HEMORRHAGIC FEVER VIRUSES AS BIOLOGICAL WEAPONS: MEDICAL AND PUBLIC HEALTH MANAGEMENT
[Borio L et al. JAMA 2002;287:2391]
This is another in the series of recommendations for management of the category A agents of bioterrorism from the Johns Hopkins Center for Civilian Biodefense Strategies, this one dealing with hemorrhagic fever viruses with authorship from the Center, NIH, USAMRIID, CDC, DHHS, New York City Health Department, FDA, and multiple academic institutions.
The major agents in terms of properties for utility as bioweapons are: Ebola, Marburg, Lassa, New World Arenaviridae, Rift Valley fever, Yellow fever, Omsk hemorrhagic fever and Kyasanur Forest Disease viruses. Other viruses that may cause viral hemorrhagic fever, but not considered likely agents for bioterrorism include dengue, Hantavirus and Crimean-Congo Hemorrhagic Fever virus.
1) transmitted to humans by contact with infected animal reservoirs or arthropod vectors (the natural reservoir and vectors of Ebola and Marburg viruses are not known); 2) all are small RNA viruses with lipid envelopes; 3) all lead to thrombocytopenia and some also cause platelet dysfunction.
There are only two BSL-4 facilities in the US with appropriate diagnostic expertise, the CDC and USAMRIID. The preferred tests are antigen detection by antigen-capture EIA, IgM detection by EIA, RT-PCR and viral isolation. The CDC requires one working day with prior notification to provide preliminary laboratory diagnostic test results. The requirements for packaging specimens is available at http://www.bt.cdc.gov/Agent/ VHF/VHF.asp. Criteria for BSL-4 is available at http://www.cdc.gov/od/ohs/biosfty/bmbl4/bmbl4S3.htm. The authors emphasize that the diagnosis of VHF should be based on clinical criteria and judgment with laboratory testing used to confirm or exclude the diagnosis.
Naturally occurring VHF is found in Africa (Ebola, Marburg, Lassa, Rift Valley fever and Yellow fever), Asia (Omsk hemorrhagic fever), India (Kyasanur Forest Disease) and Saudi Arabia and Yemen (Rift Valley fever). Naturally occurring disease is associated with risk factors including travel to these areas, handling of animal carcasses, contact with sick people or animals, or arthropod bites, all within 21 days of the onset of illness. The detection of VHF in the absence of travel combined with these risks specifically suggests bioterrorism.
Clinical features are summarized in the following table, which includes the clinical findings, incubation period, mortality rate, and the potential for person-person transmission.
- Antiviral treatment: There are no FDA-approved drugs for VHV. Ribavirin has some in vitro activity against some of these agents and benefit in clinical trials with Lassa fever (NEJM 1986;314:20) and Argentine hemorrhagic fever (Antiviral Res 1994;23:23). Recommendations for use of this drug are shown in the table above. This includes empiric treatment with ribavirin pending identification of the putative agent as recommended by the CDC (MMWR 1995;44:475) using doses previously tested with Lassa fever (NEJM 1986;314:20). The specific dose is 30 mg/kg IV x 1 followed by 16 mg/kg IV q6h for 4 days and then 8 mg/kg IV q8h for 6 days. The alternative oral dose for mass casualty settings or non-availability of the IV form is 2 gm po x 1 followed by 1,000–1,200 mg/day in two divided doses for 10 days (based on the dose used for HCV infection).
- Vaccine: There are no vaccines for these agents other than Yellow fever, which is the live attenuated 17 D vaccine and has proven highly effective for travelers to endemic areas. This vaccine would not be helpful for postexposure application due to the short incubation period and time required for antigenic response.
- Infection control: Most transmissions from person-to-person involve infected blood and body fluids for transmission of Filoviruses and Arenaviruses (Ebola, Marburg, Lassa and New World Arenaviridae). Nevertheless, airborne transmission cannot be excluded. The recommendations are to implement VHF-specific barrier precautions as summarized below for both patient isolation and management of laboratory specimens.
- Hand hygiene: Clean hands before and after protective equipment
- Double gloves
- Impermeable gowns
- N95 masks or PAPRs
- Negative isolation rooms with 6–12 air exchanges/hr
- Leg and shoe coverings
- Face shields/goggles
- Restricted access
- Dedicated medical equipment
- Disinfectant such as 1:100 household bleach
- Lab specimens
- Identified, double bagged, hand carried at scheduled times
- Dedicated/trained lab personnel
- Serum—pretreat with Trifon × 100
- Lab personnel with protective equipment using BSL-3 practices
All suspected cases of VHF should be immediately reported to local or state health departments and to infection control and laboratory personnel. For the suspected index case, the recommendations are based on suspicion according to a modified version of WHO surveillance standards using the following clinical criteria: 1) temperature >101°F of less than three weeks duration, 2) severe illness, 3) no predisposing factors for hemorrhagic manifestations, 4) at least two of the following symptoms: hemorrhage or purple rash, epistaxis, hematemesis, hemoptysis, blood in stool, and 5) no alternative diagnosis. High-risk contacts should be placed under medical surveillance for 21 days from the time of exposure. If the contacts develop fever to 101°F or signs or symptoms consistent with VHF, diagnostic workup and treatment with infection control should be done. If there is no fever or symptoms for 21 days after contact, medical surveillance can be discontinued.