Viral Hemorrhagic Fevers, Bioterrorism

SYMPTOMS

VHFs are febrile illnesses which can feature flushing of the face and chest, petechiae, bleeding, edema (swelling), hypotension (low blood pressure), and shock. Malaise, myalgias (muscle aches), headache, vomiting, and diarrhea may occur in any of the hemorrhagic fevers.

DIAGNOSIS

Definitive diagnosis rests on specific virologic techniques. Significant numbers of military personnel with a hemorrhagic fever syndrome should suggest the diagnosis of a viral hemorrhagic fever.

TREATMENT

Intensive supportive care may be required. Antiviral therapy with ribavirin may be useful in several of these infections (Available only as IND under protocol). Convalescent plasma may be effective in Argentine hemorrhagic fever (Available only as IND under protocol).

PROPHYLAXIS

The only licensed VHF vaccine is yellow fever vaccine. Prophylactic ribavirin may be effective for Lassa fever, Rift Valley fever, CCHF, and possibly HFRS (Available only as IND under protocol).

ISOLATION AND DECONTAMINATION

Contact isolation, with the addition of a surgical mask and eye protection for those coming within three feet of the patient, is indicated for suspected or proven Lassa fever, CCHF, or filovirus infections. Respiratory protection should be upgraded to airborne isolation, including the use of a fit-tested HEPA filtered respirator, a battery powered air purifying respirator, or a positive pressure supplied air respirator, if patients with the above conditions have prominent cough, vomiting, diarrhea, or hemorrhage. Decontamination is accomplished with hypochlorite or phenolic disinfectants.

OVERVIEW

The viral hemorrhagic fevers are a diverse group of illnesses caused by RNA viruses from four viral families. The Arenaviridae include the etiologic agents of Argentine, Bolivian, and Venezuelan hemorrhagic fevers, and Lassa fever. The Bunyaviridae include the members of the Hantavirus genus, the Congo-Crimean hemorrhagic fever virus from the Nairovirus genus, and the Rift Valley fever virus from the Phlebovirus genus; the Filoviridae include Ebola and Marburg viruses; and the Flaviviridae include dengue and yellow fever viruses. These viruses are spread in a variety of ways; some may be transmitted to humans through a respiratory portal of entry. Although evidence for weaponization does not exist for many of these viruses, they are included in this handbook because of their potential for aerosol dissemination or weaponization, or likelihood for confusion with similar agents that might be weaponized.

HISTORY AND SIGNIFICANCE

There are some significant characteristics that may provide insight into their importance as biological threat agents.

  • Arenaviridae: Argentine hemorrhagic fever (AHF), caused by the Junin virus, was first described in 1955 in corn harvesters. From 300 to 600 cases per year occur in areas of the Argentine pampas. Bolivian, Brazilian, and Venezuelan hemorrhagic fevers are caused by the related Machupo, Guanarito, and Sabia viruses. Lassa virus causes disease in West Africa. These viruses are transmitted from their rodent reservoirs to humans by the inhalation of dusts contaminated with rodent excreta.

  • Bunyaviridae: Congo-Crimean hemorrhagic fever (CCHF) is a tick-borne disease that occurs in the Crimea and in parts of Africa, Europe and Asia. It can also be spread by contact with infected animals, and in healthcare settings. Rift Valley fever (RVF) is a mosquito-borne disease that occurs in Africa. The hantaviruses are rodent-borne viruses with a wide geographic distribution. Hantaan and closely related viruses cause hemorrhagic fever with renal syndrome (HFRS), (also known as Korean hemorrhagic fever or epidemic hemorrhagic fever). This is the most common disease due to hantaviruses. It was described prior to WW II in Manchuria along the Amur River, among United Nations troops during the Korean conflict, and subsequently in Japan, China, and in the Russian Far East. Severe disease also occurs in some Balkan states, including Bosnia, Serbia and Greece. Nephropathia epidemica is a milder disease that occurs in Scandinavia and other parts of Europe, and is caused by strains carried by bank voles. In addition, newly described hantaviruses cause Hantavirus Pulmonary Syndrome (HPS) in the Americas. The hantaviruses are transmitted to humans by the inhalation of dusts contaminated with rodent excreta.

  • Filoviridae: Ebola hemorrhagic fever was first recognized in the western equatorial province of the Sudan and the nearby region of Zaire in 1976. A second outbreak occurred in Sudan in 1979, and in 1995 a large outbreak (316 cases) developed in Kikwit, Zaire, from a single index case. Subsequent epidemics have occurred in Gabon and the Ivory Coast. The African strains cause severe disease and death. It is not known why this disease appears infrequently. A related virus (Ebola Reston) was isolated from monkeys imported into the United States from the Philippines in 1989, and subsequently developed hemorrhagic fever. While subclinical infections occurred among exposed animal handlers, Ebola Reston has not been identified as a human pathogen. Marburg epidemics have occurred on 6 occasions: 5 times in Africa, and once in Europe. The first recognized outbreak occurred in Marburg, Germany, and Yugoslavia, among people exposed to African green monkeys, and resulted in 31 cases and 7 deaths. Filoviruses can be spread from human to human by direct contact with infected blood, secretions, organs, or semen. Ebola Reston apparently spread from monkey to monkey, and from monkeys to humans by the respiratory route. The natural reservoirs of the filoviruses are unknown.

  • Flaviviridae: Yellow fever and dengue are two mosquito-borne fevers that have great importance in the history of military campaigns and military medicine. Tick-borne flaviruses include the agents of Kyanasur Forest disease in India, and Omsk hemorrhagic fever in Siberia.

All of the VHF agents (except for dengue virus) are infectious by aerosol in the laboratory. These viruses could conceivably be used by an adversary as biological warfare agents, in view of their aerosol infectivity, and, for some viruses, high lethality.

CLINICAL FEATURES

  • The clinical syndrome that these viruses may cause is generally referred to as viral hemorrhagic fever, or VHF. The target organ in the VHF syndrome is the vascular bed; accordingly, the dominant clinical features are usually due to microvascular damage and changes in vascular permeability.

  • Not all infected patients develop VHF. There is both divergence and uncertainty about which host factors and viral strain characteristics might be responsible for the mechanisms of disease. For example, an immunopathogenic mechanism has been identified for dengue hemorrhagic fever, which usually occurs among patients previously infected with a heterologous dengue serotype. Antibody directed against the previous strain enhances uptake of dengue virus by circulating monocytes. These cells express viral antigens on their surfaces. Lysis of the infected monocytes by cytotoxic T-cell responses results in the release of pro-inflammatory cytokines, pro-coagulants, and anticoagulants, which in turn results in vascular injury and permeability, complement activation, and a systemic coagulopathy.

  • DIC has been implicated in Rift Valley, Marburg and Ebola fevers, but in most VHFs the cause of the coagulopathy is multifactorial (e.g., hepatic damage, consumptive coagulopathy, and primary marrow injury to megakaryocytes).

  • Common symptoms are fever, myalgia, and prostration. Physical examination may reveal only conjunctival injection, mild hypotension, flushing, and petechial hemorrhages. Full-blown VHF typically evolves to shock and generalized mucous membrane hemorrhage, and often is accompanied by evidence of pulmonary hematopoietic, and neurologic involvement. Renal insufficiency is proportional to cardiovascular compromise, except in HFRS, which features renal failure as an integral part of the disease process.

  • Apart from epidemiologic and intelligence information, some distinctive clinical features may suggest a specific etiologic agent. While hepatic involvement is common among the VHFs, a clinical picture dominated by jaundice and other features of hepatitis is only seen in some cases of Rift Valley fever, Congo-Crimean, Marburg, and Ebola HFs, and yellow fever. Kyanasur Forest disease and Omsk hemorrhagic fever are notable for pulmonary involvement, and a biphasic illness with subsequent CNS manifestations. Among the arenavirus infections, Lassa fever can cause severe peripheral edema due to capillary leak, but hemorrhage is uncommon, while hemorrhage is commonly caused by the South American arenaviruses. Severe hemorrhage and nosocomial transmission are typical for Congo-Crimean HF. Retinitis is commonly seen in Rift Valley fever, and hearing loss is common among Lassa fever survivors.

  • Because of their worldwide occurrence, additional consideration should be given to hantavirus infections. Classic HFRS has a severe course that progresses sequentially from fever through hemorrhage, shock, renal failure, and polyuria. Nephropathia endemica features prominent fever, myalgia, abdominal pain, and oliguria, without shock or severe hemorrhagic manifestations. North American cases of Hantavirus Pulmonary Syndrome (HPS) due to the Sin Nombre virus lack hemorrhagic manifestations and renal failure, but nevertheless carry a very high mortality due to rapidly progressive and severe pulmonary capillary leak, which presents as ARDS. These syndromes may overlap. Subclinical or clinical pulmonary edema may occur in HFRS and nephropathica endemica, while HFRS has complicated HPS due to South American hantaviruses and the Bayou and Black Creek Canal viruses in North America.

  • Mortality may be substantial, ranging from 0.2% percent for nephropathia endemica, to 50 to 90 percent among Ebola victims.

DIAGNOSIS

  • A detailed travel history and a high index of suspicion are essential in making the diagnosis of VHF. Patients with arenavirus or hantavirus infections often recall having seen rodents during the presumed incubation period, but since the viruses are spread to man by aerosolized excreta or environmental contamination, actual contact with the reservoir is not necessary. Large mosquito populations are common during Rift Valley fever or flavivirus transmission, but a history of mosquito bite is too common to be of diagnostic importance, whereas tick bites or nosocomial exposure are of some significance in suspecting Congo-Crimean HF. Large numbers of military personnel presenting with VHF manifestations in the same geographic area over a short time period should lead treating medical care providers to suspect either a natural outbreak in an endemic setting, or possibly a biowarfare attack, particularly if this type of disease does not occur naturally in the local area.

  • VHF should be suspected in any patient presenting with a severe febrile illness and evidence of vascular involvement (postural hypotension, petechiae, easy bleeding, flushing of face and chest, non-dependent edema) who has traveled to an area where the virus is known to occur, or where intelligence information suggests a biological warfare threat. Symptoms and signs suggesting additional organ system involvement are common (headache, photophobia, pharyngitis, cough, nausea or vomiting, diarrhea, constipation, abdominal pain, hyperesthesia, dizziness, confusion, tremor), but usually do not dominate the picture with the exceptions listed above under "Clinical Features." A positive tourniquet test has been particularly useful in dengue hemorrhagic fever, but should be sought in other hemorrhagic fevers as well.

  • The clinical laboratory can be very helpful. Thrombocytopenia (exception: Lassa) and leukopenia (exceptions: Lassa, Hantaan, and some severe CCHF cases) are the rule. Proteinuria and/or hematuria are common, and their presence is the rule for Argentine HF, Bolivian HF, and HFRS. High AST elevation correlates with severity of Lassa fever, and jaundice is a poor prognostic sign in yellow fever.

  • In most geographic areas, the major item in the differential diagnosis is malaria. It must be borne in mind that parasitemia in patients partially immune to malaria does not prove that symptoms are due to malaria. Other items in the differential may include typhoid fever, nontyphoidal salmonellosis, leptospirosis, rickettsial infections, shigellosis, relapsing fever, fulminant hepatitis, and meningococcemia. Additional illnesses which could mimic VHF include acute leukemia, lupus erythematosus, idiopathic or thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and the multiple causes of disseminated intravascular coagulation.

  • Definitive diagnosis in an individual case rests on specific virologic diagnosis. Most patients have readily detectable viremia at presentation (exception: hantaviral infections). Rapid enzyme immunoassays can detect viral antigens in acute sera from patients with Argentine HF, Lassa fever, Rift Valley fever, Congo-Crimean HF, and yellow fever. Lassa- and Hantaan-specific IgM often are detectable during the acute illness. Diagnosis by virus cultivation and identification will require 3 to 10 days or longer. With the exception of dengue, specialized microbiologic containment is required for safe handling of these viruses. Appropriate precautions should be observed in collection, handling, shipping, and processing of diagnostic samples. Both the Centers for Disease Control and Prevention (CDC, Atlanta, Georgia) and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID, Frederick, Maryland) have diagnostic laboratories functioning at the highest (BL-4 or P-4) containment level.

MEDICAL MANAGEMENT

  • General principles of supportive care apply to hemodynamic, hematologic, pulmonary, and neurologic manifestations of VHF, regardless of the specific etiologic agent. Only intensive care will save the most severely ill patients. Health care providers employing vigorous fluid resuscitation of hypotensive patients must be mindful of the propensity of some VHFs (e.g., HFRS) for pulmonary capillary leak. Pressor agents are frequently required. The use of intravascular devices and invasive hemodynamic monitoring must be carefully considered in the context of potential benefit versus the risk of hemorrhage. Restlessness, confusion, myalgia, and hyperesthesia should be managed by conservative measures, and the judicious use of sedatives and analgesics. Secondary infections may occur as with any patient undergoing intensive care utilizing invasive procedures and devices, such as intravenous lines and indwelling catheters.

  • The management of clinical bleeding should follow the same principles as for any patient with a systemic coagulopathy, assisted by coagulation studies. Intramuscular injections, aspirin and other anticoagulant drugs should be avoided.

  • The investigational antiviral drug ribavirin is available via compassionate use protocols for therapy of Lassa fever, HFRS, Congo-Crimean HF, and Rift Valley fever. Separate Phase III efficacy trials have indicated that parenteral ribavirin reduces morbidity in HFRS, and lowers both the morbidity and mortality of Lassa fever. In the HFRS field trial, treatment was effective if begun within the first 4 days of fever, and continued for a 7 day course. A compassionate use protocol, utilizing intravenous ribavirin as a treatment for Lassa fever, is sponsored by the CDC. Doses are slightly different, and continued for a 10 day course; treatment is most effective if begun within 7 days of onset. The only significant side effect of ribavirin is a modest anemia due to a reversible inhibition of erythropoiesis, and mild hemolysis. Although ribavirin is teratogenic in laboratory animals, the potential benefits must be weighed against the potential risks to pregnant women with grave illness due to one of these VHFs. Safety in infants and children has not been established. Ribavirin has poor in vitro and in vivo activity against the filoviruses (Ebola and Marburg) and the flaviviruses (dengue, yellow fever, Omsk HF and Kyanasur Forest Disease).

  • Argentine HF responds to therapy with 2 or more units of convalescent plasma containing adequate amounts of neutralizing antibody and given within 8 days of onset.

  • This therapy is investigational, and available only under protocol.

PROPHYLAXIS

  • The only licensed vaccine available for any of the hemorrhagic fever viruses is yellow fever vaccine, which is mandatory for travelers to endemic areas of Africa and South America. Argentine hemorrhagic fever vaccine is a live, attenuated, investigational vaccine developed at USAMRIID, which has proved efficacious both in an animal model and in a field trial in South America, and seems to protect against Bolivian hemorrhagic fever as well. Both inactivated and live-attenuated Rift Valley fever vaccines are currently under investigation. An investigational vaccinia-vectored Hantaan vaccine is offered to laboratory workers at USAMRIID. There are currently no vaccines for the other VHF agents available for human use in the United States.

  • Persons with percutaneous or mucocutaneous exposure to blood, body fluids, secretions, or excretions from a patient with suspected VHF should immediately wash the affected skin surfaces with soap and water. Mucous membranes should be irrigated with copious amounts of water or saline.

  • Close personal contacts or medical personnel exposed to blood or secretions from VHF patients (particularly Lassa fever, CCHF, and filoviral diseases) should be monitored for symptoms, fever and other signs during the established incubation period. A DoD compassionate use protocol exists for prophylactic administration of oral ribavirin to high risk contacts (direct exposure to body fluids) of Congo-Crimean HF patients. A similar post-exposure prophylaxis strategy has been suggested for high contacts of Lassa fever patients. Most patients will tolerate this dose well, but patients should be under surveillance for breakthrough disease (especially after drug cessation) or adverse drug effects (principally anemia).

ISOLATION AND CONTAINMENT

  • These viruses pose special challenges for hospital infection control. With the exception of dengue (virus present, but no secondary infection hazard) and hantaviruses (infectious virus not present in blood or excreta at the time of clinical presentation), VHF patients generally have significant quantities of virus in blood and often other secretions. Special caution must be exercised in handling sharps, needles, and other potential sources of parenteral exposure. Strict adherence to standard precautions will prevent nosocomial transmission of most VHFs.

  • Lassa, Congo-Crimean HF, Ebola, and Marburg viruses may be particularly prone to aerosol nosocomial spread. Secondary infections among contacts and medical personnel who were not parenterally exposed are well documented. Sometimes this occurred when the acute hemorrhagic disease (as seen in CCHF) mimicked a surgical emergency such as a bleeding gastric ulcer, with subsequent exposure and secondary spread among emergency and operating room personnel. Therefore, when one of these diseases is suspected, additional management measures are indicated. The patient should be hospitalized in a private room. An adjoining anteroom for putting on and removing protective barriers, storage of supplies, and decontamination of laboratory specimen containers, should be used if available. A room with non-recirculated air under negative pressure is advised for patients with significant cough, hemorrhage, or diarrhea. It may be wise to place the patient in such a room initially, to avoid having to transport the patient in the event of clinical deterioration. All persons entering the room should wear gloves and gowns (contact isolation). In addition, face shields or surgical masks and eye protection are indicated for those coming within three feet of the patient. Respiratory protection should be upgraded to airborne isolation, including the use of a fit-tested HEPA filtered respirator, a battery powered air purifying respirator, or a positive pressure supplied air respirator, if patients with the above conditions have prominent cough, vomiting, diarrhea, or hemorrhage. Caution should be exercised in evaluating and treating the patient with suspected VHF. Over-reaction on the part of health care providers is inappropriate and detrimental to both patient and staff, but it is prudent to provide as rigorous isolation measures as feasible.

  • Laboratory specimens should be double-bagged, and the exterior of the outer bag decontaminated prior to transport to the laboratory. Excreta and other contaminated materials should be autoclaved, or decontaminated by the liberal application of hypochlorite or phenolic disinfectants. Clinical laboratory personnel are also at risk for exposure, and should employ a biosafety cabinet (if available) and barrier precautions when handling specimens.

  • No carrier state has been observed for any VHF, but excretion of virus in urine (e.g., Lassa fever) or semen (e.g., Argentine hemorrhagic fever) may occur during convalescence. Should the patient die, there should be minimal handling of the body, with sealing of the corpse in leak-proof material for prompt burial or cremation.