2) Haiti

deficiency before prescribing it.

3) Dominican Republic

Prophylaxis

4) Middle East

chloroquine. Start it 1-2 weeks before patient departs to

P falciparum from other areas must be assumed to be chloroquine-resistant. Non-severe disease (i.e., no end organ damage) should receive atovaquone/proguanil or mefloquine.

chloroquine-sensitive

the endemic area and continue

areas:

Use

4-6 weeks after leaving

the area. Prophylaxis in chloroquine-resistant areas: Use mefloquine or atovaquone/proguanil. Primaquine should be given the last 2 weeks of a prophylaxis period after travel to areas where there is

P vivax or P ovate to eradicate the

liver stage. Know that the main causes of malaria in the U.S. are either not taking prophylaxis or stopping pro phylaxis too soon after returning from travel to endemic areas! Atovaquone/proguanil is considered the drug of choice for prophylaxis. Specifically, the main advantage is that

Image 2-15: P falciparum. ""banana-shaped gametocyres"

it can be started just prior to leaving and stopped soon

PARASITES

Ameba Human amebiasis is caused by the protozoan Entamoeba

•

UIZ •

histolytica. Transmission is fecal-oral and can be food

Which form of malaria is associated with the banana-shaped gametocyte?

•

and men who have sex with men. It can be asymptom

Chloroquine is useful against which species of

atic or cause dysentery: profuse diarrhea, abdominal pain, fever, and bloody stools. The organism sometimes

malaria? •

or waterborne. In the U.S., the usual population groups in which it is found are the institutionalized, immigrants,

For travel to chloroquine-resistant areas, what drugs are used for malaria prophylaxis?

invades the portal circulation and can cause usually soli tary liver abscesses. Diagnosis of intestinal disease is by stool for ova and parasites. Amebic liver abscesses often

•

What is the presentation of Babesia infection?

show no ameba or PMNs. These cases can be diagnosed

•

How do you diagnose and treat extraintestinal

by serology.

amebiasis?

Treatment is with metronidazole (or tinidazole) for both

How is a Giardia infection diagnosed?

forms of the disease. Although metronidazole treats

•

ameba that have invaded, it does not kill intraluminal after return-and has fewer side effects. The disadvantage is that it must be taken daily. Doxycycline has activity against chloroquine-sensitive and chloroquine-resistant malaria, and it can be used for

cysts. This must be accomplished with the administra tion of paromomycin, diiodohydroxyquin, or diloxanide furoate.

prophylaxis at a dose of I 00 mg daily. The advantage is

Flagellates

that it is very inexpensive. The disadvantages are that it

The flagellates: Giardia lamblia, Trichomonas vagina/is,

can cause photosensitivity, has to be taken daily, and has

Trypanosoma, Leishmania.

to be taken for 4 weeks after leaving the endemic area.

Giardia /amblia (a.k.a. G. duodena/is)

Babesia Babesia microti is an intra-RBC protozoan parasite that causes babesiosis. This disease causes a febrile, hemo lytic anemia. Asplenic patients are at increased risk for severe babesiosis.

Giardia infections are found in campers, travelers, children in day care, HIV-infected persons, men who have sex with men, and in patients with IgA deficiency and/or hypogammaglobulinemia. It infects the duode num and proximal jejunum by adhering to the mucosa

The organism is naturally transmitted via the Ixodes

and causing a malabsorption syndrome, yet 75% of

tick from rodents, as is the spirochete B. burgdor

infected persons are asymptomatic. If they occur, symp

feri, which causes Lyme disease. It is most prevalent

toms include a watery, smelly diarrhea and flatulence.

in the Northeast U.S. and upper Midwest-usually in

Diagnosis is made by microscopic examination of fresh

summer or early autumn. Rare cases result from blood

stool samples. Antigen excretion is intermittent, and

transfusion.

up to 3 specimens may need to be obtained. Detection

Symptoms, which may persist for months, include fever,

assays have a similar yield with a single stool.

profuse sweats, myalgias, and shaking chills. Severe

Treatment is available with many agents: tinidazole,

cases cause liver, renal, and neurological failure, and

nitazoxanide (both FDA approved); non-FDA approved

death. Hemoglobinuria is a predominant sign. Because

alternatives include metronidazole, albendazole, and

of the symptoms and the parasitized RBCs, it may be

paromomycin (which is approved in pregnancy).

misdiagnosed as malaria. B. microti is distinguished from Plasmodium by the classic intra-RBC pear shapes, which occasionally form a tetrad appearing as a "Maltese cross." (See Image 2-16; the malarial parasites have a ring form.) PCR assays are available and more sensitive than peripheral smears. Mild babesiosis infections are

usually

self-limited.

metronidazole. More under Vaginitis, page 2-65.

Trypanosomiasis Tiypanosoma species causes trypanosomiasis. There are 2 main types. The African disease is sleeping sickness,

with atovaquone + azithro

which is caused by Trypanosoma brucei gambiense and

clindamycin

qumme

and consider an exchange

Trichomonas vagina/is causes an STD. Treat with

Treat moderate infections mycin. If severe, treat with

Image 2-16: Ma/Iese cross Babesia microti

Trichomonas vagina/is

transfusion.

Tiypanosoma brucei rhodesiense. These are transmitted via the tsetse fly. The American illness, Chagas disease, is caused by T cnrzi and is found in South America and Mexico. You can impress your friends by knowing that it's transmitted by bites of the triatoma or reduviid bug.

2-35

2-36

PARASITES

Usually, it is self-limited, but the chronic form can cause problems with the heart (from heart block to CHF), the GI system (especially achalasia, megaesophagus, and megacolon, as discussed in Gastroenterology, Book

I),

and occasionally the CNS. Treatment is species specific.

T brucei gambiense responds to pentamidine (for early disease) and eflomithine + nifurtimox (for late disease).

T brucei rhodesiense is treated the same way, but nifur timox is not needed. T cruzi is treated with benznidazole or nifurtimox.

Nematodes The

following list summarizes diseases

caused by

roundworms:

I) Ascaris Jumbricoides (roundworm; causes ascariasis) (Image 2-17): • Epidemiology: Worldwide,> I billion people are infected, and the sole host is humans. Jn the U.S., 2% overall infected-worse in rural South with up to 30% of young children affected in some areas. • Life cycle: Eggs are ingested, hatch in the small intestine, and the larvae penetrate the intestinal wall

Leishmaniasis

Another

deadly

tropical

protozoan

Leishmania.

Leishmaniasis is caused by any of the following 4 spe

Leishmania protozoa: L. donovani, L. tropica, mexicana, and L. braziliensis. L. donovani is spread

cies of the L.

by sand flies and causes visceral leishmaniasis, also called kala-azar. Infected patients may have GI symp toms, hepatomegaly, and massive splenomegaly. The other species cause cutaneous and mucocutaneous forms of the disease. Recent reports indicate there is a higher susceptibility for leishmaniasis in HIV-infected patients who travel to endemic areas.

and migrate to the lungs where they mature over I 0 days. Then they ascend the bronchial tree and are swallowed, mature into adult worms in the small intestine, and excrete eggs in the stool. Eggs can live for up to I 0 years in dark, moist conditions. Worms may migrate into the biliary tree and the appendix. • Presentation if symptomatic: pulmonary eosinophilic syndrome, acute appendicitis, ascending cholangitis. •Diagnosis: eggs (and rarely worms) in stool. • Treatment: albendazole or mebendazole. 2) Enterobius vermicularis (pinworm) (Image 2-18):

Sodium stibogluconate (pentavalent antimony), pent amidine, or amphotericin B are the treatments of choice.

• Epidemiology: Most common helminthic infection in the U.S.; humans are the only host. • Life cycle: Eggs are ingested and hatch in the small intestine. Gravid females migrate to the rectum and,

HELMINTHIC ORGANISMS

at night, lay eggs in the perianal area.

Overview

• Clinical presentation if symptomatic: perianal itching.

Helminthic organisms are the other major type of para site. (Remember:

I) protozoa and 2) helminthic organ

isms.) Helminthic organisms are multicellular worms that cause eosinophilia. Helminthic organisms consist of

was touched upon the perianal area demonstrating eggs and sometimes female worms. • Treatment: single dose of albendazole, followed by repeat dose in 2 weeks to kill worms from hatched

nematodes (roundworms), tapeworms, and flukes. With the exception of

•Diagnosis: microscopic exam of transparent tape that

Strongyloides, helminthic organ

isms do not multiply in the human body.

eggs. 3) Necator americanus (hookworm): • Epidemiology: requires coming into contact with larva in the soil that have hatched from eggs excreted by humans. Especially at risk are people walking barefoot or with open sandals in contaminated areas. • Life cycle: Larvae penetrate the skin and migrate to the lungs, up the bronchial tree, and are swallowed. Once in the small intestine, they mature and attach to the intestinal wall where they feed. Eggs are excreted in stool. • Presentation if symptomatic: cutaneous: itching at the site of larval entry ("ground itch"); serpiginous erup tion along the course of the larva's migration ("cuta neous larval migrans"). Chronic infection leads to iron deficiency anemia from chronic GI blood loss and hypoalbuminemia in persons already malnourished. •Diagnosis: eggs in stool.

Image 2-17: Roundworm egg

• Treatment: single dose of albendazole.

Image 2-18: Pinworm eggs

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PARASITES

similar to malaria (filarial fever). There may be associated tender lymphadenopathy (acute adenolymphangitis). 0 •

•

Tropical pulmonary eosinophilia is due to

What is kala-azar?

microfilariae trapped in the lungs and causes

Disseminated strongyloidiasis can be seen in which patient population?

nocturnal wheezing. °

Chronic infection leads to lymphatic obstruction, scarring, and severe lymphedema (elephantiasis).

• Diagnosis: Blood smears best demonstrate microfi

Trichiura (whipworm):

• Epidemiology: affects over

lariae between

1.5 billion people

worldwide. Found in warm moist places with

adult worms. It must

poor sanitation, similar to Ascaris; coinfection is not uncommon.

• Life cycle: eggs ingested, hatch in small intestine, mature in caecum and ascending colon; excrete eggs in stool.

Strongyloides stercoralis (strongyloidiasis):

• Epidemiology: endemic throughout tropical regions of the world and in parts of the southeastern U.S. It

•Treatment: albendazole for

its life cycle within the human body, resulting in autoinfection and persistence of infection. This also

pain, blood in stool, rectal prolapse.

permits overwhelming infection in immunocom

• Diagnosis: eggs in stool.

3 days; repeat

Rx pm.

Trichine/la (trichinosis):

• Epidemiology:

T. spiralis is the most common

Trichinella species in the U.S. The main sources of the disease are from undercooked wild game (e.g., bear, wild boar) and domesticated pigs. In the U.S., about 20 cases are reported each year, although there is a much higher incidence on autopsy. • Life cycle: Eggs are ingested, and larvae attach to the small intestine wall. Larvae are released, and these larvae spread via the blood vessels to the muscle, where they burrow and encyst in a muscle cell. • Presentations if symptomatic: muscle pain, tender ness, and weakness. High worm burdens can affect the CNS, lungs, heart, and kidneys.

promised patients. • Life cycle: Like hookworm, the Strongyloides larvae penetrate the skin and migrate to the lungs. They then migrate up the tracheobronchial tree and are swal lowed. Once in the small intestine, they attach to

eggs that hatch into noninfectious rhabditiform larvae that are mostly excreted in the stool. However, some of these noninfectious larvae convert to infectious filariform larvae while still within the small intestine. These larvae penetrate the wall of the colon or peri anal skin to hematogenously travel to the lung, just like exogenously introduced larvae do. • Presentations if symptomatic: 0

("ground itch") and a serpiginous eruption along larval migrans") may occur. 0

GI symptoms include abdominal pain, nausea,

Pulmonary eosinophilic syndrome may occur.

Immunosuppression may lead to strongyloides

•Treatment: for mild cases is supportive. For systemic infections, treat with albendazole for I 0-14 days. Glucocorticoids should be given to suppress the inflammatory consequences of worm death. Wuchereria bancrofti, Brugia malayi, and Brugia timori (filariasis):

• Epidemiology: More than

100 million people worldwide are infected, and 1/3 of those are symptomatic. These worms are transmitted via

mosquito bites. • Life cycle: Mosquito introduces larvae into skin

Like hookworm, itching at the site of larval entry the course of the larva's migration ("cutaneous

after several weeks. Muscle biopsy may be performed to look for organisms.

the

mucosa and mature. Adult female worms produce

• Diagnosis: Serology is available and turns positive

be obtained from the CDC.

is the only helminthic organism that can complete

• Presentation if symptomatic: diarrhea, abdominal

10 p.m. and 2 a.m.

•Treatment: Diethylcarbamazine kills the larvae and

vomiting, and diarrhea.

hyperinfection syndrome . This represents an augmented and accelerated autoinfection cycle. Patients generally present in shock resulting from gram-negative sepsis. (Bacteria are car ried from the intestine into the bloodstream.) Gram-negative meningitis may also occur. • Diagnosis: Larvae in the stool are diagnostic but are seen in< 50% of those infected. Yield is increased by

during feeding. Larvae enter the lymphatics and

inoculating the stool in agar and looking for the trail

mature over 9 months. Adult worms then produce

left by migrating larvae. Serology is useful in imrnu

microfilariae that migrate into the bloodstream

nocompetent patients. In hyperinfection syndrome,

(usually at night) where they are ingested by feeding

many larvae are usually seen in respiratory samples.

mosquitos. • Presentation if symptomatic: 0

Acute infection causes a nonspecific febrile illness in a traveller that may be

•Treatment: Ivermectin is the drug of choice; albendazole is a less effective alternative. Repeat treatment after 2 weeks for eradication.

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PARASITES

Toxocara canis and T. cati (toxocariasis, visceral

larva migrans):

T canis (the dog ascarid) is more common than T cati (the cat ascarid). It occurs world wide with a 14% prevalence in the U.S. Humans are

• Epidemiology:

not normal hosts for these helminths and are not a required part of their life cycle. • Life cycle: The adult tapeworm sheds eggs in the stool of its animal host. If humans ingest these eggs, they hatch into larvae that travel through tissue, elicit an immune response, and subsequently die. • Presentation if symptomatic: Migrating larvae may cause injury to liver, heart, lungs, brain, muscle, and eyes. F leeting migratory pulmonary infiltrates that self-resolve are typical. •Treatment: If systemic symptoms, give albendazole for 5 days.

Tapeworms Clinically important tapeworms include

Taenia solium

(pork tapeworm) and Echinococcus.

T solium is endemic in many regions of Central and South America, sub-Saharan Africa, India, and Asia. It is

T solium in order to 2 manifestations of human disease it may

important to recall the life cycle of understand the

cause. Although it is called the pork tapeworm, humans are the definitive host (the host in which the adult worm lives). If eggs are ingested, these hatch into oncospheres that travel through the blood to encyst in tissues (most commonly the central nervous system) as cysticerci causing neurocysticercosis. CNS cysticerci can be in the parenchyma or be extraparenchymal in the CSF where they usually lodge in the aqueduct of Sylvius. Cysticerci are able to suppress the human host response and thus remain asymptomatic until the organism dies, when

Angiostrongylus cantonensis and A. costaricensis

an inflammatory response ensues. If the cysticerci are

( angiostrongyliasis ):

intraparenchymal, they cause seizures; if in the CSF,

• Epidemiology: A.

they cause hydrocephalus. If cysts are ingested from

cantonensis (the rat lungworm) is

endemic in Southeast Asia and tropical Pacific islands

undercooked pork, the organism excysts and grows into

and is the most common parasitic cause of eosino

the adult tapeworm in the gut (taeniasis). A person car

philic meningitis. A.

costaricensis is endemic in Latin

rying a tapeworm will then start shedding eggs. Most

America and the Caribbean. Both parasites have rats

people with tapewonn disease limited to the gut have no

as their definitive hosts.

symptoms.

• Life cycle: A.

cantonensis adult worms live in the

pulmonary arteries of rats, and eggs laid there hatch into larvae that migrate to the pharynx, are swal lowed, and are passed in the rats stool. These larvae infect snails that, if eaten by humans, migrate to the central nervous system. A.

costaricensis lives in the mesenteric arterioles of

rats. They shed eggs that hatch into larvae that are when ingested by snails. If these infected snails are ingested by humans, the larvae migrate to mesenteric arteries and shed eggs that cause severe endothelial damage and enteric tissue necrosis. Humans do not shed the eggs.

self-limiting or neuroinvasive. Headache is the most prominent symptom, and lumbar puncture yields an eosinophilic inflammatory response.

costaricensis causes abdominal pain, fever, vomit

ing, and may progress to GI bleeding and perforation. •Diagnosis: A.

cantonensis is rarely visualized in the

CSF, so the diagnosis is based on the presence of eosinophilic meningitis in the appropriate epidemio logic setting. A.

organism is the only way to make a diagnosis because the worms and eggs are not shed in the stool.

cantonensis: The disease is self-limited,

and no antiparasitic drugs have been shown to be effective. A.

Antiepileptic treatment is important in patients with inflamed brain lesions or with a history of seizures and calcified lesions. These patients (and those with disease of the extraocular muscles or optic nerve) should be bral edema or lots of inflammation is present, hold off on treating with antiparasitics and give corticosteroids first. No treatment is necessary for patients with only calcified lesions and no history of clinical disease. Cutaneous and intramuscular disease can be treated with analgesics.

Echinococcus.

It causes a condition known as "hydatid disease" in which hydatid cysts proliferate throughout the body. It is acquired after ingesting food contaminated with feces from the definitive hosts, which are other mam mals (sheep, dogs, rodents, foxes, etc.) Most cases are diagnosed in immigrants from China, South and Central America, the former Soviet Union, and the Middle East. Hunters and veterinarians are also susceptible. Initial phase of infection is typically asymptomatic, and most people are infected as children. The liver is the most common organ affected (especially with E.

costaricensis: Tissue specimens revealing the

•Treatment: A.

(151 choice) or praziquantel are

the antiparasitic drugs used to treat neurocysticercosis.

Another tapeworm to be aware of is the

cantonensis

causes symptoms typical of meningitis that may be

tapeworms. Albendazole

treated with an antiparasitic plus corticosteroids. If cere

passed in the rat's feces, which hatch into larvae

• Manifestations if symptomatic: A.

Niclosamide is the usual treatment for all intestinal

costaricensis: Antiparasitic drugs are not

effective and may cause worm migration and worsen ing symptoms. Perform surgery for complications.

followed by the lungs (especially with E.

granulosus), multilocularis).

The right lobe of the liver is most commonly affected and generally presents as a single large cyst. Complications can occur if the cyst ruptures into the biliary tree or peritoneum. Ultrasound or other imaging is diagnos tic and can be confirmed with a serologic test (ELISA usually). Treatment with newer surgical techniques is

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VIRUSES

Q�uiz

HERPES SIMPLEX VIRUS (HSV) Herpes simplex virus (HSY): a DNA virus. Many HSY

•

What is visceral larval migrans?

•

When do you not treat patients with

infections are spread by asymptomatic shedding of virus.

neurocysticercosis with an antiparasitic drug? •

Multinucleated giant cells can be seen

�

40% of the popu

and ulcers are usually localized to the oral mucosa,

associated with which infections? •

HSV-1 causes orofacial infections in

lation. In the primary infection, the vesicular lesions lips, and surrounding skin and may have constitutional

When are most cases of neonatal HSV infection

symptoms. Recurrent

acquired?

infection

ulcers

are

typically just on the evolving; but open surgery is recommended for large cysts

outer lip. It is possible

(> I 0 cm), and chemotherapy with albendazole before

and after surgery is useful.

virus, so the infection

Tapeworm infections are zoonoses. Common vectors of tapewonn disease are listed below: •

•

can spread from the lips (or other areas) to the eyes of a patient.

Diphyllobothrium latum: from eating undercooked fish

•

autoinoculate the

Recurrent HSY-I eye infection resulting in

Hymenolepis nana: rodent exposures

keratitis is the most

Sparganosis: frogs/snakes

common

infectious

cause of blindness in

Image 2-19: M11/1i1111clea1ed giant cell

Flukes ("Flatworms")

industrialized nations.

Clonorchis sinensis is the Chinese liver fluke, which is

Tzanck smears are perfom1ed by scraping down to the

endemic in the F ar East. Infection is caused by eating

bottom of a vesicle, placing the material on a slide, then

raw fish, and it is often associated with biliary obstruc

staining with either Giemsa or Wright. In herpes simplex

tion. It increases the risk of cholangiocarcinoma. Other

and varicella zoster virus infections, it shows multinu

2-19). However, in current

flukes in the liver? Opisthorchis or Metorchis. Flukes in

cleated giant cells (Image

the lung? Paragonimus species.

clinical practice, PCR, and DFA (direct fluorescent anti

Schistosoma haematobium is found in North Africa,

body) are the most commonly used diagnostic tests.

sub-Saharan Africa, the Middle East, Turkey, and India.

HSV-2

Schistosoma mansoni is a fluke found in Africa, the

75% of HSY genital infections-the rest are due to

Middle East, and South America; Schistosoma japoni

HSY-I. Note that the prevalence of HSY-2 is 25%, and

cum is found in Asia. The flukes themselves do not cause symptoms, but the eggs they shed do.

S. hematobium

causes

"genital

herpes."

of those, only 25% have symptoms. In

causes

about

I 0% of patients,

the initial occurrence of I-ISY-2 is associated with only

eggs cause inflammation and fibrosis of the bladder wall,

a herpetic exudative pharyngitis. Most cases of neonatal

with symptoms of urinary tract infection, and predispose

HSY are from intrapartum contact, so a C-section is rec

S. mansoni and S. japonicum shed

ommended if the mother has symptoms or signs of genital

to bladder cancer.

eggs into the portal venous system, leading to portal

herpes, or its prodrome, at the time of delivery. The risk

hypertension, cirrhosis, and esophageal varices.

for transmission to the neonate is high (30-50%) among

Schistosoma

species

are

acquired

contact with

freshwater containing cercarial larva. Initial manifestation of schistosomiasis (Katayama fever) occurs

�

2 months

after inoculation. This presents with fever, lymphadenop athy, hepatosplenomegaly, and marked eosinophilia. Diagnosis is made by finding the eggs in the stool or urine, depending on the species. Treatment is a I-day course of praziquantel.

women who get their I st episode of genital herpes near the time of delivery and is low(< 1%) among women with a history of recurrent herpes. HSY reactivates in 2/3 of seropositive transplant patients within 6 weeks of trans plant, but this rate is drastically lower in patients receiving antiviral prophylaxis. HSY encephalitis is the most common cause of sporadic viral encephalitis and causes the highest number of deaths due to viral encephalitis in adults. Patients with herpes encephalitis usually present with altered mental status, seizures and/or focal neurologic deficits. The virus has a predilection for the temporal lobes. Prognosis is poor, and more than 60% have neurologic sequelae.

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VIRUSES

MR imaging is often abnormal on presentation, but LP

myalgias, nausea, and headache. Children have a short

and empiric treatment should not be delayed to obtain an

prodromal phase

MRI. CSF usually shows increased protein, lymphocytic

the 1st symptom.

pleocytosis, and increased red cells, but it can be normal in early infection. Diagnosis of HSY DNA by PCR in CSF is the most sensitive (98%) and specific (97%) test, not brain biopsy.

(< 24 hours),

or a papular rash may be

Chicken pox symptoms are typically mild in children but may be severe in adolescents and adults, and especially pregnant women in whom pneumonia is more likely to occur. In pregnancy, besides increased disease sever

HSY is one of the many causes of erythema multiforme.

ity and pneumonia, birth defects are more likely if the

(See Dermatology, Book 5.)

mother is infected between 8- and 20-weeks gestation.

Treatment of HSY: Initial or recurrent mucocutaneous

Diagnosis is usually made clinically based on the classic

HSY can be treated with acyclovir PO but is of bene

appearance of the rash. DFA or PCR can be used for

fit only if treatment is given within the first 72 hours.

atypical appearing rashes.

Famciclovir and valacyclovir are similarly effective but more expensive. Give acyclovir after 72 hours if the patient is immunocompromised. For HSY, give enceph alitis IV acyclovir for 14-21 days. IV acyclovir should also be given if there is disseminated HSY (e.g., lung, skin, liver). Acyclovir (or famciclovir or valacyclovir) can also be given chronically to suppress infection in

Treatment: All adult patients should be treated with PO acyclovir if they present within 24 hours of rash onset. This treatment decreases the number of lesions and the duration of disease. Give IV acyclovir for non-skin organ involvement and to patients who are immunocompromised.

those with frequent recurrences, especially if they are

Prophylaxis: Development of chicken pox in persons

complicated by erythema multiforme. Use foscarnet to

who have come in contact with a case of chicken pox and

treat those with HSY resistant to acyclovir; ganciclo

are at risk for developing chicken pox can be prevented

vir is not used because cross-resistance is common in

in 2 ways. Persons at risk are those who are not currently

acyclovir-resistant strains.

immune (because they have never had chicken pox or the chicken pox vaccine) or are currently immunocom promised or pregnant. Immunocompetent persons should

VARICELLA-ZOSTER VIRUS

receive the varicella vaccine. lmmunocompromised or pregnant patients should not receive this vaccine because

Overview Varicella-zoster virus (VZV; DNA) causes chicken pox (Image 2-20) and herpes zoster (shingles).

it is a live vaccine. These people should receive vari cella zoster immune globulin (VZlG) as soon as possible after exposure. In 2012, the FDA approved its use up to 10 days after exposure.

Chicken Pox Chicken pox is an airborne, highly contagious disease

Herpes Zoster (Shingles)

that causes a characteristic pruritic vesicular erup

Overview

tion that comes in successive crops. On exam, these skin lesions are typically found in various stages, from new erythematous papules, to vesicles, to crusted-over lesions. Patients are contagious for 1-2 days before eruption and stay contagious until the last lesion has crusted over. These pox marks do not leave scars unless superinfected. Adolescent and adult patients also have a characteris tic prodromal phase with fever, malaise, pharyngitis,

Herpes zoster is caused by reactivation of the varicella zoster virus after the initial infection. After the initial infection, virus becomes dormant and asymptomatic in sensory ganglia neurons until it is reactivated and spreads down the nerve, causing a painful rash. Reactivation causes a prodromal phase with constitutional symptoms followed by hyperesthesia and a burning, frequently lancinating pain over the dermatome. This is followed by the characteristic vesicular skin rash. In about 10-20% of patients, the ophthalmic branch of the trigeminal cranial nerve is involved, which can be sight-threatening if zoster keratitis results. The most common dermatomes involved are the thoracic derma tomes. Usually one thoracic dermatome is involved, but occasionally it may involve 1-2 more. If there are more than 3 dermatomes involved, or more than 30 lesions outside of the primary dermatomes, it is considered disseminated zoster. Just as with chicken pox, the zoster lesions are contagious until crusted over-and can give a nonimmune person chicken pox.

Image 2-20: VZV.- Chicken pox

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VIRUSES

CMV infection in the normal population is typically asymptomatic, but

Q�uiz •

•

hepatitis. Exudative pharyngitis is rare though. Think of

What is the most sensitive and specific method

this in a monospot-negative adult with these symptoms

for diagnosing HSV encephalitis?

(especially if younger-to-middle-aged because EBY

In what situation should a pregnant woman be given varicella vaccine?

•

Which patients should receive the zoster vaccine?

•

I 0% have a mononucleosis-type

illness with fever, sore throat, adenopathy, fatigue, and

mono usually occurs more in adolescents). Also, con sider acute HIV with this presentation. CMV is a very common infection in patients with decreased cellular immunity (post-transplant and AIDS). 75% of seronegative transplant recipients get CMV if

How is CMV diagnosed?

the donor is seropositive. With a post-transplant sys

What is the clinical presentation of EBV

temic CMV infection, the patient can have concurrent "-itises," which may include encephalitis, hepatitis,

mononucleosis?

retinitis, colitis, and adrenalitis (causing adrenal insuf Disease duration is about 2--4 weeks. If there are any new lesions after 7-10 days, consider underlying eel) mediated

immunodeficiency.

ficiency); these are especially common and more severe if the recipient is seronegative prior to the transplant.

lmmunocompromised

HIV /AIDS: When the CD4 count gets< 50, CMV can

patients are at increased risk for dissemination, which

cause chorioretinitis, pneumonitis, esophagitis, and coli

may include organ involvement (CNS, lung, liver).

tis. This CMV retinitis is distinctive; it has both retinal

Shingles recurs in< 5% of immunocompetent patients.

blanching and hemorrhage and follows along the path of the retinal arteries.

Postherpetic Neuralgia

Diagnose acute CMV infection by demonstrating DNA

Postherpetic neuralgia is the most common complication

in peripheral blood. Immunohistochemical stains can

(- 12% overall) of zoster, and it is more likely to occur

be used to stain CMV-infected cells in tissue-invasive

with increasing age (20% in those > 80 years of age). It can cause a lancinating, sometimes debilitating pain for

without viremia.

many months to years.

disease. Occasionally, tissue-invasive disease presents Treat susceptible CMV infection with valganciclovir or ganciclovir. For resistant virus, foscamet or cidofovir

Vaccination for Herpes Zoster

may be used.

The zoster vaccine decreases the incidence of zoster by 1/2 and the incidence of postherpetic neuralgia by 2/3. It is currently FDA approved for those 50 years of age or older, but the Advisory Committee on Immunization Practices (ACIP) recommends the vaccine for those 60 years of age or older.

EBV Epstein-Barr virus nucleosis.

(EBY )

Incubation

causes infectious mono

period

1-2

months. Most

(> 90%) patients have pharyngitis (which is commonly exudative) or tonsillitis, fever, lymphadenopathy, and abnormal liver function. Splenomegaly may be seen.

Treatment

Oral acyclovir, famciclovir and valacyclovir are shown

Lymphocytosis is

commonly

infection

with

usually

found in acute

10%

"atypical

EBY

lympho

to decrease the incidence of postherpetic neuralgia. They

cytes." Atypical lymphs are enlarged with abundant

also shorten the duration and severity of the initial pain.

cytoplasm, vacuoles, and indentations of the cell mem

Adding prednisone provides no additional benefit and even prolongs the course of herpes zoster in immuno suppressed patients. For pain control, tricyclic antidepressants, gabapentin, and lidocainc patches have some efficacy. Narcotics are effective and underused in this instance. Capsaicin cream is useful after the lesions have healed.

brane. These are T cells that are actively trying to fight the EBY-infected B cells. 90% of patients with acute EBY develop a macular rash if given ampicillin, which can occur if the exudative pharyngitis is mistaken for

S. pyogenes infection. Diagnosis of infectious mononucleosis may be made clinically

and

confirmed

serology.

Heterophile

antibody titers (monospot) are nonspecific antibod ies that cross-react with RBCs of other mammals.

CYTOMEGALOVIRUS (CMV)

They are absent - 25% of the time in the l st week of

Cytomegalovirus (CMV) is a DNA virus in the herpes

illness ("heterophile-negative mononucleosis"). Thus,

virus family. CMV infection in the normal population is fairly common; 1/2 of the population has anti-CMV antibodies by the age of 35.

the most common cause of heterophile-negative mono nucleosis of I-week duration is still EBY. The diagno sis can be made by testing for IgM capsid antibody in these patients. Other causes of heterophile-negative

2-41

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VIRUSES

mononucleosis are CMV toxoplasmosis, acute HIV, and HHV-6 infection.

Retroviruses are RNA viruses.

Treatment of acute EBY infection remains supportive because of its excellent prognosis and unavailability of any antivirals active against EBY. EBY causes oral hairy leukoplakia, which may be fatigue has no proven association with EBY. EBY is oncogenic and is associated with nasopharyngeal car and

non-Hodgkin

lymphoma,

specifically

Burkitt lymphoma. Other cancer-causing viruses include hepatitis B and C.

(ssRNA

syndrome, spastic tropical paraparesis, seen in Japan • HTLV-2 causes a rare T-cell variant of hairy cell leukemia. •HIV- I causes AIDS (much more on page 2-52). •HIV-2, found in West Africa and parts of the U.S., is a virus that causes an illness indistinguishable from AIDS. (Both HIV- I and -2 are now picked up by EIA/ELISA.) More on HIV on page 2-46.

RUBELLA (GERMAN MEASLES) Rubella

•HTLV-1 causes T-cell leukemia and a neurologic and the Caribbean.

seen as an early manifestation of HIV disease. Chronic

cinoma

RETROVIRUS

virus)

"German

RESPIRATORY VIRUSES measles"

(Image 2-21 ). If it is acquired by a pregnant patient in the

I st trimester, there is a 50% chance that the baby will

Rhinoviruses Rhinoviruses are a common cause of URI in adults.

have congenital defects. It is diagnosed by the hemag glutination inhibition test or by EL ISA. If this test is negative in a newly exposed pregnant patient, repeat it in 3 weeks (after incubation period) before any deci sions are made. If it is then positive, offer the patient the option of a therapeutic abortion. Immune globulin does not prevent the infection, but it may give some fetal pro tection in the patient who refuses therapeutic abortion.

Respiratory Syncytial Virus RSV infections occur year round, usually during the autumn and winter. RSV infections are more severe in the infant, occasionally resulting in pneumonia. Only I% of infected infants are hospitalized. RSV infection has similar morbidity as influenza and especially affects the elderly and those with immunodeficiency. It is now thought to be responsible for up to 25% of excess winter

RUBEOLA (MEASLES)

season mortality that was previously attributed solely to

Rubeola is "measles" caused by an ssRNA virus. Symptoms start - I 0 days after the initial exposure.

influenza. RSV is also an important pathogen in hematopoietic

Symptoms at the onset are the "3 Cs": cough, coryza,

stem cell transplant recipients and lung transplant recipi

and conjunctivitis (with photophobia). Patients also have

ents. Diagnosis can be made by detecting RSV antigen or

malaise and fever. Koplik spots (whitish spots on an ery

with PCR of nasal secretions. Ribavirin (oral or inhaled)

thematous base) appear on the buccal mucosa before the

is used as an antiviral therapy in immunocompromised

onset of the skin rash (Image 2-22). The skin rash starts

hosts, but the efficacy is limited.

at the hairline and spreads downward. It lasts - 5 days and then resolves, also from the hairline downward. Outbreaks continue to occur in at-risk persons who have

Influenza Influenza is still a major cause of death, especially if

not been vaccinated.

the patient is> 55 years of age with COPD. Vaccination decreases mortality.

Image 2-21: Rubella infection with postauricu/ar adenopathy

Image 2-22: Measles; Koplik �pols, small white spots that occur before the rash

2014 MedStudy-Please Report

VIRUSES

specific agent is dependent on the circulating strains and is steadily increasing.

Q�uiz •

Prevention: All individuals

What are the clinical symptoms of measles? How do you diagnose influenza A?

•

What drugs are recommended for empiric treatment of probable influenza?

•

6 months old should

are targeted at the serotypes that are most likely to be present when the influenza season occurs. The better

•

receive annual influenza vaccination. Influenza vaccines

the antigenic match between this year's strains and next year's, the better the vaccine works. There are 2 types of influenza vaccines in the US: inactivated and intranasal

Which patient groups can receive the intranasal

live-attenuated. The live-attenuated (intranasal) vaccine

influenza vaccine?

is available for healthy, non-pregnant patients ages

Name some animals that are high-risk for transmission of rabies.

2-49 years. All others should receive the inactivated vaccine. Vaccines should be administered when they become available each year, which is usually in October.

There are 3 types of influenza viruses: influenza A, B, and C. Subtypes of influenza A exist based on their

Coronavirus

specific neuraminidase (NI and 2) and hemagglutinin

Usual Coronavirus Infection

(Hl-3) antigens. A and B cause the yearly epidemics of respiratory illnesses. Influenza C causes very mild, if any, symptoms. Example: The major circulating influenza A subtypes in 2009-20 I0 were seasonal H3N2, seasonal HINI, and novel HIN! (swine flu). The novel HINI subtype

Coronavirus is an enveloped RNA virus. In its usual form, it is responsible for 3-5% of "common colds." Coronavirus "colds" are more likely to occur in winter and early spring.

was especially virulent in the following situations: preg

Severe Acute Respiratory Syndrome (SARS)

nancy, children

Severe acute respiratory syndrome (SARS) is due to

24 years of age, adults

65 years of

age, and immunodeficient states.

SARS-associated

Influenza presents as an acute febrile respiratory illness

November 2002 to July 2003, there were

with fever and cough. Serious complications include viral pneumonia, secondary bacterial pneumonia, rhab domyolysis, and encephalitis. Diagnosis: A positive antigen test or PCR for influenza A and B on nasopharyngeal swab or respiratory secretions is diagnostic. While a positive test does not always have to result in antiviral treatment, it is quite useful to rule out bacterial infection (antibiotic stewardship) and has a role in infection control. Treatment should be given in 3 settings: I) Those at high risk of complications (immunocom promised, pregnancy; underlying heart, lung, liver, kidney disease;

age 65; residents of chronic care

facilities; active malignancy, diabetes, hemoglobin opathies, neurologic conditions causing compromise of handling respiratory secretions; Native Americans; Alaska Natives; and morbid obesity)

coronavirus

(SARS-CoV ). >

From

8,000 cases

worldwide and 916 deaths according to the World Health Organization. Patients typically had early "flu like" symptoms that quickly progressed to severe respi ratory distress. The elderly were far more likely to be severely affected. Novel SARS-like coronaviruses con tinue to emerge, posing an ongoing threat; e.g., Middle East respiratory syndrome MRES-CoV in 20I3.

POLIO 90% of polio is self-limited. Its onset is characterized by aseptic meningitis and an asymmetric flaccid paralysis with loss of reflexes. It is essentially eliminated in the western hemisphere and developed countries worldwide secondary to vaccination, but it is still a problem in the developing world, especially India. Spinal cord infec tion with enterovirus 68 mimics polio, and should also be considered in children with flaccid paralysis. More in Neurology, Book 5.

2) Hospitalized patients 3) Severe, progressive, or complicated illness In addition, anyone outside of these high-risk groups who presents with influenza within 48 hours of onset may be treated based on clinical judgment. Two classes of drugs have been used to treat influenza. The newer neuraminidase inhibitors (oseltamivir, zana mivir) have replaced the older M2 ion channel inhibitors (amantadine, rimantadine). Oseltamivir and zanamivir decrease duration of illness and spread of disease and are most effective if given within 48 hours of onset of symptoms. The prevalence of antiviral resistance to any

RABIES Rabies is especially found in bats, raccoons, skunks, foxes, dogs, cats, and ferrets; but not in squirrels, rats, or any other rodents. Worldwide, the vast majority of rabies is transmitted to humans by dogs. By contrast, in the U.S., 24 of the 25 cases of human rabies that occurred between 1995 and 2006 were from bats. Rabies usually presents within 1-3 months after exposure with a viral prodrome followed by encephalitis, a Guillain-Barre mimic, or neuropathic pain +/- sensorimotor deficits.

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VIRUSES

The encephalitis is commonly associated with the classic

Diagnosis: Testing for IgM antibody can be used in

rabies symptoms of hydrophobia, choking, and delirium.

immunocompetent patients. Diagnosis in immunocom

Preexposure prophylaxis explorers,

veterinarians,

is recommended for cave animal control workers in

endemic areas, and anybody who handles bats-but not for hunters, mail carriers, or the average person.

promised patients (who may not mount an antibody response) is made with a serum PCR assay for parvovi rus DNA. Therapy: No specific antiviral therapy for parvo is

Diagnosis: evaluation of several specimens, including saliva, skin, and brain biopsy, and CSF. Serology is not useful. Post-exposure prophylaxis: The need for prophylaxis is based on the suspected animal source. Bites from bats, raccoons, foxes, and skunks are considered high-risk, and prophylaxis should be given. Pet dogs, cats, and ferrets should be observed for I 0 days, and if no signs of rabies, prophylaxis is not needed. Small rodent bites never need prophylaxis. Prophylaxis consists of human rabies immune globulin (HRIG) injected in the tissue around the wound with the remainder administered IM, and vaccination with human diploid cell vaccine may be indicated. Each should be given in a separate site. If a person has been vaccinated previously, they need only a booster vaccine after a bite, not HRIG. Remember: "Woke up with bat in room" means that the patient should receive prophylaxis regardless of documented bite.

available. !VIG may be used in immunocompromised hosts, and antiretroviral therapy for patients with HIV / AIDS may be helpful.

ARBOVIRUSES Arboviruses (short for "arthropod-borne" viruses) are transmitted by mosquitoes or ticks. Various arbovi ruses occur in the U.S., typically in the late spring and summer. Until recently, most cases occurred along the Gulf Coast in Louisiana and Florida. Now, with West Nile virus, the arboviruses are seen from coast to coast. West Nile virus (WNV ) is the most commonly identified arbovirus. Besides WNV, La Crosse, St. Louis, Eastern and Western equine, Venezuelan equine, Powassan, and Colorado tick fever viruses occur on occasion in the U.S. Clinical manifestations: Almost all symptomatic arboviral infections have similar symptoms: fever, headache, chills, and varied severity of encephalitis or aseptic meningitis. Symptomatic cases of WNV usually present as a nonspe

MUMPS

cific viral illness, but most cases (80%) are asymptomatic.

Mumps (RNA virus) occurs most commonly in winter and early spring. Although it often is asymptomatic, it can present with uni- or bilateral parotitis, aseptic men ingitis, and/or encephalitis. 15-20% of post-pubertal males with mumps get an epididymo-orchitis, which is usually unilateral. Postinfection sterility is a rare occur

Neuroinvasive disease (encephalitis, meningitis, or an asymmetric flaccid paralysis similar to polio) occurs in about 1/150 patients. Since polio is no longer present in the U.S., a person with this presentation should be tested for WNV. Less common presentations are tremor, myoclonus, parkinsonism, and cranial neuropathics.

rence. To differentiate mumps from bacterial parotitis,

Diagnosis: virus-specific IgM antibody in the CSF or

check a Gram stain of the parotid secretions. There are

serum.

many WBCs and organisms in bacterial parotitis and none in mumps. Other causes of enlarged parotid glands are frequent vomiting or parotid duct stones. Always consider bulimia in an adolescent or adult with parotid

Treatment: supportive; no specific antiviral therapy available. Control: mosquito netting, mosquito repellents, insect

gland enlargement.

control.

PARVOVIRUS

HANTAVIRUS

Parvovirus is a small DNA virus. One parvovirus, B l9,

Hantavirus pulmonary syndrome (HPS) starts as a

causes human disease. It is spread by respiratory secre tions and is usually acquired early in life, commonly manifesting as erythema infectiosum (Fifth disease) with a high fever and a "slapped cheek" appearance. Clinical manifestations: Adult-acquired illness is typically a self-limited fever, symmetric small joint arthritis, and a lacy rash on the extremities. Immunocompromised hosts and patients with chronic anemias (e.g., sickle cell) are at risk of chronic severe "aplastic" anemia second ary to parvo B 19. In aplastic anemia, the bone marrow stops producing blood-forming cells, and fat replaces hematopoietic cells.

nondescript viral syndrome, often with GI symptoms; patients then develop muscle pain, fever, headache and cough, which quickly progresses to hypoxia, hemor rhagic pneumonia, ARDS, and death in more than 50% of cases. Laboratory findings include hemoconcentra tion and thrombocytopenia. The primary reservoir in the U.S. is the deer mouse. On the East Coast and in the Southeast, the cotton rat is the main reservoir. The infection occurs when the excreta or saliva are inhaled. Transfer of the virus can also occur through broken skin, possibly by insect bites. No person to-person transfer is known to have occurred. No specific antiviral therapy is available.

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VIRUSES

Papillomavirus Papillomavirus is transmitted by direct contact and

a.�uiz

causes warts.

•

What are complications of mumps in the male?

•

Which virus is associated with the "slapped cheek" rash?

•

What does the bone marrow show in patients

•

are many variants, and

15 of these variants found world 16 and

with pure red cell aplasia from parvo 819?

18 are the most common causes of cervical cancer (60% and 10%, respectively). The strains that cause

Are arboviruses spread by a) biting insects, or b)

cervical cancer are usually subclinical. Much more on

How is West Nile virus encephalitis diagnosed? What other viral infection does it mimic in the

•

cervical, vaginal, vulvar, penile, and anal cancer. There wide are designated high-risk for cancer. HPV

person-to-person contact? •

Genital warts are associated with an increased risk of

cervical cancer in Oncology, Book 4. HPV

6 and 11 are the most common causes of the 6 and 11

exophytic, grossly visible genital warts. HPV

peripheral nervous system?

carry little risk for cervical cancer.

Characterize a patient with hantavirus

HPV

pulmonary syndrome.

HPV vaccines contain the most oncogenic serotypes and

How does dengue hemorrhagic fever present?

are recommended for all men and women ages

1, 2, and 5 are common causes of plantar warts. 9-26.

Where is it most often contracted? •

What virus causes PML, and how does it present?

Polyomavirus JC Reactivation of the JC virus in the immunosuppressed host, generally HIV/AIDS and CD4

DENGUE The dengue virus causes a spectrum of disease ranging from asymptomatic infection to dengue fever or, most ominously, to dengue hemorrhagic fever. It is the most common mosquito-borne viral disease and is seen throughout the tropics. Virus is transmitted to humans via

the

day-biting

200, results in pro

gressive multifocal leukoencephalopathy (PML), which

Aedes mosquitoes.

(Anopheles

is due to progressive demyelination of the white matter. PML, because it is multifocal, has varied presentations. Usually, the patient suffers altered mental status, followed by various focal motor/sensory deficits. Diagnosis is suggested by an MRI showing multifocal demyelinating lesions in the white matter and can be con

mosquitoes carry malaria.)

firmed by CSF PCR, which has a sensitivity of

Dengue fever symptoms are rapid onset of high fever,

No specific antiviral therapy is available, but some

70--90%.

markedly severe myalgias, arthralgias, and headache

patients may have improvement if immunosuppression

("breakbone fever"). This may be followed by a macular

can be reversed.

red rash that covers most of the body.

Dengue hemorrhagic fever is due to a diffuse capillary leak syndrome that results in hemoconcentration, ana sarca, thrombocytopenia, and spontaneous bleeding. Death due to circulatory collapse may occur. It is more common in people who have had a prior infection with

PRION DISEASE Prions are proteinaceous infectious particles that lack nucleic acid and constitute a previously unknown means of transmitting disease. The most important prion diseases are Creutzfeldt-Jakob

dengue. Diagnosis is via a serum lgM antibody assay. Treatment is supportive with IV fluids. No specific antiviral therapy is available, and there is no vaccine.

disease (CJD), and variant of CJD (vCJD). In animals, prions cause mad cow disease (= bovine spongiform encephalopathy = vCJD when transmitted to humans). CJD is almost always sporadic but

SLOW VIRUSES Overview There are

2 classes of slow viruses:

5% are infectious

(e.g., corneal transplants, cadaveric human growth hor mone), and very few are genetic. Its incubation period is

18 months. Patients with CJD get myoclonus and

severe dementia. MRls show diffuse cerebral disease, and EEGs classically show periodic synchronous bi- or

I) Normal viruses, such as papillomavirus (warts) and

triphasic sharp wave complexes. An abnormal protein,

polyomavirus (progressive multifocal leukoencepha

14-3-3, may be present in the CSF. Course is one of

lopathy [PML])

progressive deterioration with the majority of patients

2) Defective viruses, such as the defective measles virus (subacute sclerosing panencephalitis)

dead within

6 months of diagnosis. There is no effective

therapy for CJD. vCJD, probably transmitted from beef with bovine spongiform encephalopathy (BSE, mad cow disease),

2-45

2-46

HIV

AND AIDS

has been contracted worldwide, with most cases in the

For this reason, infectious diseases in AIDS patients

United Kingdom. No endemic U.S. human cases of

include not only the cell-mediated infections (PCP,

vCJD have been reported, although some veterinary

viruses, mycobacteria, and fungi), but also those seen

cases have been reported.

with humoral deficiency (pneumococcus, meningococ

vCJD patients have early-on psychiatric symptoms, late

cus,

Giardia).

appearing neurologic symptoms (typically ataxia), and rapidly developing dementia-occurring over months rather than years. Once neurologic symptoms appear, progression to death is rapid. Related illnesses include kuru and fatal familial insomnia.

EPIDEMIOLOGY The latest U.S. statistics are representative of 2008-2011. The numbers given are estimates made by the CDC, based on a statistical analysis that corrects for reporting delays and missing risk factor information. Relevant epidemiology:

HIV AND AIDS

•New diagnoses of HIV in 2011 = 49,273.

OVERVIEW

•Age group with the highest rate of infection

Changes in the treatment and management of HIV infec tion are evolving rapidly. The following covers the basics. Antiretroviral drugs are listed in the content spec ifications for the exams, so this information is presented here. However, realize that exam questions are more

= 40--44 years (27.4/100,000). •Race/ethnicity with the highest rate of infection= African-Americans (60/100,000) compared with Caucasians (7 .Oil 00,000). • The transmission category with the greatest number

likely to focus on diagnosis and complications of disease

of new diagnoses was male-to-male sexual contact=

and side effects of medications than on having you start

62% of all new diagnoses.

or change antiretroviral treatment (ART) regimens.

•Heterosexual transmission represented 9% of all new diagnoses. •Injection drug use accounted for 5% of cases.

HIV STRUCTURE The HIV particle is composed of a dense, single-strand RNA core surrounded by a lipoprotein envelope. The

DIAGNOSIS

RNA contains reverse transcriptase, which allows the

HIV infection is diagnosed by demonstrating the presence

RNA to be transcribed into DNA, which is then inte

of the virus or antibody to the virus.

grated into the host's genome. The cell then becomes an HIV-producing machine.

The standard screening test for HIV is an enzyme immunoassay (EIA). This test detects antibody to the

The receptor in the lipoprotein envelope that allows the

vims and is 99% sensitive and 90-99% specific. Positive

HIV to attach to the CD4+ T cell is named gpl 20. As

responders are confirmed by the Western blot. Antibody

opposed to influenza, the envelope on HIV is highly

to HIV is usually detectable 3-7 weeks after inoculation.

variable; therefore, it is much more difficult to make a vaccine against it.

The presence of HIV can be assessed with tests that measure the actual levels of HIV RNA (viral load) by amplifying the RNA. The main use for determining the level of HIV RNA (viral load) is to assess prognosis

HOW HIV INFECTS HIV gp 120 envelope glycoprotein binds to the CD4 receptors and coreceptors (such as CCR5) on the helper T cells, macrophages, and monocytes. The virus must bind to both the CD4 and CCR5 molecule to fuse with the cell. After fusion, the viral core material enters the cell and is reverse transcribed into DNA that integrates into the human genome and codes for the production of more virion RNA and structural proteins. These pro teins, after being cleaved by a protease, then combine

and monitor response to ART (antiretroviral therapy). Disadvantages of its use as a tool to diagnose HIV include cost and time. However, it may have a role in some clinical situations such as acute infection, inde terminate results of serologic testing, and neonatal infection. A number of rapid tests are available which assay blood, serum, plasma, or saliva; many are able to provide results in less than 30 minutes. Positive tests must be

with the viral RNA and bud off of the cell using the

confirmed with EIA and Western blot tests.

CD4 cell membrane as a new envelope. This eventually

Again:

causes destruction of the CD4 cells. The CD4 cells are the major regulator cells in the body; they suppress B lymphocytes and regulate the CD8 suppressor cells. With the decrease in CD4+ counts, B cells become deregulated and are no longer suppressed, causing a polyclonal increase in total serum immunoglobulins, even though overall antibody function is decreased.

I) EIA for HIV antibody is the usual means of deter mining HIV infection. A positive test is confirmed by Western blot. 2) HIV RNA test determines actual RNA levels or "viral load," which may be undetectable in a person under treatment for HIV infection.

HIV AND AIDS

For exam questions regarding

HIV treatment, you

mainly need to know:

•

when to initiate treatment (page

Patients with HIV/AIDS are at risk for developing

•

the main treatment protocols (page

infections with what organisms?

•

How is HIV infection diagnosed in the acute and chronic stages? What is the utility of measuring

Antiretroviral Drugs Drug acronyms for the major classes of anti-HIV drugs:

HIV RNA? •

What is the viral set point, and what is its

•

What are side effects of ZDV? ddl? d4T?

•

What is the serious side effect of abacavir?

NRTis

nucleoside reverse transcriptase inhibitors

and nucleotide reverse transcriptase inhibitors

significance? •

2-50) 2-50), and the main side effects and Quick Quiz (page 2-49).

•

NNRTis

nonnucleoside reverse transcriptase

inhibitors •

After initial infection, the virus replicates quickly and robustly, until the body controls the infection with cell mediated immunity. The body establishes a kind of homeostasis with the virus, where the virus is contained to some degree; however, the body does not contain the virus entirely (e.g., viral load of zero). Some people con tain their virus better than others.

Pis= protease inhibitors

•

FI = entry/fusion inhibitor

•

lntegrase inhibitors

NRTls Nucleoside Reverse Transcriptase Inhibitors

These drugs are analogs of the deoxynucleotides needed to synthesize viral DNA. They inhibit the replication of

The viral set point is that viral load which is established

HIV by competing with the normal deoxynucleotides.

after a patient's immune system controls primary infec

When a NRTI is incorporated into the growing viral

tion, and it varies from person to person. When a patient

DNA, the growing chain terminates and that DNA cannot

stops ART (antiretroviral treatment), their virus typically

then be incorporated into the cell's DNA and produce

rebounds to a level that is at least as high as their set

more HIV. Note that nucleotide RTis work the same way

point.

(see page 2-48) and the term "NRTI" covers both. Zidovudine (ZDV)= azidothymidine (AZT). This is the

oldest of the antiretroviral drugs but still remains very

TREATMENT OF HIV INFECTION

useful, especially in the settings of resistant virus or

Combination drug ART is the standard of care.

pregnancy. ZDV is well tolerated at currently used doses,

When to start treatment is easy: Start ART on all

but may cause bone marrow suppression (anemia, gran

treatment-nai've HIV patients (discussed more under

ulocytopenia) and myopathy. A macrocytosis (elevated

When to Initiate Antiretroviral Therapy on page

2-50).

Adherence to the ART regimen is a key determinant in the degree and duration of viral suppression. It is extremely important to actively involve the patient in the treatment decision-making process. Guide decisions

MCV) always occurs but has no clinical consequence. ZDV does not usually cause problems for the kidneys or lungs and does not cause pancreatitis. ZDV is associated with lipoatrophy when taken chronically. Currently, ZDV is only rarely used as initial therapy.

regarding initiation or changes in ART by monitoring

Some patients, who have been on treatment for a long

plasma HIV R NA (viral load) and CD4 T-cell counts,

period of time, remain on ZDV, typically in combination

in addition to the patient's clinical condition. The effec

with 3TC.

tiveness of all drugs decreases if drugs are used in regi mens that are not fully suppressive due to development of resistant mutations. All treatment decisions should be based on treatment guidelines that are released yearly and are posted on the Internet (http://www.aidsinfo.nih. gov/guidelines). Know that treatment options are always evolving in HIV disease. First, we will review the major classes of anti-HIV drugs, then the treatment protocols. To get a good under standing of how these drugs work, refer frequently to the earlier paragraphs on HIV Structure and How

Lamivudine (3TC) is a very effective drug, and it is well

tolerated. 3TC has been the most commonly prescribed antiretroviral agent. Side effects are rare. Emtricitabine (FTC) is a drug that is not only extremely

effective, but it has minimal toxicity. FTC is an analog of 3TC and exhibits complete cross-resistance (i.e., if patients have resistance to 3TC, they have resistance to FTC). It is used in all the recommended combinations for ART-nai've patients. Abacavir (ABC) is very effective. The most serious

HIV Infects as you go through the different classes of

reaction is a hypersensitivity reaction, which usually

anti -HIV drugs.

occurs within

4 weeks. The reaction consists of a gen

eralized rash and/or a flu-like illness with fever, chills, NN, myalgias, cough, and shortness of breath. In

2-47

2-48

HIV AND AIDS

patients with this hypersensitivity reaction, a rechallenge with abacavir (after discontinuation of the drug) causes an accelerated hypersensitivity reaction that causes multiple organ failure, which can be rapidly fatal. gene, and now it is recommended that all patients be tested for this gene before beginning abacavir therapy. <

Nonnucleoside RTis work very differently from the NRTis. These make the reverse transcriptase ineffective by binding to a different site on the enzyme.

Abacavir hypersensitivity is linked to the HLA B-57:01

If negative, the hypersensitivity rate decreases to

NNRTls

2%.

The following NRTis are rarely used:

Nevirapine is the 1st of this class of drugs. Rash, which

can be severe, is the primary toxicity. Fatal hepatic tox icity, especially in women with CD4 count> 250 and in patients coinfected with hepatitis, has been reported. Efavirenz

Didanosine (ddI): This is now less commonly used

due to toxicity. The most severe side effects are pan creatitis (which can be life-threatening) and peripheral neuropathy. ddI is also associated with lipoatrophy and mitochondrial toxicity, and low CD4 counts (even with a suppressed viral load). Fatal lactic acidosis can occur with concomitant use of d4T.

(EFV) is effective and commonly used.

However, it is associated with teratogenicity, absolutely contraindicated in pregnancy, and discouraged from use in women of childbearing potential. Other side effects include rash, vivid dreams, insomnia, fuzzy thinking, and mood swings. A fixed-dose coformulation with TDFIFTC is available (Atripla). Etravirine was approved in 2008. It may cause a serious

Stavudine (d4T): d4T is now used only in salvage

therapy because of toxicity. d4T can cause lipoatrophy

skin rash. It is useful in HIV infection that has been pre viously resistant to the other NNRTis.

and mitochondrial toxicity syndromes. Side effects

Rilpivirine (Edurant®) is a new NNRTI just released for

include pancreatitis and peripheral neuropathy. Also,

use in nai"ve patients. A fixed combination with TDF/

d4T in combination with ddI can cause a fatal lactic

FTC is available (Complera).

acidosis-especially in pregnant women. This combina tion of d4T and ddI is basically used only for salvage regimens in the U.S.

Pis HIV protease inhibitors-Pis (ataza-, daru-, rito-, lopi-,

fosampre-, saqui-, indi-, nelfi-, tipranavir) inhibit the

Nucleotide Reverse Transcriptase Inhibitors

HIV protease enzyme that is involved with processing

Tenofovir (TDF; Viread®) is a nucleotide-RT! very similar

the final assembly of the virion. Except for nelfinavir,

to the above nucleoside analogs, except that nucleotide

all Pis are given with low-dose ritonavir (another PI)

RTis are chemically pre-activated and, therefore, require

because ritonavir interferes with the catabolism of the

less biochemical processing than the nucleoside RTis.

drug and thus boosts the drug levels of the coadminis

Tenofovir has once-daily dosing and a good side-effect profile-mainly asthenia/headache/N/VID/flatulence. Azotemia and a Fanconi-like syndrome have been seen with tenofovir, particularly in patients predisposed to renal disease.

tered PI (termed "ritonavir boosting"). Atazanavir and darunavir are the most commonly used protease inhibitors. Lopinavir is less commonly used due to side effects, but remains useful in pregnancy and for those patients who tolerate it well. Tipranavir is used only very rarely for highly resistant virus not sensitive to other Pis. Fosamprenavir is sometimes used because

NRTI Combinations

of its flexibility of dosing and lack of drug interactions.

NRTI combinations:

Fat redistribution, lipid abnormalities (increased tri

Combivir®

(3TC/ZDV)

glycerides and cholesterol), new-onset Type 2 diabetes,

•

Trizivir®

(3TC/ZDV/abacavir)

and osteoporosis have been recognized with the use of

•

Epzicom®

(3TC/abacavir)

•

Truvada®

(TDF/FTC)

•

Atripla®

(TDF/FTC/efavirenz)

•

Complera®

(TDF/FTC/rilpivirine)

•

Stribild®

(TDF !FTC!elvitegravir/cobicistat)

•

Pis. When treating lipid abnormalities in HIV-infected persons, it is important to note that Pis inhibit the P450mediated metabolism of simvastatin and lovastatin, and coadministration may cause high drug levels of the statins and precipitate rhabdomyolysis. These drugs are contraindicated in patients on Pis. Also avoid other drugs that cause

Know that the 2 drugs, TDF and FTC, are included in all recommended combinations for initial treatment of ART-nai"ve patients.

interactions:

rifampin,

astemizole,

cisapride, and St. John's wort. Atazanavir is a once-daily PI that doesn't have adverse

lipid effects. For maximum potency, the drug needs to be

Do not use ZDV and d4T together due to antagonism.

boosted with ritonavir. It is associated with unconjugated

Avoid the combination of tenofovir and ddI because

(indirect) hyperbilirubinemia of no clinical consequence.

of drug interactions and intracellular accumulation of metabolites that can actually cause T-lymphocyte levels to drop.

Darunavir was approved in 2006. Monitor use closely

in patients with underlying hepatitis virus coinfection.

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HIV AND AIDS

Tipranavir was approved in late 2005. It has adverse

lipid effects, and its main side effects are GI related and

uiz •

rash. Used only rarely for extremely resistant virus.

Which NRTI can be associated with development of kidney disease?

Entry I Fusion Inhibitors Maraviroc (Selzentry®) is the first drug approved for

•

What is the primary toxicity of nevirapine?

•

Which antiretroviral is teratogenic?

HIV that appear early in the disease and require binding

Which Pl is used to boost the drug concentrations of other Pis?

to this coreceptor to allow cell entry. A coreceptor tropism

•

treatment of CCR5-tropic HIV-which are the strains of

assay to confirm the presence of the CCR5 coreceptor should be performed prior to use of maraviroc. It is an

What metabolic defects have been associated with use of protease inhibitors?

oral agent and carries an FDA boxed warning for drug induced hepatitis. Maraviroc is approved for use in combination therapy in all lines of therapy, including

Which antiretroviral drug is associated with indirect hyperbilirubinemia?

nai"ve patients. It is generally well tolerated. Enfuvirtide

(Fuzeon®) is the only fusion inhibitor

Currently, darunavir is used in all lines of therapy from

available. It binds to and alters the structure a glycopro

nai·ve to salvage. It can be used qd or bid and is better

tein on the HIV envelope, gp41, which is required for

tolerated than lopinavir/ritonavir (Kaletra®).

fusion of the virus with the CD4+ cell. Given by subcu

Ritonavir (usually shown as "/r" in its low-dose boost

taneous injection, its main side effects are local reactions

ing role) is now mainly used in low doses to boost the levels of most other Pls. It is a potent drug, but patient tolerability is poor due to side effects. The main side

at the injection site and increased risk of bacterial pneu monia. It is not part of most regimens because it requires injection and is used only for salvage treatment.

effects are NN, flushing, distorted taste, and paresthe sias. There are many drug interactions because of inter ference with the p450 enzyme system. is

Raltegravir was the 1st integrase strand transfer inhibitor

(INST!) available. It prevents the HIV integrase enzyme

lopinavir and low-dose ritonavir. Lopinavir is available

from inserting HIV's reverse transcribed DNA into an

Lopinavir/ritonavir

(LPV /r)

lntegrase Inhibitors

coformulation

only in this coformulation. It is very potent and well toler

infected cell's own DNA, halting this critical step in

ated. Currently, it is not generally used for initial therapy

the life cycle of HIV. It is an oral agent. Raltegravir is

because it is less well tolerated than atazanavir or daruna

now indicated for all lines of therapy, including na"ive

vir and causes more lipid abnormalities. Fosamprenavir is the prodrug of amprenavir. It requires

fewer pills and eliminates the major side effects of amprenavir. Primarily used because of lack of drug interactions and flexibility of qd or bid dosing. These Pis are rarely used:

patients. Its twice-daily dosing is well tolerated with few drug interactions and no effect on lipids. Integrase inhib itors decrease viral load more rapidly than any other class of antiretroviral. Elvitegravir is an integrase inhibitor that is given with

cobicistat to boost its levels. It is available as a 4-drug fixed combination with FTC and tenofovir to allow

Saquinavir is not used much, having been replaced by

once-daily dosing. It is indicated for treatment in nai"ve

newer, simpler Pis. In 2010, the FDA added a warning

patients only. Renal function needs to be monitored

that ritonavir-boosted saquinavir has been associated

closely because of the interaction between tenofovir and

with prolongation of the QT interval and development of

cobicistat.

torsade de pointes. Do an ECG before prescribing, and do not give the regimen to any patient with a QT interval >

450 ms. Also, recheck the ECG after 2 weeks for new

prescriptions. lndinavir has side effects that include an asymptomatic

Key Words and Side Effects Key words/phrases to remember for side effects: •

NRTis

hyperbilirubinemia and a high incidence of nephroli

ZDV: bone marrow suppression and myopathy

thiasis. Indinavir is rarely used because of the develop

Abacavir: potentially fatal hypersensitivity reaction

ment of Pis that are less toxic and have more convenient

dosing. Nelfinavir side effects include diarrhea and rash. It is

only PI that is not boosted with ritonavir.

Tenofovir: acute kidney injury with possible renal failure

less commonly used because of the GI intolerance and the better efficacy of the newer Pis. Nelfinavir is the

The "Os" (ddl and d4T): pancreatitis, peripheral neuropathy, mitochondrial toxicity (lipoatrophy)

•

NNRTis 0

Nevirapine: rash Efavirenz: teratogenic; CNS side effects (bad dreams)

MedStudy

2-49

2-50

HIV AND AIDS

•Pis: 0

It is indicated for treatment-naive patients immediately

All Pis: lipodystrophy, hyperlipidemia (except

before initiating treatment; e.g., if ART is deferred,

atazanavir), Type 2 diabetes, osteoporosis

resistance testing should also be deferred and done just

Atazanavir: indirect hyperbilirubinemia

before initiation of ART.

Indinavir: kidney stones

Currently,

Boosted saquinavir: prolonged QT

genotypic and phenotypic. Either or both can be used

Nelfinavir: diarrhea

2 types of resistance testing are available

in the setting of increased viral load with presumed HIV-resistance to help determine change in therapy. If resistance is determined, then you can switch from

State of Current Treatment

ineffective drugs to ones that are theoretically effective.

Overview

Again, combination ART is the standard of care. Many factors go into the choice of when to start ART and which regimen to choose. Patients should understand the risks and benefits of therapy, that treatment regimens are currently lifelong, and the importance of adherence. Base selection of an ART regimen for an individual patient on many factors including efficacy, side effects, dosing frequency, pill burden, comorbidities, and drug interactions. The goal of ART is undetectable HIV- I RNA. HIV RNA assays are available for accurately determin ing viral load. Prior to the availability of these assays, most believed the HIV virus entered a prolonged latency

The genotype test detects specific genes in the individual patient's HIV virus known to confer resistance toward a specific antiretroviral drug. It is a cheaper and faster test; it also gives more information. As such, it is recom mended over the phenotype. The phenotype test determines if the gene is operating and resistance is being expressed. This is sort of like a crude antibiogram for the HIV virus. This phenotype test becomes more useful as the number of mutations increases and as the interpretation of genotypes becomes more difficult and less reliable. When to Initiate Antiretroviral Therapy (ART)

period until the onset of symptoms. It turns out that there

The following is the newer (and much more simplified)

is continuous replication from the onset of infection to

guideline regarding when to initiate therapy for treat

death. HIV is not ever eradicated, even in people with

ment-naive patients based on the Panel on Antiretroviral

undetectable viral loads on ART. The virus remains in

Guidelines for Adults and Adolescents

"reservoirs," although we do not fully understand where all the reservoirs are.

(2012).

Consider initiating treatment without delay for all HIV infected patients.

Long-lived memory T cells seem to be an important site of reservoir virus.

Which Combination of Drugs to Use

The CD4 T helper lymphocytes are the principal cells targeted by reproducing HIV virions. Tremendous and continuous CD4 lymphocyte destruction-eventually causing decreased levels-occurs after HIV infection. CD4 levels are a good indicator of disease severity and level of immunity.

The following recommendations come from the DHHS

2012 treatment guidelines. They consist of a "backbone" 2 NRTis (tenofovir + emtricitabine) with a "base"

of either an NNRTI (efavirenz), a ritonavir-boosted Pl (atazanavir or darunavir), or an integrase inhibitor (raltegravir).

Know the following regarding HIV treatment:

Preferred

• Remember that CD4 count is no longer used to deter mine when to start ART therapy. ART therapy is now recommended for all patients with HIV infection.

initial

regimens

for

antiretroviral-nalve

patients (after resistance testing): • Tenofovir/emtricitabine/efavirenz (TDF /FTC/EFV)

• Always use combination therapy for HIV. Combination therapy decreases serum viral Ioad sometimes tremendously-for prolonged periods. Combination therapy prolongs survival and decreases AIDS-associated opportunistic infections.

• Tenofovir/emtricitabine/ritonavir-boosted atazanavir (TDF/FTC/ATV/r) • Tenofovir/emtricitabine/ritonavir-boosted darunavir (TDF /FTC/DRY/r) • Tenofovir/emtricitabine/raltegravir

• The degree of decrease in viral load induced by

(TDF /FTC/RAL)

combination ART is of good prognostic value.

Remember: EFV (efavirenz) is absolutely contraindicated Indications for Using Drug-Resistance Assays

in pregnancy.

R esistance testing is now a standard of care and recom mended for those:

When to Change HIV Therapy

• initially presenting for HIV care, or

Consider changing therapy when there is failure to

• who may be developing drug resistance, or

completely suppress viral load to an undetectable level

• who are pregnant.

based on > I viral load or when the patient becomes

Infringements to copyright@medstudy.com

HIV AND AIDS

Treat all HIV-infected pregnant

Q�uiz •

•

Commonly used ART

What is the best predictor of long-term outcome

women:

Below what CD4 count is initiation of ART recommended?

•

Which new HIV+ patients should receive resistance testing?

•

Which exposures should not receive PEP for HIV?

•

make their viral load undetectable. Always do initial resistance testing.

Which Pl is associated with kidney stones?

in the patient infected with HIV?

Which pregnant women should be treated for

women with ART

regardless of CD4 level or viral load. The goal is to

drugs to avoid in pregnant

• Efavirenz (EFV) due to association with teratogenicity. • Nevirapine (NVP) is not recommended for women with CD4 counts > 250, and caution is advised for use in any pregnant woman. Preferred therapy for ART-na'ive pregnant women is ZDV/lamivudine + lopinavir boosted with ritonavir (ZDV/3TC + LPV/r).

HIV? With what? What is the treatment goal?

Two scenarios in pregnancy:

What are the symptoms of primary HIV

1) If the patient is already on ART and has undetectable

infection?

virus, continue her current regimen except avoid EFV, NVP, and d4T/ddI as discussed above.

intolerant to 1 or more of the drugs. What therapy to change to is based on resistance testing, which should be done while the patient is still taking the current regi men. Place the patient on a regimen of 3 drugs to which the virus is susceptible and that will not cross-react with side effects of prior medications.

2) If the patient is not on ART at time of pregnancy, initiate therapy immediately if indicated for her health (high viral load/low CD4, etc.). If she is ART-na'ive, give the same ART therapy as above: ZDV/3TC + LPV/r. Therapy should be started before resistance testing results are back-especially if she is in the 3rct trimester. So, notice that the same therapy is recommended to

Pre-Exposure Prophylaxis (PREP) to Prevent Sexual Acquisition of HIV

Several studies have shown that administration of tenofovir-emtricitabine (Truvada) significantly decreases

ART-na'ive pregnant women whether they need it for their health or solely to prevent transmission to the child.

If she is not ART-na'ive, use past ART history and do resistance testing to determine the best course.

rates of HIV transmission in high-risk populations such as men who have sex with men, promiscuous hetero sexuals, and HIV-discordant heterosexual couples. In July 2012, the FDA approved Truvada for HIV-negative persons in such risk groups. It is administered once daily. Post-Exposure Prophylaxis (PEP) for Health Care Workers

First, recommend cleaning the site of exposure with water and soap, if applicable. Then, determine the expo

Labor and Delivery

All HIV-infected pregnant women should be given ZDV as a continuous infusion during labor in addition to their current ART therapy. C-section is recommended if viral load

1,000 copies at

38-weeks gestation. Infants born to HIV-infected mothers should receive ZDV for 6 weeks starting within 6-12 hours of birth.

sure risk: Was the source material blood or bloody fluid? If so, then determine if it was a percutaneous exposure (PEP recommended), or mucous membrane or skin with compromised integrity (PEP probably recommended). It is easier to remember to whom not to give PEP: Do not give PEP for intact skin exposures and urine-source exposures. When PEP is indicated, use potent combination therapy.

PRIMARY HIV INFECTION Primary HIV infection was previously termed acute retroviral syndrome. This is a flu- or mononucleosis-like syndrome that occurs 2-4 weeks after initial infection and lasts 1-2 weeks. Patients with primary HIV infection may present with:

Start treatment ASAP-within hours of exposure-and

•Fever

continue for 4 weeks. HIV testing is recommended at 0,

•Lymphadenopathy

6, and 12 weeks, and 6 months after the exposure.

•Pharyngitis •Rash (usually erythematous maculopapular with

Pregnancy

and ART Therapy

Lowering viral loads in pregnant women decreases the risk of vertical transmission to the child.

lesions on face, trunk, or extremities; can include palms and soles) •Mucocutaneous ulcerations involving the mouth, esophagus or genitals

2·51

2-52

HIV AND AIDS

•Myalgias/arthralgias

Common infections and skin findings in HIV disease

•Aseptic meningitis

include:

Consider primary HIV infection in any person at risk for

• Persistent or recurrent seborrheic dermatitis

HIV who presents with signs/symptoms of mononucleo

• Tinea infections

sis, scarlet fever, or aseptic meningitis.

• Psoriasis

Diagnosis is made by assaying plasma for RNA viral

•Molluscum contagiosum

load or the p24 antigen. Low viral loads(< 10,000 copies)

• Folliculitis

may be false-negative tests and should be repeated with referral to a provider experienced with HIV HIV EIA antibody test becomes positive at 3-7 weeks after expo sure, so it is usually not positive during primary HIV infection. Current treatment guidelines recommend that ART should be considered for patients with primary HIV infection.

•Recurrent HSY, varicella-zoster virus •Recurrent vaginal and oral candidiasis • Oral hairy leukoplakia

PULMONARY INFECTIONS Pneumocystis Pneumonia Epidemiology: Pneumocystis jiroveci (formerly P. cari

nii) pneumonia is acquired via the respiratory route. This

HIV I AIDS OPPORTUNISTIC INFECTIONS Introduction

pneumonia is the most common opportunistic infection in patients with HIV and is the presenting illness in 50% of AIDS patients. 90% of patients with PJP have CD4

Opportunistic infections (Ols) are caused by micro

counts < 200.

organisms that do not usually cause disease unless the

Presentation:

host is immunocompromised. However, in the setting

Pneumocystis jiroveci pneumonia (PJP) has an insidious

of immunosuppression such as HIV IAIDS, these micro organisms are able to take advantage of the weakened host. The opportunistic infections a patient is at risk for depend on the patient's CD4+ cell count. present in 1 of 4 ways:

although it may also be lobar or unilateral. Jn 10--15%, the chest x-ray is normal.

0"Routine" causes of pneumonia, S. pneumoniae, endemic fungi, etc.

induced sputum or bronchoalveolar lavage (BAL).

•Think of:

Because of the high inoculum of the organism present during active disease, BAL is highly sensitive.

0MAI/MAC 3) CNS: altered mental status, focal defect, seizure

Treatment: Treatment is based on disease severity.

Moderate-to-severe infection is defined as a P.02 < 70 or

•Think of:

A-a gradient > 35. All other cases are considered mild. Treat PJP with TMP/SMX. Use oral regimens for mild disease. Give the drug intravenously for severe disease,

0PML

e.g., in the patient with significant dyspnea or hypox

Neurosyphilis

emia. AIDS patients have a high incidence of sulfa

4) Gastrointestinal:

allergy, so 2nd line drugs are often used. Mild disease

•Esophagitis-Think of: °

Candida infection

Viral(CMV, HSY )

2nd line drugs are dapsone + trimethoprim and prima quine + clindamycin. Moderate-to-severe 2nd line drugs are clindamycin + primaquine or pentamidine.

• Chronic diarrhea-Think of: 0Parasitic infections (Cystoisospora, Cyclospora, Cryptosporidium) 0

Diagnosis: The best method of diagnosis is by methe

namine silver stain of pulmonary secretions either from

2) Systemic: fever and wasting

Lab: ABGs typically show a pH > 7.40. Hypoxia is

chest x-ray usually shows a diffuse "batwing" infiltrate,

Tuberculosis

Toxoplasmosis

inflammatory response, which accounts for the lack of

is commonly low (from respiratory alkalosis). LOH is

0 Pneumocystis

onset of fever, shortness of breath, and dry cough that usually worsens over weeks, not days. There is minimal

elevated (> 400), and liver enzymes are nonnal. The

•Think of:

Cryptococcus

pneumonia,

common. A-a gradient is commonly increased. pC02

I) Pulmonary: shortness of breath, cough, fever

bacterial

sputum production and rarity of pleuritic pain.

Opportunistic infections in HIV-infected persons often

Unlike

Bacteria (Shigella, Salmonella, Campylobacter)

All drug regimens are for a 21-day course. All patients with moderate-to-severe hypoxemia should receive glucocorticoids within 72 hours of receiving antibiotics.

HIV AND AIDS

Presentation:

pneumonia

Q.�uiz •

•

may

sometimes resemble?

clinically

What is the most common

in the patient with

also

Diagnosis:

What is the usual CD4 count in the patient with

chronic from

and

cavitation

present

with

similar

uncommon.

bacterial

acute

Patients

pneumonia,

community-acquired

Diagnosis is made in the usual fashion

demonstrating

AFB

sputum,

BAL,

bronchial biopsy.

How is PJP best diagnosed?

Treatment: Patients commonly respond very well to the

What ancillary treatment should be given to

usual treatment regimens: isoniazid, rifampin (or rifabu

2 months; then

tin), ethambutol, and pyrazinamide x

narrow to isoniazid + rifampin (rifabutin) x 4 months.

When should patients be given primary

Rifampin may have to be replaced by rifabutin or other

prophylaxis for PJP?

drugs in patients with HIV and TB coinfection because of extensive drug interactions. Rifabutin also needs

What is the treatment duration for latent TB in

adjustments because of drug interactions.

patients with HIV/AIDS? •

different

HIV-infected persons.

hypoxemia due to PJP?

•

presents

a presentation

pneumonia. Disseminated disease is more common in

patients who develop moderate-to-severe

•

diffuse

What illnesses does primary HIV infection

HIV/AIDS who develops PJP? •

typically

with

patients without HIV in that infiltrates may be absent

HIV/AIDS? •

but

See

When should patients be given primary

Pulmonary

Medicine,

Book

2, for more on

treatment.

prophylaxis for MAC?

Prophylaxis: Prevention of active TB in HIV-infected Side

effects:

TMP/SMX

neutropenia/leukopenia,

skin

side

effects

rash,

nausea/vomiting,

include

and, occasionally, fever. Pentamidine may cause neutropenia/leukopenia, fever, nausea, vomiting, renal failure, and diarrhea. Long courses of pentamidine may destroy the beta cells

persons is facilitated by annual screening for latent infection with either a TB skin test or interferon gamma-releasing assay (IGRA). All patients with a positive PPD

(> 5 mm) or +IGRA

without signs of active disease should receive INH for

9 months.

of the pancreas, causing initial release of insulin and hypoglycemia and then eventual diabetes.

SYSTEMIC INFECTIONS

Prophylaxis: Primary prophylaxis is the term used when

prophylaxis is given to a patient with no prior history of the 01. Secondary prophylaxis is what is given when the patient has a history of previous treatment for that

01.

TMP/SMX DS I/day or 3/week is the drug of choice. Start primary prophylaxis when the CD4 count is < or if the patient has

200

Candida esophagitis. Secondary

prophylaxis should occur after a full course of treatment for PJP. Stop PJP prophylaxis if and when CD4 is >

200 for

2'. 3 months in response to ART.

Mycobacterium Avium Complex I Mycobacterium Avium-intracellulare Mycobacterium avium complex (MAC)

Epidemiology:

is ubiquitous in the environment. The MAC consists of

2 species, M avium and M avium-intracellulare (MAI); 95% of isolated strains are the former. It is acquired by the respiratory or gastrointestinal route without clear association with any activity and reactivates when CD4

50.

counts drop to <

Presentation:

usually

presents

disseminated

infection in patients with AIDS and causes a wasting

If the patient cannot tolerate TMP/SMX, dapsone or

syndrome

atovaquone are alternative therapies. Atovaquone is more

lymphadenopathy, hepatosplenomegaly, diarrhea, and

efficacious than dapsone and has a lower incidence of

abdominal pain.

side effects than TMP/SMX but is much more expensive than either. TMP/SMX also provides prophylaxis against toxoplasmosis (page 2-54).

with

fever,

weight

loss,

night

sweats,

Diagnosis: Diagnosis is confirmed by growing MAC

from otherwise sterile body fluids or from biopsies. Treatment: Treat with clarithromycin and ethambutol

Tuberculosis Epidemiology: Most tuberculosis in HIV is reactiva

tion of prior asymptomatic infection and thus occurs in those with the usual risk factors for TB (e.g., homeless, institutionalized, IV drug abuse, born in an endemic country). Reactivation occurs at the rate of 3-16% per year in patients coinfected with HIV and TB.

+/- rifampin. Prophylaxis:

Start

primary

prophylaxis

for

MAC

with clarithromycin or azithromycin when CD4 is <

50. Azithromycin has the advantage of once-weekly

dosing. Stop primary prophylaxis when CD4 is

> 100 for

2'. 3 months in response to ART. Secondary prophylaxis is

the same as the treatment regimen. Secondary prophy laxis may be stopped if CD4 is >

100 for 6 months.

2-53

2-54

HIV AND AIDS

CNS INFECTIONS

primary prophylaxis. It gets more complex in patients who cannot tolerate sulfa. Most would not give primary

Cryptococcus Epidemiology:

prophylaxis, but alternative regimens include a combi

C. neoformans is endemic worldwide.

Although it causes disease in both immunocompetent and immunosuppressed individuals, most HIV-infected patients have CD4 counts of< 100 at the time of diagno sis, and the fungus commonly presents as disseminated disease with CNS involvement. Presentation:

subacute

The most common presentation

meningitis

meningoencephalitis

is a

that

very different than bacterial meningitis. Subtle signs of decreased mental status, personality changes, and memory loss may be the only manifestations and are due to increased intracranial pressure, not invasion of the organism. Diagnosis: Detection of cryptococcal antigen in the

nation of dapsone + pyrimethamine + leucovorin. Secondary prophylaxis includes slightly lower doses of pyrimethamine + sulfadiazine + leucovorin.

Syphilis Syphilis, even if previously treated, may reactivate in AIDS patients and cause neurosyphilis. Syphilis is treated the same in AIDS as in non-AIDS. Some experts recommend that you should have a low threshold for evaluating a patient for neurosyphilis with lumbar punc ture; however, controversy remains on this issue. CDC guidelines recommend evaluation of CSF if neurological symptoms are present.

CSF or serum is diagnostic and is seen in the vast major ity of patients.

GI INFECTIONS

Treatment: Meningitis is treated in 3 stages: induction

Esophagitis

with amphotericin B deoxycholate + flucytosine x 2 weeks; consolidation with fluconazole 400 mg/d for 2:

8 weeks; maintenance with fluconazole 200 mg/d for 2: I year.

Repeat LPs should be done, and CSF removed, to obtain normal CSF pressures. If this is not possible, CSF shunts should be inserted. Prophylaxis: Do not give primary prophylaxis for

Cryptococcus. Secondary prophylaxis is given with daily fluconazole and usually continued irrespective of the CD4 count.

same time. Consider coexistent viral infection if symp toms don't improve after treating the Candida.

Diarrhea Chronic

diarrhea

AIDS

patients

commonly

caused by Crypto:,poridium, microsporidia (includes Enterocytozoon bieneusi and Encephalitozoon intestina lis), Cyclospora cayetanensis, Cystoisospora (previously Shigella, Campylobacter). Special stains on stool speci

Presentation: Toxoplasma gondii is the most common

cause of focal lesions in the CNS in HIV-infected persons. Typical symptoms: headache, new onset of seizures, neurologic deficit and/or altered conscious ness, and multiple lesions on MRI or CT. The main differential diagnoses are primary B cell lymphoma, and infections that may produce focal lesions (TB, fungal, bacterial, nocardial). CT scan shows CNS abscesses due to toxo as ring-enhancing lesions. toxoplasmosis

seropositive

patient

(modified

trichrome),

and

There is no reliable treatment of cryptosporidiosis except to start ART and increase the CD4 count. Nitazoxanide is an option for patients with substantial symptoms, but may not be effective without concurrent CD4 increases. Treat Cyclospora and Cystoisospora with TMP/SMX.

acid). Clindamycin should be used in sulfa-allergic patients. Failure to respond warrants other testing, including brain biopsy. is

ciprofloxacin.

MISCELLANEOUS INFECTIONS

Treatment: Pyrimethamine + sulfadiazine (and folinic

prophylaxis

microsporidia

Cystoisospora (modified acid-fast).

and

confirmed by a response to empiric treatment.

Primary

mens are needed to diagnose Cryptosporidium (modified acid-fast),

Treat Salmonella, Shigella, and Campylobacter with

Diagnosis: Diagnosis is made by imaging consistent

Prophylaxis:

esophagitis in patients with HIV. Common viral causes

include CMV and HSY. Note that these can occur at the

lsospora) belli, or bacterial pathogens (Salmonella,

Toxoplasma

with

Candida infection is the most common cause of infectious

indicated

patients with CD4 count < 1OO/mm3 with a positive Toxoplasma gondii lgG. It is accomplished with the same regimen used for PJP prophylaxis (e.g., TMP/ SMX DS I/day or 3/week). Primary prophylaxis for Toxoplasma encephalitis can be stopped when the CD4+ cell is > 200 cell/mm3 for 3 months, similar to PJP

HCV Test all HIV-infected patents for HCV . Treat those with combined disease the same as those without. Treatment for

both

generally initiated simultaneously

but,

because of pill burden, overlapping toxicities, and drug interactions, if the CD4 count is > 500, some hold ART therapy until the completion of the HCV treatment. Conversely, in patients with very low CD4 counts, most generally treat HIV first and hold HCV treatment until the HIV is stable.

COMMON ID SYNDROMES

Native Valve Endocarditis Native valve endocarditis is more common on the left side of the heart and usually occurs on regurgitant AV valves (although it can also occur with VSDs and

•

How is cryptococcal meningitis diagnosed?

•

Name some of the organisms that can cause

Endocarditis (ICE), which is a prospective study of over

chronic diarrhea in a patient with HIV/AIDS?

2,700 patients with definite infective endocarditis, the

•

What is the typical presentation of CNS

The most common organism infecting native valves is

Which side of the heart is more prone to

S. aureus, followed by viridans streptococci and then

What is the usual cause of prosthetic valve endocarditis in the 1st year after surgery?

•

median age of endocarditis is 58 years old.

toxoplasmosis?

developing native valve endocarditis? •

PDAs). According to the International Collaboration on

enterococci. Patients with S. aureus endocarditis are more likely to die and develop emboli. Enterococci seem to be the least virulent cause of IE. HACEK organisms (Haemophilus species, Aggregatibacter actinomycetem [previously Actinobacillus

What are some specific physical exam signs of

comitans

endocarditis?

comitans ], Cardiobacterium hominis, Eikenella species,

actinomycetem

and Kingella kingae) also cause endocarditis.

CMV Eye problems are commonly due to CM V retinitis. (See

Prosthetic Valve Endocarditis

page 2-41.) CM V retinitis is treated with ganciclovir

Early prosethtic

or valganciclovir. Primary prophylaxis is not given.

2 months of valve insertion) is usually due to seed

Secondary prophylaxis is with valganciclovir.

ing

during

valve endocarditis

surgery. Acute

cardiac

([PYE]; within decompensation

means emergent surgery on the valve or neighboring

Kaposi Sarcoma Kaposi lesions are a neoplasia of blood vessels and are due to human herpesvirus 8. Lesions are nodular and well localized, often with some surrounding bruising. Treat with chemotherapy, surgery, or radiotherapy.

tissue is necessary. Even with surgery, PYE still has a 40% mortality. Late PYE (> 2 months after valve insertion) invades the

annulus, and surgery is commonly required. S. epidermidis is seen in 55--60% of the cases in the 151 year after surgery. If the infecting organism is a viridans streptococcus, streptococci, or enterococci, the likelihood of cure with

And Again: PJP and MAC Prophylaxis

antibiotics is higher than it is with staphylococci. Better

For both primary and secondary prophylaxis:

antibiotic treatment success is seen with porcine bio

•Start PJP prophylaxis when CD4 is< 200 or oropharyngeal candidiasis occurs. •Start MAC prophylaxis when CD4 is< 50. •Stop PJP prophylaxis when CD4 is> 200 for

� 3 months in response to ART. •Stop MAC prophylaxis when CD4 is> I 00 for

� 3 months in response to ART.

prosthesis, as opposed to metal valves.

History and Physical Exam History should focus on potential exposures to typical organisms: •Skin infections •Dental work • Genitourinary manipulation or obstruction

COMMON ID SYNDROMES INFECTIVE ENDOCARDITIS (IE) Overview The current approach to endocarditis is based on the 2008 update to the 2005 guidelines published by the American Heart Association and endorsed by IDSA.

•I V catheters •Injection drug use Also look for uncommon organisms, especially if blood cultures are negative. (Animal exposures predispose to Coxiel/a, Bartone/la, and Tropheryma whipplei.) Physical exam may show the following classic stigmata: •Fever

For treatment purposes, endocarditis is typed as follows:

• Conjunctiva! hemorrhages

native valve, prosthetic valve, culture-negative, and

•Petechiae (most common skin finding)

injection drug user. The previous designations of"acute" and "subacute" are no longer used.

•Splinter hemorrhages (of the fingernails) •Janeway lesions (nonblanching, painless, reddish lesions on hands/feet) •Osler nodes (painful, purplish lesions on fingers/toes) •Roth spots (retinal hemorrhage)

2-55

2-56

COMMON ID SYNDROMES

Since IE is usually diagnosed earlier in the course than previously, these classic signs are less common now.

Echocardiography The 2005 AHA guidelines were reevaluated in 2006 for

Systemic involvement commonly includes neurologic

the use of echo to diagnose valvular heart disease. IDSA

deficits (most common cause of death), infarctions of

has endorsed the 2006 ACC/AHA recommendations,

spleen and kidneys, immune-complex

which include:

glomerulone

phritis, and septic pulmonary infarction in right-sided disease. Some of the above clinical characteristics are included in the modified Duke Criteria for diagnosis (discussed under Diagnosis, below).

•Only patients with moderate-to-high clinical probability of endocarditis should get echocardiography. •Transthoracic echo (TTE) has a low sensitivity (but high specificity), so a negative test does not exclude a valvular lesion. If clinical suspicion is moderate to

Laboratory Evaluation

high, these patients should progress to transesophageal

Blood cultures are vital in diagnosing endocarditis of any type, and 3 sets should be drawn before starting empiric antibiotics. Blood cultures in IE patients are positive in over 95% of cases due to the constant level of bacteremia. However, bacterial concentration in the blood is low in IE, so a proper amount of blood should be inoculated into each culture bottle. Ideally, 3 sets separated by at least 8 hours are drawn from peripheral sites, prior to starting antibiotics. If a patient is unstable, get 3 sets up front from various sites and repeat blood cultures later, after antibiotics are started.

echo (TEE). • TEE, as a I st test, is recommended for patients with prosthetic valves and for patients in whom you suspect a perivalvular abscess. Even though it's the best test, be aware that TEE can miss an abscess in a signifi cant number of patients. •A negative TEE in a patient with native valves has a negative predictive value of almost I 00%. • If a patient does not have a high clinical probability or a technically limited TTE, then a negative TTE is a definitive study (meaning no further workup with TEE is necessary). To be diagnosed with endocarditis, the patient would have to fulfill the Duke criteria without the echocardiographic findings (rare).

Laboratory abnormalities commonly seen in endocarditis include:

Diagnosis

• Increased ESR and CRP

Diagnosis is based on fulfillment of the modified Duke

•Anemia of chronic disease

criteria, which includes clinical, laboratory, and echo

• Leukocytosis or leukopenia

cardiographic

•Thrombocytopenia •Active urine sediment (proteinuria and red cell casts) • Immune activation evidence (low complement levels, cryoglobulinemia, rheumatoid factor, and RPR+)

whether

approach is useful because not all patients have positive blood cultures or obvious murmur. Using these crite ria also makes it unlikely that a case of endocarditis is missed, which is important because it is universally fatal

If blood cultures are negative, there is no history of pre-culture antibiotic treatment, and the patient has clini cal criteria for endocarditis, consider the following:

Definite endocarditis is diagnosed when the patient has any of the following: •Pathologic evidence of disease •2 major criteria (see below)

•Fungi

• l major criterion + 3 minor criteria

•Q fever ( Coxiella burnetii)

• 5 minor criteria

Bartonella species

Pathologic evidence would be visible organisms from a

• Tropheryma whipplei

vegetation or valve lesion or a positive culture from the

• Legionella

same tissue.

• Chlamydia psittaci

Possible endocarditis is diagnosed with I major +

•Nutritionally deficient streptococci If you alert the microbiology lab, it will hold blood cul tures longer when endocarditis is clinically likely. Still, HACEK organisms are only rarely found this way. The other organisms are diagnosed with serology or pathol ogy and culture of the valve. Coxiella is diagnosed by serology.

regardless

if untreated.

Culture-Negative Endocarditis

•

characteristics,

a patient has native or prosthetic valve. A structured

3 minor criteria. The 2 major criteria are:

I) Positive blood cultures. There are 3 ways that the blood culture major criteria can be met: •If the organism is one that typically causes endocarditis and is found in at least 2 blood cultures

12 hours apart, the criteria are met. These organisms are S. aureus, viridans streptococci, S. bovis, entero cocci, or HACEK.

COMMON ID SYNDROMES

Preferred Treatment of Bacterial Endocarditis We outline the recommendations from the 2005 AHA guidelines •

•

How many sets of blood cultures should be drawn on the patient with suspected

Viridans Streptococci and

endocarditis?

Sensitive to PCN:

What organisms should be considered as a

(2 g/d). Adding gentamicin can reduce duration to

cause of culture-negative endocarditis?

2 weeks; keep at 4 weeks if there is an abscess.

What 2 types of tests make up the major criteria for the diagnosis of endocarditis?

•

If a patient has a high clinical probability of endocarditis, should a negative TTE dissuade you from the diagnosis?

•

Which patients should definitely receive a TEE in

What is the negative predictive value of a TEE in a patient with native heart valves?

•

Review and commit to memory the modified Duke criteria. What is required for the definite diagnosis of endocarditis?

•

Study and know the various regimens to treat endocarditis based on resistance patterns and type of valve ( native vs. prosthetic ) .

•If the organism is not one that typically causes endocarditis, there must be at least 3 cultures (+) or the majority of� 4 cultures drawn at least an hour apart from first to last. •A single blood culture (+) for

Coxiella burnetii meets

the criteria. This is the only organism that meets the criteria with a single positive blood culture. 2) Abnormal echocardiogram. Significant echo findings include any of the following: •An oscillating mass on a valve, or supporting structures •An oscillating mass in the path of a regurgitant jet •An oscillating mass on an implanted device. •An abscess • Prosthetic valve dehiscence •A new regurgitant valve The 5 minor criteria are: 1) Predisposing condition (valve disease or injection drug use) 2) Fever> 38.0° C

(I 00.4° F)

3) Vascular phenomena (arterial emboli, pulmonary infarcts, mycotic aneurysms, stroke, conjunctiva( hemorrhages, Janeway lesions)

Immunologic phenomena (acute glomerulonephritis, Osler nodes, Roth spots, +RF)

5) Positive blood culture that does not meet a major criterion

weeks of PCN G or ceftriaxone

Gentamicin is not recommended for patients with renal insufficiency. Vancomycin can be used x

MedStudy

weeks in

patients unable to tolerate the beta-Iactam, but it is not preferred for initial treatment. If there is intermediate resistance to PCN, the regimen is Prosthetic valve treatment is generally the same regimen, but the duration of treatment is lengthened. Endocarditis caused by either

Clostridium septicum)

S. bovis bacteremia (or

should lead to a colonoscopy,

given the high prevalence of colon cancer in these patients. Staphylococcus aureus

without Prosthetics

MSSA left-sided or right-sided disease with emboli requires nafcillin x

6 weeks+/- gentamicin for 3-5 days

(if isolate is susceptible). This recommendation was included because of data showing that aminoglycoside synergy sterilized the blood more quickly. However, this recommendation became controversial in 2010 because of data showing that inclusion of the aminoglycoside is associated with an increase in nephrotoxicity but no other difference in outcome (despite the more rapid blood sterilization). Most experts are not including the aminoglycoside to treat staph endocarditis now. MRSA isolates are treated with vancomycin x

6 weeks.

Alternatively, daptomycin may be used, especially if the vancomycin MIC is> 1. MSSA uncomplicated right-sided disease: nafcillin

gentamicin x 2 weeks; or daptomycin. If the isolate is not gentamicin-susceptible, then the 2-week regimen cannot be used. MRSA isolates are treated x

6 weeks

with vancomycin only. Surgery may be required for S.

aureus endocarditis,

even

with native valves. Exact optimal timing and indication for surgery remain controversial. Staphylococcus aureus

with Prosthetic Valves

MSSA/MRSA prosthetic valve disease: nafcillin (or vancomycin) + rifampin + gentamicin x

6 weeks or

longer. Surgery is almost always indicated.

Enterococci Sensitive to PCN: ampicillin or PCN G or vancomycin, depending on susceptibility,

S. bovis

the same but the dose of PCN G is increased.

the evaluation of possible endocarditis? •

(Table 2-5).

+ gentamicin x 4-6 weeks.

2-57

2-58

COMMON ID SYNDROMES

Table 2-5: Treatment of Bacterial Endocard1tis Organisms Vi,ridans streptococci,

Susceptibility Testing

Drug Regimen

PCN-sensitive

Duration 4weeks

S. bovis 2 weeks

4weeks PCN-intermediate

Increased dose PCN G or ceftri-

4weeks

axone S.

aureus

Nafcillin

6 weeks

coagulase-negative

Pros�etic valve

add rifampin and

6 weeks

gentatµicin Methicillin-

Vancomycin

6 weeks

resistant

Prosthetic valve gentamicin

Staph, uncomplicated

Nafcillin

right-sided

daptomycin

Enterococci

gentamicin or

PCN-sensitive

(PCN G or ampicillin or

4-6 weeks

(depending on amp

vancomycin) + gentamicin

Prosthetic valve

Ceftriaxone

4weeks

and vane susceptibilities)

Vancomycin resistant HACEK

Prosthetic valve

Prosthetic valve treatment is generally the same regimen,

•

but the duration of treatment is lengthened.

Valve dysfunction 0

Heart failure

For enterococcal species resistant to ampicillin, PCN G,

Valve perforation

and vancomycin, treatment is difficult and specialized,

Rupture

utilizing variations of linezolid or daptomycin (if sensi tive) +/- imipenem/cilastatin with either ampicillin or ceftriaxone. HACEK

Organisms

Treat HACEK organisms with ceftriaxone x 4 weeks. Alternatives include ampicillin-sulbactam or ciprofloxa

•

Perivalvular extension °

Fistula

Valve dehiscence

Heart block

Large abscess

Persistent bacteremia on appropriate antibiotic therapy

cin. If a prosthetic valve is involved, duration is 6 weeks.

MENINGITIS Complications of Endocarditis

Bacterial Meningitis

Surgery is often required for endocarditis with: •

Overview

Vegetations embolized

S. pneumoniae is the most common cause of meningitis. Next is N. meningitidis (meningococcus). See Table 2-6. Older data show that Listeria meningitis became more

Vegetation > I 0 mm

prevalent again in those > 50 years old, but data pub

Vegetation on the anterior mitral leaflet

lished in 2011 show that Listeria has actually decreased

An increasing vegetation size while on antibiotics

in incidence (from 20% to 4%).

Persistent emboli while on antibiotics

Persistent vegetation after one has already

COMMON ID SYNDROMES

If CSF is obtained, it should undergo testing via Gram stain, culture and sensitivity, cell count with differential, protein, and glucose. Rapid antigen testing is no longer recommended because it uncommonly alters treatment. •

List some complications of endocarditis.

Culture results are the gold standard but can be negated

•

What organism is the most common cause of

by prior antibiotic therapy.

bacterial meningitis in adults? •

What is standard empiric treatment for bacterial

Antibiotics in Bacterial Meningitis

meningitis? For elderly and neonates?

Bacterial meningitis is routinely fatal without treatment. The major caveats related to treatment: Start treatment

The main culprit in the meningococcal group is B (B for

as soon as possible; use bactericidal drugs that cross

Bad). There are effective vaccines against A, C, Y, and

the blood brain barrier; and treat based on the epide

W-135, but not type B. (See page 2-20 for a discussion

miologic setting, which is highly predictive of causative

of meningococcemia.)

organisms.

Approach to the Patient with Suspected Bacterial

Drugs that are or can be bactericidal and easily cross

Meningitis

into the CSF:

Time is of the essence in this disease, and an organized

•Quinolones

approach

•Chloramphenicol

diagnosis

and

treatment

essential.

Bacterial meningitis should be suspected in anyone with

•TMP/SMX

fever, headache, and stiff neck. Kemig and Brudzinski signs are very insensitive but highly specific

•Metronidazole

(> 95%).

Lumbar puncture (LP) should be performed as soon as

Antibiotics that are or can be bactericidal and cross into

possible, but caution must be taken to avoid precipi

the CSF only with inflamed meninges:

tating herniation in patients who may have focal CNS lesions. Two studies have shown that the following param

•PCN

eters are predictive of finding such lesions on CT scan:

•Vancomycin

immunocompromised,

•yct generation cephalosporins

prior

CNS

disease,

seizures

in the last week, altered consciousness, papilledema,

•Aztreonam

focal neurologic deficit, age 2: 60 years. These people

•Imipenem

need a CT prior to LP yet should not have a delay in the administration of antibiotics. Stat blood cultures

Antibiotics that are or can be bactericidal and poorly

should be obtained, followed by empiric antibiotics and

cross the blood-brain barrier:

dexamethasone (see next), and then they should be sent for CT scan. LP is then performed if the CT shows no

•Tetracycline

contraindication. In patients who do not warrant a stat CT,

•Aminoglycosides

stat blood cultures and LP should be done, immediately

•Cefoxitin

followed by empiric antibiotics and dexamethasone (see

• I st generation cephalosporins

next).

Table 2-6: Etiology of Mening1t1s in the United States

0-2 months

o/o

Gram-neg (E. coli & Klebsiel/a)

20--3 0

Strep (Group B) (S. agalactiae)

40-50

Listeria

2-10

3 mo to 15 years S. pneumoniae

o/o 30-- 50

o/o

Adult S. pneumoniae

3().:-50

Notes on

10-- 35

N.. meningitidis

H. injluenzae

0--7

listeria

10..:.35

2-11

Staphylococci

2-5

Streptococci

2-4

Gram-negative

1-10

S. pneumoniae H. influenzae N. meningitidis

0-- 5

Gram-negative

1-2

Streptococci

0--3

Staphylococci

1-2

Staphylococci

0-- 1

Listeria

1-2

1-3

influenzae

60 years

S. pneumoniae N.

N. meningitidis

meningitidis

See more often:

E.coli H. influenzae Pseudomonas

Remember: For the newborn and adults> 50 yrs, empiric therapy now includes ceftriaxone, ampicillin (for Listeria), and vancomycin (for resistant S. pneumoniae). Although

Listeria is now decreasing in> 50, guidelines still have ampicillin.

2-59

2-60

COMMON ID SYNDROMES

Selecting Empiric Therapy

•Mumps in the spring (very rare in U.S. today,

Decades of microbiologic data have shown us which

although sporadic outbreaks may occur)

organisms are typical in various epidemiologic settings.

• HSV-2

Age is the most useful predictor. In adolescents and

• Acute HIV infection (remember!)

adults

50 years of age, S. pneumoniae and N. menin

gitidis are the predominant organisms. Empiric therapy for this age group is ceftriaxone (which covers> 90% of

S. pneumoniae and I 00% of N. meningitides) and van comycin (which covers 100% of S. pneumoniae). In adults> 50 years of age, L. monocytogenes becomes more common and should be empirically treated with ampicillin until culture results are known. Immunocompromised patients are at risk for L. monocy togenes and gram-negative aerobes, so empiric therapy consists of ampicillin and ceftazidime. Patients with bacterial meningitis after neurosurgical procedures are at risk of staphylococcal and gram-negative aerobic infection and should be treated with vancomycin and ceftazidime.

Fungal and bacterial causes of an aseptic meningitis picture include: • Coccidioides and Histoplasma (suspect in endemic areas-arid Southwest and Mississippi/Ohio River valleys, respectively) •Cryptococcal meningitis (common in AIDS, Hodgkin disease, and ALL) •Chronic neutrophilic meningitis-unusual (think of Nocardia or fungus as possible causes) In AIDS patients, the CSF may have no WBCs with cryptococcal meningitis.

TB Meningitis Tuberculous meningitis is sometimes manifested by

Again, empiric treatment of meningitis: 3'd generation cephalosporin + vancomycin +/- ampicillin (if elderly or neonate).

cranial nerve palsies, especially of the 61h cranial nerve. It has a thick basilar enhancement on CT scan. CSF glucose is extremely low.

Lyme Meningitis

Selecting Definitive Therapy Cultures grow organisms from the CSF in the majority of patients with bacterial meningitis and should be used to narrow or change empiric therapy.

Lyme meningitis can cause peripheral and cranial nerve palsies, especially of the 7th cranial nerve; so think of Lyme disease or herpes simplex virus infection when a patient presents with Bell's palsy. (See Treatment of Lyme Disease on page 2-28.)

Use of Dexamethasone Dexamethasone has been shown to decrease morbidity and mortality in adults with pneumococcal meningitis.

Spinal Epidural Abscess

Dexamethasone should be started 15-20 minutes prior

Spinal epidural abscesses may be caused by either

to antibiotic administration and continued for 4 days if

hematogenous spread or local extension (i.e., from

pneumococci are cultured, and discontinued if another

osteomyelitis). S. aureus is the most common cause. Patients can present with the classic triad of fever, spinal

causative agent is found.

pain, and nerve compression problems. Rule out spinal epidural abscess anytime any 2 of these 3 symptoms

Settings to Consider Non-bacterial Meningitis In AIDS, ALL, or Hodgkin disease, think Cryptococcus and do a cryptococcal antigen. Amebic meningitis should be the primary consideration when the meningitis patient has been swimming in brackish water (e.g., cow ponds).

occur. CSF analysis may resemble aseptic meningitis. Do an MRI. CT is not as good as MRI because it is susceptible to bony artifacts. Drainage is required. Empiric coverage should include drugs effective against staphylococci.

Aseptic Meningitis In aseptic meningitis, CSF contains inflammatory cells,

Neurosyphilis

but Gram stain and culture are negative. Patients present

See prior discussion on page 2-25.

with similar complaints as with bacterial meningitis, although generally, symptoms are less acute and severe. Viruses are the most common cause of aseptic meningi tis-these include: • Enteroviruses •Mosquito-borne arboviruses (West Nile virus) in the summer/early fall

Brain Abscess Location of the abscess is often related to the source. Frontal lobe-paranasal sinus: pneumococcus, H. inftu enzae, and anaerobes. Temporal or cerebellum-middle ear: pneumococcus, H. influenzae, S. aureus, and gram

COMMON ID SYNDROMES

INFECTIOUS DIARRHEA Overview Fecal WBCs suggest an invasive bacterial etiology and •

What lab results are consistent with viral meningitis?

•

Name 2 infectious diseases that can cause Bell's palsy.

•

You should assume that a patient with fever and back pain has what illness until proven otherwise?

•

for ova and parasites should be reserved for patients with diarrhea for > 10 days. The yield of stool for O&P in noso comial diarrhea is essentially zero. See Gastroenterology,

I, for more on diarrhea.

What are acceptable empiric regimens for a

What finding on stool evaluation suggests

Also see previous discussions of specific organisms.

Salmonella is discussed on page 2-21. Note:

invasive diarrhea? What is a possible adverse consequence of treating infectious diarrhea due to E. coli

0157:H7

Diarrhea due to Shigella, Salmonella, or Campylobacter

brain abscess?

•

ease. All of these organisms can be found on C&S. Stool

Book

epidural abscess should cover what organism,

•

infections. They are also seen in inflammatory bowel dis

Empiric coverage for a patient with a spinal specifically?

•

are evident in Shigella, Salmonella, Campylobacter jejuni, Yersinia enterocolitica, C. difficile, and amebic GI

Start cultures

for Shigella (usually Shigella

sonnei) as soon as possible after the bowel movement because Shigella dies soon after exposure to air. Treatment: If there are fecal WBCs, do a stool C&S.

with antibiotics?

However, ftuoroquinolones or TMP/SMX are typically negatives. Both frontal and parietal abscesses can be due to hematogenous spread from lung infections and endocarditis. Diagnosis is by CT scan with contrast(> 95% sensitivity). If accessible, aspirate the abscess and give antibiotic treatment based on results. Occasionally, you need to surgically excise the lesion. Lumbar puncture is abso lutely contraindicated if signs of increased intracranial pressure are present-such as focal neurologic signs. LP rarely helps with diagnosis anyway because the infec tion is not in the meningeal space. Overall, the risk of

given empirically, although antibiotics may prolong

Salmonella infection. Do not give antimotility agents for any infectious diarrhea. Campylobacter is resistant to TMP/SMX, so give erythromycin or quinolones instead if treatment is indicated.

Like Salmonella,

Campylobacter does not usually need to be treated. Shigella should always be treated. Prolonged, intermit tent diarrhea with malaise and flatus suggests

Giardia or

Cyclospora.

Diarrhea due to E. coli

herniation is as high as 20%.

E. coli is the most common cause of bacterial diarrhea

Treatment of brain abscesses is initially empiric. Pick 1 of

(generally without blood or WBCs) worldwide, affecting

the following for 4-8 weeks: •(PCN or ceftriaxone or cefotaxime) + metronidazole to cover aerobes and anaerobes. •PCN-allergic: Give metronidazole +a

3'ct generation

cephalosporin. •If you suspect Enterobacteriaceae(e.g., if ear focus), give a

3'ct generation cephalosporin +metronidazole.

•If there was a history of bacteremia/endocarditis or a neurosurgical procedure, or penetrating head trauma, think

S. aureus and add vancomycin (high incidence

of MRSA). For neurosurgical patients, use ceftazi dime/cefepime to cover hospital-related gram negatives including Pseudomonas.

Nocardia pulmonary disease can spread and cause focal

both the resident children and travelers in developing countries. Hemorrhagic

coli (serotype

0157:H7)

causes

localized outbreaks of hemorrhagic colitis, thrombocyto penic thrombotic purpura (TTP), and hemolytic uremic syndrome (HUS), usually after eating undercooked beef or unpasteurized milk. Fever is conspicuously absent. Do not treat diarrhea caused by E. coli 0157:H7 with antibiotics because you increase the risk of HUS by killing the organism and releasing more toxin. Enterotoxigenic E. coli is the usual cause of travelers' diarrhea. Prophylaxis and treatment are discussed on page 2-72.

lesions in the brain. It is also a rare cause of neutrophilic

Diarrhea due to Vibrio

aseptic meningitis.

Vibrios grow in salt water and are transmitted via sea food and shellfish.

V cholerae serogroup 01 (causes

cholera) is occasionally associated with Gulf Coast crabs. The non-01

V cholerae, V parahaemolyticus,

and other vibrios are even more frequent causes of

MedStudy

2-61

2-62

COMMON ID SYNDROMES

shellfish-associated diarrhea. These are usually self limited.

causes skin infections and

Vibrio vulnificus

sepsis, especially in the setting of immunocompromise or chronic liver disease(see page

2-68).

Viral Gastroenteritis There are many viral causes of diarrhea. Rotavirus is frequently found in children. It is the most important cause of severe diarrhea in infants and is easily identi fied in their stools. Noroviruses (formerly known as Norwalk-type viruses) are associated with clams and

Diarrhea due to C. difficile Antibiotic-associated diarrhea is typically caused by alteration of fecal flora resulting in an osmotic diar rhea, or the promotility action of some antibiotics (e.g.,

oysters, causing "winter vomiting disease," but it can also be waterborne. Identify noroviruses with the ELISA test. Look for outbreaks on cruise ships.

macrolides). Antibiotic-associated colitis is caused by

SEXUALLY TRANSMITTED DISEASES

Clostridium difficile. Clindamycin,

cephalosporins,

especially likely to cause

and

quinolones

are

C. difficile disease, but any

antibiotic may cause it. Symptoms can occur up to

8 weeks after the antibiotics are stopped. Diagnosis is made by assay for the not do cultures for

Clostridium difficile cytotoxin. Do C. difficile.

IDSA released guidelines in

2010 with the following

recommendations:

There are many causes of STDs. Most can be categorized into those that cause urethritis, cervicitis, and pelvic inflammatory disease (gonorrhea and

HSY, and lymphogranuloma venereum [LGV]). The latest treatment guidelines were released by the CDC in

recommendations.

> 15,000 or an increase in 50%; treat with PO vancomycin.

•Severe disease has WBC

•Mild-to-moderate disease has neither; treat with PO metronidazole.

The U.S. Preventive Services Task Force (USPSTF) says evidence does not exist for or against screening for most STDs. CDC gives a couple of recommendations. Generally, screen populations that are "at risk." Some established risk factors:

•Severe disease is considered complicated in the

15-24 years

presence of ileus, megacolon, or hypotension. Treat

•Age

these patients with PO vancomycin(+rectal, if ileus

• African-American

is present) +/- IV metronidazole. Colectomy should

•New partner in past

be considered for patients with very severe disease with rising lactate levels. -

repeat the l 51 regimen---either metronidazole or van comycin. But do not use metronidazole for more than

2 relapses. Patients with more than one relapse can be treated with tapering doses of vancomycin over several

2011 and has

only - I 0% relapse rate and thus can be considered in

C. difficile patients as well. Fecal microbiota transplanta tion([FMT]; or fecal transplant, fecal bacteriotherapy) is a highly successful procedure for treating severe, recurrent

C. difficile colitis. Hand gels do not prevent transmission because they do not kill the spores of

2 months

•Multiple partners • History of previous STDs

25% of patients. Treatment is to

weeks. Fidaxomicin was FDA approved in

C. difficile. Only hand washing pre C. difficile diarrhea should

vents spread. Patients with

•Drug use •Recent exposure to jail or detention facility •Finding sex partners from the Internet • Contact with prostitutes •Men who have sex with men Screen for gonorrhea by sending an intraurethral swab specimen for Gram stain and culture or DNA probe. Alternatively, DNA amplification by PCR can be done on swab or urine. Screen

for

Chlamydia

women (per

USPSTF) in the sexually active any woman

CDC

and

25 years of age and

25 years who has the above risk factors.

USPSTF has no opinion on screening men (because

be isolated to a private room and placed on contact

most are symptomatic). Screen for

precautions.

either urine or cervical swab for DNA amplification.

Chlamydia by sending

Screen for syphilis in the above risk factor groups, plus

Diarrhea due to Cryptosporidium

Oyptosporidium

and

2010. An update on the treatment of gonorrhea was cir 2011. The following discussion reflects these

•Stop the current offending antibiotics, if possible.

Relapses occur in

Chlamydia)

those that cause genital ulcers (syphilis, chancroid,

culated in

• Treat based on disease severity. creatinine by

Overview and Screening

during pregnancy. Order a serum RPR or VDRL, followed

is known to cause prolonged diarrhea

by an FTA-ABS if(+).

in AIDS patients and a self-limited diarrhea in travelers.

Screen for hepatitis viruses in patients with risk factors

Animals (including humans) are the reservoirs. It is

(e.g., sexual contact and/or injection drug use). Screen

found with acid-fast stains of the stool (small, round,

for HBV by sending serum for HBsAg and anti-HBc.

red organisms on a green background). HIV-infected

Anti-HBs are the only antibody present in patients who

patients should receive ART, and nitazoxanide can be

have been vaccinated in the absence of exposure; screen

added with variable results.

for HCV by sending serum for anti-HCV.

COMMON ID SYNDROMES

common than syphilis in the U.S. as a cause of ulcerative STD, it is the most common ulcerative STD in Africa.

uiz •

•

The initial lesion transfonns from a papule to pustule to a ragged ulcer, all of which are painful. It can progress

Vibrio vulnificus can cause severe disease in

to secondary chancroid with tender inguinal lymphade

which groups of patients?

nopathy (buboes), which may drain. Spread from there (tertiary chancroid) is rare.

What is the current treatment of choice in

LGV is due to specific serogroups of Chlamydia trachomatis (LGY-1, -2, -3). It is extremely rare in the U.S. (< 500 cases/year) but is endemic in many parts

patients with severe C. difficile diarrhea? •

What is the recommendation for treatment of first recurrence of C. difficile?

•

What infection control precautions must be used on patients with C. difficile diarrhea?

•

tually forms a clean, painless ulcer. This stage is present in only 1/3. Most patients present in the 2"d stage with

How do you screen for gonorrhea? For

tender inguinal masses on both sides of the inguinal liga

Chlamydia? For syphilis? •

ment (groove sign).

Characterize the ulceration caused by syphilis.

Granuloma inguinale ("Donovanosis") is very rare. Klebsiella granulomatis (formerly Calymmatobacterium granulomatis) is the causative gram-negative organ

By chancroid? •

of Asia, Africa, and South America. It initially presents with a commonly painless papule and vesicle that even

Discuss the clinical manifestations of LGV and granuloma inguinale.

ism that produces beefy red oozing and paradoxically

Screen for HIV /AIDS in pregnancy and in groups with the above risk factors. Send serum for an HIV-I antibody test (with reflex confirmatory Western blot in positive

painless genital ulcers. Spread to the inguinal area pro duces bilateral soft tissue granulomas that look like lymphadenopathy (pseudo-buboes).

specimens). Do not screen for HIV using DNA tests

Diagnostic tests for painless ulcers:

except in very specific circumstances, when the likeli

Syphilis: dark field exam of deep swab, RPR (+ in

hood of a false-negative serum antibody test is high (e.g., acute infection, neonatal HIV, and in patients with indeterminate test results). No general screening is recommended for herpes simplex infections.

70% of cases).

LGV: culture of lesions (low yield), serology by CF or micro-immunofluorescence.

Granuloma inguinale: Culture (low yield) biopsy showing intracellular dark staining organisms (Donovan bodies).

GU Infections with Genital Ulcerations

Diagnostic tests for painful ulcers:

Genital ulcerative diseases include syphilis, chancroid, HSY, lymphogranuloma venereum (LGV), and granuloma inguinale. With syphilis, the ulcer is usually single, clean with raised borders, and painless. Patients with syphilis

Chancroid: culture H ducreyi. Probable diagnosis can be made in the presence of a painful ulcer that has a negative RPR and no detectable HSY.

HSV: culture or antigen detection.

also typically have large, painless lymph nodes. (See

page 2-24 for more on syphilis.)

Treatment

HSY presents with tender, grouped vesicles on a reddish

Treatments of syphilis and HSY have been discussed

base with or without regional adenopathy. Treat with

previously.

oral acyclovir for the initial episode. You may also try this for severe, recurrent disease.

Chancroid should be treated with directly observed single-dose therapy whenever possible with ceftriaxone

Haemophilus ducreyi causes chancroid in which there

(250 mg IM) or oral azithromycin I g. In patients who

are tender genital papules, which become painful, puru

cannot take these, ciprofloxacin 500 mg bid x 3 d may

lent ulcers with irregular borders. There is associated,

be used. Erythromycin 500 mg tid x 7 d also is effective

very painful lymphadenopathy, which rapidly becomes

but requires a full week of treatment, has considerable GI toxicity, and patients that can take this should be able

fluctuant and ruptures. Treat with: •

I dose ofceftriaxone (250 mg IM), or

•

oral azithromycin I g oral single dose, or

•

ciprofloxacin 500 mg bid x 3 d, or

•

erythromycin 500 mg tid x 7 d.

to take azithromycin. LGY: Preferred treatment is doxycycline I 00 mg bid x 21 d. Erythromycin 500 mg tid x 21 d is a 211d line choice.

Chancroid is caused by Haemophilus ducrevi, a small gram-negative

coccobacillus.

Although

much

less

Granuloma

inguinale:

doxycycline

100

minimum of2 I d or until all lesions have healed.

bid

2-63

2-64

COMMON ID SYNDROMES

PIO

Cervicitis

Pelvic inflammatory disease can be caused by N. gon

Cervicitis is usually caused by Chlamydia (especially

orrhoeae, Chlamydia, or mixed genitourinary flora (aer

if the discharge is mucopurulent), but also N. gonor

obes and anaerobes). Oral contraceptives reduce the risk

rhoeae, HSY, and papillomaviruses. Because Chlamydia

of symptomatic PID caused by gonococci, but "silent"

is intracellular, you must have cervical cells for a valid

PID has the same incidence of sequelae (e.g., infertility)

smear/culture (so scrape or use a brush). Chlamydia cer

as does that associated with peritoneal signs.

vicitis commonly has a mucopurulent discharge. Gram

Presentation is with bilateral lower quadrant pain, fever, +/- vaginal discharge. Physical exam commonly reveals bilateral adnexal tenderness, lower quadrant tenderness,

stain of cervical secretions is not sensitive or specific in the diagnosis of gonococcal cervicitis (in contrast to male gonococcal urethritis).

and cervical motion tenderness. The clinical diagnosis has a PPV of<

90% so laparoscopy should be used when the

diagnosis is uncertain.

Urethritis Urethritis may be gonococcal (GC) or nongonococcal.

If there is no cervical discharge and cervical swabs fail

From the

to show WBCs, PID is unlikely. All other patients should

infection with N. gonorrhoeae can be determined by test

be tested for gonorrhea and chlamydia. Occasionally, PID

ing endocervical, vaginal, urethral (men only), or urine

patients get a perihepatitis (Fitz-Hugh-Cmtis syndrome)

specimens. Culture, nucleic acid hybridization tests, and

2010 CDC guidelines: Specific diagnosis of

with mild LF T abnormalities; this has been caused by

NAATs are available for the detection of genitourinary

both N. gonorrhoeae and Chlamydia.

infection with N. gonorrhoeae. With GC urethritis, the

Treatment depends on whether the patient requires admission or not. Patients should be admitted if: • Clinical response to prior oral antimicrobial therapy is inadequate. outpatient oral regimen.

diplococci on Gram stain (Image

Ureaplasma urealyticum, HSY. For

are present.

2-23).

Trichomonas vagina/is, or

35% of cases, the cause is unknown.

Patients with nongonococcal urethritis usually have a

•You suspect or find a tubo-ovarian abscess.

clear urethral discharge, and a Gram stain shows WBCs

• The patient is pregnant.

and no bacteria. Gonococcal urethritis has a shorter incu

Outpatient treatment for PID:

bation period

250 mg IM, then doxycycline 100 mg bid

x 14 d +/- metronidazole 500 mg bid x 14 d; or

(2-6 days vs. 1-4 weeks for Chlamydia)

and produces a more purulent and more productive discharge. In all of these patients, check a VDRL and, if negative,

1 gm x 1 plus

repeat it in

doxycycline +/- metronidazole; or

2 months (in case the syphilis was incubating

when blood for the 151 test was drawn). Offer HIV testing

• other parenteral cephalosporin plus doxycycline

to all urethritis patients.

+/- metronidazole. Because of the rate of fluoroquinolone-resistant gonorrhea, fluoroquinolones are no longer recommended.

observed azithromycin ycycline

2 grams IV q 6 hours and doxycycline 100 mg orally or IV q 12 hours; or • clindamycin 900 mg IV q 8 hours + gentamicin.

• cefoxitin

An alternative to these

Treatment of urethritis: Treat non-GC urethritis with a single does of directly

Inpatient treatment for PID:

1 g orally. Less desirable is dox 100 mg bid x 7 d. Levofloxacin and ofloxacin

are also effective but should be avoided in pregnancy. GC urethritis: Resistance to penicillins, tetracyclines,

2 is ampicillin/sulbactam and

doxycycline. When treating gonorrhea, always cover for Chlamydia. Tubo-ovarian abscesses require inpatient, intravenous antibiotic therapy-same as the inpatient PID choices above. Note that ampicillin/sulbactam + doxycycline is also recommended for tubo-ovarian abscesses. Follow up with patients treated for chlamydia! infections with a test for cure at

the finding of gram-negative intracellular (within PMNs)

ally due to Chlamydia trachomatis and, less frequently,

• Severe illness, nausea and vomiting, or high fever

•cefoxitin 2 gm IM and probenecid

nosis is confirmed from either positive culture results or

Otherwise, consider it non-GC urethritis, which is gener

• The patient is unable to follow or tolerate an

• ceftriaxone

patient virtually always has a purulent discharge. The diag

3 weeks. The PCR test can remain

and fluoroquinolones is commonly found. As a result, the CDC recommends dual therapy for gonorrhea infections of the cervix, urethra, and rectum with a cephalosporin plus azithromycin-in hopes that routine cotreatment might hinder the development of further antimicrobial resistant N. gonorrhoeae. The

following

recommended

for

uncomplicated

gonococcal infections of the cervix, urethra, and rectum: • Ceftriaxone

250 mg IM x 1 + azithromycin 1 g PO x 1

positive for many weeks.

COMMON ID SYNDROMES

Epididymitis

Q�uiz True or false? Pregnant women with PIO rarely

•

need hospitalization.

treatment of PIO. What is the typical clinical presentation of

•

disseminated gonorrhea? What is the best way to diagnose disseminated

•

gonorrhea? What 3 tests are useful to determine the etiology

•

of vaginitis? In what way?

For treatment of uncomplicated gonococcal infections of the pharynx:

•

E. coli, in prepubertal boys and men

35 years of age

and STD pathogens in sexually active men

35 years

especially C. trachomatis

Know the outpatient and inpatient regimens for

•

Epididymitis is an inflammation of the epididymis. It is usually caused by Enterobacteriaceae, especially

Ceftriaxone 250 mg IM x 1 Plus, if Chlamydia has not been ruled out: 0

Azithromycin 1 g PO x 1, or

Doxycycline 100 mg PO bid x 7 days

Consider gonococcal disease in acute exudative pharyn

Vaginitis Vaginitis presents with change in or increase in vaginal dis charge. There are 3 major causes. A systematic approach diagnoses the etiology in the vast majority of cases. Approach to the Etiology of Vaginitis

3 tests on vaginal secretions/discharge almost always lead to an etiologic agent on initial exam: pH, wet prep, and KOH prep. pH: Normal vaginal pH is vaginal candidiasis. A pH

< >

5.0, and remains so with 5.0 is seen in bacterial

vaginosis and trichomoniasis. Wet prep (secretions placed in normal saline under

microscopy): reveals epithelial cells studded with caus ative organisms in bacterial vaginosis and trichomonads

gitis in a sexually active adolescent, especially if tests

in trichomoniasis. It may show fungal elements in

for S. pyogenes are negative.

candidiasis.

Pregnant women: Do not use a quinolones or tetracycline.

KOH prep (secretions placed in KOH under microscopy):

Use a cephalosporin for gonorrhea and either erythromy

yields a fishy odor in bacterial vaginosis and trichomo

cin or azithromycin for C. trachomatis. If she is allergic

niasis. KOH dissolves epithelial cells and increases the

to cephalosporins, the 2010 CDC guideline recommends

yield of finding fungal elements in candidiasis.

azithromycin 2 g PO x 1 . Always treat the sexual partners of patients with either type of urethritis, even if they are not symptomatic! And always treat suspected cases immediately-don't wait for C&S results.

Bacterial Vaginosis

Bacterial vaginosis is a clinical syndrome resulting from the replacement of the normal H20z-producing Lactobacillus in the vagina with high concentrations of anaerobic bacteria (Mobiluncus, Gardnerella vagina/is).

Gonococcemia Disseminated gonorrhea: Patients present with fever, arthralgias, and asymmetric oligoarthritis-usually of the knee or ankle. A typical rash of< 10 papules/pustules is classic. Tenosynovitis is common. Gram stain and culture have a very low yield (15%) from the lesions, but if you swab all orifices, there is an

85% yield. Even though the lesions have a low yield, they should still be tested because similar lesions can be caused by other disseminated diseases, such as staph endocarditis (which does have a positive Gram stain and C&S). Treat patients diagnosed with gonococcemia-including tenosynovitis-with a 3rd generation cephalosporin (cef triaxone, ceftizoxime, or cefotaxime). Pending culture and sensitivity, single-dose azithromycin, levofloxacin, or doxycycline is included to cover for Chlamydia. Image 2-:!3: Gram-negative diplococci-these are extracellular; require intracellularfor Dx

2-65

2-66

COMMON ID SYNDROMES

There is a thin, "skim milk," scanty, foul-smelling, non-irritating discharge that has 2 identifying features: 1) Clue cells (an epithelial cell with many adherent bacteria; Image 2-24) 2) Fishy odor when mixed with KOH(+ whiff/sniff test)

•

A subgroup of patients has recurrent VVC. Weekly topical clotrimazole and oral fluconazole 150 mg one-time doses are equally effective.

Trichomonas

Trichomonas vagina/is

infection causes

a vagm1t1s

There is no cervical discharge.

in women. Men may also be infected but are usually

Treatment is metronidazole-oral (500 mg bid x 7 d)

asymptomatic. Trichomonas vaginitis presents with a

or vaginal gel (0.75% bid x 5 d)-altemately tinidazole

profuse, thin, frothy, yellow-green, foul-smelling dis

or clindamycin orally or as a cream 2% intravaginally

charge (which, like bacterial vaginosis, has a positive whiff test), vaginal erythema, and a strawberry cervix.

(at bedtime x 7 d).

Treat Trichomonas vaginitis with metronidazole 2 grams

Treatment guidelines for pregnant women: •

metronidazole 500 mg bid x 7 days, or

•

metronidazole 250 mg tid x 7 d, or

•

clindamycin 300 mg orally bid x 7 d.

single dose or tinidazole 2 grams single dose. Even though these are the best treatments, they are only mod erately effective. If pregnant, recommendations say it is OK to give a one-time dose of 2 grams metronidazole.

Creams are not recommended in pregnancy. The reason to treat systemically is that there is a much higher risk of preterm labor and delivery than of compli cations from a short course of therapy with metronidazole or clindamycin. The male sex partner does not need to be treated.

URINARY TRACT INFECTION The standard definition of a positive urine culture remains

2'. 105 organisms/mL of urine. However, a posi

tive urine culture does not equal UTI. If a person has bacteriuria without symptoms and no urinary catheter, this is considered asymptomatic bacteriuria (ASB). The

Vaginal Candidiasis Vulvovaginal

diagnosis of UTI can be difficult especially in older

candidiasis (VVC)

almost

always

caused by Candida albicans. I t presents with adherent

adults. Classic symptoms include dysuria, frequency, stranguria, and urgency.

white plaques with an erythematous base and is almost

Pyuria has good negative predictive value; the absence

always pruritic. Remember that this may be a sign of

of pyuria essentially rules out UTI. On the other hand,

undiagnosed diabetes or HIV, especially if recurrent.

presence of pyuria even with bacteriuria does not make

Women with recurrent vaginal candidiasis should be

the diagnosis ofUTI.

screened for both illnesses.

A wide variety of organisms may cause UTI, but E. coli and other enterics are the most common. S. saprophyticus

Treatment: •

is a coagulase-negative staphylococcus that may cause

Uncomplicated VVC in a non-pregnant patient:

UT! as well.

butoconazole, miconazole, or terconazole vaginal creams. Oral azoles are equally effective-especially oral fluconazole 150 mg x •

Treat pregnant patients with only the azole creams for 7 days.

UTis are the most common nosocomial infections. Risk factors for UTis in women include diabetes mellitus, sexual activity, diaphragm use, vaginal atrophy, and genetic predisposition. UT!s are rare in men and are not associated with male sexual activity, except in men who have sex with men. In heterosexual men, UTis are usually a result of an abnormality in the urinary tract, such as obstruction, ureterovesical reflux, or prostatic hypertrophy. In either gender, UTis are increased in the presence of diabetes mellitus, sickle cell disease, hyperparathyroidism, or gout. Proteus infections are associated with neurogenic bladder or urinary stones; therefore, when Proteus is indentified in the urine, order imaging tests to look for stones. Group

B strep (S. agalactiae) infections are seen in pregnancy. [Know!] UTI and ASB in pregnant women: Treat asymptomatic bacteriuria in pregnant women. ( 1/3 go on to pyelonephritis if untreated!) Also, always admit and treat pregnant patients with pyelonephritis as a Image 2-24: Clue cells

COMMON ID SYNDROMES

•Complicated pyelonephritis and/or hospitalized patients: quinolone, or ceftriaxone, or beta-lactam +

uiz •

beta-lactamase inhibitor, or ampicillin + aminoglyco side for 10-14 d.

Women with recurrent or recalcitrant candidal

Asymptomatic bacteriuria should be treated in only

vulvovaginitis should be tested for what

2 settings: pregnancy and anticipated urologic surgery

infection? For what metabolic disease? •

(e.g., transurethral resection of the prostate).

What is the standard treatment for

Urinary catheters do not need to be changed unless there

uncomplicated cystitis, complicated cystitis,

is a symptomatic UTI.

uncomplicated pyelonephritis, and complicated

Recurrent UTis are common and should be approached

pyelonephritis? •

in a systematic way. First, define the type of recurrence.

In what 2 settings would you treat asymptomatic

Recurrences can be relapses (same strain within 2 weeks

bacteriuria? •

of the end of therapy) vs. reinfection (different strain

Otitis externa is usually due to what organism?

than the initial infection). Relapses are usually due to a persistent nidus of infection (stones, abscess, urethral/

complicated

pyelonephritis

(below).

Pregnancy-safe

ureteral/bladder diverticula, obstruction) so CT of the

antibiotics to use for UTI/pyelonephritis are ampicil

abdomen and pelvis should be performed. Reinfection

lin, cephalosporins, and TMP/SMX-but do not give

may be related to sexual activity. If so, very low dose

TMP/SMX in late pregnancy or to early-nursing moth

prophylaxis (e.g., TMP/SMX 1/2 SS tablet, nitrofuran

ers because it might cause kemicterus in the child. Avoid

toin 50 mg) before or after sexual activity should be

tetracycline, doxycycline, and quinolones in pregnancy, infancy, and early childhood because they are toxic. The Infectious Diseases Society of America updated the

given. If there is no such relationship and< 3 episodes a year, treat as they occur. If:'.:'. 3 episodes a year, consider chronic low-dose suppression for 6 months.

approach to diagnosis and therapy of UTis in 2010. The

I st step in treating UTis is to determine whether they are lower tract (cystitis) vs. upper tract (pyelonephri tis). Cystitis typically has no systemic signs of infection or flank tenderness. Pyelonephritis typically has fever

OTITIS AND SINUSITIS Otitis Media Otitis media is very uncommon in adults, and its presence

(often> 102° F) and flank pain. Sepsis may be present,

suggests structural anomalies or immunocompromise.

and blood cultures are positive in

It presents with ear pain and hearing loss +/- fever.

I 0%.

The next step is to determine whether it is complicated or not. Complicated UTis are those in persons with dia betes, immunocompromise, structural anomalies, foreign bodies, prior resistant organisms, or male gender. Uncomplicated

cystitis

may

treated

based

Diagnosis is made by visualizing both inflammation of the tympanic membrane and fluid in the middle ear. S. pneumoniae is the most common bacterium. H. influenzae and

M catarrhalis are also common.

Treat with amoxicillin alone if the patient hasn't taken on

antibiotics recently. Treat with amoxicillin/clavulanate,

symptoms alone and does not require a urine culture.

cefuroxime, ceftriaxone, or clindamycin if the patient

All other patients should have a urine culture. Imaging

has recently taken other antibiotics. Treatment failure:

of the urinary tract (ultrasound or CT) should not be

Consider tympanocentesis. In patients on mechanical

performed in cystitis, and should be performed in pyelo

ventilation: Rx for Pseudomonas or Enterobacter with

nephritis only if symptoms persist after 72 hours of

ceftazidime, imipenem, piperacillin/tazobactam.

culture-guided therapy. Treatment: • Uncomplicated cystitis: TMP/SMX x 3 days is the

I st line treatment but only if the known level of E. coli resistance is :::; 20%. Jf it exceeds this, nitrofu rantoin for 5 days or fosfomycin x I dose should be given. Quinolones should be reserved for complicated infections (because overuse is creating resistance), and beta-lactams should be avoided due to decreased efficacy. •Complicated cystitis: quinolone x 7 d. • Uncomplicated pyelonephritis: quinolone x 7 d if E. coli resistance is:::; I 0%. An initial dose of rv

ceftriaxone may be given pending cultures.

Otitis Externa Otitis extema is also predominantly a pediatric infection. It presents with unilateral pain and itching in the exter nal auditory canal. It is predisposed by trauma, foreign bodies, dermatitis and moisture, especially swimming ("swimmer's ear"). The causative organism is usually P. aeruginosa. Treat with a topical quinolone. If moder

ately severe, give an oral quinolone. This should be differentiated from malignant (necrotizing) otitis cxtema, which initially presents the same but pro gresses to an invasive and destructive infection of soft tissue and bone. It is also due to Pseudomonas infection, and> 90% of patients are diabetic. Others at risk: AIDS and chemo patients. IV antibiotics are usually required.

2-67

2-68

COMMON ID SYNDROMES

Sinusitis

In addition to the frontal and maxillary areas, it shows

Sinusitis is inflammation in the paranasal sinuses. Acute sinusitis is defined as persisting up to 4 weeks. Chronic sinusitis is defined as persisting > 4--8 weeks. Recurrent sinusitis is ::=: 3 separate episodes of acute sinusitis per year. The most important factor in the development of sinusitis is obstruction of the ostia (blocked with thickened sinus secretions, sinus congestion, nasal polyps, and trauma). Most sinusitis is viral, and clinical criteria (see below) should be used to decide whether there is a likelihood of bacterial infection, and thus a response to antibacterials. According to IDSA guidelines, 3 clinical findings are predictive of bacterial sinusitis: duration of> I 0 days, fever> 102° F with purulent drainage or facial pain, and worsening of symptoms after an initial improvement. The most common causative bacterial organisms are

S. pneumoniae, H. influenzae, and Moraxella catarrhalis. Chronic sinusitis may also be caused by S. aureus, group A strep, P aeruginosa (especially with cystic fibrosis),

and anaerobes such as Fusobacterium and Bacteroides. Fungal sinusitis is seen in patients with diabetes (especially zygomycetes), cancer, and in those receiving corticoste roid therapy. A patient with rhinocerebral zygomycosis may present with symptoms of only a sinus infection or unilateral nasal congestion. Tissue necrosis occurs as

the ethmoid and ostiomeatal complex. CT also shows subtle thickening. The Tl-weighted MRI is useful for differentiating an inflammatory process (high-intensity bright) :!Tom a tumor (intermediate-intensity bright). X-rays showing opacification, air-fluid level (Waters view of the :fTontal and maxillary sinuses), and thickening indicate sinusitis. Treatment:

acute bacterial sinusitis is suspected

based on above criteria, start amoxicillin-clavulanate.

211ct line drugs are the fluoroquinolones and doxycycline. Recommended duration of therapy is I 0 days. Intranasal corticosteroids and saline irrigation may be used as adjunc tive treatment. Chronic sinusitis rarely responds to antibacterial therapy. ENT consultation may prove helpful. Use endoscopic sinus surgery when medical therapy fails. Treatment of rhinocerebral zygomycosis is emergent and aggressive-with radical surgical debridement and lipid amphotericin B. (Lipid formulation is used so that you can give higher ampho doses with less toxicity.) Most other fungal meds are not effective. Posaconazole has been used successfully in conjunction with debridement; it is considered a good agent to use after patients stabilize and begin to improve on amphotericin.

infection spreads outside of the sinuses with the resulting distinctive black eschar sometimes visible on the palate and/or nasal mucosa.

SKIN I SOFT TISSUE, BONES, JOINTS Classic Soft Tissue Infections

Symptoms may assist in localizing which sinus is involved. Frontal sinusitis may have headache that is worse when leaning forward ("bowler's headache"). Maxillary sinusitis may have maxillary tooth pain. Sphenoid sinusitis may have headache at the vertex of the skull. Note: Patients with similar headache and pressure, along with rhinorrhea and sneezing, usually have allergic or viral rhinitis-not sinusitis. Patients with chronic sinusitis present differently, often with signs/symptoms such as chronic refTactory sinus con gestion, bad breath, postnasal drip, cough, and headache. Sinusitis symptoms, especially if seasonal, should be differentiated :!Tom allergic rhinitis. Nasal smears with a high number of eosinophils are seen with both allergic rhinitis and nonallergic rhinitis with eosinophils syn drome (NARES). Bacterial sinusitis shows large numbers of neutrophils and bacteria. Bacterial sinusitis is treated empirically, but failure to respond or frequent relapses warrants sinus aspiration. Consider cystic fibrosis if Pseudomonas grows from a sinus culture (especially in a young adult with history of recurrent respiratory issues).

Vibrio

vulnificus

causes

necrotizing

soft

tissue

infection after inoculation into non-intact skin (e.g., skin penetrated by fishing hook). It almost always only does so in patients with liver disease. Vibrios are found in warm salt water, and infection occurs mostly in the areas of Chesapeake Bay and the Gulf of Mexico. Diagnose by culture, and treat with a combination of ceftriaxone and doxycycline. Mycobacterium marinum is also called "fish tank

bacillus." It causes nonhealing skin ulceration in people who work with fish tanks. Infection may present as a single granuloma, but the organism often invades the lymphatics and can cause a series of lesions over a lymphatic drainage similar to the lesions seen in sporotrichosis. Lesions tend to localize in the distal extremities because the organism does not grow well at body temperature. Diagnosis is made by biopsy and AFB stain and culture. Treat

with

clarithromycin

plus

either

ethambutol

or rifampin for at least 1-2 months after the lesions have resolved. Erysipe/othrix rhusiopathiae infects a large number

of domestic and marine animals and causes skin infec

Radiography: Sinusitis is generally a clinical diagnosis and imaging is not usually required. If indicated, non contrast CT scan is the gold standard for diagnosing sinusitis but cannot differentiate viral from bacterial.

tion after occupational exposure in fishermen and meat handlers. Lesions are usually localized nodules with lymphangitis in

25%. Systemic disease is uncom

mon and more likely in alcoholics. Treat with PCN.

Infringements to copyright@medstudy.com

COMMON ID SYNDROMES

presumptive evidence of microbiologic causation. Blood cultures are often

•

IZ •

In chronic osteomyelitis, a sinus tract may be present.

How many days of symptoms are required

organism that has any predictive value as the causative organism is S.

and prescribe antibiotics? What are the usual

joint infection, you must remove all necrotic bone and

True or false? A patient with 5 days of facial

prosthetic material before a chronic osteomyelitis can be

100.6° F, and clogged nasal

cured with antibiotics.

passages should be treated for bacterial

of cases.

Manifestations are wound drainage, cutaneous ery

What are some symptoms of rhinocerebral

thema, or prosthetic joint pain. Plain x-rays are helpful

zygomycosis? •

1-5%

Prosthetic joint infection occurs in

sinusitis. •

aureus.

Except for small bone disease and very early prosthetic

causative organisms?

pain, fever to

osteomyelitis .

A culture of the tract may be performed, but the only

to diagnose a patient with bacterial sinusitis

•

(50%) positive in acute

G R

if they show a widening of the bone-cement interface,

How can you differentiate allergic rhinitis from

changes in the position of prosthesis, cement fractures,

bacterial?

periosteal reaction, or motion of components on stress views. Other imaging techniques commonly are not

•

Treat bacterial sinusitis with which antibiotics?

•

What is the clinical presentation of M.

•

What organism is associated with osteomyelitis

a joint aspiration should be performed to document

in a patient with sickle cell anemia (besides

infection and determine the infecting organism (prior to

helpful because of a high degree of false-positives. If

marinum?

S. aureus)? •

V d ti e

clinical suspicion is high based on symptoms+/- x-ray,

antibiotics).

How is osteomyelitis in a prosthetic joint

If the infection occurs within

diagnosed?

patients may be treated with antibiotics and debride

n U

days of surgery,

ment with retention of the prosthesis. All others should

PCN-allergic patients should receive quinolones or

3'd generation cephalosporins.

rary spacer implant and

Impetigo presents as honey-colored crusts over nodular

aureus is the most common cause; occasion ally S. pyogenes is the culprit. Lesions are often present lesions. S.

around the nose or mouth.

9 9

Osteomyelitis

Osteomyelitis may be acute or chronic, the distinction

being that the latter has necrotic bone. Acute is usually caused by S.

aureus.

have removal of the prosthesis, followed by a tempo

Some organisms have certain epi

h ta

demiologic niches. In IV drug abusers,

Pseudomonas

6 weeks of IV antibiotics.

If this results in a sterile joint space, a new prosthetic

joint can then be implanted. This is the so-called 2-stage procedure.

NOSOCOMIAL INFECTIONS Important nosocomial infections include pneumonia (hospital-acquired

and

ventilator-associated),

blood

stream infections, urinary tract infections, surgical site infections, and

Clostridium difficile infections.

Nosocomial pneumonia is almost always bacterial and

has a predilection for several: the stemoclavicular joint,

has the highest mortality rate of all the nosocomial

symphysis pubis, and vertebrae. Sickle cell patients have

infections

a high incidence of

bacteremic!). It is usually caused by gram-negative

joints are infected

Salmonella osteomyelitis. Prosthetic most commonly by S. aureus and

coagulase-negative staph (see below).

(30%

if bacteremic;

50%

organisms; next most frequent is S.

if gram-negative

aureus.

The most

common risk factor is mechanical ventilation. The diag

Diagnosis of diabetic foot osteomyelitis can be made with high accuracy if a solid probe is able to reach bone on exam. Otherwise, imaging is needed to demonstrate osteomyclitis prior to recommending bone biopsies for culture. Initial plain x-rays may be done with the

50%

nosis of ventilator-associated pneumonia is not straight forward and depends on documenting a combination of increased secretions, positive respiratory cultures, and radiographic infiltrates. Intravenous catheter-related infections may present as a

demin

generalized illness without symptoms localizing to the

eralization of the bone, and this takes weeks to occur.

line. (This is the most common scenario.) Alternatively,

understanding that radiolucency requires

The most sensitive image is MRI, which is the study of

a localized infection either of the subcutaneous tunnel

choice. Pyrophosphate bone scans are also sensitive but

and/or of the site of entry may be present. Finally, and

are very nonspecific because they are positive whenever

least commonly, signs and symptoms of a septic clot

there is new bone formation (trauma, fracture, prosthetic

may be present in line-related thrombophlebitis.

joint incorporation).

Secondary endocarditis is more likely to occur in patients

Cultures of the bone are the gold standard. Evidence of

with catheters that extend into or close to the heart. IV

osteomyelitis on imaging and a positive blood culture are

lines commonly become infected after

�

days. Metal

2-69

2-70

VACCINES

needles are less likely than plastic angiocatheters to become infected. IV catheter infections are usually due to S. epidermidis and S. aureus. Some other causes are

Candida, Corynebacteriumjeikeium (especially in bone marrow transplant units), and gram-negative rods.

Vaccine Schedules The specific schedule for vaccinations changes very frequently. The current schedule can be found on the web page for the Advisory Council on Immunization Practices at: http://www.cdc.gov/vaccines/schedules/index.html.

The key decision in treating catheter-related infections is whether the line should be removed. Per IDSA guide lines all catheters should be removed if associated with any of the following conditions: severe sepsis; suppura

Vaccinations that are recommended for adults, accord ing to age groups: •

for all> 7 years of age. Tdap needs to be given only

that continues despite 7 days of appropriate antimicrobial

once if the usual childhood series was given; after

therapy. In addition, all lines should be removed in infec

that, Td can be given.

tions with the following: S. aureus, P aeruginosa, fungi, or mycobacteria. In the case of enterococcal infection,

•

Varicella (chicken pox vaccine): 2 doses, if no history

•

Zoster (booster to prevent shingles): adults> 50 years

of immunity or vaccination.

•

MMR: 2 doses if not vaccinated or I more if received

•

Influenza: given annually to all persons> 6 months old.

•

Pneumococcal vaccination:> 65 years and those at

only I vaccine as a child.

tion may cause fungal infections. Treat with vori- or an echinocandin if candidiasis is present. If line salvage is attempted, an antibiotic lock solution

risk (see below).

should be used.

Vaccine Types Vaccines

used

solely

•

childhood

9 9

r i h

Varicella

Zoster

0 Smallpox

0 Typhoid oral 0BCG

0 Yellow fever

are

not

Tdap Polio

Cholera

Rabies

This vaccine is contraindicated in patients with immuno deficiency because it is live virus.

Zoster vaccine is licensed for patients 2: 50 years of age and recommended after age 60, even if they have had a recent outbreak of shingles. Because it is live virus, this vaccine is contraindicated in patients with immunodefi ciency or who are pregnant. Both the varicclla and the zoster vaccine have the same virus, but the latter has a much higher dose. MMR: It is recommended that persons born after

1956

receive 2 doses of live measles vaccine. These should be given not less than 1 month apart but can be given years apart. The present recommendations are the 151 dose at 12 months and the 2nct dose at age 4-6 years. All young

0 Japanese encephalitis 0

a history of chicken pox by the patient is not sufficient

for assuming immunity. If the adult patient doesn't know immune status by serologic testing (lgG Ab) before

0HAV 0

Varicella virus vaccine is recommended for all individ uals 2: I 2 months of age who are not immune. Note that

giving the vaccine because most adults are immune.

Killed (inactivated) are safe for immunocompromised: 0

Meningococcal polysaccharide or conjugate:

or believes he/she has had no previous infection, check

0 Intranasal influenza •

•

I 9-55 years.

immunocompromised (including pregnancy): Measles-mumps-rubella

HBV: at-risk adults without evidence of immunity

everyone ages I 1-18 years and at-risk adults ages

Live-attenuated vaccines should not be given to the 0

HAV: at-risk adults without evidence of immunity.

•

and no history of childhood vaccination.

Adult Vaccinations

discussed.

•

n U

VACCINES

Note:

V d ti e

of age.

S. aureus infection of long-term catheters, 4-6 weeks of antibiotics are needed. Lines used for hyperalimenta

G R

•

Patients should be treated with antibiotics (e.g., vanco for staph) for 14 days after line removal. In the case of

HPV: 3 doses for ages 9-26 (but not older), both genders.

short-term catheters should be removed; for long-term catheters salvage may be attempted.

Td or Tdap: I dose q 10 years. (DTaP and DT are for children< 7 years.) Tdap is now approved

tive thrombophlebitis; endocarditis; bloodstream infection

adults (since they would have been born after 1956) who

Typhoid polysaccharide

have had only I live measles vaccine should receive another.

0HSY and HPV, which are recombinant 0

Pneumococcal vaccines (PPSV-23 and PCV-13)

Meningococcal polysaccharide and conjugate

Trivalent influenza (TIV )

VACCINES

•Leukemia •Lymphoma

Q�uiz •

•Hodgkin disease •Generalized malignancy

Which vaccines contain live virus? To which

•Iatrogenic immunosuppression

patients should they not be given? •

•Solid organ transplant

Which vaccines are safe to be given to

•Multiple myeloma

immunocompromised or pregnant patients? •

HAV:

Know which vaccines are recommended to adults and in what age groups.

•

HBV is universally recommended at birth and for all of

Which patient groups should be given the

Serologic testing for immunity is recommended only for

Which patient groups should receive some form

specific groups:

•Health care and public safety workers

How do you decide how to prevent tetanus in

V d ti e

• Chronic hemodialysis patients

a patient presenting with a wound? Is a crush

•HIV-infected persons

injury "tetanus-prone?"

•Immunocompromised persons

Pneumococcal vaccines include the 23-valent polysac charide vaccine (PPSV-23) and the 13-valent conjugate vaccine (PCV-13). The rules for giving these vaccines

•Sexual partners of HBsAg-positive persons

Persons who do not develop a protective response (anti-HBs concentration of

mIU/mL) should

receive another full vaccine series.

are a little complicated:

n U -

Meningococcal vaccines include conjugate and poly

1) Timing:

•After PCV-13, you need to wait 8 weeks before you give PPSV-23.

•After PPSV-23, you need to wait a year before giving

saccharide vaccines. If exposure is ongoing, a booster should be given every 5 years.

• All persons 11-18 years of age should be vaccinated with 2 doses of the conjugate vaccine.

PCV-13.

•A booster dose of PPSV-23 should be given 5 years

9 9

after the 1st dose of PPSV-23. 2) Indications:

r i h

•All patients 2: 65 years of age should receive PPSV-23.

•Patients19-64 years of age with the following condi tions should also receive PPSV-23: °

G R

adolescents.

of the meningococcal vaccine? •

contraindicated, inactivated

those who were not immunized in childhood, particularly

pneumococcal polysaccharide vaccine? •

otherwise

after age 1 year.

How many doses of MMR are considered most desirable and protective?

•

Unless

hepatitis A vaccine is universally recommended at or

Chronic heart disease

Chronic lung disease

Alcoholism

Chronic liver disease

Cigarette smoking

3) Patients 19-64 years of age with the following condi tions should receive PCV-13 followed by PPSV-23 8 weeks later: •Cerebrospinal fluid leak •Cochlear implant •Sickle cell disease/other hemoglobinopathy •Congenital or acquired asplenia •Congenital or acquired immunodeficiency •HIV •Chronic renal failure •Nephrotic syndrome

•Previously unvaccinated at-risk patients (see list below) between 18 and 55 years should receive

conjugate vaccine.

• Previously unvaccinated at-risk patients (see list below)> 55 years of age should receive polysaccharide

vaccme. At-risk patients for meningococcal disease: • Asplenia or complement deficiencies • 1st year college students who live in dorms; military recruits • People who are traveling to the meningitis belt of sub-Saharan Africa, Saudi Arabia (e.g., for the Hajj), or Nepal •Lab workers who work with Neisseria

Approach to Tetanus Prevention Tetanus can be prevented with the appropriate use of tetanus toxoid (Td) and tetanus immune globulin (TIG). The use of these depends on the type of wound .and the vaccination status of the patient.

Tetanus-prone wound: At-risk wounds include crush injury, bite injuries, dirt or focally contaminated wounds, puncture or missile wounds, deep penetrating wounds, compound fractures, wounds containing foreign bodies (e.g., wood splinters), and re-implantation of an avulsed tooth. Tetanus can be prevented based on whether it is

2-71

2-72

PROPHYLAXIS

certain patients have had the primary series of 3 injec

Typhoid

tions of Td or not. Those who have had a primary series

(> 2 years old) who go outside of the usual tourist areas

should receive a booster dose of Td if they have not

within Latin America, Asia, and Africa. An oral live

vaccine

recommended

for

travelers

received Td in the last 5 years. This allows production

attenuated vaccine is recommended for those > 2 years

of antitoxin antibodies prior to the ability of the tetanus toxin to travel from the wound site to the central ner

of age. It has a protection rate of 70-90% and is recom

vous system. Patients who have not received the primary series (or of uncertain immunization history) should be considered at high risk of tetanus. The patients should receive Td to begin or attempt to complete the primary series. However, since they did not have adequate prior immunization, boosting

their immune

response

cannot be relied upon. Therefore, these are the only patients for whom TIG is indicated. Non-tetanus-prone wound: Persons who do not have

tetanus prone wounds (often called "clean wounds") are not at risk for tetanus. However, the patient encounter provides an opportunity to begin immunization in the previously unvaccinated or to boost immunity in people who haven't received a booster in the last 10 years. Thus, those who have not received all 3 primary series injec

mended every 5 years. Smallpox vaccine is available on demand. Military

personnel and select health care workers have been vac cinated in the past. In the event of a bioterrorist attack with smallpox, large numbers of people will be vac cinated to prevent epidemic spreading of the disease. Contraindications to smallpox vaccine include pregnancy, age < 12 months, and immunosuppression.

G R

Polio vaccine is not routinely recommended to persons

> 18 years of age. Polio vaccine is recommended for previously unimmunized travelers to endemic areas. A booster is indicated for travelers who have had only the primary vaccination and who travel to areas where expo

V d ti e

sure to the wild-type virus is likely. Only the inactivated vaccine is recommended in the U.S.

tions of Td (or are uncertain) should receive as many Td injections needed to complete the 3-shot primary

Yellow fever vaccine is recommended for travel in equatorial Africa and much of tropical South America.

immunization sequence. Those who have completed the primary series but have not been boosted in the last

It is a live vaccine and should not be given to immuno suppressed patients.

n U -

10 years should receive a Td booster. TIG is never indi cated in the management of non-tetanus-prone wounds. Unusual Vaccines for Special Situations

Anthrax: AVA is the only licensed human anthrax vaccine

in the U.S. It contains proteins only, no dead or live bac teria. The vaccine is recommended for people who work

9 9

with anthrax cultures or who are exposed to activities

with high potential for aerosolization of B. anthracis. In addition, a course should be given after potential exposure

r i h

in previously unvaccinated persons.

BCG is not recommended in the U.S. but is commonly

given to children in other countries where TB is common. BCG immunization may cause a positive

tuberculin skin test, complicating later evaluation of tuberculosis. Having received the BCG vaccine does not change the interpretation of the TB skin test in the U.S. (An indurated test should still be subjected to the same cut-offs for significance as in any other patient. See Pulmonary Medicine, Book 2, for discussion of TB skin

Cholera vaccine is not very effective and is rarely

required.

PROPHYLAXIS

Meningococcemia Meningococcemia

chemoprophylaxis

may

done

with rifampin, ciprofloxacin, or ceftriaxone. Each is 90-95% effective in reducing nasopharyngeal carriage of N. meningitidis. Remember that ciprofloxacin is not

routinely given to children or pregnant women (possible cartilage damage). Ceftriaxone is usually reserved for pregnant women. Health care workers do not receive chemoprophylaxis unless they had direct contact with the index patient's secretions (e.g., mouth-to-mouth resuscita tion, airway suctioning, or intubation).

Travelers' Diarrhea Travelers' diarrhea (TD): Educate patients on what to

testing.) Interferon-gamma-releasing assays (IGRAs) are not affected by BCG.

first place. When traveling in a country where it may

Japanese encephalitis vaccine is recommended for

occur, they should:

travelers who plan to stay a long time in rural Asia.

avoid so they do not contract travelers' diarrhea in the

•Not drink the local untreated water or eat ice, including

Rabies vaccine is discussed in the section on rabies

mixed alcoholic drinks with ice

disease (page 2-43). Preexposure vaccination is recom

•Ensure the water or ice is either boiled or filtered first

mended for those at occupational risk and for travelers

• Remember that dishes are washed in local water, so

(and especially their children) planning extended stays in areas where dog rabies is enzootic.

drink from the can with a straw, instead of from a glass •Avoid fresh fruits (but peeled ones are safe, like apples), vegetables, and meat salads, like tuna, as well as condiments, such as salsas

FOR FURTHER READING

FOR FURTHER READING [Guidelines in blue]

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BCG vaccine is used to prevent which illness? Is it used for this purpose in the U.S.?

•

Atkinson TP. Immune deficiency and autoimmunity. Curr Opin Rheumatol. 2012 Sep;24(5):515-52 l.

Can IGRA tests distinguish patients with BCG vaccination vs. those with active tuberculosis?

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Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin lmmunol. 2008

What are the contraindications to receiving the smallpox vaccine?

Feb; 121 (2 Suppl):S388-392; quiz S4 I 7.

Know the recommendations for prophylaxis and

Fishman JA, Issa NC. Infection in organ transplantation: risk factors and evolving patterns of infection. Infect Dis Clin

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HOST DEFENSE

North Am. 20 l 0 Jun;24(2):273-283.

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Gee K, Guzzo C, et al. The IL-12 family of cytokines in

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Fancy hotels do not guarantee healthy food and water. Carbonated drinks and hot tea or coffee are usually safe.

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Prophylactic antibiotics are justified for patients with

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immunodeficiencies, severe manifestations, or history of

J Chemother. 20I0Feb;22(1):5-12.

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Pan-Hammarstri:im Q, Hammarstri:im L. Antibody deficiency diseases. Eur J Immunol. 2008;38:327-333.

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Ciprofloxacin 500 mg qd

•

Rifaximin 200 mg qd or bid

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Bismuth subsalicylate 2 tablets chewed qid

For self-treatment once travelers' diarrhea is acquired,

Rosenzweig SD, Holland SM. Recent insights into the patho

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day, bloody or mucopurulent stools, or fever should be treated with I of the following: •

•

r i h

Ciprofloxacin 500 mg bid x 1-2 days Norfloxacin 400 mg bid x 3 days Azithromycin 1,000 mg x I dose Rifaximin 200 mg tid x 3 days

The 3-day regimens can be abbreviated to I day if the diarrhea has completely ceased after a day of treatment. Loperamide can be used cautiously with the antibiotics but should not be used alone as a form of treatment in severe disease.

Malaria

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2011 ;52:e56--e93.

ANTIBIOTIC THERAPY Abramowicz M, Zuccotti G, ct al. Antifungal drugs. Treat Guide! Med lei/. 2012 Aug;10(120):61--68; quiz 69-70. Baltz RH. Daptomycin: mechanisms of action and resistance, and biosynthetic engineering. Curr Opin Chem Biol. 2009 Apr;13(2): 144-151.

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Rybak M, Lomacstro B, et al. Therapeutic monitoring of

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American Society of Health-System Pharmacists, the Infec

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tious Diseases Pharmacists. Aln J Healrh Sys/ Phann. 2009 Jan I ;66( I):82-98.Erratum in: Am J Health Srst Phann. 2009 May 15;66( 10):887.

Kanoh S, Rubin BK. Mechanisms of action and clinical appli cation of macrolides as immunomodulatory medications. Clin Microbiol Rev. 20 I0 Jul;23(3):590-615.

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Shulman ST, Bisno AL. ct al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society or America. Cli11 !11fec1 Dis. 2012

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Chapman SW, Dismukes WE, et al. Clinical practice guide lines !or the management orblastomycosis: 2008 update by the Infectious Diseases Society of America. Cli11 /11fect Dis. 2008 Jun 15;46(12):1801-1812.

Taylor Z, Nolan CM, el al. Controlling tuberculosis in the United States. Recommendations Ji·om the American Thoracic Society, CDC, and the lnlectious Diseases Society of America. : 05 Nov 4;54(RR-l 2):1-81. Erratum MMWR Reco111111 Rep. W in: MMWR Iv/orb Morla/ Wk/I' Rep. 2005 Nm I 8;54( 45): 1161.

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Slack A. Leptospirosis. Aust Fam Physician. 20 JO

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Pappas PG, Kauffo1an CA, ct al; Clinical practice guidelines lor the management of candidiasis: 2009 update by the lnlec tious Diseases Society of America. Cli11 !11/ect Dis. 2009 Mar I ;48(5):503-535. Perlect JR, Dismukes WE, ct al. Clinical practice guidelines for the management or cryptococcal diseasc: 20 I 0 update by the infectious diseases society of America. Clin Infect Dis. 20I 0 Feb I ;50(3):291-322. Walsh TJ, Anaissie EJ, ct al. Treatment of aspcrgillosis: clini cal practice guidelines ot'the Infectious Diseases Society of America. Clin fl?fect Dis. 2008 Feb I :46(3):327-360.

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r i h

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