Andrew

June 30, 2022

Arenavirus

Arenaviridae

INTRODUCTION

Lymphocytic choriomeningitis (LCM) is a rodent borne viral infectious disease that presents as aseptic meningitis, encephalitis or meningoencephalitis in Europe, the Americas, Australia and Japan. The causative agent is lymphocytic choriomeningitis virus (LCMV ), which was the first of the arenavirus family isolated in 1933 during an epidemic of St Louis encephalitis. Other viruses of this family are Lassa virus (causing Lassa fever in Africa), Junin, Machupo, Guanirato and Sabia virus (all causing haemorrhagic fever in parts of South America). No case reports exist from India.

Arenaviruses are pleomorphic, round or oval viruses with diameters ranging from 50 to 300 nm. The virion surface has club-shaped projections and the virus itself contains a variable number of characteristic electron-dense granules that represent residual, non-functional host ribosomes. Arenavi- ruses are responsible for Lassa fever and also for lymphocytic choriomeningitis, Argentinian and Bolivian haemorrhagic fevers.

ETIOPATHOGENESIS

LCMV is transmitted from the common house mouse (Mus musculus) to humans by aerosols of excreta and secretions. It is maintained in the mouse mainly by vertical transmission from infected female mouse.The vertically infected mouse remains viremic for life, with high concentrations of virus in all tissues. Infected colonies of pet hamsters have also served as a link to humans. Individuals become infected with LCMV after exposure to fresh urine, droppings, saliva, or nesting materials. Transmission can also occur when these materials are directly introduced into broken skin, the nose, the eyes or the mouth or presumably, via the bite of an infected rodent. Person-to- person transmission has not been reported, with the exception of vertical transmission from infected mother to foetus. Recent investigations indicate that organ transplantation may also be a means of transmission. Patients with LCM may have a history of residence in rodent-infested housing or other exposure to rodents. An antibody prevalence of approximately 5-10% has been reported among adults from the United States, Argentina and endemic areas of Germany.

CLINICAL MANIFESTATIONSLymphocytic choriomeningitis (LCM)

LCM presents with gradual fever and myalgia. Other symptoms are orchitis,transient alopaecia, arthritis, pharyngitis, cough and maculopapular rash. Less than 25% patients experience a febrile phase of 3 to 6 days with transient remission followed by recurrence of fever with severe headache, nausea and vomiting, and meningeal signs lasting for approximately 1 week. These patients virtually always recover fully, as do the uncommon patients with clear-cut signs of encephalitis. Recovery may be delayed by transient hydrocephalus.

The dominant clinical features of VHF are a consequence of microvascular damage and changes in vascular permeability. Patients commonly present with fever, myalgia, and prostration. Full- blown VHF syndrome typically evolves to shock and generalized mucous membrane hemorrhage, and often is accompanied by evidence of neurological, hematopoietic, or pulmonary involvement. A viral hemorrhagic fever should be suspected in any patient who presents with a severe febrile illness and evidence of vascular involvement (subnormal blood pressure, postural hypotension, petechiae, easy bleeding, flushing of the face and chest, nondependent edema), and who has traveled to an area where the virus is known to occur, or where intelligence suggests a biological warfare threat.

Lymphocytic choriomeningitis/meningoencephalitis is the only human arenavirus infection resulting predominantly in fever and myalgia. Lymphocytic choriomeningitis virus is transmitted to humans from the common house mouse (Mus musculus) by aerosols of excreta and secreta. The virus is maintained in the mouse mainly by vertical transmission from infected dams. The vertically infected mouse remains viremic and sheds virus for life, with high concentrations of virus in all tissues. Infected colonies of pet hamsters also can serve as a link to humans. Infections among scientists and animal caretakers can occur because the virus is widely used in immunology laboratories as a model of T cell function and can silently infect cell cultures and passaged tumor lines. In addition, patients may have a history of residence in rodent-infested housing or other exposure to rodents. An antibody prevalence of ~5–10% has been reported among adults from Argentina, Germany, and the United States.

Lymphocytic choriomeningitis/meningoencephalitis differs from the general syndrome of fever and myalgia in that the onset is gradual. Conditions occasionally associated with the disease are orchitis, transient alopecia, arthritis, pharyngitis, cough, and maculopapular rash. An estimated one-fourth of patients (or fewer) experience a febrile phase of 3–6 days. After a brief remission, many develop renewed fever accompanied by severe headache, nausea and vomiting, and meningeal signs lasting for ~1 week (the CNS phase). These patients virtually always recover fully, as do the rare patients with clear-cut signs of encephalitis. Recovery may be delayed by transient hydrocephalus. During the initial febrile phase, leukopenia and thrombocytopenia are common, and virus can usually be isolated from blood. During the CNS phase, the virus may be found in the CSF, and antibodies are present in the blood.

The pathogenesis of lymphocytic choriomeningitis/meningoencephalitis is thought to resemble that following direct intracranial inoculation of the virus into adult mice. The onset of the immune response leads to T cell–mediated immunopathologic menin- gitis. During the meningeal phase, CSF mononuclear-cell counts range from the hundreds to the low thousands per microliter, and hypoglycorrhachia is found in one-third of patients. IgM-capture ELISA, immunochemistry, and RT-PCR are used in the diagnosis of lymphocytic choriomeningitis/meningoencephalitis. IgM-capture ELISA of serum and CSF usually yields positive results; RT-PCR assays have been developed for probing CSF. Because patients who have fulminant infections transmitted by recent organ transplantation do not mount an immune response, immunohistochemistry or RT-PCR is required for diagnosis. Infection should be suspected in acutely ill febrile patients with marked leukopenia and thrombocytopenia. In patients with aseptic meningitis, any of the following suggests lymphocytic choriomeningitis/meningoencephalitis: a well- marked febrile prodrome, adult age, occurrence in the autumn, low CSF glucose levels, or CSF mononuclear-cell counts of >1000/μL.

In pregnant women, infection may lead to fetal invasion with consequent congenital hydrocephalus and chorioretinitis. Because the maternal infection may be mild, causing only a short febrile illness, antibodies to the virus should be sought in both the mother and the fetus under suspicious circumstances, particularly in TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and HIV)–negative neonatal hydrocephalus.

Lymphocytic Choriomeningitis and Other Arena Virus InfectionsDeepti Vibha, Garima Shukla

In pregnant women, LCM virus infection may lead to foetal invasion with consequent congenital hydrocephalus and chorioretinitis. Since the maternal infection may be mild, consisting of only a short febrile illness, antibodies to the virus should be sought in both the mother and the fetus in suspicious circumstances, particularly TORCH-negative neonatal hydrocephalus.

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.

Lassa virus causes Lassa fever, a major febrile disease of West Africa, where it is associated with 10% to 15% of adult febrile admissions to the hos- pital and perhaps 40% of nonsurgical deaths.1 In addition, Lassa fever is a pediatric disease and the cause of high mortality in pregnant women. While nosocomial infections do occur, most Lassa virus infections can be traced to contact with the carrier rodent, Mastomys natilensis.

The Junin virus that causes Argentine hemorrhagic fever is carried by a field mouse, Calomys colosus, and is associated with agricultural activities in the pampas of Argentina, where 300 to 600 cases have occurred every year since 1955. In Bolivia, Machupo virus is the agent associated with Bolivian hemorrhagic fever, a disease that was associated with outbreaks in the 1960s but only with sporadic disease subsequently. Guanarito virus is a newly described arenavirus, first recognized in association with an outbreak of VHF involving several hundred patients in Venezuela beginning in 1989. More recently, yet another VHF arenavirus has been recognized: Sabia virus was associated with a fatal VHF infection in Brazil in 1990, followed by a severe laboratory infection in Brazil in 1992 and another laboratory infection in the United States in 1994.

DIAGNOSIS

During the initial febrile phase, leucopaenia and thrombo- cytopaenia are common and virus can usually be isolated from blood. In cases of aseptic meningitis, any of the following should suggest a suspicion of LCM: well-marked febrile prodrome,adult age, autumn seasonality, low cerebrospinal fluid (CSF) glucose levels, or CSF mononuclear cell counts of >1000/L. The IgM-capture ELISA of serum and CSF is usually positive; RT- PCR assays have been developed for application to CSF. Recent infections transmitted by organ transplantation did not include evidence of an immune response, followed a fulminant course, and required immunohistochemistry or RT-PCR for diagnosis.

Lassa fever

This illness was first documented in the town of Lassa, Nigeria, in 1969 and is confined to sub-Saharan West Africa (Nigeria, Liberia and Sierra Leone). The multimammate rat, Mastomys natalensis, is known to be the reservoir. Humans are infected by ingesting foods contaminated by rat urine or saliva containing the virus. Person-to-person spread by body fluids also occurs. Only 10–30% of infections are symptomatic.

Clinical features

The incubation period is 7–18 days. The disease is insidious in onset and is characterized by fever, myalgia, severe back- ache, malaise and headache. A transient maculopapular rash may be present. A sore throat, pharyngitis and lymphaden- opathy occur in over 50% of patients. In severe cases, epistaxis and gastrointestinal bleeding may occur; hence the classification of Lassa fever as a viral haemorrhagic fever. The fever usually lasts 1–3 weeks and recovery within 1 month of the onset of illness is usual. However, death occurs in 15–20% of hospitalized patients, usually from irreversible hypovolaemic shock.

Diagnosis

The diagnosis is established by serial serological tests (including the Lassa virus-specific IgM titre) or by genome detection by means of RT-PCR in throat swab, serum or urine.

Viral infections associated with haemorrhagic manifestationsFlavivirus

Yellow fever (urban and sylvan) Dengue haemorrhagic fever Kysanur Forest disease Omsk haemorrhagic fever Bunyavirus Rift Valley fever Congo–Crimean haemorrhagic fever Hantavirus infections Arenavirus Argentinian haemorrhagic fever Bolivian haemorrhagic fever Lassa fever Epidemic haemorrhagic fever Filovirus Marburg Ebola aMost of these are arboviruses. Some (e.g. Hantavirus, Lassa fever) have a rodent vector. The source and transmission route of filoviruses is not known. Table 4.22 Human lymphotropic retroviruses Sub-family Virus Disease Lentivirus HIV-1 AIDS HIV-2 AIDS Oncovirus HTLV-1a Adult T-cell leukaemia/lymphoma Tropical spastic paraparesis HTLV-2 Myelopathy aHTLV, human T-cell lymphotropic virus. 112

Transmissible spongiform encephalopathies (TSE or prion diseases) 4 î ª î ª Non-nervous-system illness, with fever, malaise, myalgia, headache, arthralgia and vomiting Aseptic meningitis in addition to the above symptoms. if brain tissue enters another host. There is no convincing evidence for the presence of nucleic acid in association with prions; thus these agents cannot be considered ortho- dox viruses and it is the abnormal prion protein itself that is infectious and can trigger a conversion of the normal protein into the atypical isoform. After infection, a long incu- bation period is followed by CNS degeneration associated with dementia or ataxia, which invariably leads to death. Histology of the brain reveals spongiform change with an accumulation of the abnormal prion protein in the form of amyloid plaques. The human prion diseases are Creutzfeldt–Jakob disease, including the sporadic, familial, iatrogenic and variant forms of the disease, Gerstmann–Straussler–Scheinker syndrome, fatal familial insomnia and kuru. î ª Creutzfeldt–Jakob disease (CJD) usually occurs sporadically worldwide with an annual incidence of one per million of the population. Although, in most cases, the epidemiology remains obscure, transmission to others has occurred as a result of administration of human cadaveric growth hormone or gonadotrophin, from dura mater and corneal grafting and in neurosurgery from reuse of contaminated instruments and electrodes (iatrogenic CJD). î ª Variant CJD. In the UK, knowledge that large numbers of cattle with the prion disease, bovine spongiform encephalopathy (BSE) had gone into the human food chain, led to enhanced surveillance for emergence of the disease in humans. The evidence is convincing, based on transmission studies in mice and on glycosylation patterns of prion proteins, that this has occurred and, to date, there have been approximately 170 confirmed and suspected cases of variant CJD (human BSE) in the UK and 40 in the rest of the world. In contrast to sporadic CJD, which presents with dementia at a mean age of onset of 60 years, variant CJD presents with ataxia, dementia, myoclonus and chorea at a mean age of onset of 29 years. The epidemic curve of vCJD in the UK is shown in Figure 4.22. 150 100 50 0 Figure 4.22 Creutzfeldt–Jakob disease. Deaths of confirmed variant and sporadic cases of CJD (to early Dec. 2010) in the UK. (Courtesy of Professor JW Ironside, Director National CJD Surveillance Unit, University of Edinburgh.) 113 Occasionally, a more severe form occurs, with encephalitis leading to disturbance of consciousness. This illness is generally self-limiting and requires no spe- cific treatment.

This infection is a zoonosis, the natural reservoir of LCM virus being the house mouse. Infection is characterized by:

DIAGNOSIS

Definitive diagnosis rests on specific virological diagnosis, including detection of viremia or IgM by ELISA at presentation. Diagnosis by viral cultivation and identification requires 3 to 10 days or longer and specialized microbiologic containment. Appropriate precautions should be observed in collection, handling, shipping, and processing of di- agnostic samples. It is prudent to provide isolation measures that are as rigorous as feasible.

IMPORTANCE

The VHF agents are a taxonomically diverse group of RNA viruses that cause serious diseases with high morbidity and mortality. Their existence as endemic disease threats or their use in biological warfare could have a formidable impact on unit readiness. Significant human pathogens include the arenaviruses (Lassa, Junin, and Machupo viruses, the agents of Lassa fever and Argentinean and Bo- livian hemorrhagic fevers, respectively). Bunyavirus pathogens include RVF virus, the agent of Rift Valley fever; C-CHF virus, the agent of Crimean- Congo hemorrhagic fever; and the hantaviruses. Filovirus pathogens include Marburg and Ebola viruses. The flaviviruses are arthropod-borne vi- ruses and include the agents of yellow fever, dengue, Kyasanur Forest disease, and Omsk hemor- rhagic fever.

Definitive diagnosis rests on specific virological diagnosis, including detection of viremia or IgM by ELISA at presentation. Diagnosis by viral cultiva- tion and identification requires 3 to 10 days or longer and specialized microbiologic containment. Appropriate precautions should be observed in col- lection, handling, shipping, and processing of di- agnostic samples. It is prudent to provide isolation measures that are as rigorous as feasible.

Patients with viral hemorrhagic fevers generally benefit from rapid, nontraumatic hospitalization to prevent unnecessary damage to the fragile capillary bed. Aspirin and other antiplatelet or anticlotting- factor drugs should be avoided. Secondary and con- comitant infections including malaria should be sought and aggressively treated. The management of bleeding includes administration of fresh frozen plasma, clotting factor concentrates and platelets, and early use of heparin to control DIC. Fluids should be given cautiously, and asanguineous colloid or crystalloid solutions should be used. Mul- tiple organ system support may be required. Ribavirin is an antiviral drug with efficacy for treatment of the arenaviruses and bunyaviruses.

Passively administered antibody is also effective in therapy of some viral hemorrhagic fevers. The only licensed vaccine available for VHF agents is for yellow fever. Experimental vaccines exist for Junin, RVF, hantaan, and dengue viruses, but these will not be licensed in the near future.

TREATMENT

Treatment is supportive. In addition, clinical benefit and reduction in mortality can be achieved with ribavirin therapy, if given in the first week. In non-endemic countries, strict isolation procedures should be used, the patient ideally being nursed in a flexible-film isolator. Specialized units for the management of Lassa fever and other haemorrhagic fevers have been established in the UK. As Lassa fever virus and other causes of haemor- rhagic fever (Marburg/Ebola and Congo-Crimean haemor- rhagic fever viruses) have been transmitted from patients to staff in healthcare situations, great care should be taken in handling specimens and clinical material from these patients.

The patients require hospitalisation and supportive care,based on the severity of symptoms.Although studies have shown that ribavirin, a drug used to treat several other viral diseases, is effective against LCMV in vitro, there is no established evidence to support its routine use for treatment of LCM in humans.

Treatment of Hypotension and ShockManagement of hypotension and shock is difficult. Patients often are modestly dehydrated from heat, fever, anorexia, vomiting, and diarrhea, in any combination. There are covert losses of intravascular volume through hemorrhage and increased vascular permeability. Nevertheless, these patients often respond poorly to fluid infusions and readily develop pulmonary edema, possibly due to myocardial impairment and increased pulmonary vascular permeability. Asanguineous fluids—either colloid or crystalloid solutions—should be given, but cautiously. Although it has never been evalu- ated critically for VHFs, dopamine would seem to be the agent of choice for patients with shock who are unresponsive to fluid replacement. α-Adrenergic vasoconstricting agents have not been clinically helpful except when emergent intervention to treat profound hypotension is necessary. Vasodilators have never been systematically evaluated. Pharmacological doses of corticosteroids (eg, methylprednisolone 30 mg/kg) provide another possible but untested therapeutic modality in treat- ing shock.

Particular Problems With Dengue and Hantaviral InfectionsTwo hemorrhagic fevers should be clearly separated from the other VHF diseases. Severe consequences of dengue infection are largely due to systemic capillary leakage syndrome and should be managed initially by brisk infusion of crystalloid, followed by albumin or other colloid if there is no response.

Severe hantaviral infections have many of the management problems of the other hemorrhagic fevers but will culminate in acute renal failure with a subsequent polyuria during the patient’s recovery. Careful fluid and electrolyte management, and often renal dialysis, are necessary for optimal treatment.

Isolation and ContainmentPatients with VHF syndrome generally have sig- nificant quantities of virus in their blood, and perhaps in other secretions as well (with the excep- tions of dengue and classic hantaviral disease). Well-documented secondary infections among contacts and medical personnel not parenterally exposed have occurred. Thus, caution should be exercised in evaluating and treating patients with suspected VHF syndrome. Over-reaction on the part of medical personnel is inappropriate and detrimental to both patient and staff, but it is prudent to provide isolation measures as rigorous as feasible. At a minimum, these should include the following:

  • stringent barrier nursing;
  • mask, gown, glove, and needle precautions;
  • hazard-labeling of specimens submitted to the clinical laboratory; restricted access to the patient; and
  • autoclaving or liberal disinfection of contaminated materials, using hypochlorite or phenolic disinfectants.
For more intensive care, however, increased pre- cautions are advisable. Members of the patient care team should be limited to a small number of selected, trained individuals, and special care should be directed toward eliminating all parenteral exposures. Use of endoscopy, respirators, arterial catheters, routine blood sampling, and extensive laboratory analysis increase opportunities for aerosol dissemination of infectious blood and body fluids. For medical personnel, the wearing of flex- ible plastic hoods equipped with battery-powered blowers provides excellent protection of the mucous membranes and airways.

Specific Antiviral Therapy

Ribavirin is a nonimmunosuppressive nucleoside analogue with broad antiviral properties,31 and is of proven value for some of the VHF agents. Ribavirin reduces mortality from Lassa fever in high-risk patients,32 and presumably decreases morbidity in all patients with Lassa fever, for whom current 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. The only significant side effects have been ane- mia and hyperbilirubinemia related to a mild hemolysis and reversible block of erythropoiesis. The anemia did not require transfusions or cessation of therapy in the published Sierra Leone study or in subsequent unpublished limited trials in West Africa. Ribavirin is contraindicated in pregnant women, but, in the case of definite Lassa fever, the predictability of fetal death and the need to evacuate the uterus justify its use. Safety of ribavirin in infants and children has not been established.

A similar dose of ribavirin begun within 4 days of disease is efficacious in patients with HFRS. In Argentina, ribavirin has been shown to reduce viro- logical parameters of Junin virus infection (ie, Argentine hemorrhagic fever), and is now used routinely as an adjunct to immune plasma. However, ribavirin does not penetrate the brain and is expected to protect only against the visceral, not the neurological phase of Junin infection.

Small studies investigating the use of ribavirin in the treatment of Bolivian hemorrhagic fever and Crimean-Congo hemorrhagic fever have been promising, as have preclinical studies for Rift Val- ley fever. Conversely, ongoing studies conducted at USAMRMC predict that ribavirin will be ineffective against both the filoviruses and the flaviviruses. No other antiviral compounds are currently available for the VHF agents.

Interferon alpha has no role in therapy, with the possible exception of Rift Valley fever, where fatal hemorrhagic fever has been associated with low interferon responses in experimental animals. However, as an adjunct to ribavirin, exogenous interferon gamma holds promise in treatment of arenaviral infections.

MEDICAL MANAGEMENT

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.

Supportive CarePatients with VHF syndrome generally benefit from rapid, nontraumatic hospitalization to prevent unnecessary damage to the fragile capillary bed. Transportation of these patients, especially by air, is usually contraindicated because of the effects of drastic changes in ambient pressure on lung water balance. Restlessness, confusion, myalgia, and hyperesthesia occur frequently and should be managed by reassurance and other supportive measures, including the judicious use of sedative, pain-relieving, and amnestic medications. Aspirin and other antiplatelet or anticlotting-factor drugs should be avoided.

Secondary infections are common and should be sought and aggressively treated. Concomitant malaria should be treated aggressively with a regimen known to be effective against the geographical strain of the parasite; however, the presence of ma- laria, particularly in immune individuals, should not preclude management of the patient for VHF syndrome if such is clinically indicated. Intravenous lines, catheters, and other invasive techniques should be avoided unless they are clearly indicated for appropriate management of the patient. Attention should be given to pulmonary toilet, the usual measures to prevent superinfection, and the provision of supplemental oxygen. Immunosuppression with steroids or other agents has no empirical and little theoretical basis, and is contra- indicated except possibly for HFRS.

The diffuse nature of the vascular pathological process may lead to a requirement for support of several organ systems. Myocardial lesions detected at autopsy reflect cardiac insufficiency antemortem. Pulmonary insufficiency may develop, and, particularly with yellow fever, hepatorenal syndrome is prominent.

BleedingThe management of bleeding is controversial. Uncontrolled clinical observations support vigorous administration of fresh frozen plasma, clotting factor concentrates, and platelets, as well as early use of heparin for prophylaxis of DIC. In the absence of definitive evidence, mild bleeding manifestations should not be treated at all. More-severe hemorrhage indicates that appropriate replacement therapy is needed. When definite laboratory evidence of DIC becomes available, heparin therapy should be employed if appropriate laboratory support is available.

Patients with viral hemorrhagic fevers generally benefit from rapid, nontraumatic hospitalization to prevent unnecessary damage to the fragile capillary bed. Aspirin and other antiplatelet or anticlotting- factor drugs should be avoided. Secondary and concomitant infections including malaria should be sought and aggressively treated. The management of bleeding includes administration of fresh frozen plasma, clotting factor concentrates and platelets, and early use of heparin to control DIC. Fluids should be given cautiously, and asanguineous colloid or crystalloid solutions should be used. Multiple organ system support may be required. Ribavirin is an antiviral drug with efficacy for treatment of the arenaviruses and bunyaviruses.

Passively administered antibody is also effective in therapy of some viral hemorrhagic fevers. The only licensed vaccine available for VHF agents is for yel- low fever. Experimental vaccines exist for Junin, RVF, hantaan, and dengue viruses, but these will not be licensed in the near future.

IMMUNOPROPHYLAXIS & IMMUNOTHERAPY

Passive immunization has been attempted for treatment of most VHF infections. This approach has often been taken in desperation, owing to the limited availability of effective antiviral drugs. Anecdotal case reports describing miraculous successes are frequently tempered by more systematic studies, where efficacy is less obvious. For all VHF viruses, the benefit of passive immunization seems to be correlated with the concentration of neutralizing antibodies, which are readily induced by some—but not all—of these viruses.

Passive Immunization

Antibody therapy (ie, passive immunization) also has a place in the treatment of some VHFs. Argentine hemorrhagic fever responds to therapy with two or more units of convalescent plasma that contain adequate amounts of neutralizing antibody (or an equivalent quantity of immune globulin), provided that treatment is initiated within 8 days of onset.

Antibody therapy is also beneficial in the treatment of Bolivian hemorrhagic fever. Efficacy of immune plasma in treatment of Lassa fever and Crimean-Congo hemorrhagic fever is limited by low neutralizing antibody titers and the consequent need for careful donor selection.

In the future, engineered human monoclonal antibodies may be available for specific, passive immunization against the VHF agents. In HFRS, a passive immunization approach is contraindicated for treatment, since an active immune response is usually already evolving in most patients when they are first recognized, although plasma containing neutralizing antibodies has been used empirically in prophylaxis of high-risk exposures.

Active Immunization

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. For prophylaxis against Argentine hemorrhagic fever (AHF) virus, a live- attenuated Junin vaccine strain (Candid #1) was developed at USAMRMC and is available as an Investigational New Drug (IND). Candid #1 was proven to be effective in Phase III studies in Argentina, and plans are proceeding to obtain a New Drug license. This vaccine also provides some cross-protection against Bolivian hemor- rhagic fever in experimentally infected primates. Two IND vaccines were developed at USAMRMC against Rift Valley fever; an inactivated vaccine that requires three boosters, which has been in use for 20 years; and a live-attenuated RVF virus strain (MP-12), which is presently in Phase II clinical trials.

For Hantaan virus, a formalin-inactivated rodent brain vaccine is available in Korea, but is not generally considered acceptable by U.S. standards. Another USAMRMC product, a genetically engineered vaccinia construct, expressing hantaviral structural proteins, is in Phase II safety testing in U.S. volun- teers. For dengue, a number of live attenuated strains for all four serotypes are entering Phase II efficacy testing. However, none of these vaccines in Phase I or II IND status will be available as li- censed products in the near term. For the remaining VHF agents, availability of effective vaccines is more distant.

COMPLICATIONS & MORTALITY

No chronic infection has been described in humans. Nerve deafness and arthritis have been reported. Infection of the human foetus during the early stages of pregnancy may lead to developmental deficits that are permanent. Mortality is less than 1% except in transplant recipients where high mortality has been reported.