Bioterrorism Update: Viral Hemorrhagic Fever

The viruses that can cause hemorrhagic fever could be very dangerous in terrorist hands: All but one can be aerosolized, their mortality rates typically exceed 50%, and their initial presentation is often nonspecific.

By Mark Graber, MD

Among the organisms on the Centers for Disease Control and Prevention's (CDC's) "A" list as potential biological weapons are the viruses that cause hemorrhagic fever. These include the Filoviridae (Ebola and Marburg), Flaviviridae (yellow and dengue fever), Bunyaviridae (Hantavirus), and other less well known viruses. This article will review the significance and presentation of these viruses, with a special emphasis on Hantavirus, which has already been identified in the United States, and the Ebola virus, which is associated with high mortality and recurrent epidemics in Africa.
 

What is the history of the viruses that cause hemorrhagic fever?

Historical descriptions of yellow fever epidemics in Africa and the Americas date back about 400 years. By contrast, the first description of the Marburg virus was in 1967, and the first description of the Ebola virus was in the late 1970s. More recently, Hantavirus emerged as an identified pathogen in 1993, although it undoubtedly has been present for far longer.

The public health impact of these viruses varies widely. The Ebola virus, for example, is of little health significance worldwide except for its potential use as a biological weapon. Dengue fever, on the other hand, is a leading cause of childhood mortality in parts of Asia.
 

What is the target of the hemorrhagic viruses?

While there are clinical differences between the viruses, all of them have an affinity for the microvascular bed, which generally leads to a coagulopathy. This may be multifactorial (for example, a combination of hepatic failure, marrow failure, and factor consumption) or it may manifest as disseminated intravascular coagulation.
 

Why are these viruses considered potential agents of biological warfare?

With the exception of the dengue fever virus, they can all be transmitted as an aerosol. Thus, they could be introduced into a city through the air (using a crop duster, for example), infecting a large population. Also, they have a relatively high mortality rate—more than 50% in most cases, depending on the strain of the virus.
 

Do these viruses produce any common symptoms?

Patients infected with these viruses generally present with nonspecific findings such as fever, myalgia, and weakness. Physical examination may reveal hypotension, conjunctival injection, and, in some cases, a petechial rash. In many patients, bleeding develops as a result of a coagulopathy. This can take the form of gastrointestinal bleeding or pulmonary hemorrhage, for example. Further complications include renal failure, adult respiratory distress syndrome, and shock.

Not all infected patients develop full-blown viral hemorrhagic fever. Host factors that modulate an individual's response to the infection are largely unknown.
 

How does the presentation of these viruses differ?

It may be difficult to differentiate these viral syndromes from each other. Use of epidemiologic data and consultation with the CDC or another agency are crucial in helping to identify the virus. However, there are some clues that may aid the clinician in determining the source of the infection (see table below).

Is there any treatment available for these viruses?

Currently, there are no approved treatments for viral hemorrhagic fevers, although there is an ongoing trial of ribavirin for Hantavirus. Vaccines are available for yellow fever and Argentine hemorrhagic fever.
 

What kind of isolation precautions must be used with these viruses?

Patients with suspected hemorrhagic fever should be isolated in a private room. Health care personnel should maintain contact precautions and respiratory isolation, using a properly fitted respirator, a battery-powered air-purifying respirator, or positive-pressure respirator containing an air source. Once the virus has been identified, isolation precautions may be modified based on health department recommendations.
 

How is Hantavirus transmitted?

The North American hantavirus is transmitted by inhalation of infected rodent droppings, urine, or saliva. Ingestion of or direct contact with rodent excretions has also been implicated. Human-to-human transmission has not occurred so far.
 

What are the signs and symptoms of Hantavirus pulmonary syndrome (HPS)?

Most patients present with fever, chills, and myalgia. Less common symptoms include headache, nausea, vomiting, and cough. Around day seven of the illness, patients develop cardiac and pulmonary symptoms such as cough, dyspnea, and tachypnea, which progresses rapidly to adult respiratory distress syndrome. There is a direct cardiodepressor effect, manifested by bradycardia, decreased cardiac output, and hypotension.

According to the CDC, findings that make the diagnosis of HPS unlikely include rash, conjunctival or other hemorrhages, throat or conjunctival erythema, petechiae, and peripheral or periorbital edema.
 

What are the typical laboratory and radiographic findings in HPS?

Laboratory findings include leukocytosis with a left shift and possibly atypical lymphocytes. Also, 80% of patients will have thrombocytopenia with a platelet count below 150,000. Occasionally, a patient may develop disseminated intravascular coagulation, but this is uncommon with HPS. Chest x-ray may show evidence of adult respiratory distress syndrome with pulmonary edema and, in most patients, a normal-sized heart.
 

What diagnostic tests are available to confirm the presence of Hantavirus?

Hantavirus-related illness can be confirmed by serum antibody tests (IgM and IgG) demonstrating the presence of the virus in tissue, as well as by RNA polymerase chain reaction testing.
 

Is there any treatment available for HPS?

Despite initial enthusiasm for intravenous ribavirin, a controlled trial showed no survival benefit. Therefore, this should still be considered experimental therapy. The CDC has an ongoing placebo-controlled trial.
 

What is the mortality rate of HPS?

The mortality rate of the North American strain of this virus is approximately 50%.
 

How is the Ebola virus transmitted?

The primary vector and natural reservoir of the Ebola virus remain unknown. Humans are an incidental host. The virus may be transmitted through contact with blood or body fluids or by inhalation of an aerosol, in which form the virus is stable and highly infectious. It can also be transmitted through contact with semen up to seven weeks after the patient has recovered from the illness.
 

What is the incubation period of the Ebola virus?

The incubation period averages five to eight days, but it may be as short as two days or as long as 21 days.
 

What are the signs and symptoms of Ebola virus infection?

The first phase of the illness is marked by fever, diarrhea, nausea, severe asthenia, vomiting, anorexia, headache, and myalgia. During this phase, patients develop bilateral conjunctival injection. Around day five, a maculopapular rash develops in the groin area and progresses to involve the entire body except for the head and neck. The rash may become petechial. The presence of a rash during the illness is unique among the hemorrhagic viruses and strongly suggests that the patient is infected with the Ebola virus. Another possible symptom is severe pain on swallowing.

This first phase lasts about a week and is usually followed by a one- to two-day remission period. Patients either recover at this point or progress to the second phase of the illness, characterized by tachypnea, shock, anuria, mental status changes, and generalized bleeding. Death generally occurs in several days. Hiccups, which develop in 15% of patients, herald a poor outcome.
 

What are the typical laboratory and radiographic findings in Ebola virus infection?

Thrombocytopenia and leukopenia are common. Transaminases are generally elevated, with aspartate aminotransferase higher than alanine aminotransferase.
 

What diagnostic tests are available to confirm the presence of Ebola virus?

Viral cultures may be done. Seroconversion occurs around day eight of the illness, and tests are available for IgM and IgG antibodies. Viral antigen can be detected in the blood and a polymerase chain reaction technique is also available.
 

Is there any treatment available for Ebola virus?

No specific treatment is available at this time. Treatment is supportive only.
 

What is the mortality rate of Ebola virus infection?

Mortality rates during epidemics have ranged between 53% and 88%.

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Emerg Med 34(5):44, 2002