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Overview of Viral Hemorrhagic Fevers
65 Overview of Viral Hemorrhagic Fevers C. J. PETERS SHERIF R. ZAKI
INTRODUCTION Several viruses regularly cause a syndrome that is referred to as hemorrhagic fever (HF). They belong to four different families of RNA viruses, but all are lipid enveloped and zoonotic in their maintenance strategies. The taxonomy is helpful in understanding their natural history and pathogenesis but does not accurately predict the clinical syndromes following infection with a given family member. For example, virtually all the arenaviruses are maintained by chronic infection of a single rodent host and spread to humans by aerosols of rodent excreta and related mechanisms, with the details of the human epidemiology mainly predictable by rodent dynamics and human behavior. However, Tamiami and Whitewater Arroyo viruses are North American arenaviruses not associated with any disease, and the best known American arenavirus is lymphocytic choriomeningitis virus, which came to the Americas when the common house mouse, Mus musculus, was introduced in post-Columbian times. Lymphocytic choriomeningitis virus infection of humans mainly causes subclinical infection, acute undifferentiated febrile disease, and febrile central nervous system illnesses such as aseptic meningitis, but two cases have resembled the HF syndrome. AGENT The HF viruses occur worldwide (Table 65-1) and the geographic site of infection is an important determinant of the risk to an individual patient. The geography and knowledge of the incubation period are important in suspecting an exported viral HF. The syndrome characteristically begins with fever, myalgia, and malaise, which then progress to prostration, gastrointestinal and other system involvement, and signs of vascular damage. Involvement of the vascular system is usually manifest by vascular dysregulation (mild hypotension, postural hypotension, flushing, and injected conjunctivae), vascular damage (nondependent edema and organ dysfunction), and hemorrhage. Hemorrhage is usually diffuse in microvascular beds throughout the body and occurs particularly in patients with thrombocytopenia or marked platelet dysfunction. Many patients have little or no bleeding, but some present with extensive cutaneous and mucosal hemorrhage. Severe cases will have shock, central nervous system
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involvement, or extensive hemorrhagic phenomena. The clinical findings in the different HFs vary in a characteristic way for each virus, but any individual patient is difficult to classify without virologic diagnosis (Tables 65-2 and 65-3). The detailed manifestations of each VHF are often based on fragmentary clinical observations and lack proper appreciation of the entire spectrum, which in some cases includes such manifestations as pancreatitis. PATHOGENESIS Although there are common themes, the different viruses also differ in their pathology and pathogenesis (Table 65-4). Usually, hemorrhages are present in many organs, and effusions are commonly found in serous cavities, but they may be minimal or absent in some patients. There is widespread necrosis, which may be present in any organ system and that varies from modest and focal to massive in extent. Liver and lymphoid systems are usually extensively involved, and the lung regularly has varying degrees of interstitial pneumonitis, diffuse alveolar damage, and hemorrhage. Acute tubular necrosis and microvascular thrombosis may also be seen. The inflammatory response is usually minimal. These changes, which may be a direct effect of viral infection or a consequence of cytokine secretion, have considerable variation among the different viruses (see Table 65-4). DIAGNOSIS Correct diagnosis in most of the diseases depends on demonstration of the infecting virus or one of its products in acute serum samples. Viral antigens are readily demonstrable, and often an antigen detection enzyme-linked immunosorbent assay (ELISA) is the best test for identifying patients because of its rapidity and robustness; it is particularly likely to be positive in the more severely ill patient, who is in greatest need of therapy and who may provide the greatest risk of dissemination. Reverse transcription-polymerase chain reaction (RT-PCR) is usually more sensitive but also more subject to artifact and contamination. RT-PCR has a unique role in providing an amplicon that can be sequenced for genetic analysis, although this very genetic variation may be a source of difficulty in ensuring that appropriate primers are applied to unknown samples. In general, viremia and antigenemia are readily detected during the acute phase and disappear as the patient improves. RT-PCR is usually positive during the same period and perhaps 1 or 2 days longer. IgM antibodies may be detectable during illness and usually appear early in convalescence, providing a sensitive, specific method of diagnosis, particularly if they are measured by an IgM capture ELISA technique. Diagnosis of initial patients in any outbreak, particularly if there are unusual features, benefits from study of virus isolates and classic serologic responses, particularly the neutralization test, animal pathogenesis, and genomic analysis. Most of the viruses are hazardous and should only be isolated or studied under BSL4 containment. Hantaviruses are an exception to the generalizations: The patients typically present with an ongoing immune response and are best diagnosed with the IgM capture ELISA; virus isolation is difficult, but RT-PCR on acute blood clot may give valuable genetic information about the infecting virus.
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Bolivian HF
Venezuelan HF
Brazilian HF
Lassa fever
Machupo
Guanarito
Sabia
Lassa
CrimeanCongo HF
Hemorrhagic fever with renal syndrome (HFRS)
CrimeanCongo HF
Hantaan, Seoul, Puumala, and others
Rift Valley fever
Argentine HF
Arenaviridae Junin
Bunyaviridae Rift Valley fever
Disease
Worldwide depending on rodent reservoirs
Africa, Middle East, Balkans, southern Russia, western China
Sub-Saharan Africa
Portuguesa state, Venezuela Rural area near Saõ Paulo, Brazil West Africa
Beni Department, Bolivia
Argentine pampas
Geography
Horizontal infection in a single rodent genus or species typical of the virus. Viruses associated with HFRS have been obtained from Muridae (subfamilies Murinae or Avicolinae) rodents (rats, mice, and voles).
Vertical infection of floodwater Aedes mosquitoes. Epidemics occur from horizontal transmission by many different mosquito species between domestic animals, particularly sheep and cattle. Tick–mammal–tick infection. Vertical infection occurs in ticks. Hyalomma ticks are thought to be the natural reservoir, but other genera may become infected and transmit.
Chronic infection of field rodent, Zygodontomys brevicauda. Presumably chronic infection of unidentified rodents. Chronic infection of rodents of the genus Mastomys.
Chronic infection of small field rodent, Calomys musculinus. Chronic infection of small field rodent, Calomys callosus.
Vector/Reservoir
Geography and Epidemiology of Hemorrhagic Fever Viruses
Virus
Table 65-1
Continued
Tick bite; squashing ticks; and exposure to aerosols or fomites from slaughtered cattle and sheep. (Domestic animals do not show illness but may become infected when transported to market or when held in pens for slaughter.) Nosocomial epidemics observed on numerous occasions. Aerosols from freshly shed urine of infected rodents. Some infections may be acquired from secondary aerosols or droplets from previously shed rodent excreta and secreta or from rodent bites. Interhuman transmission never documented.
Humans acquire virus by mosquito bite; contact with blood of infected sheep, cattle, or goats; and aerosols generated from infected domestic animal blood. No interhuman transmission observed.
Single infection observed in nature: little information on epidemiologic potential. The reservoir rodent is very common in Africa, and the disease is a major cause of severe febrile illness in West Africa. Spread to man occurs by aerosols and by capturing the rodent for consumption, as well as person-to-person transmission. Lassa fever is the most commonly exported HF.
Infects agricultural workers disproportionately. Major transmission in fall: Aerosol transmission to humans. Rural residents and farmers main target; rodent can invade towns to cause epidemics. Aerosol transmission to humans. Interhuman transmission not usual, but occurs. Rural residents in recently developed area with small farms.
Human Infection
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Disease
Dengue HF (DHF), dengue shock syndrome (DSS)
Yellow fever
HF, Hemorrhagic fever.
Al Kumrah
Kyasanur KFD Forest disease (KFD) Omsk HF OHF (OHF)
Dengue (types 1–4)
Flaviridae Yellow fever
Poorly understood cycle involving ticks, voles, muskrats, and possibly water-borne and mosquito transmission. Unknown. Surmised to involve tick–domestic livestock–tick cycle by analogy to genetically related tick-borne flaviviruses.
Western Siberia
Middle East? Africa?
Tick–vertebrate–tick
Maintained by Ae. aegypti–human– Ae. aegypti transmission with frequent geographic transport of viruses by travelers.
Karnataka state, India
Tropics and subtropics worldwide
Mosquito–monkey–mosquito maintenance with occasional human infection when unvaccinated humans enter forest. Large epidemics among humans with Aedes aegypti as mosquito vector.
Unknown
Africa, ?Philippines
Africa, South America
As for hantaviruses causing HFRS. All viruses associated with HPS have come from Muridae (subfamily Sigmodontinae) rodents, if the reservoir is known.
Vector/Reservoir
Americas
Geography
Geography and Epidemiology of Hemorrhagic Fever Viruses—cont’d
Sin Nombre, Hantavirus Black pulmonary Creek Canal, syndrome (HPS) Bayou, and others Filoviridae Marburg, Marburg HF Ebola Ebola HF
Virus
Table 65-1
Transmitted to humans working in livestock-related occupations by unknown route. Genetically related to KFD virus.
Mosquito infection of humans entering forest and encountering infected sylvatic vector. Emergence of epidemics into African savannas via specific Aedes mosquito vectors. In cities or villages, interhuman transmission by Ae. aegypti. Fully developed cases are no longer viremic and direct interhuman transmission not believed to be a problem although the virus is highly infectious (including aerosols) in the laboratory. DHF/DSS is a problem in areas where multiple dengue viruses are being transmitted. With the increased worldwide distribution of Ae. aegypti and movement of dengue viruses in travelers, this zone is enlarging. The disease was first noted in Southeast Asia but is now common in the Americas and the Caribbean, as well as the Pacific rim countries. Most infections occur from tickbite acquired in rural areas of the endemic zone. Monkey die offs may accompany increased virus activity. Few cases in recent years.
Infection of index case occurs from unknown source. Infected nonhuman primates sometimes provide link to humans. Later spread among human or nonhuman primates by close contact with another case. Aerosol transmission suspected in one captive monkey outbreak.
As for hantaviruses causing HFRS. Entering abandoned, closed buildings may be a particular risk in some settings. Interhuman transmission rarely observed with Andes virus
Human Infection
729
3–8
Kyasanur Forest disease (KFD) Omsk HF
50% of nonimmune <5% of heterologous flavivirus immune 0.007% of nonimmune and 1.0% of heterologous immune Variable
High (particularly Zaire subtype of Ebola)
1/20 Puumala virus Very high
20%–100% >3/4 Hantaan virus
≈1%
Mild infections probably common
Most (>1/2) result in disease
Case Infection Ratio
HF, Hemorrhagic fever. *Uncomplicated disease; incubation for HF may differ.
3–15*
3–6
3–16
7–28
3–12 9–35
2–5*
Dengue HF (DHF), dengue shock syndrome (DSS)
Flaviviridae Yellow fever
Hantavirus pulmonary syndrome Filoviridae Marburg or Ebola HF
Crimean-Congo HF HF with renal syndrome
Bunyaviridae Rift Valley fever
5–16
7–14
Arenaviridae South American HF
Lassa fever
Incubation Period (Days)
Typical cases have hypotension, shock, obvious bleeding, and neurologic symptoms such as dysarthria and intention tremor. Some cases have virtually pure neurologic syndrome. Prostration and shock; fewer hemorrhagic or neurologic manifestations than South American HF except in severe cases. Thrombocytopenia less common and less severe. Deafness develops in convalescence in 20%.
Characteristic Features
0.5%–9.0%
Untreated, 10%–15% Treated, < 1%
20%–50%
25%–90%
Typical biphasic disease with a febrile or hemorrhagic period often followed by CNS involvement. Similar to tick-borne encephalitis except hemorrhagic manifestations are not characteristic of first phase of tick-borne encephalitis.
High fever for 3–5 days with the development of shock lasting 1–2 days. DHF is not equated to DSS. DSS is the most dangerous manifestation and is due to an acute vascular leak. Attack rates, mortality quite variable with epidemic virus strain and surveillance.
Acute febrile period with defervescence accompanied in severe cases by jaundice and renal failure.
Most severe of the HFs. Marked weight loss and prostration. Maculopapular rash common. Patients have had late sequelae (hepatitis, uveitis, orchitis) often with virus isolation from biopsy or aspiration.
Severe disease associated with bleeding, shock, anuria, and icterus. Encephalitis and retinal vasculitis also occur, but without overlap with HF syndrome. 15%–30% Most severe bleeding and ecchymoses of all the HFs. 5%–15% Febrile stage followed by shock and renal failure. Bleeding during febrile stage, Hantaan virus shock, and renal failure. Puumala virus infections have a similar course but <1% Puumala virus are much milder. 40%–50% Febrile stage followed by acute pulmonary edema and shock. Manifestations largely limited to thoracic cavity.
≈50%
2%–15%
15%–30%
Case Fatality
Clinical Features of the Viral Hemorrhagic Fevers
Disease
Table 65-2
730 +++ + +++ +++ +++ ++ +++ ++ +++ ++
+/S
+++
+++
+++ +
++
+++ ++ ++
Thrombocytopenia
+++
Hemorrhage
N/⇓⇓ ⇑⇑ ⇓⇓
⇑⇑⇑ ⇑⇑
⇓⇓/⇑
⇓⇓/⇑⇑
N
⇓⇓⇓
Leukocyte Count
0 +++ 0
+++
0 0
0
0
++
0
Rash
+++ + 0
++
0 0
++
++
0
0
Icterus
++ 0 0
0
+++ +
0
+
0
0
Renal Disease
+ + ++
+
+ +++
+
0
+
+
Pulmonary Disease
0 0 0
0
0 0
0
0
+
+++
Tremor, Dysarthria
++ + E
++
+ +
+
E
+/S
++
0 0 0
+
0 0
0
0
++
0
Encephalopathy Deafness
0 0 Retina
Uveitis
0 0
0
Retina
0
0
Eye Lesions
DHF, dengue hemorrhagic fever; DSS, dengue shock syndrome; E, develop true encephalitis either after HF (KFD, Omsk) or in other patients (Rift Valley fever); HF, hemorrhagic fever; HFRS, hemorrhagic fever with renal syndrome; HPS, Hantavirus pulmonary syndrome; KFD, Kyasanur Forest disease; N, normal; OHF, Omsk hemorrhagic fever; S, characteristic, seen in severe case; +, occasional or mild; + +, commonly seen, may be severe; + + +, characteristic and usually marked; ⇑, occasionally or mildly increased; ⇓⇓, decreased; ⇑⇑, commonly increased, may be marked; ⇑⇑⇑, characteristically increased and usually marked; 0, absent.
Arenaviridae South American HF Lassa fever Bunyaviridae Rift Valley fever CrimeanCongo HF HFRS HPS Filoviridae Marburg and Ebola HFs Flaviviridae Yellow fever DHF, DSS KFD, OHF
Disease
Table 65-3 Specific Clinical Findings in Different Hemorrhagic Fevers
Overview of Viral Hemorrhagic Fevers
Table 65-4
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Viral Tropism and Pathologic Features of Viral Hemorrhagic Fevers
Disease Arenaviridae Argentine HF Bolivian HF Venezuelan HF Lassa fever Bunyaviridae Rift Valley fever (RVF) Crimean-Congo HF Hemorrhagic fever with renal syndrome (HFRS) Hantavirus pulmonary syndrome (HPS) Filoviridae Ebola HF Marburg HF Flaviviridae Yellow fever Dengue HF, dengue shock syndrome Kyasanur Forest disease (KFD) Omsk HF
Pathologic Features* Multifocal hepatocellular necrosis with minimal inflammatory response, interstitial pneumonitis, myocarditis, and lymphoid depletion; extensive parenchymal cell and reticuloendothelial infection, more than morphologic lesions would suggest.
Widespread hepatocellular necrosis and hemorrhage, sometimes with midzonal distribution, minimal inflammatory response, disseminated intravascular coagulation, lymphoid depletion; RVF antigens in few individual hepatocytes; encephalitis and retinal vasculitis also seen. Widespread hepatocellular necrosis and hemorrhage with minimal or no inflammatory cell response and lymphoid depletion; hepatic and endothelial cell infection and damage. Retroperitoneal edema in severe HFRS, mild to severe renal pathologic changes; congestion and hemorrhagic necrosis of renal medulla, right atrium of the heart, and anterior pituitary; extensive endothelial infection mainly in renal and cardiac microvasculature. Large bilateral pleural effusions and severely edematous lungs, mild to moderate interstitial pneumonitis, immunoblasts, and atypical lymphocytes in lymphoid tissues and peripheral blood; extensive infection of endothelial cells in pulmonary microvasculature. Extensive and disseminated infection and necrosis in major organs such as liver, spleen, lung, kidney, skin, and gonads; extensive hepatocellular necrosis associated with formation of characteristic intracytoplasmic viral inclusions; lymphoid depletion, microvascular infection, and injury. Similar to Ebola HF. Midzonal hepatocellular necrosis; minimal inflammatory response; Councilman bodies and microvesicular fatty change; hepatocellular and Kupffer cell infection; lymphoid necrosis (nodes, spleen); focal myocarditis; acute renal tubular necrosis. Centrilobular and midzonal hepatocellular necrosis with minimal inflammatory response; Councilman bodies and microvesicular fatty change; hyperplasia of mononuclear phagocytic cells in lymphoid tissues and atypical lymphocytes in peripheral blood; widespread infection of mononuclear phagocytic and endothelial cells. Focal hepatocellular degeneration, fatty change, and necrosis; pulmonary hemorrhage, depletion of malpighian follicles, sinus histiocytosis, erythrophagocytosis, mild myocarditis, and encephalitis. Little known; scattered focal hemorrhage, interstitial pneumonia, and normal lymphoid tissues.
HF, Hemorrhagic fever. *These features represent the characteristic pathologic findings in the different viral HFs. More general findings seen to variable degrees in all HFs are not listed.
Ideally, blood samples from HF patients should be collected early in the course of illness, and both serum and blood clot should be frozen as soon as possible. A second sample should be obtained before discharge or death for comparative serology, and this can be supplemented by a later follow-up blood sample. In fatal cases, a full autopsy should be performed with a complete set of organs collected in formalin for diagnostic studies; spleen, liver, and lymph nodes should be collected frozen for virus isolation. Classic histopathology is often useful in suspecting yellow fever, Rift Valley fever, or a filovirus infection and in diagnosing some of the confounding diseases. Immunohistochemistry on fixed tissues can usually make a definitive diagnosis possible. Precautions appropriate to each virus should be taken to prevent infection while processing samples or performing a necropsy. Frozen samples should be appropriately packed and, whenever possible, shipped on dry ice, although diagnoses can sometimes be made on mishandled specimens. The receiving laboratory should be advised of the shipment, its estimated time of arrival, and the waybill number to allow for tracing the materials if, as
often happens, there is a delay en route. Diagnostic expertise and consultation are available from several laboratories. TREATMENT AND PREVENTION Approaches to the prevention and treatment of the viral HFs vary with the infecting virus (Table 65-5). Barrier nursing and avoidance of parenteral exposures of hospital staff are important in management of all these diseases, but they are particularly important in Crimean-Congo HF and the filovirus diseases because of the regularity with which nosocomial transmission has been seen. The general principles of therapy are similar for all the HFs and require rapid atraumatic hospitalization, careful maintenance of fluid balance to avoid overhydration in the face of fragile systemic and pulmonary capillary beds, as well as probable myocardial compromise, management of the bleeding diathesis according to the usual principles, and the specific therapy appropriate to each disease (see Table 65-5). It is extremely important to exclude or empirically treat the conditions that may be most
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HF, Hemorrhagic fever.
Tick-borne flaviviruses
Dengue HF
Flaviviridae Yellow fever
Hantavirus pulmonary syndrome Filoviridae Ebola/Marburg HF
HF with renal syndrome (HFRS)
Crimean-Congo HF
Bunyaviridae Rift Valley fever
Lassa fever
Bolivian HF
Arenaviridae Argentine HF
Disease
Vaccine is probably the safest and most effective in the world; control of Aedes aegypti would eliminate urban transmission but sylvatic transmission remains. Reduction of dengue transmission by A. aegypti control; investigational vaccines will probably be available soon; possibly useful in travelers but may be limited in solving hyperendemic dengue transmission that leads to dengue HF. Avoidance of ticks; vaccination; postexposure prophylaxis with virus-specific IgG.
Barrier nursing and needle sterilization in African hospitals particularly important; avoid close contact with suspected patients; do careful evaluation of sick nonhuman primates.
Rodent avoidance useful; care should be taken before entering or cleaning closed buildings with potential rodent infestations.
Vaccination of domestic livestock prevents epizootics/ epidemics but not sporadic, endemic infections of humans; human vaccine safe and effective but limited supply; veterinarians and virology workers in subSaharan Africa candidates for vaccine. Tick avoidance; no slaughter of acutely infected animals (healthy but viremic and therefore an undetected threat); barrier nursing of suspected patients particularly important. Rodent control and avoidance impractical in most cases; investigational vaccines deserve further evaluation.
Safe, effective vaccine used for high-risk residents of endemic area. Elimination of specific reservoir rodents from towns practical and effective; sporadic cases due to exposure outside towns, person-to-person transmission in families and institutions cannot be prevented; Argentine HF vaccine protects experimental animals against Bolivian virus. None; intensive village-based rodent control may reduce risk.
Prevention
Table 65-5 Prevention and Treatment of Viral Hemorrhagic Fevers
Supportive care.
Supportive care effective and greatly reduces mortality.
None other than supportive.
None other than supportive, which may be of limited utility; antiviral therapies urgently needed.
Early diagnosis and supportive care lifesaving; ribavirin has positive effect during initial 4 days illness and should be used in severe HFRS if available. Early diagnosis and supportive care potentially lifesaving; avoidance of hypoxia and excessive hydration coupled with careful management of shock.
Ribavirin should be used based on in vitro sensitivity and on uncontrolled South African experience.
Ribavirin and antibody therapy should be tried in HF patients based on studies in experimental animals.
Ribavirin effective in reducing mortality; use in higher risk patients, e.g., if aspartate transaminase >150 U/L.
Infusion of convalescent plasma during first 8 days of illness reduces mortality from 15%–30% to <1%. Ribavirin likely to be effective and should be used in this and other arenavirus diseases unless proven effective alternative therapy available.
Treatment
Overview of Viral Hemorrhagic Fevers
important in the differential diagnosis, particularly malaria, rickettsial infections, leptospirosis, relapsing fever, typhoid, and shigellosis. SUGGESTED READING Hemorrhagic Fevers Management of patients with suspected viral hemorrhagic fever. MMWR 37:1–15, 1988. Peters, CJ: Pathogenesis of viral hemorrhagic fevers. In Nathanson N, Ahmed R, Gonzalez-Scarano F, et al (eds): Viral Pathogenesis. Philadelphia, Lippincott-Raven, 1996. Peters CJ, Jahrling PB, Khan AS: Management of patients infected with high-hazard viruses. Arch Virol 11(suppl):1–28, 1996. Peters, CJ, Zaki SR, Rollin PE: Viral hemorrhagic fevers. In Mandell GL (ed): Atlas of Infectious Diseases, vol 8, Fekety R (ed). Philadelphia, Current Medicine, 1997, pp 10.1–10.26. Smorodintsev AA, Kazbintsev LI, Chudakov VG: Virus Hemorrhagic Fevers. Jerusalem, Israel Program for Scientific Translations, 1964. Update: Management of patients with suspected viral hemorrhagic fever— United States. MMWR 44:475–479, 1995. Zaki SR, Peters CJ: Viral hemorrhagic fevers. In Connor DH, Schwartz DA, Chandler FW (eds): Diagnostic Pathology of Infectious Diseases. Norwalk, Conn, Appleton & Lange, 1997, pp 347–364.
Arenaviridae Barry M, Russi M, Armstrong L, et al: Brief report: Treatment of a laboratory-acquired Sabiá virus infection. N Engl J Med 333:294–296, 1995. Enria D, Maiztegui JI: Antiviral treatment of Argentine hemorrhagic fever. Antiviral Res 23:23–31, 1994. Fulhorst, C, Ksiazek TG, Mills, JN, et al: Venezuelan hemorrhagic fever: Clinical and epidemiologic studies of 165 cases. Clin Infect Dis 26:308–313, 1998. Johnson KM, Halstead SB, Cohen SN: Hemorrhagic fevers of Southeast Asia and South America: A comparative appraisal. Prog Med Virol 9:105–158, 1967. Johnson KM, McCormick JB, Webb PA, et al: Clinical virology of Lassa fever in hospitalized patients. J Infect Dis 155:456–464, 1987. McCormick JB, King IJ, Webb PA, et al: A case–control study of the clinical diagnosis and course of Lassa fever. J Infect Dis 155:445–455, 1987. Molinas FC, de Bracco MME, Maiztegui JI: Hemostasis and the complement system in Argentine hemorrhagic fever. Rev Infect Dis 11(suppl 4): 762–767, 1989. Peters CJ: Arenaviruses. In Richman DD, Whitley RJ, Hayden FG (eds): Clinical Virology. Washington, DC, ASM Press, 2002, pp 949–969. Peters CJ, Kuehne RW, Mercado RR, et al: Hemorrhagic fever in Cochabamba, Bolivia. Am J Epidemiol 99:425–433, 1971.
Bunyaviridae Al Hazmi M, Ayoola EA, Abdurahman M, et al: Epidemic Rift Valley fever in Saudi Arabia: A clinical study of severe illness in humans. Clin Infect Dis 36:245–252, 2003. Bruno P, Hassell LH, Brown J, et al: The protean manifestations of hemorrhagic fever with renal syndrome. A retrospective review of 26 cases from Korea. Ann Intern Med 113:385–391, 1990. Bui-Mansfield LT, Torrington KG, Kim T: Acute pancreatitis in patients with hemorrhagic fever with renal syndrome. Military Med 166:167–170, 2001.
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Duchin JS, Koster F, Peters CJ, et al: Hantavirus pulmonary syndrome: A clinical description of 17 patients with a newly recognized disease. N Engl J Med 330:949–955, 1994. Huggins JW, Hsiang CM, Cosgriff TM, et al: Prospective, double-blind, concurrent, placebo controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis 164:1119–1127, 1991. Ketai LH, Williamson MR, Telepak RJ, et al: Hantavirus pulmonary syndrome (HPS): Radiographic findings in 16 patients. Radiology 191:665–668, 1994. Laughlin LW, Meegan JM, Strausbaugh LJ, et al: Epidemic Rift Valley fever in Egypt: Observations of the spectrum of human illness. Trans R Soc Trop Med Hyg 73:630–633, 1979. Peters CJ, Khan AS: Hantavirus pulmonary syndrome: The new American hemorrhagic fever. Clin Infect Dis 34:1224–1231, 2002. Peters CJ, LeDuc JW: Bunyaviridae: Bunyaviruses, phleboviruses, and related viruses. In Belshe R (ed): Textbook of Human Virology, ed 2. St. Louis, Mo, Mosby-Year Book, 1991, pp 571–614. Swanepoel R, Gill DE, Shepherd AJ, et al: The clinical pathology of Crimean-Congo hemorrhagic fever. Rev Infect Dis 11(suppl 4): S794–S800, 1989. Swanepoel R, Shepard AJ, Leman PA, et al: Epidemiologic and clinical features of Crimean-Congo hemorrhagic fever in South Africa. Am J Trop Med Hyg 6:120–132, 1987. Symposium on Epidemic Hemorrhagic Fever, May 1954. Am J Med 16:617–709, 1954. Zaki SR: Hantavirus-associated diseases. In Connor DH, Schwartz DA, Chandler FW (eds): Diagnostic Pathology of Infectious Diseases. Norwalk, Conn, Appleton & Lange, 1997, pp 347–364. Zaki SR, Greer PW, Coffield LM, et al: Hantavirus pulmonary syndrome: Pathogenesis of an emerging infectious disease. Am J Pathol 146:552–579, 1995.
Filoviridae Ebola haemorrhagic fever in Zaire, 1976. Report of an international commission. Bull World Health Organ 56:271–293, 1978. Martini GA, Siegert R (eds): Marburg Virus Diseases. Berlin, Springer-Verlag, 1971. Pattyn SR (ed): Ebola Virus Haemorrhagic Fever. Amsterdam, Elsevier/North-Holland, 1978. http://www.itg.be/ebola. Peters CJ, Leduc JW: An introduction to Ebola: The virus and the disease and articles in the supplement. J Infect Dis 179(suppl 1), 1999. http://www.journals/uchicago.edu/JID/journal/contents/v179nS1.html. WHO/International Study Team: Ebola hemorrhagic fever in Sudan, 1976. Bull World Health Organ 56:247–270, 1978.
Flaviviridae Burke DS, Monath TP: Flaviviruses. In Knipe DM, Howley PM (eds): Fields’ Virology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 1043–1126. Halstead SB: Antibody, macrophages, dengue virus infection, shock, and hemorrhage: A pathogenic cascade. Rev Infect Dis 11(suppl 4): S830–S839, 1989. Halstead SB: Dengue and dengue hemorrhagic fever. In Feigin RD, Cherry JD (eds): Textbook of Pediatric Infectious Disease. Philadelphia, Saunders, 1987, pp 1510–1521. Kerr JA: The clinical aspects and diagnosis of yellow fever. In Strode GR (ed): Yellow Fever. New York, McGraw-Hill, 1951, pp 385–425. Touatre J: Yellow fever. Clinical notes (C Chassaignac, trans). New Orleans Med Surg J, 1898.
INTRODUCTION Several viruses regularly cause a syndrome that is referred to as hemorrhagic fever (HF). They belong to four different families of RNA viruses, but all are lipid enveloped and zoonotic in their maintenance strategies. The taxonomy is helpful in understanding their natural history and pathogenesis but does not accurately predict the clinical syndromes following infection with a given family member. For example, virtually all the arenaviruses are maintained by chronic infection of a single rodent host and spread to humans by aerosols of rodent excreta and related mechanisms, with the details of the human epidemiology mainly predictable by rodent dynamics and human behavior. However, Tamiami and Whitewater Arroyo viruses are North American arenaviruses not associated with any disease, and the best known American arenavirus is lymphocytic choriomeningitis virus, which came to the Americas when the common house mouse, Mus musculus, was introduced in post-Columbian times. Lymphocytic choriomeningitis virus infection of humans mainly causes subclinical infection, acute undifferentiated febrile disease, and febrile central nervous system illnesses such as aseptic meningitis, but two cases have resembled the HF syndrome. AGENT The HF viruses occur worldwide (Table 65-1) and the geographic site of infection is an important determinant of the risk to an individual patient. The geography and knowledge of the incubation period are important in suspecting an exported viral HF. The syndrome characteristically begins with fever, myalgia, and malaise, which then progress to prostration, gastrointestinal and other system involvement, and signs of vascular damage. Involvement of the vascular system is usually manifest by vascular dysregulation (mild hypotension, postural hypotension, flushing, and injected conjunctivae), vascular damage (nondependent edema and organ dysfunction), and hemorrhage. Hemorrhage is usually diffuse in microvascular beds throughout the body and occurs particularly in patients with thrombocytopenia or marked platelet dysfunction. Many patients have little or no bleeding, but some present with extensive cutaneous and mucosal hemorrhage. Severe cases will have shock, central nervous system
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involvement, or extensive hemorrhagic phenomena. The clinical findings in the different HFs vary in a characteristic way for each virus, but any individual patient is difficult to classify without virologic diagnosis (Tables 65-2 and 65-3). The detailed manifestations of each VHF are often based on fragmentary clinical observations and lack proper appreciation of the entire spectrum, which in some cases includes such manifestations as pancreatitis. PATHOGENESIS Although there are common themes, the different viruses also differ in their pathology and pathogenesis (Table 65-4). Usually, hemorrhages are present in many organs, and effusions are commonly found in serous cavities, but they may be minimal or absent in some patients. There is widespread necrosis, which may be present in any organ system and that varies from modest and focal to massive in extent. Liver and lymphoid systems are usually extensively involved, and the lung regularly has varying degrees of interstitial pneumonitis, diffuse alveolar damage, and hemorrhage. Acute tubular necrosis and microvascular thrombosis may also be seen. The inflammatory response is usually minimal. These changes, which may be a direct effect of viral infection or a consequence of cytokine secretion, have considerable variation among the different viruses (see Table 65-4). DIAGNOSIS Correct diagnosis in most of the diseases depends on demonstration of the infecting virus or one of its products in acute serum samples. Viral antigens are readily demonstrable, and often an antigen detection enzyme-linked immunosorbent assay (ELISA) is the best test for identifying patients because of its rapidity and robustness; it is particularly likely to be positive in the more severely ill patient, who is in greatest need of therapy and who may provide the greatest risk of dissemination. Reverse transcription-polymerase chain reaction (RT-PCR) is usually more sensitive but also more subject to artifact and contamination. RT-PCR has a unique role in providing an amplicon that can be sequenced for genetic analysis, although this very genetic variation may be a source of difficulty in ensuring that appropriate primers are applied to unknown samples. In general, viremia and antigenemia are readily detected during the acute phase and disappear as the patient improves. RT-PCR is usually positive during the same period and perhaps 1 or 2 days longer. IgM antibodies may be detectable during illness and usually appear early in convalescence, providing a sensitive, specific method of diagnosis, particularly if they are measured by an IgM capture ELISA technique. Diagnosis of initial patients in any outbreak, particularly if there are unusual features, benefits from study of virus isolates and classic serologic responses, particularly the neutralization test, animal pathogenesis, and genomic analysis. Most of the viruses are hazardous and should only be isolated or studied under BSL4 containment. Hantaviruses are an exception to the generalizations: The patients typically present with an ongoing immune response and are best diagnosed with the IgM capture ELISA; virus isolation is difficult, but RT-PCR on acute blood clot may give valuable genetic information about the infecting virus.
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Bolivian HF
Venezuelan HF
Brazilian HF
Lassa fever
Machupo
Guanarito
Sabia
Lassa
CrimeanCongo HF
Hemorrhagic fever with renal syndrome (HFRS)
CrimeanCongo HF
Hantaan, Seoul, Puumala, and others
Rift Valley fever
Argentine HF
Arenaviridae Junin
Bunyaviridae Rift Valley fever
Disease
Worldwide depending on rodent reservoirs
Africa, Middle East, Balkans, southern Russia, western China
Sub-Saharan Africa
Portuguesa state, Venezuela Rural area near Saõ Paulo, Brazil West Africa
Beni Department, Bolivia
Argentine pampas
Geography
Horizontal infection in a single rodent genus or species typical of the virus. Viruses associated with HFRS have been obtained from Muridae (subfamilies Murinae or Avicolinae) rodents (rats, mice, and voles).
Vertical infection of floodwater Aedes mosquitoes. Epidemics occur from horizontal transmission by many different mosquito species between domestic animals, particularly sheep and cattle. Tick–mammal–tick infection. Vertical infection occurs in ticks. Hyalomma ticks are thought to be the natural reservoir, but other genera may become infected and transmit.
Chronic infection of field rodent, Zygodontomys brevicauda. Presumably chronic infection of unidentified rodents. Chronic infection of rodents of the genus Mastomys.
Chronic infection of small field rodent, Calomys musculinus. Chronic infection of small field rodent, Calomys callosus.
Vector/Reservoir
Geography and Epidemiology of Hemorrhagic Fever Viruses
Virus
Table 65-1
Continued
Tick bite; squashing ticks; and exposure to aerosols or fomites from slaughtered cattle and sheep. (Domestic animals do not show illness but may become infected when transported to market or when held in pens for slaughter.) Nosocomial epidemics observed on numerous occasions. Aerosols from freshly shed urine of infected rodents. Some infections may be acquired from secondary aerosols or droplets from previously shed rodent excreta and secreta or from rodent bites. Interhuman transmission never documented.
Humans acquire virus by mosquito bite; contact with blood of infected sheep, cattle, or goats; and aerosols generated from infected domestic animal blood. No interhuman transmission observed.
Single infection observed in nature: little information on epidemiologic potential. The reservoir rodent is very common in Africa, and the disease is a major cause of severe febrile illness in West Africa. Spread to man occurs by aerosols and by capturing the rodent for consumption, as well as person-to-person transmission. Lassa fever is the most commonly exported HF.
Infects agricultural workers disproportionately. Major transmission in fall: Aerosol transmission to humans. Rural residents and farmers main target; rodent can invade towns to cause epidemics. Aerosol transmission to humans. Interhuman transmission not usual, but occurs. Rural residents in recently developed area with small farms.
Human Infection
728
Disease
Dengue HF (DHF), dengue shock syndrome (DSS)
Yellow fever
HF, Hemorrhagic fever.
Al Kumrah
Kyasanur KFD Forest disease (KFD) Omsk HF OHF (OHF)
Dengue (types 1–4)
Flaviridae Yellow fever
Poorly understood cycle involving ticks, voles, muskrats, and possibly water-borne and mosquito transmission. Unknown. Surmised to involve tick–domestic livestock–tick cycle by analogy to genetically related tick-borne flaviviruses.
Western Siberia
Middle East? Africa?
Tick–vertebrate–tick
Maintained by Ae. aegypti–human– Ae. aegypti transmission with frequent geographic transport of viruses by travelers.
Karnataka state, India
Tropics and subtropics worldwide
Mosquito–monkey–mosquito maintenance with occasional human infection when unvaccinated humans enter forest. Large epidemics among humans with Aedes aegypti as mosquito vector.
Unknown
Africa, ?Philippines
Africa, South America
As for hantaviruses causing HFRS. All viruses associated with HPS have come from Muridae (subfamily Sigmodontinae) rodents, if the reservoir is known.
Vector/Reservoir
Americas
Geography
Geography and Epidemiology of Hemorrhagic Fever Viruses—cont’d
Sin Nombre, Hantavirus Black pulmonary Creek Canal, syndrome (HPS) Bayou, and others Filoviridae Marburg, Marburg HF Ebola Ebola HF
Virus
Table 65-1
Transmitted to humans working in livestock-related occupations by unknown route. Genetically related to KFD virus.
Mosquito infection of humans entering forest and encountering infected sylvatic vector. Emergence of epidemics into African savannas via specific Aedes mosquito vectors. In cities or villages, interhuman transmission by Ae. aegypti. Fully developed cases are no longer viremic and direct interhuman transmission not believed to be a problem although the virus is highly infectious (including aerosols) in the laboratory. DHF/DSS is a problem in areas where multiple dengue viruses are being transmitted. With the increased worldwide distribution of Ae. aegypti and movement of dengue viruses in travelers, this zone is enlarging. The disease was first noted in Southeast Asia but is now common in the Americas and the Caribbean, as well as the Pacific rim countries. Most infections occur from tickbite acquired in rural areas of the endemic zone. Monkey die offs may accompany increased virus activity. Few cases in recent years.
Infection of index case occurs from unknown source. Infected nonhuman primates sometimes provide link to humans. Later spread among human or nonhuman primates by close contact with another case. Aerosol transmission suspected in one captive monkey outbreak.
As for hantaviruses causing HFRS. Entering abandoned, closed buildings may be a particular risk in some settings. Interhuman transmission rarely observed with Andes virus
Human Infection
729
3–8
Kyasanur Forest disease (KFD) Omsk HF
50% of nonimmune <5% of heterologous flavivirus immune 0.007% of nonimmune and 1.0% of heterologous immune Variable
High (particularly Zaire subtype of Ebola)
1/20 Puumala virus Very high
20%–100% >3/4 Hantaan virus
≈1%
Mild infections probably common
Most (>1/2) result in disease
Case Infection Ratio
HF, Hemorrhagic fever. *Uncomplicated disease; incubation for HF may differ.
3–15*
3–6
3–16
7–28
3–12 9–35
2–5*
Dengue HF (DHF), dengue shock syndrome (DSS)
Flaviviridae Yellow fever
Hantavirus pulmonary syndrome Filoviridae Marburg or Ebola HF
Crimean-Congo HF HF with renal syndrome
Bunyaviridae Rift Valley fever
5–16
7–14
Arenaviridae South American HF
Lassa fever
Incubation Period (Days)
Typical cases have hypotension, shock, obvious bleeding, and neurologic symptoms such as dysarthria and intention tremor. Some cases have virtually pure neurologic syndrome. Prostration and shock; fewer hemorrhagic or neurologic manifestations than South American HF except in severe cases. Thrombocytopenia less common and less severe. Deafness develops in convalescence in 20%.
Characteristic Features
0.5%–9.0%
Untreated, 10%–15% Treated, < 1%
20%–50%
25%–90%
Typical biphasic disease with a febrile or hemorrhagic period often followed by CNS involvement. Similar to tick-borne encephalitis except hemorrhagic manifestations are not characteristic of first phase of tick-borne encephalitis.
High fever for 3–5 days with the development of shock lasting 1–2 days. DHF is not equated to DSS. DSS is the most dangerous manifestation and is due to an acute vascular leak. Attack rates, mortality quite variable with epidemic virus strain and surveillance.
Acute febrile period with defervescence accompanied in severe cases by jaundice and renal failure.
Most severe of the HFs. Marked weight loss and prostration. Maculopapular rash common. Patients have had late sequelae (hepatitis, uveitis, orchitis) often with virus isolation from biopsy or aspiration.
Severe disease associated with bleeding, shock, anuria, and icterus. Encephalitis and retinal vasculitis also occur, but without overlap with HF syndrome. 15%–30% Most severe bleeding and ecchymoses of all the HFs. 5%–15% Febrile stage followed by shock and renal failure. Bleeding during febrile stage, Hantaan virus shock, and renal failure. Puumala virus infections have a similar course but <1% Puumala virus are much milder. 40%–50% Febrile stage followed by acute pulmonary edema and shock. Manifestations largely limited to thoracic cavity.
≈50%
2%–15%
15%–30%
Case Fatality
Clinical Features of the Viral Hemorrhagic Fevers
Disease
Table 65-2
730 +++ + +++ +++ +++ ++ +++ ++ +++ ++
+/S
+++
+++
+++ +
++
+++ ++ ++
Thrombocytopenia
+++
Hemorrhage
N/⇓⇓ ⇑⇑ ⇓⇓
⇑⇑⇑ ⇑⇑
⇓⇓/⇑
⇓⇓/⇑⇑
N
⇓⇓⇓
Leukocyte Count
0 +++ 0
+++
0 0
0
0
++
0
Rash
+++ + 0
++
0 0
++
++
0
0
Icterus
++ 0 0
0
+++ +
0
+
0
0
Renal Disease
+ + ++
+
+ +++
+
0
+
+
Pulmonary Disease
0 0 0
0
0 0
0
0
+
+++
Tremor, Dysarthria
++ + E
++
+ +
+
E
+/S
++
0 0 0
+
0 0
0
0
++
0
Encephalopathy Deafness
0 0 Retina
Uveitis
0 0
0
Retina
0
0
Eye Lesions
DHF, dengue hemorrhagic fever; DSS, dengue shock syndrome; E, develop true encephalitis either after HF (KFD, Omsk) or in other patients (Rift Valley fever); HF, hemorrhagic fever; HFRS, hemorrhagic fever with renal syndrome; HPS, Hantavirus pulmonary syndrome; KFD, Kyasanur Forest disease; N, normal; OHF, Omsk hemorrhagic fever; S, characteristic, seen in severe case; +, occasional or mild; + +, commonly seen, may be severe; + + +, characteristic and usually marked; ⇑, occasionally or mildly increased; ⇓⇓, decreased; ⇑⇑, commonly increased, may be marked; ⇑⇑⇑, characteristically increased and usually marked; 0, absent.
Arenaviridae South American HF Lassa fever Bunyaviridae Rift Valley fever CrimeanCongo HF HFRS HPS Filoviridae Marburg and Ebola HFs Flaviviridae Yellow fever DHF, DSS KFD, OHF
Disease
Table 65-3 Specific Clinical Findings in Different Hemorrhagic Fevers
Overview of Viral Hemorrhagic Fevers
Table 65-4
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Viral Tropism and Pathologic Features of Viral Hemorrhagic Fevers
Disease Arenaviridae Argentine HF Bolivian HF Venezuelan HF Lassa fever Bunyaviridae Rift Valley fever (RVF) Crimean-Congo HF Hemorrhagic fever with renal syndrome (HFRS) Hantavirus pulmonary syndrome (HPS) Filoviridae Ebola HF Marburg HF Flaviviridae Yellow fever Dengue HF, dengue shock syndrome Kyasanur Forest disease (KFD) Omsk HF
Pathologic Features* Multifocal hepatocellular necrosis with minimal inflammatory response, interstitial pneumonitis, myocarditis, and lymphoid depletion; extensive parenchymal cell and reticuloendothelial infection, more than morphologic lesions would suggest.
Widespread hepatocellular necrosis and hemorrhage, sometimes with midzonal distribution, minimal inflammatory response, disseminated intravascular coagulation, lymphoid depletion; RVF antigens in few individual hepatocytes; encephalitis and retinal vasculitis also seen. Widespread hepatocellular necrosis and hemorrhage with minimal or no inflammatory cell response and lymphoid depletion; hepatic and endothelial cell infection and damage. Retroperitoneal edema in severe HFRS, mild to severe renal pathologic changes; congestion and hemorrhagic necrosis of renal medulla, right atrium of the heart, and anterior pituitary; extensive endothelial infection mainly in renal and cardiac microvasculature. Large bilateral pleural effusions and severely edematous lungs, mild to moderate interstitial pneumonitis, immunoblasts, and atypical lymphocytes in lymphoid tissues and peripheral blood; extensive infection of endothelial cells in pulmonary microvasculature. Extensive and disseminated infection and necrosis in major organs such as liver, spleen, lung, kidney, skin, and gonads; extensive hepatocellular necrosis associated with formation of characteristic intracytoplasmic viral inclusions; lymphoid depletion, microvascular infection, and injury. Similar to Ebola HF. Midzonal hepatocellular necrosis; minimal inflammatory response; Councilman bodies and microvesicular fatty change; hepatocellular and Kupffer cell infection; lymphoid necrosis (nodes, spleen); focal myocarditis; acute renal tubular necrosis. Centrilobular and midzonal hepatocellular necrosis with minimal inflammatory response; Councilman bodies and microvesicular fatty change; hyperplasia of mononuclear phagocytic cells in lymphoid tissues and atypical lymphocytes in peripheral blood; widespread infection of mononuclear phagocytic and endothelial cells. Focal hepatocellular degeneration, fatty change, and necrosis; pulmonary hemorrhage, depletion of malpighian follicles, sinus histiocytosis, erythrophagocytosis, mild myocarditis, and encephalitis. Little known; scattered focal hemorrhage, interstitial pneumonia, and normal lymphoid tissues.
HF, Hemorrhagic fever. *These features represent the characteristic pathologic findings in the different viral HFs. More general findings seen to variable degrees in all HFs are not listed.
Ideally, blood samples from HF patients should be collected early in the course of illness, and both serum and blood clot should be frozen as soon as possible. A second sample should be obtained before discharge or death for comparative serology, and this can be supplemented by a later follow-up blood sample. In fatal cases, a full autopsy should be performed with a complete set of organs collected in formalin for diagnostic studies; spleen, liver, and lymph nodes should be collected frozen for virus isolation. Classic histopathology is often useful in suspecting yellow fever, Rift Valley fever, or a filovirus infection and in diagnosing some of the confounding diseases. Immunohistochemistry on fixed tissues can usually make a definitive diagnosis possible. Precautions appropriate to each virus should be taken to prevent infection while processing samples or performing a necropsy. Frozen samples should be appropriately packed and, whenever possible, shipped on dry ice, although diagnoses can sometimes be made on mishandled specimens. The receiving laboratory should be advised of the shipment, its estimated time of arrival, and the waybill number to allow for tracing the materials if, as
often happens, there is a delay en route. Diagnostic expertise and consultation are available from several laboratories. TREATMENT AND PREVENTION Approaches to the prevention and treatment of the viral HFs vary with the infecting virus (Table 65-5). Barrier nursing and avoidance of parenteral exposures of hospital staff are important in management of all these diseases, but they are particularly important in Crimean-Congo HF and the filovirus diseases because of the regularity with which nosocomial transmission has been seen. The general principles of therapy are similar for all the HFs and require rapid atraumatic hospitalization, careful maintenance of fluid balance to avoid overhydration in the face of fragile systemic and pulmonary capillary beds, as well as probable myocardial compromise, management of the bleeding diathesis according to the usual principles, and the specific therapy appropriate to each disease (see Table 65-5). It is extremely important to exclude or empirically treat the conditions that may be most
732
HF, Hemorrhagic fever.
Tick-borne flaviviruses
Dengue HF
Flaviviridae Yellow fever
Hantavirus pulmonary syndrome Filoviridae Ebola/Marburg HF
HF with renal syndrome (HFRS)
Crimean-Congo HF
Bunyaviridae Rift Valley fever
Lassa fever
Bolivian HF
Arenaviridae Argentine HF
Disease
Vaccine is probably the safest and most effective in the world; control of Aedes aegypti would eliminate urban transmission but sylvatic transmission remains. Reduction of dengue transmission by A. aegypti control; investigational vaccines will probably be available soon; possibly useful in travelers but may be limited in solving hyperendemic dengue transmission that leads to dengue HF. Avoidance of ticks; vaccination; postexposure prophylaxis with virus-specific IgG.
Barrier nursing and needle sterilization in African hospitals particularly important; avoid close contact with suspected patients; do careful evaluation of sick nonhuman primates.
Rodent avoidance useful; care should be taken before entering or cleaning closed buildings with potential rodent infestations.
Vaccination of domestic livestock prevents epizootics/ epidemics but not sporadic, endemic infections of humans; human vaccine safe and effective but limited supply; veterinarians and virology workers in subSaharan Africa candidates for vaccine. Tick avoidance; no slaughter of acutely infected animals (healthy but viremic and therefore an undetected threat); barrier nursing of suspected patients particularly important. Rodent control and avoidance impractical in most cases; investigational vaccines deserve further evaluation.
Safe, effective vaccine used for high-risk residents of endemic area. Elimination of specific reservoir rodents from towns practical and effective; sporadic cases due to exposure outside towns, person-to-person transmission in families and institutions cannot be prevented; Argentine HF vaccine protects experimental animals against Bolivian virus. None; intensive village-based rodent control may reduce risk.
Prevention
Table 65-5 Prevention and Treatment of Viral Hemorrhagic Fevers
Supportive care.
Supportive care effective and greatly reduces mortality.
None other than supportive.
None other than supportive, which may be of limited utility; antiviral therapies urgently needed.
Early diagnosis and supportive care lifesaving; ribavirin has positive effect during initial 4 days illness and should be used in severe HFRS if available. Early diagnosis and supportive care potentially lifesaving; avoidance of hypoxia and excessive hydration coupled with careful management of shock.
Ribavirin should be used based on in vitro sensitivity and on uncontrolled South African experience.
Ribavirin and antibody therapy should be tried in HF patients based on studies in experimental animals.
Ribavirin effective in reducing mortality; use in higher risk patients, e.g., if aspartate transaminase >150 U/L.
Infusion of convalescent plasma during first 8 days of illness reduces mortality from 15%–30% to <1%. Ribavirin likely to be effective and should be used in this and other arenavirus diseases unless proven effective alternative therapy available.
Treatment
Overview of Viral Hemorrhagic Fevers
important in the differential diagnosis, particularly malaria, rickettsial infections, leptospirosis, relapsing fever, typhoid, and shigellosis. SUGGESTED READING Hemorrhagic Fevers Management of patients with suspected viral hemorrhagic fever. MMWR 37:1–15, 1988. Peters, CJ: Pathogenesis of viral hemorrhagic fevers. In Nathanson N, Ahmed R, Gonzalez-Scarano F, et al (eds): Viral Pathogenesis. Philadelphia, Lippincott-Raven, 1996. Peters CJ, Jahrling PB, Khan AS: Management of patients infected with high-hazard viruses. Arch Virol 11(suppl):1–28, 1996. Peters, CJ, Zaki SR, Rollin PE: Viral hemorrhagic fevers. In Mandell GL (ed): Atlas of Infectious Diseases, vol 8, Fekety R (ed). Philadelphia, Current Medicine, 1997, pp 10.1–10.26. Smorodintsev AA, Kazbintsev LI, Chudakov VG: Virus Hemorrhagic Fevers. Jerusalem, Israel Program for Scientific Translations, 1964. Update: Management of patients with suspected viral hemorrhagic fever— United States. MMWR 44:475–479, 1995. Zaki SR, Peters CJ: Viral hemorrhagic fevers. In Connor DH, Schwartz DA, Chandler FW (eds): Diagnostic Pathology of Infectious Diseases. Norwalk, Conn, Appleton & Lange, 1997, pp 347–364.
Arenaviridae Barry M, Russi M, Armstrong L, et al: Brief report: Treatment of a laboratory-acquired Sabiá virus infection. N Engl J Med 333:294–296, 1995. Enria D, Maiztegui JI: Antiviral treatment of Argentine hemorrhagic fever. Antiviral Res 23:23–31, 1994. Fulhorst, C, Ksiazek TG, Mills, JN, et al: Venezuelan hemorrhagic fever: Clinical and epidemiologic studies of 165 cases. Clin Infect Dis 26:308–313, 1998. Johnson KM, Halstead SB, Cohen SN: Hemorrhagic fevers of Southeast Asia and South America: A comparative appraisal. Prog Med Virol 9:105–158, 1967. Johnson KM, McCormick JB, Webb PA, et al: Clinical virology of Lassa fever in hospitalized patients. J Infect Dis 155:456–464, 1987. McCormick JB, King IJ, Webb PA, et al: A case–control study of the clinical diagnosis and course of Lassa fever. J Infect Dis 155:445–455, 1987. Molinas FC, de Bracco MME, Maiztegui JI: Hemostasis and the complement system in Argentine hemorrhagic fever. Rev Infect Dis 11(suppl 4): 762–767, 1989. Peters CJ: Arenaviruses. In Richman DD, Whitley RJ, Hayden FG (eds): Clinical Virology. Washington, DC, ASM Press, 2002, pp 949–969. Peters CJ, Kuehne RW, Mercado RR, et al: Hemorrhagic fever in Cochabamba, Bolivia. Am J Epidemiol 99:425–433, 1971.
Bunyaviridae Al Hazmi M, Ayoola EA, Abdurahman M, et al: Epidemic Rift Valley fever in Saudi Arabia: A clinical study of severe illness in humans. Clin Infect Dis 36:245–252, 2003. Bruno P, Hassell LH, Brown J, et al: The protean manifestations of hemorrhagic fever with renal syndrome. A retrospective review of 26 cases from Korea. Ann Intern Med 113:385–391, 1990. Bui-Mansfield LT, Torrington KG, Kim T: Acute pancreatitis in patients with hemorrhagic fever with renal syndrome. Military Med 166:167–170, 2001.
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Duchin JS, Koster F, Peters CJ, et al: Hantavirus pulmonary syndrome: A clinical description of 17 patients with a newly recognized disease. N Engl J Med 330:949–955, 1994. Huggins JW, Hsiang CM, Cosgriff TM, et al: Prospective, double-blind, concurrent, placebo controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis 164:1119–1127, 1991. Ketai LH, Williamson MR, Telepak RJ, et al: Hantavirus pulmonary syndrome (HPS): Radiographic findings in 16 patients. Radiology 191:665–668, 1994. Laughlin LW, Meegan JM, Strausbaugh LJ, et al: Epidemic Rift Valley fever in Egypt: Observations of the spectrum of human illness. Trans R Soc Trop Med Hyg 73:630–633, 1979. Peters CJ, Khan AS: Hantavirus pulmonary syndrome: The new American hemorrhagic fever. Clin Infect Dis 34:1224–1231, 2002. Peters CJ, LeDuc JW: Bunyaviridae: Bunyaviruses, phleboviruses, and related viruses. In Belshe R (ed): Textbook of Human Virology, ed 2. St. Louis, Mo, Mosby-Year Book, 1991, pp 571–614. Swanepoel R, Gill DE, Shepherd AJ, et al: The clinical pathology of Crimean-Congo hemorrhagic fever. Rev Infect Dis 11(suppl 4): S794–S800, 1989. Swanepoel R, Shepard AJ, Leman PA, et al: Epidemiologic and clinical features of Crimean-Congo hemorrhagic fever in South Africa. Am J Trop Med Hyg 6:120–132, 1987. Symposium on Epidemic Hemorrhagic Fever, May 1954. Am J Med 16:617–709, 1954. Zaki SR: Hantavirus-associated diseases. In Connor DH, Schwartz DA, Chandler FW (eds): Diagnostic Pathology of Infectious Diseases. Norwalk, Conn, Appleton & Lange, 1997, pp 347–364. Zaki SR, Greer PW, Coffield LM, et al: Hantavirus pulmonary syndrome: Pathogenesis of an emerging infectious disease. Am J Pathol 146:552–579, 1995.
Filoviridae Ebola haemorrhagic fever in Zaire, 1976. Report of an international commission. Bull World Health Organ 56:271–293, 1978. Martini GA, Siegert R (eds): Marburg Virus Diseases. Berlin, Springer-Verlag, 1971. Pattyn SR (ed): Ebola Virus Haemorrhagic Fever. Amsterdam, Elsevier/North-Holland, 1978. http://www.itg.be/ebola. Peters CJ, Leduc JW: An introduction to Ebola: The virus and the disease and articles in the supplement. J Infect Dis 179(suppl 1), 1999. http://www.journals/uchicago.edu/JID/journal/contents/v179nS1.html. WHO/International Study Team: Ebola hemorrhagic fever in Sudan, 1976. Bull World Health Organ 56:247–270, 1978.
Flaviviridae Burke DS, Monath TP: Flaviviruses. In Knipe DM, Howley PM (eds): Fields’ Virology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 1043–1126. Halstead SB: Antibody, macrophages, dengue virus infection, shock, and hemorrhage: A pathogenic cascade. Rev Infect Dis 11(suppl 4): S830–S839, 1989. Halstead SB: Dengue and dengue hemorrhagic fever. In Feigin RD, Cherry JD (eds): Textbook of Pediatric Infectious Disease. Philadelphia, Saunders, 1987, pp 1510–1521. Kerr JA: The clinical aspects and diagnosis of yellow fever. In Strode GR (ed): Yellow Fever. New York, McGraw-Hill, 1951, pp 385–425. Touatre J: Yellow fever. Clinical notes (C Chassaignac, trans). New Orleans Med Surg J, 1898.