Clinical Overview

The concept of a viral hemorrhagic fever (VHF) syndrome is useful in clinical medicine. VHF syndrome can be described as an acute febrile illness characterized by malaise, prostration, generalized signs of increased vascular permeability and abnormalities of circulatory regulation.

The viral agents that cause VHFs are taxonomically diverse; they are all ribonucleic acid (RNA) viruses and are transmitted to humans through contact with infected animal reservoirs or arthropod vectors. Four virus families contribute pathogens to the group of VHF agents: Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae. They are all natural infectious disease threats, although their geographical ranges may be tightly circumscribed. The recent advent of jet travel coupled with human demographics increase the opportunity for humans to contract these infections.

The VHF agents are all highly infectious via the aerosol route and most are quite stable as respirable aerosols. This means that they satisfy at least one criterion for being weaponized, and some clearly have the potential to be biological warfare threats.

The viral hemorrhagic fevers are listed in the following chart:

The Arenaviridae: The arenaviruses are classified into the Old World and New World groups. All the arenaviruses are maintained in nature by a life-long association with a rodent reservoir. Rodents spread the virus to humans and outbreaks can usually be related to some perturbation in the ecosystem that brings man into contact with the rodents.

The Bunyaviridae: Among the bunyaviruses, the significant human pathogens include the phlebovirus Rift Valley fever (RVF) virus, which causes Rift Valley fever. This major African disease is frequently associated with unusual increases in mosquito populations. Rift Valley fever is also a disease of domestic livestock and human infections have resulted from contact with infected blood, especially around slaughterhouses.

The Filoviridae: The Filoviridae includes the causative agents of Ebola and Marburg hemorrhagic fevers and Ebola viruses, among others. Very little is known about the natural history of any of the filoviruses. Animal reservoirs and arthropod vectors have been aggressively sought without success.

The Flaviviridae: The flaviviruses include the agents of yellow fever and dengue found throughout the Americas, Asia and Africa, and are transmitted by mosquitoes.

Clinical Presentation

The VHF syndrome develops to varying degrees in patients infected with these viruses. The exact nature of the disease depends on viral virulence and strain characteristics, routes of exposure, dose and host factors. The target organ in the VHF syndrome is the vascular bed; 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 bleeding from the mucous membranes and often is accompanied by evidence of neurological, hematopoietic or pulmonary involvement. VHF mortality may be substantial, ranging from 5 - 20percent or higher in recognized cases. Ebola outbreaks in Africa have had particularly high fatality rates, from 50 – 90 percent. The clinical characteristics of the various VHFs are somewhat variable, depending on the disease.

Diagnosis

The natural distribution and circulation of VHF agents are geographically restricted and mechanistically linked with the ecology of the reservoir species and vectors. Therefore, a high index of suspicion and elicitation of a detailed travel history are critical in making the diagnosis of VHF. When large numbers of patients present with VHF manifestations in the same geographical area over a short period of time, medical personnel should suspect the possibility of a bio-warfare attack (particularly if the virus causing the VHF is not endemic to the area).

VHF should be suspected in any patient who has traveled to an area where the etiologic virus is known to occur if the patient presents a severe febrile illness and evidence of vascular involvement (i.e., subnormal blood pressure, postural hypotension, petechiae, hemorrhagic diathesis, flushing of the face and chest, nondependent edema) 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 they rarely dominate the picture. A macular eruption occurs in most patients who have Marburg and Ebola hemorrhagic fevers; this clinical manifestation is of diagnostic importance.

Laboratory findings can be helpful, although they vary from disease to disease and summarization is difficult. Leukopenia may be suggestive, but in some patients, white blood cell counts may be normal or even elevated. Thrombocytopenia is a component of most VHF diseases, but to a varying extent. A positive tourniquet test has been particularly useful in diagnosing dengue hemorrhagic fever, but this sign may be associated with other hemorrhagic fevers as well. Proteinuria or hematuria, or both, are common in VHF and their absence virtually rules out Argentine hemorrhagic fever, Bolivian hemorrhagic fever and hantaviral infections. Hematocrits are usually normal and if there is sufficient loss of vascular integrity perhaps mixed with dehydration, hematocrits may be increased. Liver enzymes such as aspartate aminotransferase (AST) are frequently elevated. VHF viruses are not primarily hepatotropic, but livers are involved and an elevated AST may help to distinguish VHF from a simple febrile disease.

Definitive diagnosis in an individual case rests on specific virological diagnosis. Infectious virus and viral antigens can be detected and identified by a number of assays using fresh or frozen serum or plasma samples. Likewise, early immunoglobulin (Ig) M antibody responses to the VHF-causing agents can be detected by enzyme-linked immunosorbent assays (ELISA), often during the acute illness. Diagnosis by viral cultivation and identification requires 3 -10 days for most (longer for the hantaviruses); and, with the exception of dengue, specialized microbiologic containment is required for safe handling of these viruses.

When the identity of a VHF agent is totally unknown, isolation in cell culture and direct visualization by electron microscopy, followed by immunological identification by immunohistochemical techniques is often successful.

Treatment

Patients with VHF syndrome require close supervision, and some will require intensive care. Since the pathogenesis of VHF is not entirely understood and availability of specific antiviral drugs is limited, treatment is largely supportive. This care is essentially the same as the conventional care provided to patients with other causes of multisystem failure. The challenge is to provide this support while minimizing the risk of infection to other patients and medical personnel.

Patients with VHF syndrome generally benefit from rapid, nontraumatic hospitalization to prevent unnecessary damage to the fragile capillary bed. Secondary infections are common and should be sought and aggressively treated. Intravenous lines, catheters and other invasive techniques should be avoided unless they are clearly indicated for appropriate management of the patient. Immunosuppression with steroids or other agents has no empirical and little theoretical basis, and is contraindicated except possibly for HFRS. The diffuse nature of the vascular pathological process may lead to a requirement for support of several organ systems. Cardiac insufficiency, pulmonary insufficiency and hepatorenal syndrome can be prominent complications.

Ribavirin is of proven value for some, but not all of the VHF agents. Recommendations are to treat initially with ribavirin 30 mg/kg, administered intravenously, followed by 15 mg/kg every 6 hours for 4 days, and then 7.5 mg/kg every 8 hours for an additional 6 days. Treatment is most effective if begun within 7 days of onset; lower intravenous doses or oral administration of 2 g followed by 1 g/d for 10 days also may be useful.

Transmissibility and Infection Control

Appropriate isolation precautions for patients with suspected or confirmed VHF include a combination of airborne and contact precautions. Although airborne transmission of these agents appears to be rare, airborne transmission theoretically may occur. The following precautions are recommended: N-95 respirator or powered air-purifying respirator (PAPR), double (leak-proof) gloves, impermeable gowns, face shields, goggles for eye protection, leg and shoe coverings, place the patient in a private room with negative air pressure, adhere strictly to hand hygiene, place all persons (including medical and laboratory personnel) who have had a close or high-risk contact with a patient suspected of having VHF during the 21 days following onset of symptoms (and before onset of appropriate barrier precautions) under medical surveillance, and cohort patients with the same disease.

The only established and licensed virus-specific vaccine available against any of the hemorrhagic fever viruses is yellow fever vaccine, which is mandatory for travelers to endemic areas of Africa and South America.

As with any bioterrorism agent, a case or suspected case of plague in someone living or working in the County should be immediately reported by phone call to the Anne Arundel County Department of Health at 410-222-7256. To report communicable diseases, click here for instructions.