Viral Hemmorrhagic Fevers

VIRAL HEMORRHAGIC FEVERS

SUMMARY

Signs and Symptoms: VHFs are febrile illnesses which can be complicated by easy bleeding, petechiae, hypotension and even shock, flushing of the face and chest, and edema. Constitutional symptoms such as malaise, myalgias, 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. Convalescent plasma may be effective in Argentine hemorrhagic fever.

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.

Isolation and Decontamination: Contact Precautions for healthcare workers. Decontamination is accomplished with hypochlorite or phenolic disinfectants. Isolation measures and barrier nursing procedures are indicated.

OVERVIEW

The viral hemorrhagic fevers are a diverse group of human illnesses that are due to RNA viruses from several different viral families: the Filoviridae, which consists of Ebola and Marburg viruses; the Arenaviridae, including Lassa fever, Argentine and Bolivian hemorrhagic fever viruses; the Bunyaviridae, including various members from the Hantavirus genus, Congo-Crimean hemorrhagic fever virus from the Nairovirus genus, and Rift Valley fever from the Phlebovirus genus; and Flaviviridae, such as Yellow fever virus, Dengue hemorrhagic fever virus, and others. The viruses may be spread in a variety of ways, and for some there is a possibility that humans could be infected through a respiratory portal of entry. Although evidence for weaponization does not exist for many of these viruses, many are included in this handbook because of their potential for aerosol dissemination or weaponization, or likelihood for confusion with similar agents which might be weaponized.

HISTORY AND SIGNIFICANCE

Because these viruses are so diverse and occur in different geographic locations endemically, their full history is beyond the scope of this handbook. However, there are some significant events for each of them that may provide insight into their possible importance as biological threat agents.

Ebola virus disease 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. A related virus was isolated from a group of infected cynomolgus monkeys imported into the United States from the Philippines in 1989. As of yet, this Ebola Reston strain has not been determined as a cause of human disease. The African strains have caused severe disease and death, and it is not known why this disease only appears infrequently or why the most recent strain appears to be less pathogenic in humans. Marburg disease has been identified on four occasions as causing disease in man: three times in Africa, and once in Germany, where the virus got its name. The first recognized outbreak of Marburg disease involved 31 infected persons in Germany and Yugoslavia who were exposed to African green monkeys, with 7 fatalities. It is unclear how easily these filoviruses can be spread from human to human, but spread definitely occurs by direct contact with infected blood, secretions, organs, or semen. The reservoir in nature for these viruses is unknown.

Argentine hemorrhagic fever (AHF), caused by the Junin virus, was first described in 1955 in corn harvesters. It is spread in nature through contact with infected rodent excreta. From 300 to 600 cases per year occur in areas of the Argentine pampas. Bolivian hemorrhagic fever, caused by the related Machupo virus, was described subsequent to AHF in northeastern Bolivia. These viruses have caused laboratory infections, and airborne transmission via dusts contaminated with rodent excreta may occur. A related African arenavirus, Lassa virus, causes disease which is widely distributed over West Africa.

Congo-Crimean hemorrhagic fever (CCHF) is a tick-borne disease which occurs in the Crimea and in parts of Africa, Europe and Asia. It can also be spread by contact with infected animals or nosocomially in healthcare settings. Rift Valley fever occurs only in Africa, and can occasionally cause explosive disease outbreaks. Hantavirus disease was described prior to WW II in Manchuria along the Amur River, later among United Nations troops during the Korean conflict, and since that time in Korea, Japan, and China. Hemorrhagic disease due to hantaviruses also occurs in Europe (usually in a milder form) and a non-hemorrhagic Hantavirus Pulmonary Syndrome occurs in the Americas and probably worldwide.

Yellow fever and dengue fever are two mosquito-borne fevers which can cause a hemorrhagic fever syndrome and have great historic importance in the history of military campaigns and military medicine.

All of these viruses (except for dengue virus) are infectious by aerosol or fomites. Since most patients are viremic, there is a potential for nosocomial transmission to patients, medical staff, and particularly laboratory personnel. Hantavirus infections are an exception, as at the time of presentation, viremia is waning and circulating antibody is present.

The age and sex distributions of each disease as it occurs endemically generally reflect the opportunities for zoonotic exposure to the disease reservoir. The way in which the filoviruses are transmitted to humans is not well understood.

CLINICAL FEATURES

The clinical syndrome which these viruses may cause in humans is generally referred to as viral hemorrhagic fever or VHF. Not all infected patients develop VHF; there is both divergence and uncertainty about which host factors and virus strain differences might be responsible for clinically manifesting hemorrhagic disease. For instance, an immunopathogenic mechanism has been identified for dengue hemorrhagic fever, which is seen only in patients previously infected with a heterologous dengue serotype. The target organ in the VHF syndrome is the vascular bed; correspondingly, the dominant clinical features are usually a consequence of microvascular damage and changes in vascular permeability. Common presenting complaints are fever, myalgia, and prostration; clinical 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 neurologic, hematopoietic, or pulmonary involvement. Apart from epidemiologic and intelligence information, some distinctive clinical features may suggest a specific etiologic agent: high AST elevation correlates with severity of illness from Lassa fever, and jaundice is a poor prognostic sign in yellow fever. Hepatic involvement is common among the VHFs, but a clinical picture dominated by jaundice and other evidence of hepatic failure is only seen in some cases of Rift Valley fever, Congo-Crimean HF, Marburg HF, Ebola HF, and yellow fever. Neurologic symptoms and thrombocytopenia are common in Argentine and Bolivian hemorrhagic fever. Kyanasur Forest disease and Omsk hemorrhagic fever are notable for a concomitant pulmonary involvement, and a biphasic illness with subsequent CNS manifestations. With regard to the Bunyaviruses, copious hemorrhage and nosocomial transmission are typical for Congo-Crimean HF, and retinitis is commonly seen in Rift Valley fever. Renal insufficiency is proportional to cardiovascular compromise, except in hemorrhagic fever with renal syndrome (HFRS) due to hantaviruses, where renal azotemia is an integral part of the disease process. Mortality may be substantial, ranging from 5 to 20 percent or higher in recognized cases. Ebola outbreaks in Africa have been notable for the extreme prostration and toxicity of the victims, as well as frighteningly high case fatality rates ranging from 50 to 90 percent. This particularly virulent virus could conceivably be chosen by an adversary as a biological warfare agent due to its probable aerosol infectivity and high mortality.

DIAGNOSIS

A detailed travel history and a high index of suspicion are essential in making the diagnosis of VHF. Patients with arenaviral or hantaviral 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 flaviviral transmission, but a history of mosquito bite is sufficiently common to be of little assistance, whereas tick bites or nosocomial exposure are of some significance in suspecting Congo-Crimean hemorrhagic fever. 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 if in an endemic setting, or possibly a biowarfare attack, particularly if this type of disease does not occur naturally in the local area where troops are deployed.

VHF should be suspected in any patient presenting with a severe febrile illness and evidence of vascular involvement (subnormal blood pressure, 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. Signs and symptoms 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."

For much of the world, the major 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. Typhoid fever, rickettsial, and leptospiral diseases are major confounding infections, with nontyphoidal salmonellosis, shigellosis, relapsing fever, fulminant hepatitis, and meningococcemia being some of the other important diagnoses to exclude. Any condition leading to disseminated intravascular coagulation could present in a confusing fashion, as well as diseases such as acute leukemia, lupus erythematosus, idiopathic or thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome.

Because of recent recognition of their worldwide occurrence, additional consideration should be given to infection with hantavirus. Classic HFRS (also referred to as Korean hemorrhagic fever or epidemic hemorrhagic fever) has a severe course which progresses sequentially from fever through hemorrhage, shock, renal failure, and polyuria. This clinical form of HFRS is widely distributed in China, the Korean peninsula, and the Far Eastern USSR. Severe disease also is found in some Balkan states, including Bosnia/Serbia and Greece. However, the Scandinavian and most European virus strains carried by bank voles usually produce a milder disease (referred to as nephropathia epidemica) with prominent fever, myalgia, abdominal pain, and oliguria, but without shock or severe hemorrhagic manifestations. Hantavirus Pulmonary Syndrome, recently recognized in the Americas and probably worldwide, lacks hemorrhagic manifestations, but nevertheless carries a very high mortality due to its rapidly progressive and severe pulmonary capillary leak which presents as ARDS.

The clinical laboratory can be very helpful. Thrombocytopenia (exception: Lassa) and leukopenia (exception: 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. A positive tourniquet test has been particularly useful in Dengue hemorrhagic fever, but should be sought in other hemorrhagic fevers as well.

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 Lassa, Argentine HF, Rift Valley fever, Congo-Crimean HF, yellow fever and specific IgM antibodies in early convalescence. 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

Contact Precautions required for healthcare workers. General principles of supportive care apply to hemodynamic, hematologic, pulmonary, and neurologic manifestations of VHF, regardless of the specific etiologic agent concerned. Patients generally are either moribund or recovering by the second week of illness, but only intensive care will save the most severely ill patients. Health care providers employing vigorous fluid resuscitation of patients with hemodynamic compromise must be mindful of the propensity of some VHF cases (e.g., hantaviral) for pulmonary capillary leak. Pressor agents are frequently required. Invasive hemodynamic monitoring should be used where normal indications warrant, but extra caution should be exercised with regard to sharp objects and their potential for nosocomial transmission of a viral agent (see below). Intramuscular injections, aspirin and other anticoagulant drugs should be avoided. Restlessness, confusion, myalgia, and hyperesthesia should be managed by conservative measures and judicious use of sedative, pain-relieving, and amnestic medications. Secondary infections may occur as with any patient undergoing intensive care and invasive procedures, 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. DIC has been implicated specifically in Rift Valley fever and Marburg/Ebola infections, but in most VHF the etiology of the coagulopathy is multifactorial (e.g., hepatic damage, consumptive coagulopathy, and primary marrow injury to megakaryocytes). Dengue HF is a notable case where antibody-mediated enhancement of dengue virus infection of monocytes and cytotoxic T-cell responses to these presented viral antigens precipitates vascular injury and permeability, complement activation, and a systemic coagulopathy.

The investigational antiviral drug ribavirin is available via compassionate use protocols for therapy of Lassa fever, hemorrhagic fever with renal syndrome (HFRS), Congo-Crimean hemorrhagic fever, and Rift Valley fever. Separate Phase III efficacy trials have indicated that parenteral ribavirin reduces morbidity in both HFRS and Lassa fever, in addition to lowering mortality in the latter disease. In the human field trial with HFRS, treatment was effective if begun within the first 4 days of fever, and was continued for 7 days total. For Lassa fever patients, a compassionate use protocol utilizing intravenous ribavirin as a treatment is sponsored by the CDC. Dosages used were slightly different, and continued for 10 days total; treatment is most effective if begun within 7 days of onset. The only significant side effect of ribavirin is a modest anemia related to reversible block in erythropoiesis and mild hemolysis. Although ribavirin has demonstrated teratogenicity in animal studies, its use in a pregnant woman with grave illness from one of these VHFs must be weighed against potential benefit. Safety in infants and children has not been established. A similar dose of ribavirin begun within 4 days of disease may be effective in HFRS patients. It is important to note that ribavirin has poor in vitro and in vivo activity against either the filoviruses (Marburg and Ebola) or 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.

PROPHYLAXIS

The only established and licensed virus-specific 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 (AHF) 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 (BHF) as well. Both inactivated and live-attenuated Rift Valley fever vaccines are currently under investigation. There is no currently available vaccine for either the filoviruses or for dengue.

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 surface(s) with soap and water. Mucous membranes should be irrigated with copious amounts of water or saline.

Close personal contacts or medical personnel extensively exposed to blood or secretions from VHF patients (particularly Lassa fever, CCHF, and filoviral diseases) should be monitored for fever and other disease manifestations during a time equal to 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 drug dose well, but patients should be under surveillance for breakthrough disease (especially after drug cessation) or adverse drug effects (principally anemia).

ISOLATION AND CONTAINMENT

It should be noted that strict adherence to Contact Precautions has halted secondary transmission in the vast majority of circumstances. 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 diagnosis), 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. Clinical laboratory personnel are also at risk for exposure, and should employ a biosafety cabinet (if available) and barrier precautions when handling specimens.

Caution should be exercised in evaluating and treating the patient with a 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. These should include: isolation of the patient; stringent adherence to barrier nursing practices; mask, gown, glove, and needle precautions; decontamination of the outside of double-bagged specimens proceeding from the patient’s room; autoclaving or liberal application of hypochlorite or phenolic disinfectants to excreta and other contaminated materials; and biosafety cabinet containment of laboratory specimens undergoing analysis.

Experience has shown that Marburg, Ebola, Lassa, and Congo-Crimean HF viruses may be particularly prone to aerosol nosocomial spread. Well-documented secondary infections among contacts and medical personnel who were not parenterally exposed have occurred. 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 a significant suspicion of one of these diseases exists, additional management measures should include: an anteroom adjoining the patient’s isolation room to facilitate putting on and removing protective barriers and storage of supplies; use of a negative pressure room for patient care if available; minimal handling of the body should the patient die, with sealing of the corpse in leak-proof material for prompt burial or cremation.

No carrier state has ever been observed with any VHF, but excretion of virus in urine (e.g., hantaviruses) or semen (e.g., Argentine hemorrhagic fever) may occur in convalescence.