Lassa Virus

Lassa virus, part of the Arenaviridae family, is an ssRNA virus that causes Lassa fever, a type of viral hemorrhagic illness. The virus is endemic in parts of West Africa (Sierra Leone, Liberia, Guinea, and Nigeria) and neighboring countries. The reservoir is the multimammate rat (Mastomys natalensis), and transmission is via inhalation or contact with rodent excretions or consumption of rodents. Human-to-human transmission also occurs. The majority of infected patients are asymptomatic. However, symptomatic patients present with fever, malaise, headaches, vomiting, and chest pains, which can progress to hemorrhage, hypovolemia, and shock. Treatment is mainly with ribavirin and supportive care. There is no effective vaccine, but preventive measures such as avoiding rodent exposures and use of PPE can reduce transmission. Ribavirin is also given as postexposure prophylaxis.

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Classification

RNA Viruses Flowchart Classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. RNA genome viruses can be further characterized by either a single- or double-stranded RNA. “Enveloped” viruses are covered by a thin coat of cell membrane (usually taken from the host cell). If the coat is absent, the viruses are called “naked” viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is directly employed as messenger RNA (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA dependent RNA polymerase, a viral enzyme, to transcribe their genome into messenger RNA.

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General Characteristics

Basic features

  • Enveloped
  • Spherical
  • Medium-sized agent, measuring 70–150 nm in diameter
  • 2 viral surface glycoproteins on envelope: G1 and G2
  • Virus genome:
    • Encapsulated by a helical nucleocapsid
    • Segmented single-stranded, negative-sense RNA, made of:
      • Large (L) fragment: encodes the RNA-dependent RNA polymerase (RdRP) 
      • Small (S) fragment: encodes the viral structural proteins
  • Taxonomy:
    • Family Arenaviridae
    • Genus Mammarenavirus
    • Viruses contain host ribosomes, giving the virus a granular appearance (arenosus is Latin for “sandy”).
    • Other arenaviruses include:
      • Lymphocytic choriomeningitis virus (LCMV)
      • Junin virus (Argentine hemorrhagic fever)
      • Machupo virus (Bolivian hemorrhagic fever)
      • Guanarito virus (Venezuelan hemorrhagic fever)
      • Sabia (Brazilian hemorrhagic fever)
      • Chapare (Chapare hemorrhagic fever)
      • Lujo (Lujo hemorrhagic fever)

Epidemiology

  • Endemic in West Africa:
    • Guinea
    • Liberia
    • Sierra Leone
    • Nigeria
    • Benin
    • Ghana
    • Mali
  • Higher incidence in March, when the seasons transition from dry to wet
  • Morbidity and mortality:
    • Estimated 300,000 cases per year 
    • 5000 deaths annually
    • Overall case fatality rate: 1%

Pathogenesis

Reservoir and transmission

  • Reservoir:
    • Multimammate rat (Mastomys natalensis)
    • Mastomys rodent infestation is commonly seen in households built with materials such as crumbling mud, which allow rodent burrows. 
  • Transmission:
    • Contact with rodent(s): 
      • Direct contact with urine or feces of infected rats
      • Inhalation of aerosolized excretions of rodents
      • Consumption of infected rodents
    • Human-to-human transmission:  
      • Direct contact with the blood, urine, feces, or other bodily secretions of an infected person 
      • Viral shedding in the urine can last for up to 9 weeks
      • Sexual transmission: viral shedding in semen occurs for up to 3 months

Host risk factors

  • Inhabitants in and visitors to endemic regions 
  • Hospital staff (requires protective measures and proper sterilization methods)

Viral entry and disease process

  • Entry via nasopharyngeal mucosa and Lassa virus targets antigen-presenting cells: 
    • Dendritic cells
    • Macrophages
    • Monocytes
  • Lassa viruses primarily attach to cells with the surface G1 binding to cell receptor α-dystroglycan (α-DG). 
  • The viral particle enters the cell (endocytosis) and is then engulfed by an endosome. 
  • Rearrangement of the viral envelope glycoprotein complex (GPC) occurs (in low pH), leading to G2-mediated fusion of the particle with the vesicle membrane.
  • This subsequently releases the viral genome into the cytoplasm for replication and transcription.
  • Maturation of the new viral particles takes place by budding from the host cell membrane. 
  • Virus spreads to lymph nodes, and dissemination to other tissues follows.
  • Macrophages and dendritic cells release mediators that cause endothelial dysfunction, impaired hemostasis, and reduced platelet aggregation, leading to:
    • Hepatic and/or splenic necrosis
    • Alveolar edema
    • Myocarditis
    • GI hemorrhage

Clinical Presentation

Lassa fever

  • Incubation period: 6–21 days
  • Approximately 80% of people who become infected have mild symptoms:
    • Low-grade fever
    • Malaise
    • Headache
    • Improvement in 8–10 days
  • Approximately 20% of infections progress further to develop:
    • Cough, sore throat, conjunctivitis
    • Abdominal pain, nausea, vomiting
    • Chest pain
    • Severe potentially life-threatening conditions:
      • Facial swelling
      • Pleural effusion, pulmonary edema
      • Myocarditis
      • Hemorrhage from the mouth, nose, vagina, or GI tract 
      • Hypotension
      • Renal failure
      • Shock
      • Seizures, tremor, disorientation, and coma

Complications and mortality

  • Deafness (most common complication) in up to 30% of patients, with close to 20% developing permanent hearing loss
  • In fatal disease, death usually occurs within 2 weeks after onset of symptoms.
  • In pregnancy:
    • Course usually severe
    • Fetal loss (> 60%) and maternal death in majority of infections that occur in the 3rd trimester
    • “Swollen baby syndrome”: 
      • Abdominal distention, anasarca, bleeding
      • Babies born to mothers infected in the 3rd trimester
  • Even after recovery, viral shedding can persist for up to 3 months.

Diagnosis and Management

Tests

  • Diagnostic:
    • ELISA: detects antigen, IgM, and IgG antibodies
    • RT-PCR
    • Culture: performed only in high-containment laboratories
  •  Other lab findings:
    • CBC:
      • Leukopenia
      • Thrombocytopenia
    • Elevated transaminases and amylase
    • Coagulation studies usually normal
    • Renal function abnormality (associated with increased mortality)

Management

  • Ribavirin:
    • IV preferred over oral preparation, but oral form can be given if IV is not available
    •  Shown to improve treatment outcomes when given early in the disease course
  • Supportive care:
    • IV fluids (take precautions to avoid overload)
    • Respiratory support (oxygenation)
    • Blood transfusions as indicated

Prevention

  • Currently no current effective vaccines
  • Avoid rodents
  • Isolation of patients
  • Use of PPE in hospital or patient care settings
  • Body of deceased patient should be handled properly (sealed body bag and buried by trained personnel).
  • To reduce risk of sexual transmission, wait for 3 months (after resolution) before unprotected sex.
  • Postexposure prophylaxis:
    • Ribavirin
    • Close monitoring

Comparison of Arenaviruses

Arenaviruses can cause hemorrhagic fevers (Lassa virus) and/or neurologic disease (lymphocytic choriomeningitis virus (LCMV)).

Table: Comparison of Arenaviruses
OrganismLCMVLassa virus
FamilyArenaviridaeArenaviridae
GenusMammarenavirusMammarenavirus
Characteristics
  • Enveloped
  • Mid-sized
  • Spherical
  • Segmented genome
  • ssRNA
  • Enveloped
  • Mid-sized
  • Spherical
  • Segmented genome
  • ssRNA
ReservoirRodentsRodents
Transmission
  • Aerosols
  • Direct contact
  • Vertical transmission
  • Organ transplantation
  • Aerosols
  • Direct contact
  • Ingestion
  • Person-to-person (through exposure to blood
  • Secretions
  • Tissue of infected individual)
Clinical courseBiphasic:
  • Flu-like illness
  • Meningitis, encephalitis
  • Majority asymptomatic or with mild symptoms
  • Hemorrhagic manifestations
  • Deafness is common
Diagnosis
  • Serology
  • RT-PCR
  • Serology
  • RT-PCR
Management
  • Supportive
  • Supportive
  • Ribavirin
Prevention
  • Avoid contact with rodents and their body fluids
  • Avoid contact with rodents and their body fluids
  • PPE
LCMV: lymphocytic choriomeningitis virus

Differential Diagnosis

Other viral hemorrhagic fevers:

  • Ebola: highly contagious and potentially lethal hemorrhagic fever caused by Ebola virus (Filoviridae). Ebola has similar endemic regions and presentation to those for Lassa virus. Patients present with symptoms of fever, malaise, nausea, vomiting, and abdominal pain. These symptoms can progress to hemorrhage, multiorgan failure, and shock. The diagnosis is confirmed PCR, serology, and electron microscopy of tissue or blood. Management is supportive.    
  • Dengue hemorrhagic fever: acute febrile illness caused by the dengue virus (Flaviviridae). The virus is transmitted by Aedes aegypti mosquitoes. The majority of infections are asymptomatic. Symptomatic individuals may progress through different phases, with severe manifestations occurring in those with previous infections. The disease presents with high fever, headache and retro-orbital pain, myalgias and arthralgias (“breakbone” pain), and macular or maculopapular rash. Hemorrhage and shock can follow. The diagnosis is made by serology, antigen testing, or PCR. Management is supportive. 
  • Yellow fever: caused by the yellow fever virus (Flaviviridae). Humans and primates serve as reservoirs, and transmission occurs from the bite of an infected female mosquito. Patients present with fever and flu-like symptoms in most cases. Severe disease can cause multiorgan dysfunction, resulting in jaundice, renal dysfunction, hemorrhage, shock, and potential death. Diagnosis is by serology and PCR. There is no antiviral treatment, so management is supportive. Prevention includes mosquito avoidance and vaccination. 
  • Crimean-Congo hemorrhagic fever (CCHF): zoonotic disease caused by a virus (Bunyaviridae) transmitted by ticks. Symptoms and signs include fever, myalgias, abdominal pain, nausea, and vomiting. Most patients recover from this illness after 1 week, but it can progress to hemorrhage, shock, and multiorgan failure. The virus is endemic in parts of Africa, the Middle East, Asia, and southeastern Europe. The diagnosis is established via RT-PCR or serology.
  • Hantavirus: causes hemorrhagic fever with renal syndrome. Hantavirus (Bunyaviridae) is transmitted by rodents (inhalation, direct contact, or ingestion of rodent excretions). Cases are noted worldwide (Americas, Europe, Asia, Africa). Infections can cause pulmonary symptoms, hemorrhage, and renal damage from vascular endothelial injury. Diagnosis is by RT-PCR and serology. Management is supportive.

Conditions caused by other nonviral pathogens:

  • Malaria: mosquito-borne infectious disease caused by Plasmodium species. Malaria often presents with fever, rigors, diaphoresis, jaundice, abdominal pain, hemolytic anemia, hepatosplenomegaly, and renal impairment. Malaria should be suspected in those with typical presentation and with residence in or travel to endemic areas (generally, tropical areas). Diagnosis is by blood smear. Rapid testing for Plasmodium antigens can also be performed. Management requires a prolonged course of multiple antimalarial drugs.
  • Leptospirosis: disease caused by Leptospira interrogans. Bacteria shed in the urine of rodents and other animals can be transmitted to humans via contaminated water. Patients present with a mild flu-like illness in most cases, and the manifestations are biphasic. In about 10% of infections, icterohemorrhagic leptospirosis develops, manifesting as hemorrhage, renal failure, and jaundice. Bacterial culture takes weeks, so other diagnostic tests, such as serology and dark-field microscopy are used. Treatment is primarily with penicillin.

References

  1. Centers for Disease Control and Prevention. (2019). Lassa fever. Centers for Disease Control and Prevention. https://www.cdc.gov/vhf/lassa/index.html
  2. Ryan K.J. (2017). Arthropod-borne and other zoonotic viruses. Chapter 16 of Sherris Medical Microbiology, 7th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2268&sectionid=176083946
  3. Schieffelin, J. (2021). Lassa fever. UpToDate. Retrieved June 15, 2021, from https://www.uptodate.com/contents/lassa-fever
  4. Shao, J., Liang, Y., Ly, H. (2015). Human hemorrhagic fever causing arenaviruses: molecular mechanisms contributing to virus virulence and disease pathogenesis. Pathogens 4:283–306. https://doi.org/10.3390/pathogens4020283
  5. Yun, N.E., Walker, D.H. (2012). Pathogenesis of Lassa fever. Viruses 4:2031–2048. https://pubmed.ncbi.nlm.nih.gov/23202452/

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