Viral hemorrhagic fevers

Treatment Overview

General principles of supportive care apply to the hemodynamic, hematologic, pulmonary, and neurologic manifestations of VHF, regardless of the specific etiologic agent. Intensive care is required for 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. Vasoactive or inotropic agents are frequently required. The benefits of intravascular devices and invasive hemodynamic monitoring must be carefully weighed against the significant risk of hemorrhage. Restlessness, confusion, myalgia, and hyperesthesia should be managed by conservative measures, including the judicious use of sedatives and analgesics. Mechanical ventilation, renal dialysis, and anti-seizure therapy may be required. Secondary infections may occur as with any patient managed with invasive procedures and devices.

Management of the hemorrhagic component of VHFs mirrors that for any patient with a systemic coagulopathy. Red blood cells, platelets and clotting factors should be replaced, guided by clinical indicatation and coagulation studies. Intramuscular injections, aspirin, and other anticoagulant drugs should be avoided. Steroids are not indicated.

The antiviral drug ribavirin is available for therapy of Lassa fever, HFRS, CCHF, and RVF under an IND protocol. A controlled clinical trial has clearly indicated that parenteral ribavirin reduces morbidity in HFRS. Several trials have suggeste that ribavirin lowers both the morbidity and mortality of Lassa fever. In the HFRS field trials, treatment was effective if begun within the first 4 days of fever, and continued for a 10 day course. Both the CDC and DOD (USAMRIID) have IND protocols for the treatment of viral hemorrhagic fevers with intravenous ribavirin. Since the supply of intravenous ribavirin is small, oral ribavirin may be required in a mass-casualty situation. Oral ribavirin is licensed for the treatment of hepatitis C infection and is commercially available in the United States. Since it is not approved for use in VHF, it should be used under an IND protocol if possible. Dosing recommendations for IV and oral ribavirin are included in Table 2. Side effects of ribavirin include modest reversible hemolytic anemia and bone marrow suppression. Ribavirin is teratogenic in laboratory animals, but no human data exist. Risks to the fetus must be weighed against the potential life-saving benefit in pregnant women with grave illness due to one of these VHFs. Safety in infants and children has not been established for intravenous ribavirin, but inhaled ribavirin has been used extensively in the treatment of respiratory syncitial virus infection in infants. Ribavirin has poor in vitro and in vivo activity against the filoviruses (Ebola and Marburg) and the flaviviruses (dengue, yellow fever, Omsk hemorrhagic fever and Kyanasur Forest disease).

Argentine hemorrhagic fever responds to therapy with two or more units of convalescent plasma containing adequate amounts of neutralizing antibody and given within 8 days of onset. Bolivian hemorrhagic fever appears to respond to passive immune therapy as well. Convalescent serum or immune globulin for South American HF's is not readily available in the United States. This therapy is investigational and should be done only in consultation with experts.

TABLE 2: Recommended ribavirin dosing for treatment of viral hemorrhagic fevers* (from Borio et al. JAMA 2002;287:2391-2405)

Age Dosage Intravenous Oral
Adults Loading dose 30 mg/kg IV (max 2 grams) once 2000 mg PO once
Maintenance dose 16 mg/kg IV (max 1 gram) q6 hours for 4 days

8 mg/kg IV (max 500 mg) q8 hours for 6 days
Wt > 75 kg: 600 mg PO bid for 10 days

Wt < 75 kg: 400 mg PO in AM, 600 mg PO in PM for 10 days
Children Loading dose Same as for adult 30 mg/kg PO once
Maintenance dose Same as for adult 7.5 mg/kg PO bid for 10 days
*for confirmed or suspected arenavirus or bunyavirus or VHF of unknown etiology

Supportive care is essential for patients with all types of VHF and includes the following:

  • Maintenance of fluid and electrolyte balance, with hemodynamic monitoring as needed
  • Mechanical ventilation, as indicated
  • Dialysis, as indicated
  • Steroids have not been shown to be of value; however, because adrenal involvement may occur in VHF cases, steroids could be considered in certain situations (see References: Abraham 2002, Annane 2002)
  • Anticoagulant therapies, aspirin, nonsteroidal anti-inflammatory medications, and intramuscular injections are contraindicated
  • Appropriate therapy for secondary infections

Management of severe bleeding complications is controversial. Potential therapies include (see References: Jahrling 1997):

  • Clotting factor concentrates
  • Platelets
  • Fresh frozen plasma
  • Heparin for DIC

Convalescent human plasma has been shown to be effective in the treatment of Argentine hemorrhagic fever and has been suggested for treatment of other New World arenavirus infections (see References: Enria 2008; Peters 2005: Lymphocytic choriomeningitis, Lassa virus, and South American hemorrhagic fevers).

Ribavirin has some in vivo and in vitro activity against:

  • Arenaviruses (Lassa fever and New World hemorrhagic fevers) (see References: Enria 1994; Enria 2008; Huggins 1989; Kilgore 1997; McCormick 1986)
  • Bunyaviruses (Rift Valley fever and others) (see References: Borio 2002); ribavirin appears to be effective in animals (see References: Peters 1986) and could potentially be used cautiously in humans

Antiviral agents have not been shown to be effective, and are not recommended, for infections caused by:

  • Filoviruses (Ebola and Marburg hemorrhagic fever)
  • Flaviviruses (yellow fever, Kyasanur Forest disease, and Omsk hemorrhagic fever)

The recommended regimens for use of ribavirin are shown in the table below.

Ribavirin Therapy Recommendations for Patients With Viral Hemorrhagic Fever of Unknown Cause or Known to Be Caused by an Arenavirus or Bunyavirusa

Patient Group

Contained-Casualty Setting

Mass-Casualty Settingb

Adults (including pregnant women)c

—Loading dose of 30 mg/kg (maximum dose, 2 gm) IV once
Then 16 mg/kg (maximum dose, 1 gm) IV every 6 hr for 4 days
Then 8 mg/kg (maximum dose, 500 mg) IV every 8 hr for 6 days

Loading dose of 2,000 mg PO once, then:
    ~Weight >75 kg: 1,200 mg/day PO in 2 divided doses for 10 daysd
    ~Weight <75 kg: 1,000 mg/day PO in divided doses (400 mg in am and 600 mg in pm) for 10 daysd

Children

—Loading dose of 30 mg/kg (maximum dose, 2 gm) IV once
Then 16 mg/kg (maximum dose, 1 gm) IV every 6 hr for 4 days
Then 8 mg/kg (maximum dose, 500 mg IV) every 8 hr for 6 days

—Loading dose of 30 mg/kg PO once
Then 15 mg/kg/d PO in 2 divided doses for 10 days

Abbreviations: IV, intravenously; PO, orally.

aThese are the recommendations of the Working Group on Civilian Biodefense; ribavirin is not approved by the US Food and Drug Administration for treatment of viral hemorrhagic fever and must be used under an Investigational New Drug (IND) protocol, although in a mass-casualty setting, this requirement may need to be modified.
bThe decision to use oral rather than parenteral medication will depend on available resources.
cGenerally, ribavirin is contraindicated in pregnant women; however, the Working Group believes that the benefits appear to outweigh the fetal risk of ribavirin therapy. Also, the mortality of viral hemorrhagic fever appears to be higher in pregnancy.
dA 1,000-mg dosage per day given in 3 divided doses has been used to treat patients with Lassa fever; however, this regimen cannot be used in the United States, because the current available formulation of ribavirin is 200-mg capsules, which cannot be broken open.

Adapted from Borio 2002 (see References).

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