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Viral hemorrhagic fever with focus on Lassa fever
- 1. ALONGE RICHARD O. MD, B.sc Department of Pediatrics Kubwa General Hospital.
- 2. DEFINITION INCIDENCE/EPIDEMIOLOGY PATHOPHYSIOLOGY PRESENTATION/CASE DIFFERENTIAL DIAGNOSIS WORK UP (lab investigations, imaging studies) TREATMENT COMPLICATIONS conclusion
- 4. Viral hemorrhagic fever (VHF) refers to a group of illnesses caused by several distinct families of viruses that infect humans and non-human primates. VHF is a severe multi-system syndrome characterised by diffuse vascular damage. Bleeding often occurs and, depending on the virus, can be life threatening. Some VHF’s cause mild disease while others may cause severe disease and death.
- 8. Lassa fever is responsible for an estimated 100,000-300,000 infections per year, with 5,000 deaths. Cases have been reported throughout West Africa, particularly in Nigeria, Sierra Leone, Guinea, and Liberia. Other arenaviruses are responsible for sporadic VHF outbreaks throughout South America. Rift Valley fever (RVF) virus and Crimean-Congo hemorrhagic fever (CCHF) are responsible for intermittent epidemics in Africa (for RVF) and in areas of Africa, Asia, and Europe (for CCHF). HFRS due to Hantavirus infection continues to be an ongoing health concern, particularly in Asia, affecting up to 200,000 patients annually.
- 9. Ebola virus appears sporadically in endemic areas of the former Zaire and Sudan. Ebola virus also has been reported in Gabon, the Ivory Coast, and Uganda. Outbreaks appear to propagate in hospital settings, often involving health care providers. In the 2014-2016 outbreak centered in Guinea, Sierra Leone and Liberia, over 28,652 confirmed cases and 11,325 deaths were reported. Yellow fever continues to be a serious problem in tropical areas of South America and Africa, where vaccination is not widespread. World Health Organization 2013 estimates suggest that 84,000 to 170,000 cases per year occur in Africa.As of early 2017, an ongoing Yellow Fever outbreak in Brazil has led to >300 cases and 220 deaths.
- 10. Dengue HF is endemic in Southeast Asia, Africa, Central America, and South America. Recent statistical models suggest that as many as 390 million cases may occur annually, of which 96 million manifest clinically. In 2016, Rio de Janeiro recorded more than 25,000 cases of dengue infection (see the image below).
- 11. Case-fatality rates of patients with VHF vary from less than 10% (eg, in dengue HF) to as high as 90%, as has been reported in some filovirus outbreaks. The case-fatality rate for the 2014- 2016 West Africa Ebola outbreak was ~40%. Complications from VHF infection include retinitis, orchitis, hepatitis, transverse myelitis, and uveitis. In patients who recover from Lassa fever infection, deafness is the most common complication. Spontaneous abortion also is common. Renal insufficiency is associated with HFRS infection.
- 12. Following the recent West Africa Ebola outbreak, a post-Ebola syndrome has been reported, including myalgias, arthralgias, and visual problems including blindness and uveitis, as well as neurological findings including memory problems, lethargy and fatigue. Persistence of Ebola virus RNA has been noted in semen samples even 13 months after infection, although a recent statistical analysis suggests that semen from 50% of survivors will be Ebola-free at 4 months.
- 13. The primary defect in patients with viral hemorrhagic fever (VHF) is that of increased vascular permeability. Hemorrhagic fever viruses have an affinity for the vascular system, leading initially to signs such as flushing, conjunctival injection, and petechial hemorrhages, usually associated with fever and myalgias. Later, frank mucous membrane hemorrhage may occur, with accompanying hypotension, shock, and circulatory collapse. The relative severity of the clinical presentation may vary depending on the virus in question, amount, and route of exposure.
- 14. In acute disease, patients are extremely viremic, and messenger ribonucleic acid (mRNA) evidence of multiple cytokine activation exists. In vitro studies reveal these cytokines lead to shock and increased vascular permeability, the basic pathophysiologic processes most often seen in viral hemorrhagic fever infection. Another prominent pathologic feature is pronounced macrophage involvement.
- 15. Inadequate or delayed immune response to these novel viral antigens may lead to rapid development of overwhelming viremia. Extensive infection and necrosis of affected organs also are described. Hemorrhagic complications are multifactorial and are related to hepatic damage, consumptive coagulopathy, and primary marrow injury to megakaryocytes. Aerosol transmission of some viral hemorrhagic fever infections is reported among nonhuman primates and likely is a mode of transmission in patients with severe infection
- 16. Multisystem organ failure affecting the hematopoietic, neurologic, and pulmonary systems often accompanies the vascular involvement. Hepatic involvement varies with the infecting organism and is at times seen with Ebola, Marburg, RVF, CCHF, and yellow fever. Renal failure with oliguria is a prominent feature of HFRS seen in Hantavirus infection and may be seen in other VHFs as intravascular volume depletion becomes more pronounced. Bleeding complications are particularly prominent with Ebola, Marburg, CCHF, and the South American arenaviruses.
- 17. Although the pathophysiology of dengue infection is complex and incompletely understood, severe dengue infection can be differentiated from milder forms by the presence of increased vascular permeability. The greatest risk factor for severe dengue infection is secondary infection with a dengue serotype different from the initial dengue infection. This increased vascular permeability is thought to be secondary to widespread T-cell activation and apoptosis and is also thought to be related to a process known as antibody-dependent enhancement, best described as the balance between neutralizing versus enhancing antibodies after an initial dengue infection, which can contribute to the severity of secondary dengue infection.
- 18. History Obtain a detailed travel history, paying particular attention to recent travel to tropical or rural areas, such as Central or South America (yellow fever, arenaviruses), West Africa (Lassa fever), or to endemic portions of Central Africa (Ebola, Marburg, Rift Valley fever [RVF], Crimean-Congo hemorrhagic fever [CCHF]). Ask about contact with potential arthropod or rodent reservoirs.
- 19. Contacts of patients with known viral hemorrhagic fever (VHF), especially family members or health care workers caring for infected patients, are at risk for infection if appropriate barrier precautions are not used. Transmission of VHF has occurred from the reuse of unsterile needles and syringes used for treatment of infected patients. Transmission of VHF also has occurred to individuals handling the deceased in preparation for burial or to individuals involved in the slaughter of infected livestock (as in RVF or CCHF).
- 20. Incubation periods for VHF vary from 2-21 days. The initial symptoms correspond to development of viremia and include the following: High fever Headache Fatigue Abdominal pain Myalgias Prostration
- 21. In more advanced disease, signs and symptoms include the following: ◦ Hematemesis and bloody diarrhea ◦ Generalized mucous membrane hemorrhage ◦ Rash ◦ Altered mental status and cardiovascular collapse (preterminal events)
- 22. Physical Depending on the progress of the disease, patients with viral hemorrhagic fever (VHF) initially may present with minimal signs, suggesting a more benign viral syndrome. Maintain a high index of suspicion. As the disease progresses, more classic findings are present as follows: ◦ Fever ◦ Pharyngitis ◦ Conjunctival injection ◦ Nondependent edema ◦ Petechial or ecchymotic rash ◦ GI bleeding ◦ Hypotension and/or shock
- 23. Disseminated intravascular coagulopathy Emergent Management of Malaria Hemolytic Uremic Syndrome Leptospirosis Relapsing Fever Salmonella Infection Systemic Lupus Erythematosus Thrombotic Thrombocytopenic Purpura (TTP)
- 24. Other problems to be considered in the differential diagnosis include the following: Typhoid fever Shigellosis Meningococcemia Rickettsial infections Acute leukemia Idiopathic or thrombotic thrombocytopenic purpura
- 25. A complete blood count often indicates leukopenia and thrombocytopenia (these findings may not be present in Lassa fever) Significant electrolyte and metabolic disturbances have been reported in the recent Ebola virus disease outbreak, including hypokalemia, hypocalcemia, hyponatremia, elevated creatinine and elevated anion gap acidosis Elevated hepatic transaminases are observed in viral hemorrhagic fever (VHF) and are predictive of high mortality in Lassa fever infection Prothrombin time, activated partial thromboplastin time, international normalized ratio, and clotting times are prolonged. A disseminated intravascular coagulation profile including fibrinogen level, fibrin degradation products, and platelet count may be useful
- 26. Supportive care is based on the patient's physiologic condition. Because most patients requiring prehospital evaluation and transport are in the early stages of the disease, universal precautions should be adequate. In patients with respiratory symptoms (eg, cough, rhinitis), use face shields and high-efficiency particulate air (HEPA) filter masks. Fluid resuscitation and supportive care are the mainstays of emergency department therapy. Intravenous crystalloids, oxygen, and cardiac monitoring are the most appropriate initial steps in the treatment of patients in whom viral hemorrhagic fever (VHF) is suggested.
- 27. Other measures include the following: Administer blood and blood products as clinically indicated Avoid intramuscular injections and the use of aspirin or other anticoagulants Minimize invasive procedures because of the risk associated with viral transmission from sharp objects Minimize aerosol-generating procedures such as bilevel positive airway pressure (biPAP), intubation, bronchoscopy and sputum induction. Infection control measures include the following: Place patients in a single-patient room with a private bathroom Avoid entry of nonessential staff and visitors; facilities should maintain a log of all people entering the patient’s room All staff entering the room should wear appropriate personal protective equipment (PPE).
- 28. There’s been no drugs or vaccine for Ebola or Marburg as at yet, but research is still on going. For Lassa have been treated effectively with IV and oral ribavirin (Virazole). Other potential antiviral therapies against Lassa fever include novel benzimidazole compounds such as ST-193 and other related heterocyclic compounds. While some noted others have some vaccines, e.g Yellow fever, Dengue fever e.t.c
- 29. Treatment of hemorrhagic fever (Lassa fever) with renal syndrome • Treatment: Load 30 mg/kg IV (up to 2 g), THEN 16 mg/kg IV (up to 1 g) q6hr x4 days, THEN 8 mg/kg IV (up to 500 mg) q8hr x6 days • IV form available from CDC on compassionate basis • Prophylaxis: 500-600 mg PO q6hr x7-10 days Contraindicated in use with didanosine
- 31. Lassa fever Disease Importance of Topic Clinical Signs and symptoms Diagnosis and Treatment Preventing Lassa fever
- 32. A viral hemorrhagic fever caused by the Arenavirus Lassa, A single stranded RNA virus that is animal-bourne. This was discovered following the death of two nurses in Nigeria in 1969 and named after the town in Borno state, Nigeria, where it was first discovered. Transmitted from rodents to humans. The specis of rats transmitting this disease is prevalent in West Africa. (The multimammate rat’, mastomys species- complex), and is pread via their urine and droppings
- 33. There is secondary human to human transmission, via body fluids exchange or in hospitals, via reused needles or contaminated medical equipments. The virus can be transmitted through direct contact with there materials or via cuts and sores or via poorly stored food (as Mastomys rodents are home scavengers). It can also be airborne via inhalation of tiny particles in air contaminated with rodents excreta. Also since mastomys are consumed as food source, it may also occur via direct contact when they’re caught and prepared for food.
- 34. Its endemic in areas of West Africa including Nigeria, Liberia, Sierra leone and Guinea. Annual incidence of 100,000 to 300,000 with approximately 5,000 deaths in West Africa. Incubation period is 5-21days Its seasonal with clusters in late rainy and early dry season. Affecting all age groups and sexes.
- 35. There is a recent outbreak in Nigeria over the past weeks, which has claimed about 40 lives, with Edo state accounting for 22 of this. 18 of the 36 states in Nigeria have been affected by this and a total of 397 cases have been reported, out of which over 87 have been confirmed including cases in our very own Kubwa General Hospital in recent times.
- 36. Gradual fever onset Headache Malaise Other Non-specific symptoms Pharyngitis Myalgia, retro-sternal pain Cough Gastrointestinal symptoms Few have the Classic symptoms of ◦ Bleeding ◦ Neck/Facial swelling ◦ Shock
- 37. Case fatality of Hospitalized cases: 15-20% Its severe in pregnant women and their offspring. -Increase 3rd trimester mortality (>30%) -Increased fetal/neonatal mortality (>85%) Deafness is a common sequela, not related to severity of acute illness, maybe bilateral/unilateral and may persist for life in one-third of those affected.
- 38. Clinical diagnosis is often difficult ELISA (Enzyme-linked immunosorbent assays) for antigen, IgM, IgG Postmortem tissue immunohistochemistry Reverse transcription-PCR for research. Supportive Measures
- 39. Drug of Choice: Ribavirin ◦ Most effective when started within first 6days of illness. ◦ Its presently contraindicated in pregnancy but maybe warranted if mother is at risk. ◦ Doesn’t reduce incidence of severity of deafness. ◦ Side effects are: reversible mild hemolysis, headaches, and suppression of erythropioesis
- 40. Avoid contact with Mastomyces rodents and bush burning Store food properly in rodent-proof containers Keep homes clean and discourage rodent entry Using rodents as food source is discouraged. Clean traps and dispose carcass neatly. Prevent person-person transmission via use of PPEs (Masks, Gloves, Gowns and Goggles) especially for health workers Sterilise equipment after use Isolate infected patients from contacts.
- 41. Amorosa V, MacNeil A, McConnell R, Patel A, Dillon KE, Hamilton K, et al. Imported Lassa fever, Pennsylvania, USA, 2010. Emerg Infect Dis. 2010 Oct. 16 (10):1598- 600. [Medline]. [Full Text]. Chevalier MS, Chung W, Smith J, Weil LM, Hughes SM, Joyner SN, et al. Ebola virus disease cluster in the United States--Dallas County, Texas, 2014. MMWR Morb Mortal Wkly Rep. 2014 Nov 21. 63 (46):1087-8. [Medline]. Centers for Disease Control and Prevention. Ebola (Ebola Virus Disease). CDC. Available at https://www.cdc.gov/vhf/ebola/about.html. February 18, 2016; Accessed: December 23, 2016. Sissoko D, Duraffour S, Kerber R, Kolie JS, Beavogui AH, et al. Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors: a longitudinal analysis and modelling study. Lancet Glob Health. 2017 Jan. 5 (1):e80-e88. https://emedicine.medscape.com/article/830594- medication#showall