Arenaviruses are single-stranded ribonucleic acid (RNA) viruses that cause chronic infections in rodents and zoonotically acquired disease in humans through rodent excreta, especially urine. The genus Arenavirus includes 22 viral species and 9 additional arenaviruses that have been recently discovered, for which taxonomic status remains pending. In 1934, the prototypic arenavirus, lymphocytic choriomeningitis (LCM) virus, was first isolated during serial monkey passage of human material that was obtained from a fatal infection in the first documented epidemic of St. Louis encephalitis, a totally unrelated virus. LCM virus was the first recognized cause of aseptic meningitis in humans.
Other arenaviruses from South America and Africa are classic causes of viral hemorrhagic fever syndrome, whereas others have been identified but not found to cause disease or even infection in humans. Most of these viruses are under continuing study.
Arenaviruses have been divided into 2 groups based on whether the virus is found to infect Old World (ie, Eastern Hemisphere) rodents (family Muridae, subfamily Murinae) or New World (ie, Western Hemisphere) rodents (family Muridae, subfamily Sigmodontinae). The New World arenaviruses are further divided into 3 lineages designated clades: A, B, C. LCM virus is the only arenavirus to exist in both areas but is classified as an Old World virus. The following are the major viruses and the other recognized Arenaviridae listed in relationship to their rodent reservoirs.
LCM virus-Lassa virus (Old World)complex
Lymphocytic choriomeningitis virus
Rodent -Mus musculus and Mus domesticus (ie, house mouse) and Mesocricetus auratus (ie, Syrian hamster)
Location - Europe, Asia, and the Americas
Habitat - Peridomestic, grasslands
Season – September to October
Human contact - Primarily within households
Lassa virus
Rodent -Mastomys genus (ie, multimammate mouse)
Location - West Africa
Habitat - Savanna, forest clearing
Season – January to April
Human contact - Primarily within houses
Mopeia virus
Rodent -M natalensis
Location - Southern Africa
Habitat – Savanna
Season - Unknown
Human contact – Unclear
Mobala virus
Rodent -Praomys species (ie, soft-furred rat)
Location - Central African Republic
Habitat – Savanna
Season - Unknown
Human contact – Unclear
Ippy virus
Rodent -Arvicanthus species (ie, Nile grass rat)
Location - Central African Republic
Habitat - Grassland, savanna
Season - Unknown
Human contact – Unclear
Lujo virus
Rodent – Unknown
Location – Zambia
Habitat – Unknown, likely similar to Lassa virus
Season – Unknown, likely similar to Lassa virus
Human contact – Unclear, likely similar to Lassa virus
Arenaviruses are host plasma membrane-enveloped, spherical-to-pleomorphic particles that range in size from 50-300 nm. The envelope that surrounds the virion contains 2 major glycoprotein components (ie, GP1, GP2) that appear as spikelike or clublike projections with variable spacing along the virus lipid coat.
The Arenaviridae generally have been considered negative-sense RNA viruses that contain 2 subgenomic segments, referred to as L (large) and S (small), composed of 2.4 million bases and 1.3 million bases, respectively. The 5' ends of both the L and S strands contain positive-sense RNA; therefore, the viruses are best considered ambisense. Each of the RNA segments consists of 2 nonoverlapped long open reading frames with opposite polarity. The L segment encodes for the viral RNA-dependent RNA polymerase and for the Z protein important for viral budding and other intracellular functions. The S segment encodes for the nucleocapsid protein (N) and the glycoprotein precursor polypeptide (GPC) that is differentially cleaved and glycosylated to form the spike glycoproteins. The N protein is the most antigenic and thus usually measured in the diagnostic indirect fluorescent antibody (IFA) test.
A distinguishing characteristic of arenaviruses is the presence of internal granular structures 20-25 nm in size. On electron microscopy, these structures appear sandlike. The family name, Arena, is derived from the Latin root (arenosos), meaning sand. These sandlike components are host cell–derived ribosomes, which are incorporated into the virus during budding, but apparently not biologically functional.
Genetic susceptibility
The Human Genome Project (HGP) began in 1989 as an international scientific research project with a primary goal of determining the sequence of chemical base pairs that make up human DNA from both a physical and functional standpoint. The essentially complete genome was published in April 2003, save for the highly repetitive sequences surrounding the centromere and telomere. This database of genes has, when possible, been used to link disease with relevant genes in the human genome. The arenaviruses are no exception.
The DAG1 gene, located at 3p21 for example, encodes for 2 dystroglycan proteins, alpha and beta. Alpha dystroglycan appears to be necessary for infection with viruses of the LCM virus-Lassa complex and some New World arenaviruses (Oliveros and Latino) because null mutants were resistant to infection.
The transferrin receptor gene 1, located at 3q29 is a cell surface glycoprotein transferrin receptor that also appears to enhance susceptibility to infection with those of the Tacaribe virus complex.
Pathogenesis (in humans)
Little data are available regarding the pathogenesis of fatal LCM infection, but marked neuronal infection is seen in human encephalitis. In the case of arenavirus hemorrhagic fevers, pathogenesis likely results from direct viral infection of endothelial cells resulting in vascular dysfunction and shock. Immunopathologic events seem less likely, although as seen in most viral infections, high levels of circulating endogenous interferon-alpha and pro-inflammatory cytokines are present that may prove detrimental rather than beneficial in arenavirus infections.
The number of cases of LCM virus infection is unclear, but a number of clusters have been reported related to pet hamsters or laboratory animals. Recently, 3 fatal cases of infection with a virus similar to Whitewater Arroyo virus were reported in California.
International
Scattered outbreaks of Lassa fever in western Africa and South American hemorrhagic fever occur, representing local public health problems. Public health officials in nonendemic areas must remain vigilant for these infections because imported cases have been described, presumably due to person-to-person spread.[1]
A nosocomial outbreak of disease involving 5 patients, 4 of whom died, occurred in South Africa from September-October 2008 after the index patient was transferred there from Zambia for medical management. The source of infection was never determined, but a novel arenavirus determined by nucleotide sequencing and phylogenetic analysis, since named Lujo virus, was determined to be the cause.
In December 2003 and January 2004, a small number of hemorrhagic fever cases with classical presentation were reported in rural Bolivia. The virus was isolated from 2 of the patients and was identified as an arenavirus using polymerase chain reaction (PCR). Subsequent genome analysis showed it most closely related to Sabiá virus, but it was distinct enough to be anointed a new species named Chapare virus.
Mortality/Morbidity
Arenaviruses persist in nature by infecting rodents, primarily through a one-virus, one-rodent species relationship. Arenaviruses are transmitted to humans through aerosolization of dried excreta, especially urine that has been deposited in the environment. The distribution of the host dictates the distribution of the virus, but with environmental change due global warming and human factors and with the contemporary ease of international travel, they may occur anywhere in the world.
LCM virus
Infection occurs wherever either of the 2 closely related species of the common house mouse (M musculus, M domesticus) exists. The areas include Europe, the Americas, Australia, and Japan. Human infection is more common in rural areas, where a higher rate of infection exists in mice. Sporadic human LCM virus infections have autumn/winter predominance, when mice are more likely to seek human dwellings for shelter and food. The incubation period varies but most often ranges from 5-10 days, unless presenting with nervous system signs, then exposure likely occurred 2-3 weeks prior. Hamsters also can be infected and are more significant disease vectors in laboratory workers and pet owners.
Lassa virus (ie, Lassa fever)
Lassa fever is endemic to West Africa. Originally found in Nigeria, outbreaks have been reported from Sierra Leone, Liberia, and Guinea. Lassa virus was isolated from rodents of the genus Mastomys, members of which aggressively invade houses. Lassa fever is common in the dry season. This viral agent is noteworthy because of its ability to spread from person to person. This also occurs to some degree with South American viruses.[2, 3, 4] The incubation period varies from 3-16 days, and overall mortality rate is estimated to be 1%. The mortality rate is more than 80% in pregnant women in their third trimester and nearly always results in fetal death. Abortion decreases the risk of death to the mother.
South American viral hemorrhagic fevers
These are diseases of South American countries, including Argentina, Bolivia, and Venezuela, caused by the viruses Junin, Machupo, and Guanarito, respectively. Mortality rate in each is about 15-30%.
For Argentine hemorrhagic fever, the main reservoir rodent is C masculinus. This rodent is found in the cornfields, especially from February through May. Therefore, men harvesting corn are particularly at risk. Infectious aerosols are thought to be the most common mode of transmission, but food contamination and direct contact of abraded fingers with blood or tissue from rodents may occur.
Bolivian hemorrhagic fever is found in the tropical savanna of the Beni region in northeastern Bolivia. The reservoir rodent is C callosus, which travels freely around this area. Bolivian hemorrhagic fever is commonly found from April to July. Transmission is believed to occur through aerosols from infected rodents or, possibly, through food contaminated by rodent urine.
Venezuelan hemorrhagic fever, caused by the Guanarito virus, has the cane mouse Zygodontomys brevicauda as a reservoir. People who have moved to the cleared forest areas for agricultural work are most at risk.
Age
The risk of human acquisition of Arenavirus infection is related to age, race, or sex only to the degree that these variables impact contact with dried rodent urine.
Clinically apparent arenavirus infections typically present with fever, headache, myalgia, and malaise. Relative bradycardia and hyperesthesia are common as well. Thereafter, the various diseases pursue different courses as follows:
Lymphocytic choriomeningitis virus
This usually benign infection generally begins with fever, myalgia, and headache. Leukopenia and thrombocytopenia are revealed on laboratory studies.
The illness can be biphasic.
The second febrile period and some of the late complications (see Complications) may be immunologic in origin.
Lassa fever
Most infections due to the Lassa virus are mild or subclinical.
Severe multisystem disease is believed to occur in 5-10% of total infections.
Incubation period is 7-18 days.
Illness begins insidiously with fever, weakness, malaise, joint and/or lumbar pain, cough, and severe headache.
In severe cases, illness progresses to include prostration, dehydration, abdominal pain, and facial or neck edema. Serum aminotransferases may be elevated. Note that Lassa fever stands alone among causes of viral hepatitis to have aspartate aminotransferase (AST) levels substantially higher than alanine aminotransferase (ALT) levels. This pattern has been classic for alcoholic hepatitis.
Lymphopenia, thrombocytopenia, and defects of qualitative platelet function are found during this stage.
South American hemorrhagic fevers
Junin and Machupo viruses are similar in severity, and anecdotal reports suggest that Guanarito infections may be somewhat more severe overall.
The illnesses begin somewhat insidiously with fever, malaise, myalgia, and lumbar pain.
Progression may occur over 3-4 days, with prostration, unremitting fever, and mucosal bleeding. Hemorrhage along the gingival margins is characteristic.
After 1-2 weeks, most patients improve, but approximately one third progress to profound cutaneous and mucosal hemorrhages, delirium, and convulsions or a combination of CNS and bleeding findings. Capillary leak syndrome also may occur.
The major physical examination findings observed in the major Arenavirus illnesses are as follows:
Lymphocytic choriomeningitis virus
Conjunctival injection, facial flushing, generalized lymphadenopathy, and orthostatic hypotension are common.
Fever and more severe headaches may recur 2-4 days after recovery from the first phase, with overt lymphocytic pleocytotic meningitis with elevated cerebrospinal (CSF) protein. Papilledema may be noted.
Lassa fever
Pharyngitis, often exudative, occurs early. Conjunctivitis also may be seen.
Later, in severe disease, CNS signs can be seen, including tremors, confusion, encephalopathy, and seizures. Focal CNS signs usually are absent, and CSF is normal.
Bleeding is seen in only 15-20% of patients, it usually is limited to mucosal surfaces, and it is limited in severity.
South American hemorrhagic fever
Conjunctival injection, facial flushing, generalized lymphadenopathy, and orthostatic hypotension are common signs.
Many patients have a petechial and/or vesicular palatal enanthem and skin petechiae.
At the point of further progression, CNS signs can include tremor of hands and tongue, hyperesthesias, decreased deep-tendon reflexes, and lethargy.
Especially with deteriorating illness, leukopenia and thrombocytopenia are common but aminotransferase elevations are uncommon.
The diagnosis of acute illness with human Arenavirus is made using antigen and/or antibody measurements, virus isolation, and/or genomic detection by reverse transcriptase-polymerase chain reaction (RT-PCR). For Lassa and the South American hemorrhagic fever agents, laboratory samples from suspected cases should be handled under biosafety level 4 containment until treated chemically (10% hypochlorite, Lysol, formaldehyde, or peracetic acid) or with gamma irradiation.
Antigen/antibody detection
The serodiagnosis of Arenavirus can be made rapidly and with a high degree of sensitivity.
In Lassa fever, many acutely ill patients can be found to be immunoglobulin M (IgM) antibody–positive for the Lassa virus upon presentation. Indirect fluorescent antibody (IFA) assay or enzyme-linked immunoabsorbent assay (ELISA) methodology usually determines the IgM antibody. At least 50-75% of patients are IgM antibody–positive (ie, ≥ 1:4) by day 5 and 100% positive by days 12-14.
In ill patients, Lassa virus ELISA antigenemia has been detected by experimental technology. Antigen testing of liver biopsy specimens also has been accomplished.
In the South American hemorrhagic fevers, antibodies usually develop 1-2 weeks later than in Lassa or LCM virus, appearing during the third week of illness. IFA assay and ELISA may not easily distinguish between the different agents (ie, all members of the Tacaribe complex), but plaque-reduction neutralization antibody testing can distinguish between the different agents.
Antigen-capture ELISA of blood or tissue may offer the earliest diagnostic test for the South American hemorrhagic fevers.
For LCM virus, IgM ELISA appears to have replaced the IFA assay and other antibody assays for serological diagnosis. Antibodies also can be assessed using CSF.
Virus isolation
Lassa virus can be isolated easily (ie, in a biosafety level 4 laboratory) in tissue culture using the E6 clone of Vero cells or in suckling mice. Infected animals represent the highest risk of exposure to laboratory personnel.
Viremia can be high grade and sustained in Lassa fever with as many as 6-8 logs of median tissue culture infectious doses per milliliter. Low titers of virus can be found in throat swabs acutely and during convalescence at low titer in the urine. Viremias greater than 3 logs are associated with higher mortality.
In the South American hemorrhagic fevers, virus also can be isolated from blood or tissue samples using tissue culture or suckling mice. Cocultivation of peripheral blood mononuclear cells with Vero cells seems to increase sensitivity.
In human infection with LCM virus, the virus can be isolated from the blood early in the disease, and, in those who develop meningitis, the virus also can be isolated later from CSF.
Care must be taken to avoid false-positive results and to use appropriate primers.
RT-PCR assays detecting fragments of the S (glycoprotein) gene have been successful, and, after RNA extraction, minimal laboratory risk exists.
Serum aminotransferase testing in Lassa fever
Admission levels greater than 150 IU/L are associated with a 50% case fatality rate, and, when combined with high viremia, the mortality rate is approximately 80%.
No specific medical care is required for mild infections associated with any of the Arenaviridae. Specific and/or careful symptomatic care is needed in more severe infections associated with those agents linked to hemorrhagic fever.
LCM virus infection requires no more than symptomatic treatment.
In overt cases of Lassa fever or any of the South American hemorrhagic fevers, aggressive treatment is needed to attempt to diminish morbidity and mortality.
Supportive care related to blood pressure monitoring/control and careful attention to fluid and electrolytic balance can be lifesaving.
The antiviral drug ribavirin is used in Lassa fever and has also shown efficacy in cases of South American hemorrhagic fever.
Convalescent human plasma has been used with some success in the treatment of Junin virus infection. The lack of parallel success in Lassa fever may be related to low and delayed titers of the specific neutralizing antibody in Lassa fever.
With a compatible illness and travel history, any individual in whom either Lassa fever or one of the South American hemorrhagic fevers is suggested should have immediate consultation with an infectious disease physician and the local public health authorities.
Clinical Context:
Synthetic guanosine analog (1beta-D-ribofuranosyl- 1H-1,2,4-triazole-3-carboxamide) that inhibits viral replication by inhibiting DNA and RNA synthesis.
Phosphorylated in vivo, and the active form may interfere with viral genomic synthesis. Clinically used in combination with interferon for hepatitis C, as aerosol for respiratory syncytial virus, and as potential prophylaxis and/or treatment of Congo-Crimean hemorrhagic fever, hantavirus infections, and Arenavirus hemorrhagic fevers. In vitro evidence exists for activity against West Nile virus. IV form not readily available and the manufacturer should be contacted if the need arises.
Clinical experience with ribavirin in the treatment of Arenavirus infections is primarily with Lassa fever, but anecdotal experience in the South American arenaviruses also exists.
One study demonstrated a reduction in mortality from 55% to 5% in severe Lassa fever with intravenous ribavirin when administered within the first 6 days. Oral ribavirin may also be effective, although it has less bioavailability compared with intravenous formulations. Oral ribavirin is also sometimes used as postexposure prophylaxis, although data are limited.
Recognition of a case of Lassa fever or any of the South American Arenavirus infections is crucial from both infection control and epidemiologic standpoints. Suspected cases should be reported immediately to local public health authorities.
Rodent control
Unlike plague, in which a rodent die-off can cause an increased risk of a human outbreak, the rodents carrying arenaviruses do not become ill or shed the virus in their urine.
Aggressive rodent control (eg, trapping, rodent poisons) and avoidance of high-density rodent areas are the most important preventative maneuvers.
Procedures to avoid rodent droppings and exposure include properly disposing of trash and clutter, moving woodpiles away from residences, properly airing out cabins and buildings prior to reoccupation, and avoiding creating dust when cleaning buildings with signs of rodent infestation.
Nosocomial spread prevention
Person-to-person spread has been problematic within hospitals where Lassa fever is endemic
Patients should be placed in a single room with isolated negative-pressure airflow. Isolation should be continued until multiple blood or urine specimens are negative for the virus.
All tests with arenaviruses should be conducted in special laboratories with BSL4 containment.
Arenavirus vaccination
No commercially available vaccines are available to prevent Arenavirus infection in the United States.
In one study with Lassa virus, a recombinant vaccinia virus that expressed Lassa virus glycoprotein was found to be efficacious in primates.
Field trials with an attenuated Junin virus vaccine have shown an efficacy of 95% with minimal side effects. This vaccine also may be protective against Machupo virus because of cross-antigenicity but not against Guanarito or Sabia viruses.
Anecdotal information suggests that antigenically similar but nonpathogenic arenaviruses may be protective against Lassa fever in monkeys.
Management of contacts of imported cases of Lassa fever
Initially, imported cases of Lassa fever were treated with supportive care under conditions of total isolation. More recently, simple barrier nursing techniques have been found to be effective in preventing transmission to health care personnel. Guidelines have been developed to establish a level of risk for Lassa fever based on the degree of exposure to an index case. Similar criteria can be used for risk of exposure to South American hemorrhagic fever viruses.
High-risk: These activities include unprotected contact with index case body fluids or excreta (eg, mouth-to-mouth kissing; sharing food, liquids, or eating utensils; sexual intercourse[6] ; needle sticks). High-risk exposures usually precipitate ribavirin prophylaxis; closely monitor the contact for fever and/or illness and measure for seroconversion beginning on day 0 and on day 15.
Medium-risk: Activities that are medium-risk include unprotected contact with surfaces that probably were contaminated or possible unprotected contact with index case body fluid or excreta (eg, drawing blood or handling lab slides containing unfixed specimen, handling bed sheets or bed pans, or perceived skin or mucosal contact with the aerosolized respiratory secretions from an index case). Medium-risk exposures trigger public health officials to monitor exposure for 21 days after the last exposure. If a fever of 38.3°C or higher occurs, intravenous ribavirin should be given and diagnostic studies of Lassa virus obtained. If the fever is low grade, other criteria, such as aminotransferase levels, should be used to determine action.
Low-risk: These exposures include unprotected contact with the index case with little chance of exposure to body fluids/excreta (eg, examining index case without gloves or being within several feet of the case when a cough or sneeze occurs). Patients with low-risk exposures should be monitored for 21 days after the last exposure. If fever is higher than 38.3°C and aminotransferases are elevated, based on clinical judgment, further action (including hospitalization with or without ribavirin) may be indicated.
No risk: Such exposure includes proximity of the index case without direct contact to potentially contaminated objects (eg, brief visit to patient's room without contact or handling blood or secretions with gloves).
CNS complications beyond aseptic meningitis include encephalitis and may involve cranial nerve palsies and/or damage to the autonomic nervous system. Hypoglycorrhachia can be found.
Non-CNS complications include orchitis, myocarditis, alopecia, and small-joint arthritis. These develop, if at all, late in the illness, during the recurrence of fever.
Intrauterine infection with LCM virus has been described. Infection may manifest as hydrocephalus and/or chorioretinitis with persistent spastic pareses and death within several years.
Lassa fever
Eighth-nerve deafness, which can be bilateral and thought to be immune-mediated, is observed in as many as one third of patients. Recovery of hearing occurs in approximately 50% of patients, but the deafness can be permanent.
Maternal and fetal losses during Lassa fever infection are substantial. Maternal mortality rates can approach 30% and may be reduced with abortion. Fetal loss rates are close to 90% and are not affected by the trimester of infection.
Cerebellar ataxia, pericarditis, orchitis, and uveitis may be observed.
Renal or hepatic failure is generally not observed.
South American hemorrhagic fevers
In addition to severe hemorrhagic or CNS complications, convalescence in survivors can be quite prolonged, with weight loss, hair loss, and autonomic instability.
As with Lassa fever, South American hemorrhagic fevers have substantial effects on the developing fetus.
Survival with recovery from LCM virus infection is the rule.
Lassa fever
Hemorrhagic features are mild and rarely of prognostic significance.
Risk factors for increased mortality are facial and/or neck edema, elevated aminotransferases, and increased viremia. With these in combination, the mortality rate can be higher than 80%.
South American hemorrhagic fevers
Mortality rates can be higher than 30%.
Risk factors for mortality include a pronounced bleeding diathesis, severe neurologic deterioration, and shock.
Sandra G Gompf, MD, FACP, FIDSA, Associate Professor of Infectious Diseases and International Medicine, University of South Florida College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley Veterans Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Kevin M Smith, MD, Fellow in Infectious Disease and International Medicine, University of South Florida College of Medicine
Disclosure: Nothing to disclose.
Ulyee Choe, DO, Fellow, Department of Infectious Diseases, University of South Florida College of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Joseph F John, Jr, MD, FACP, FIDSA, FSHEA, Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina College of Medicine; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Pranatharthi Haran Chandrasekar, MBBS, MD, Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Daniel R Lucey, MD, MPH, MD, MPH,
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Larry I Lutwick, MD, to the development and writing of this article.
Buchmeier MJ, et al. Arenaviridae: the viruses and their replication. Knipe DL, and Howley, PM. Field's Virology. 4. Philadelphia, PA: Lippencott-Raven; 2007. 1791-1828.
Peters CJ. Lymphocytic Choriomeningitis Virus, Lassa Virus, and the South American Hemorrhagic Fevers. Gerald L. Mandell, John E. Bennett, Raphael Dolin. Principles and Practice of Infectious Diseases. 7. Philadelphia, PA: Churchill Livingstone Elsevier; 2010. 2: 2295-2302.
