Rodents experience silent, lifelong infection with arenaviruses, with persistent viruria, and are the primary source of contamination of the environment. Five arenaviruses cause hemorrhagic fevers: Lassa in West Africa, and Junin, Machupo, Guanarito, and Sabia in South America, causing Argentine, Bolivian, Venezuelan, and Brazilian hemorrhagic fevers, respectively. These viruses occupy circumscribed, sometimes remote ecologic niches, intrusion into which determines human infection. The viruses infect primarily through skin cuts and scratches and possibly the mucosae, contaminated with rodent urine, although there is evidence with Argentine hemorrhagic fever that dust generated by agricultural implements and laden with infected rodent urine may infect by aerosol. In endemic foci, the number of infected people may be very high. Human-to-human spread through blood contact is reported for Lassa fever both in community and hospital settings but is apparently rare with the other pathogenic arenaviruses.
Arenaviruses are enveloped, pleomorphic, membrane viruses containing two segments of single-stranded RNA, tightly associated with a nucleocapsid protein. The small RNA strand encodes the glycoprotein precursor and the nucleoprotein. Lassa and the South American hemorrhagic fever viruses are categorized as BSL4 laboratory agents. Disease may be severe and hemorrhagic, but with Lassa fever at least, mild or asymptomatic infection is also common.
Lassa fever is confined to West Africa, where it is responsible for up to 16% of all adult medical admissions and about 30% of adult deaths on medical wards.33 It has been estimated that more than 100,000 infections with Lassa virus may occur each year, with several thousand deaths. All age groups and both sexes are affected. In endemic areas, illness:infection ratios range from 9% to 26%, and the proportion of febrile illness associated with seroconversion is between 5% and 14%. Five to eight percent of infected people may be hospitalized, of whom 17% will die if untreated. However, the fatality among all infections (hospitalized and nonhospitalized) is of the order of 2%.34
Person-to-person spread of Lassa virus occurs within homes as well as in hospitals. Hospital outbreaks are associated with inadequate disinfection and direct contact with infected blood and contaminated needles. Increasing and indiscriminate use of needles for intravenous therapy, or intramuscular injections in West African hospitals along with inadequate needle and syringe sterilization has led to large-scale epidemics. These epidemics can be devastating, resulting in the deaths not only of patients but also medical staff, surgeons, nurses, and other scarce personnel.6,35
Lassa fever is an increasing threat. It now affects communities in West Africa outside of its already broad area of rural endemicity. Indeed, urban Lassa fever in West Africa has been occurring with increasing frequency. In early 2000 hospital epidemics in large towns were again being seen in Nigeria, the most populous country in Africa. Since 1990, severe social disruption from conflicts and terror campaigns in Sierra Leone and Liberia have resulted in displacement of up to two million people—25% of the population of the area—with a substantial increase in the already large number of Lassa fever cases and deaths.36
Lassa fever is the exotic hemorrhagic fever most likely to occur in developed countries due to infection in returning travelers. This is because of the prevalence of disease in the endemic areas, and the relatively long incubation period (up to 3 weeks). In the year 2000 at least four cases were imported into Europe.37 All died, due in great part to delay in diagnosis, and therefore delay in instituting antiviral therapy. Increased cases in non-West Africans in 2000 has been seen as a result of United Nations peacekeeping efforts in Sierra Leone, where the rebels' stronghold is the center of the Lassa fever endemic area. One of the fatal cases in expatriates was an Englishman who had been working to disarm the rebel soldiers in the diamond mining area of Eastern Sierra Leone.38
The only known reservoir is Mastomys natalensis, one of the most commonly occurring rodents in Africa. Direct contact between virus-contaminated articles and surfaces and cuts and scratches on bare hands and feet may be the most important and consistent mode of transmission. The sporadic pattern of human infection in the household does not suggest aerosol transmission. Nosocomial spread in hospitals was and continues to be associated with inadequate disinfection and direct contact with infected blood and contaminated needles. Ill advised surgery performed on infected patients has resulted in infection and death among medical staff. Increasing and indiscriminant use of routine intravenous therapy in West African hospitals along with inadequate needle and syringe care has led to large-scale epidemics. Nevertheless, where simple but rigorous barrier nursing techniques have been applied, Lassa virus infection does not spread.8 In a study in London, none of 173 unprotected hospital contacts of a severely ill Lassa fever patient were infected.39
Clinical and Laboratory Features
Following an incubation period of 7 to 18 days, Lassa fever begins insidiously, with fever, weakness, malaise, severe headache—usually frontal—and a very painful sore throat.15 More than 50% of patients then develop joint and lumbar pain, and 60% or more develop a nonproductive cough. Many also develop severe retrosternal chest pain, and about half will have nausea with vomiting or diarrhea and abdominal pain. On physical examination respiratory rate, temperature, and pulse rate are elevated, and blood pressure may be low. There is no characteristic skin rash in Lassa fever, and petechiae and ecchymoses are not seen. About one third of patients will have conjunctivitis. More than two thirds have pharyngitis, half with exudates, diffusely inflamed and swollen posterior pharynx and tonsils, but few if any ulcers or petechiae. The abdomen is tender in 50% of patients. Neurologic signs in the early stages are limited to a fine tremor, most marked in the lips and tongue.40
Up to one-third of hospitalized Lassa fever patients progress to a prostrating illness 6 to 8 days after onset, usually with persistent vomiting and diarrhea. Patients are often dehydrated with elevated hematocrit. Proteinuria occurs in two thirds of patients. About half of Lassa fever patients will have diffuse abdominal tenderness but no localizing signs or loss of bowel sounds. The severe retrosternal or epigastric pain seen in many patients may result from pleural or pericardial involvement. Bleeding is seen in only 15% to 20% of patients, limited primarily to the mucosal surfaces or occasionally conjunctival hemorrhages or gastrointestinal or vaginal bleeding. Severe pulmonary edema and acute respiratory distress syndrome is common in fatal cases, with gross head and neck edema, pharyngeal stridor, and hypovolemic shock.
Over 70% of patients may have abnormal electrocardiograms including nonspecific ST-segment and T-wave abnormalities, ST-segment elevation, generalized low-voltage complexes, and changes reflecting electrolyte disturbance, but none of these correlate with clinical or other measures of disease severity or outcome, and they are unassociated with clinical manifestations of myocarditis.41 Neurologic signs are infrequent but carry a poor prognosis, progressing from confusion to severe encephalopathy with or without general seizures, but without focal signs. Cerebrospinal fluid is usually normal, but with a few lymphocytes, and low titers of virus relative to serum. Pneumonitis and pleural and pericardial rubs develop in early convalescence in about 20% of hospitalized patients, occasionally in association with congestive cardiac failure.
Although the mean white blood cell count in Lassa fever on admission to hospital is often normal, there may be early lymphopenia and later relative or absolute neutrophilia, as high as 30,000/μL. Thrombocytopenia is only moderate, and petechiae are uncommon. Endothelial and platelet dysfunction (despite adequate numbers of circulating platelets) are characteristic of severe disease,42 and the capillary leak syndrome results in ARDS, as with most hemorrhagic fever viruses.
A serum aspartate aminotransferase (SGOT) level of >150 U/L is associated with a case fatality rate of 50%, and there is a correlation between an increasing level and a higher risk of fatal outcome.34 Alanine aminotransferase (SGPT) is only marginally raised, and the ratio of SGOT to SGPT in natural infections and in experimentally infected primates is as high as 11:1. Prothrombin times and glucose and bilirubin levels are near normal, excluding biochemical hepatic failure, suggesting that some of the SGOT may be nonhepatic in origin.
Nearly 30% of patients with Lassa fever infection suffer an acute loss of hearing in one or both ears, not associated with severity of the disease.43 About half show a near or complete recovery by 3 to 4 months after onset, but the remainder have persistent significant sensorineural deafness, which after about a year will be permanent. Many patients also exhibit cerebellar signs during convalescence, particularly tremors and ataxia, but these usually resolve with time. Infrequent complications are uveitis, pericarditis, orchitis, pleural effusion, ascites, and acute adrenal insufficiency.44 Renal and hepatic failure are not seen.
Lassa fever may be a common cause of maternal mortality in many areas of West Africa, with case fatality about 20%.9 Fetal loss is as much as 87%, and does not seem to vary by trimester. Lassa virus is known to be present in the breast milk of infected mothers, and neonates are therefore at risk of congenital, intrapartum, and puerperal infection with Lassa virus. Lassa fever is common in children, but may be difficult to diagnose because manifestations are so general. In very young babies marked edema has been reported. In older children the disease may manifest as diarrhea or as pneumonia or simply as an unexplained prolonged fever.
RT-PCR is the most rapid and accurate method for acute diagnosis and has been shown to be more sensitive even than virus isolation.45 Virus may persist in serum into the convalescence phase and coexist with antibody, and virus has been detected in urine as many as 60 days after onset.40 By the sixth day of Lassa illness antibodies are found in about 50% of patients. Virus is easily isolated from serum or tissues in cell culture, but this should be performed in BSL4 laboratory facilities. Virus has also been isolated from breast milk, spinal fluid, pleural and pericardial transudate, placenta, and from autopsy material, and may be recovered intermittently for 1 to 2 months in urine. Neutralizing antibodies to Lassa virus are absent in the serum of patients at the beginning of convalescence, and in most people they are never detectable.
Viral protein may be detected by monoclonal antibodies in tissue imprints (usually liver) on a microscope slide or using ELISA techniques. Efforts to detect antigen in conjunctival scrapings, buffy coat preparations, cells from pharyngeal aspirates, and urinary sediment have not been successful.
Ribavirin is effective in treating acute Lassa fever and should be given as early as possible.40,46 A five- to tenfold decrease in the case fatality ratio was demonstrated in patients treated with ribavirin compared with untreated patients when therapy was given within the first 6 days of illness. Treatment later in disease is effective, but less so.
Avoidance of contact with rodent urine and with blood and tissues from infected rodents is an obvious precaution in the field. In the hospital, spread of Lassa virus is by blood-to-blood contact and can be prevented by simple barrier precautions.8 The importance of awareness by medical teams of the possibility of Lassa fever in patients in or from endemic areas cannot be overemphasized.47 Complete support should not be denied because of the suspected diagnosis. Carefully conducted intensive care or surgery by informed and trained personnel using maximum precautions (double gloves, educated staff, limited theater personnel) does not carry major risks.
South American Hemorrhagic Fever Viruses
The New World arenaviruses causing human disease are Junin (Argentine hemorrhagic fever; AHF), Machupo (Bolivian hemorrhagic fever, BHF), Guanarito (Venezuelan hemorrhagic fever; VHF), and Sabia (Brazilian hemorrhagic fever). All are endemic in geographically limited areas, but new, related viruses may emerge in other yet unstudied areas. The major rodent hosts are Calomys species, and the viruses are related to numerous other nonpathogenic arenaviruses from South American rodents (“Tacaribe complex”).
Argentine hemorrhagic fever was first recognized in the 1950s in the fertile farmland of northwestern Buenos Aires Province in Argentina, and Junin virus was first isolated in 1958. By 1990 about 21,000 cases had been reported over 30 years, but with the recent introduction of a live attenuated vaccine, this disease has diminished. Before the introduction of the vaccine, the disease was seasonal with peaks each May. The major routes of virus transmission to humans is probably through virus-infected dust and grain products, possibly from mechanical harvesters. There is no recorded person-to-person spread.
Clinical and Laboratory Features
The South American hemorrhagic fevers are similar in presentation, although Guanarito may more closely resemble Lassa fever.48After an incubation period of about 12 days there is insidious onset of malaise, high fever, severe myalgia, anorexia, lumbar pain, epigastric pain and abdominal tenderness, conjunctivitis, and retro-orbital pain, often with photophobia and constipation. Nausea and vomiting frequently occur after 2 or 3 days of illness. There is no lymphadenopathy or splenomegaly, sore throat or cough, but there is marked erythema of the face, neck, and thorax and conjunctivitis. Petechiae may be observed in the axillae by the fourth or fifth days of the illness. There may be a pharyngeal enanthem, but pharyngitis is uncommon. Relative bradycardia is often observed.
The second stage of illness begins with epistaxis, hematemesis, or acute neurologic disease. In contrast to the relative infrequency of bleeding in Lassa fever, the South American diseases are associated with hemorrhagic manifestations in nearly half of the patients, manifest as gingival hemorrhages, epistaxis, metrorrhagia, petechiae, ecchymoses, purpura, melena, or hematuria. Hypotensive shock, hypothermia, and pulmonary edema precede death. Renal failure has been reported. There is some electrocardiographic evidence of myocarditis. Fifty percent of AHF and BHF patients also have neurologic symptoms during the second stage of illness, such as tremors of the hands and tongue, progressing in some patients to delirium, oculogyrus, and strabismus. Meningeal signs and cerebrospinal fluid abnormalities are rare.
A low white blood cell count, under 1000/μL, and a platelet count under 10,000/μL are invariable. Bleeding and clot retraction times are concomitantly prolonged, although DIC is apparently not a significant feature. Proteinuria is common, and microscopic hematuria also occurs. Liver and renal function tests are only mildly abnormal. Mortality is about 16% in laboratory-confirmed hospitalized patients with untreated AHF. There are no estimates of overall mortality from population-based surveys.
A late neurologic syndrome has been described in AHF, consisting mainly of cerebellar signs, and associated with high-titer antiserum used in treatment in about 10% of cases.49 The syndrome begins between 4 and 6 weeks after onset of acute illness and lasts less than a week. It is characterized by fever, headache, ataxia, and intention tremors, and a mild cerebrospinal fluid pleocytosis with anti-Junin virus antibody in the CSF. Most patients recover within 3 months. Mild permanent damage to acoustic centers has been detected. AHF is also reported to be severe in pregnancy, but no formal studies are available, and women are less frequently affected.
Despite the different degrees of bleeding, there are sufficient similarities between the course of disease in AHF, BHF, and Lassa fever to speculate that they share similar pathophysiologic pathways. Organ function, other than the endothelial system, appears to remain intact, and the critical period of shock is brief, lasting only 24 to 48 hours. Hepatitis is mild, and renal function is also well maintained. Bleeding is more pronounced with AHF and BHF than Lassa fever, but it is not the cause of shock and death. Capillary leakage is significant, with loss of protein and intravascular volume being much more pronounced than loss of red cells.
In marked contrast to Lassa fever, the antibody response to Junin virus is effective in clearing virus during acute disease and may also be sufficient to protect against infection. Neutralizing antibody may be detectable at the time the patient begins to recover from the acute illness, and the therapeutic efficacy of immune plasma in patients with Junin infection is directly associated with the titer of neutralizing antibody in the plasma given.
RT-PCR is the most rapid and accurate method of acute diagnosis. The IFA may be positive by the end of the second week of illness. Neutralizing and complement-fixing antibody to Junin are usually detectable 3 to 4 weeks after onset. IgM is more difficult to read by IFA, and an ELISA system may be preferred. Virus may also be cultured from serum, but this should be performed in Biosafety Level 4 conditions.
In contrast to Lassa fever, convalescent-phase plasma has been shown to be highly successful in Argentine hemorrhagic fever, reducing the mortality from 16% to 1% in patients treated in the first 8 days of illness.49 Efficacy is directly related to the concentration of neutralizing antibodies. Late initiation of therapy is less successful. Availability of appropriately screened plasma may be a problem. Ribavirin may also be effective in treating South American hemorrhagic fever.
The human-rodent encounter resulting in AHF occurs during the crop harvests, and there are no means of controlling feral rodents. A successful live attenuated vaccine, Candid 1, for AHF has now undergone phase III studies, and is in use in the endemic area of Argentina, where it has almost eliminated the disease. The vaccine has proved safe in large-scale trials, and has a protective efficacy of 84%.50