ARENAVIRUS
Overview
The arenaviruses have been separated on the basis of immunologic and geographic features into New and Old World sets. At least 19 individual viruses have been recognized. Four members of the New World family, Junin (Argentine HF), Machupo (Bolivian HF), Guanarito (Venezuelan HF), and Sabia (Brazilian HF) cause human HF (also referred to collectively as South American hemorrhagic fevers), while Lassa is an Old World virus that causes HF in West Africa (Sierra Leone, Guinea, Liberia, and Nigeria). 6 All of the arenaviruses causing HF have a specific rodent host with humans being the accidental host. Patients will usually give a history of travel within the last 21 days (maximum incubation period) to West Africa or South America in areas where the rodent host is known to inhabit and contact with rodent urine and feces, either by aerosolization, ingestion, or direct contact. 6 Nosocomial person-to-person transmission occurs with Lassa fever, but person-to-person spread of South American HF is unlikely. 3 The case-fatality rate ranges from 2% to 15% in Lassa fever and 15% to 30% in the South American HFs. 2
Clinical manifestations
Untreated, arenaviral infections are potentially fatal diseases with focal hemorrhagic manifestations and hypovolemic shock. Fever is typically insidious in onset and is accompanied by headache and significant myalgia and malaise. Relative bradycardia is common, as is dysesthesia, particularly hyperesthesia of the skin. Lassa fever, however, usually has less neurologic involvement, thrombocytopenia, leukopenia, and bleeding. 6 However, when bleeding is present, there is a high viremia or an elevated aspartate aminotransferase; a poor prognosis is more likely. 7 Most infected individuals defervesce by 10 days, but a small percentage progress rapidly to shock, delirium, respiratory distress, coma, and death. 6
Infection with South American hemorrhagic viruses typically results in symptomatic illness, the clinical features of which are remarkably similar to those to Lassa fever 3 to 4 days after the onset of fever, malaise, and myalgia. Patients manifest severe prostration, headache, dizziness, back pain, and gastrointestinal disturbances. Conjunctival injection, flushing of the face, orthostatic hypotension, petechiae on the palate and axillae, and bleeding of the gums reflect damage to the vascular bed. Hemorrhage along the gingival margin is a characteristic finding. Neurologic manifestations are common. Laboratory findings early in the course of disease nearly always include thrombocytopenia (platelet count <100000/mm3) and leukopenia (white blood cell count <4000/mm3). By the second week of the disease, 70% to 80% improve, while the remaining 20% progress over the next week or so with severe hemorrhagic or neurologic manifestations. 6
Management
General supportive therapy involves adequate hydration, management of neurologic conditions, blood transfusions, and other supportive measures. Platelet transfusions are probably not useful due to the complex nature of hemorrhage. If initiated within 8 days, transfusion of immune plasma for Argentine HF has reduced mortality to less than 1%. 8 There is limited human experience with ribavirin for the treatment of South American HFs, but at least 1 study demonstrated a significant drop in viremia for the Junin virus even in the later stages of the disease. 9 Ribavirin can be used for treatment or prophylaxis of Lassa fever. A 10-day IV course of ribavirin is effective at all stages of illness and oral dosing is effective for postexposure prophylaxis. 10 Alternatively, ribavirin may be given IV for the first 4 days followed by oral dosing to complete the 10-day course. 11 Starting ribavirin before day 7 of illness was associated with a higher survival rate. 10 An effective live attenuated Junin virus vaccine is available in South America to prevent Argentine HF in high-risk populations. 12
BUNYAVIRUS
Overview
The family Bunyaviridae contains at least 41 different tropical viruses, including those that cause Crimean-Congo hemorrhagic fever (CCHF), Rift Valley fever (RVF), HF with renal syndrome, and hantavirus pulmonary syndrome. A tick-borne viral illness, CCHF causes severe hemorrhagic manifestations and occurs mainly in tropical Africa, temperate Europe, and as far east as China. 13 The disease is generally rural in distribution and arises mainly among farm workers, many of whom recount a history of tick bite or of squeezing ticks with their fingers. Nosocomial transmission of CCHF is common. 14,15 The case-to-infection ratio approaches 100%, with a case-fatality rate of 15% to 30%. 2
Rift Valley fever is primarily a mosquito-borne (Aedes sp.) viral disease of sheep and cattle but humans can acquire the infection from aerosols generated from body fluids and tissues of diseased animals or from bites of infected mosquitoes. Person-to-person transmission has not been reported. Based on virus isolations, RVF occurs endemically during the rainy season throughout most of sub-Saharan Africa and more recently, in the Middle East. 16,17 In 1977, an epidemic of RVF occurred in Egypt, infecting over 200000 and killing 600. 18 The case-to-infection ratio is only about 1%, but the case-fatality rate is over 50% and nearly 100% for animals it infects. 2
Clinical features
Crimean-Congo hemorrhagic fever is a severe hemorrhagic fever with shock, disseminated intravascular coagulation, and severe thrombocytopenia. In about 80% of cases, CCHF is subclinical. 13 After an incubation period of 3 to 9 days, CCHF begins swiftly with fever, headache, nausea, myalgia, vomiting, abdominal pain, and conjunctival injection. 19 In about half of the cases, hepatomegaly is evident. Hemorrhagic manifestations do not generally appear before the third or fourth day of the illness. The onset of the hemorrhagic phase is marked by the appearance of purpura on the skin and mucous membranes, which lasts 3 to 6 days. Hemorrhages also develop from the nose, gums, and buccal cavity. In severe cases of CCHF, gastric, uterine, intestinal, genitourinary, and pulmonary hemorrhages occur. In patients with profuse hemorrhage, tachycardia, shock, and death may occur. If the patient survives the hemorrhagic phase of the disease, by the ninth or tenth day recovery begins and a 2- to 6-week period of slow convalescence follows. Viremia is intense and prolonged in CCHF, especially in fatal cases. Blood from these patients should be treated with extreme care. 13
The incubation period of RVF is 3 to 7 days; onset is sudden, with chills, myalgia, joint pains, headache, and a biphasic fever that lasts about 1 week. The patient often complains of nausea, vomiting, and abdominal fullness and pain. There is bradycardia, and there may be slight tenderness over the liver, which may be enlarged. Many patients become delirious, and some have hallucinations. Three main complications of RVF include encephalitis, optic neuropathy, and hepatitis. About 10% of patients experience optic neuritis, which manifests as cotton-wool exudates on the macula. 20 Death usually follows massive gastrointestinal hemorrhage, oliguria, anuria, and acute renal failure after 3 to 6 days. 13
Management
An inactivated vaccine is available from the US military for RVF and outside the United States there is a vaccine for CCHF. For RVF, interferon alpha has been used in doses of 5 x 10 5 units/kg for 5 days for primates. 13 When ribavirin was used in Rhesus monkeys with experimental RFV, a significant decline in viremia was noted, but human trials have not been done. 21 The combination of ribavirin and interferon, Rebetron(TM), is not approved for RVF and published experience is absent. For CCHF, immune serum appears useful when given early in infection and at a dose of 250 mL IV over 1 to 2 days. 13 Ribavirin has in-vitro activity against CCHF, but controlled clinical trials are lacking. A published report suggests that ribavirin given for postexposure prophylaxis at an IV or PO dose of 2 g to load, then 4 g/day in 4 divided doses for 4 days, finally dropping to 2 g/day for 6 days for a total of 10 days was beneficial at preventing death. 22
FILOVIRUS
Overview
The family Filoviridae is composed of 2 distinctive species, Marburg and Ebola, with specific subtypes for each named after the country where the virus was isolated in relation to an outbreak (eg Ebola, Zaire). Ebola was first described in 1976 in the Sudan and Zaire. Twice Ebola has surfaced in the United States as a result of infected primates, in Reston Virginia in 1989 and in Texas in 1996, but neither event resulted in spread beyond lab workers, who remained asymptomatic, or the infected primates. 23 Both Ebola and Marburg are rare infections, making it difficult to study them in a controlled manner. The natural reservoir for Ebola is unknown, but it appears to be effectively transmitted person-to-person via contaminated blood and bodily fluids or reused needles and from animal to human. 24 Filoviruses are exceedingly virulent in humans, with case-fatalities rates up to 100%. 25
Clinical features
Both Ebola and Marburg virus infections have a similar course of illness. Following a 5- to 10-day incubation period there is an abrupt onset of fever usually associated with myalgia and severe frontal headache. Disease progression is characterized by nausea, pharyngitis, photophobia, severe vomiting of blood, and diarrhea. Hemorrhagic symptoms include epistaxis, bleeding gums, hematemesis, and bleeding from sites of needle insertion. 26 After 5 to 7 days, a nonpruritic maculopapular rash develops. Neurologic symptoms include somnolence, delirium, or coma. A poor prognosis is marked by hemorrhagic signs, as well as oliguria or anuria, chest pain, shock, tachypnea, and neurologic symptoms. If fatal, death occurs 6 to 9 days after onset of the clinical disease and results from severe blood loss and shock. Clinical laboratory findings show an early lymphopenia and a thrombocytopenia. Liver function enzyme levels (aspartate aminotransferose and alanine aminotransferase) are elevated. Viral isolation is not practical since it requires a biosafety level 4 laboratory; thus samples must be sent to the Centers for Disease Control and Prevention for confirmation.
Management
Ribavirin does not have good in-vitro activity against Ebola and Marburg and has not been shown to be effective in animals. 27 Therapy centers around supportive care, primarily volume replacement, correcting electrolyte imbalances, pressure support, and transfusions and heparin for disseminated intravascular coagulation. Convalescent immune serum and human interferon probably have limited utility as clinical experience is lacking and in-vitro data suggests IV fluids have not reversed hypotension and may have contributed to pulmonary edema.
FLAVIVIRIDAE
Overview
Flaviviridae are a diverse group of RNA viruses containing Hepacivirus (Hepatitis C) and the genus flavivirus, which causes yellow fever (YF), dengue hemorrhagic fever (DHF), Japanese encephalitis, and tick-borne ecephalitis. Yellow fever is a mosquito-borne (Aedes aegypti) infection endemic to nonurban areas of tropical South America and sub-Saharan Africa. Up to 50% of hemorrhagic-fever-related mortality worldwide can be attributed to YF. 28 The World Health Organization estimates that there are over 200000 cases annually of YF and over 6400 deaths, with more than 90% acquired in Africa. 29 The case-fatality rate varies from 20% to 50%. 2 A highly effective live attenuated vaccine is available in the United States and abroad for the prevention of YF. Since 1996, 3 deaths have occurred in unvaccinated people, most recently in a returned traveler from the Amazon. 30 Dengue fever (DF) virus is fast on its way to becoming the world's major emerging infection. Transmitted by mosquito bites (A. aegypti and A. albopictus) during the day in about 101 countries, DF infects about 50 to 100 million people worldwide and DHF affects about 250000 to 500000. 31 More than half of the world's population lives in a DF-infected area, including the United States. In the United States, Texas and Hawaii have recently experienced DF outbreaks, adding to the approximate 20 cases per year of laboratory confirmed imported DF cases. 32 Case-fatality rates for DHF vary from <1% to 5% up to 12% to 44% for dengue shock syndrome, a variant of DF. 33
Clinical features
Yellow fever
After a 3- to 6-day incubation period, there is an abrupt onset of flu-like symptoms including fever, chills, malaise, headache, myalgia, nausea, and dizziness. Classic YF displays 3 clinical periods: infection (sudden onset of flu-like symptoms with bradycardia), remission (lasting about 24 hours before the return of symptoms), and intoxication (jaundice, albuminuria, oliguria, cardiovascular instability, hemorrhagic manifestations). 28 When death occurs, it usually happens around day 7 to 10 as a result of ongoing liver failure and metabolic acidosis.
Dengue hemorrhagic fever
Dengue fever manifests with a sudden onset of fever and flu-like symptoms that spontaneously resolve after 3 to 7 days. Circulating antibodies from a previously acquired DF infection appear to be a strong indicator of progression to DHF. 31 Classically, DHF is a disease of children, characterized by a sudden onset of fever with other non-specific symptoms. Unfortunately, there is no pathognomonic sign or symptom to help clinicians differentiate DHF from other childhood illnesses and many infections are asymptomatic. The World Health Organization provides a classification of DF from grade 1 to 4 based on severity of illness. As the illness progresses through the stages of infection, the patient begins to experience hemorrhagic symptoms (skin, gums, and gastrointestinal tract) with thrombocytopenia, circulatory failure, shock, and finally death.
Management
Prevention through vaccination and mosquito bite avoidance are the mainstays of minimizing the risk of YF. A single dose of the 17D live attenuated vaccine after 10 days provides nearly complete protection for at least 10 years. 34 A combination of DEET insect repellant (at least 30%) applied to the skin and permethrin insecticide applied to the clothing, both worn during the day, is an important means of preventing bites from mosquitoes carrying DF or YF. Although ribavirin may be effective in the treatment of arenaviruses and bunyaviruses, it does not appear to be effective in the treatment of flavivirus infections, including DHF and YF. 27 Experience is limited with severe YF infection, but symptomatic management of fluids, electrolytes, and circulatory support appears warranted. Dengue hemorrhagic fever often responds to early fluid replacement, often with reversal of disseminated intravascular coagulation. 35 Early intervention for shock requires knowing how much time has elapsed since the onset of infection (DHF usually occurs around day 3 to 7) and monitoring for a rapidly decreasing platelet count with a rising hematocrit. 31 There is no vaccine or drug available for the prevention or treatment of DF.
RECOMMENDATIONS
Viral hemorrhagic fevers are primarily imported diseases from the tropics. Emergency Department personnel should be aware of the clinical presentation, management, and infection control procedures for VHF. When a VHF is highly suspected, it is important to institute strict infection control procedures (ie personal protective measures, contact, and respiratory isolation) for arenaviruses, such as that causing Lassa fever, bunyaviruses, such as that causing Crimean-Congo hemorrhagic fever, and filoviruses, such as Marburg and Ebola, due to their potential for person-to-person transmission. Local and state health department and the Centers for Disease Control and Prevention should be notified immediately when a case of VHF is suspected. In the event of a VHF related to bioterrorism, the Working Group on Civilian Biodefense has issued guidelines for isolation precautions, personal protective equipment, laboratory testing, postmortem practices, and environmental decontamination. 4 In the words of one of the world's foremost virus hunters, "I don't pretend to be able to predict what the next great disease will be [horizontal ellipsis] [however] I believe it is possible to identify some of the most dangerous pieces of the puzzle beforehand." 1
REFERENCES