Bunyavirales

Bunyaviridae is a family of RNA viruses that is classified into 5 genera: Orthobunyavirus (La Crosse virus), Hantavirus, Nairovirus (Crimean-Congo hemorrhagic fever virus), Phlebovirus (Rift Valley fever virus), and Tospovirus. The common characteristics of the virus family include an enveloped spherical structure containing a single-stranded, negative-sense RNA genome, which is triple-segmented. Infections are generally either arthropod borne or rodent borne. There are several clinical manifestations, which overall present as hemorrhagic fevers and/or encephalitis. Diagnostic measures include serology and RT-PCR. Management is largely supportive.

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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 based on the presence of 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 called “positive-sense” viruses if the genome is directly used as messenger RNA (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses use RNA-dependent RNA polymerase, a viral enzyme, to transcribe their genome into messenger RNA.

Image by Lecturio. License: CC BY-NC-SA 4.0

Characteristics

Basic features

  • Taxonomy:
    • Order: Bunyavirales
    • Family: Bunyaviridae
    • 5 genera:
      • Hantavirus/Orthohantavirus (includes Sin Nombre virus)
      • Orthobunyavirus (includes La Crosse virus)
      • Phlebovirus (includes Rift Valley fever (RVF) virus, sandfly/Phlebotomus fever viruses)
      • Nairovirus (includes Crimean-Congo hemorrhagic fever)
      • Tospovirus (infects only plants)
  • Bunyaviruses:
    • Enveloped: an envelope with 2 glycoproteins
    • Spherical, 80–120 nm in diameter
    • Genome:
      • Single-stranded negative-sense RNA virus
      • Triple segmented
      • Presence of helical capsid
      • Contains RNA-dependent RNA polymerase
    • Primarily arthropod-borne or rodent-borne viruses:
      • Hantavirus (rodents)
      • Orthobunyavirus (mosquitoes)
      • Nairovirus (ticks)
      • Phlebovirus: sandfly fever virus (sandflies)
      • Phlebovirus: RVF virus (mosquitoes)
    • Associated diseases:
      • Hemorrhagic fevers (i.e., Hantavirus, Crimean-Congo hemorrhagic fever)
      • Mosquito-borne encephalitis (i.e., California encephalitis group, which includes La Crosse virus)

Related videos

Hantavirus

Etiology and epidemiology

  • Genus: Hantavirus
  • > 20 species (about 11 known to cause disease in humans) including:
    • Sin Nombre virus:
      • Etiology of the 1993 “Four Corners” outbreak in the southwestern US
      • Among the etiologies of hantavirus pulmonary syndrome (HPS)/hantavirus cardiopulmonary syndrome (HCPS), and a severe and potentially fatal respiratory illness
    • Seoul, Dobrava, and Puumala viruses: among the etiologic agents of hemorrhagic fever with renal syndrome (HFRS)
  • Epidemiology:
    • China has the highest annual incidence of hantavirus-related diseases.
    • 728 cases reported in the US in 2017 (most commonly found in the western and southwestern states)
    • Most infections in the US are sporadic.
A Sin Nombre virus particle Hantavirus Bunyavirales

A Sin Nombre virus particle shown budding from a Vero cell:
The Sin Nombre virus causes hantavirus pulmonary syndrome in North America.

Image: “A Sin Nombre virus particle shown budding from a Vero cell” by NIAID. License: CC BY 2.0

Pathophysiology

  • Primary reservoir: rodents (deer mice in the US)
  • Transmission
    • Aerosol route/inhalation (exposure to feces, saliva, or urine of infected mice)
    • Rodent bite
    • Direct contact (via nose or mouth) with materials contaminated with rodent droppings, saliva, or urine
    • Ingestion of rodent droppings, saliva, or urine
  • Major syndromes/disease processes:
    • HPS
      • Viral antigens penetrate the endothelium, leading to immunologic response → ↑ capillary permeability → pulmonary edema 
      • More fatal of the 2 hantavirus syndromes
      • Caused mainly by hantavirus species in the Americas, and generally occurs in the fall in the US
    • HFRS
      • Azotemia secondary to vascular endothelial injury (capillary leak and loss of fluids)
      • Cytokine-induced tubular and interstitial damage → tubulointerstitial nephritis
      • More common of the 2 hantavirus syndromes
      • Caused mainly by hantavirus species in Asia and Europe
Transmission of Hantavirus

Transmission of hantavirus:
Researchers found that contact with rodents and their waste puts humans at risk for exposure to hantavirus. Massive rainfall associated with the 1991–1992 El Niño boosted plant productivity.
The rodent population grew by feasting on the more abundant plant matter. Increased contact with rodents and their waste put more humans at risk for exposure to hantavirus.

Image: “Researchers found that contact with rodents and their waste puts humans at risk for exposure to hantavirus” by Zina Deretsky, National Science Foundation. License: Public Domain

Clinical presentation

  • HPS/HCPS:
    • Incubation period: 1–3 weeks
    • Prodromal phase (up to 5 days):
      • Fever
      • Headache
      • Muscle aches
      • Nausea/vomiting/diarrhea 
    • Cardiopulmonary phase (2–7 days):
      • Cough
      • Dyspnea: can progress to hypoxia and respiratory failure requiring mechanical ventilation
      • Hypotension
      • Oliguria
      • Findings: tachypnea, tachycardia
    • Convalescent phase:
      • Significant diuresis
      • Resolution of symptoms
  • HFRS:
    • Varies depending on species (i.e., Hantaan virus in Asia causes more severe disease)
    • Manifestations include:
      • Fever
      • Hypotension (can lead to shock)
      • Hemorrhage
      • AKI (↓ GFR, oliguria, proteinuria, and hematuria)

Diagnosis and management

  • Confirmatory tests:
    • Serology (i.e., ELISA), where acute infection is detected as:
      • Specific anti-hantavirus IgM (usually the nucleocapsid or N antigen)
      • A 4-fold rise in anti-hantavirus IgG titers
    • RT-PCR using plasma, blood cells, or tissues
  • Additional laboratory tests:
    • CBC: leukocytosis, thrombocytopenia
    • Hepatic panel: transaminitis, ↓ albumin
    • HFRS: abnormal BUN/creatinine, proteinuria, or hematuria
    • ↑ CRP
  • Chest X-ray:
    • HPS:
      • Interstitial edema (in most patients after 48 hours) 
      • Perihilar haziness without cardiomegaly
    • HFRS:
      • Can show abnormal chest radiography
      • Interstitial infiltrates, effusion, atelectasis
  • Management:
    • Supportive measures: 
      • Cardiorespiratory support
      • Fluid balance
      • Dialysis as indicated
    • Prevention: rodent control, avoiding rodent contact, and appropriate clean-up of nesting sites
    • No vaccination available
  • Mortality:
    • HPS: up to 50% overall
    • HFRS: 5%–10%
Table: Diagnosis and management
Hantavirus pulmonary syndromeHantavirus hemorrhagic fever
Incubation1–3 weeks1–3 weeks (up to 6 weeks)
Diagnosis
  • Serology
  • RT-PCR
  • Serology
  • RT-PCR
Clinical manifestationsProdrome: flu-like symptoms, sudden onset of shortness of breath with rapidly evolving pulmonary edemaFever, low BP/shock, AKI
AP chest x-ray hantavirus pulmonary syndrome Bunyavirus

An anteroposterior chest X-ray shows mid-staged bilateral pulmonary effusion due to hantavirus pulmonary syndrome (HPS):
The radiological evolution of HPS begins with minimal changes of interstitial pulmonary edema progressing to alveolar edema with severe bilateral involvement. Pleural effusions are common and often large enough to be evident radiographically.

Image: “This AP chest X-ray reveals the mid-staged bilateral pulmonary effusion due to hantavirus pulmonary syndrome, or HPS” by CDC/ D. Loren Ketai, M.D. License: Public Domain

Crimean-Congo Hemorrhagic Fever Virus

Etiology and epidemiology

  • Genus: Nairovirus
  • Crimean-Congo hemorrhagic fever virus
  • Associated disease: Crimean-Congo hemorrhagic fever
    • 1st characterized in Crimea in 1944 (Crimean fever)
    • It was later recognized in 1956 as the cause of illness in Congo, resulting in the disease’s current name
  • Epidemiology: 
    • Endemic areas:
      • Africa (primarily central)
      • Eastern Europe (particularly in the former Soviet Union) and Southern Europe
      • Mediterranean
      • Middle East
      • Northwestern China
      • Central Asia
      • Indian subcontinent
    • Risk of exposure:
      • Animal herders
      • Livestock workers
      • Slaughterhouse workers
Transmission electron micrograph Crimean-Congo hemorrhagic fever virus Bunyavirus

a: transmission electron micrograph of a Crimean-Congo hemorrhagic fever virus particle
b: schematic illustration of a nairovirus particle (enveloped, ssRNA containing L, M, and S segments, surrounded by external glycoproteins)

RNP: ribonucleoprotein
Image: “Transmission electron micrograph of a Crimean-Congo hemorrhagic fever virus particle” by Aura R. Garrison et al. License: CC BY 4.0

Pathophysiology

  • Vector and reservoir: Ixodid ticks (genus: Hyalomma) can transmit the virus to progeny.
  • Amplifying hosts: wild and domestic animals, such as cattle, goats, sheep 
  • Transmission:
    • Tick bites
    • Direct contact with bodily fluids of infected livestock or humans
    • Documented transmission via improperly sterilized medical equipment, needle-stick injuries, and contaminated medical supplies in hospitals
    • Vertical (mother-to-child) transmission
  • Disease process:
    • Virus replicates at the site of inoculation within epithelial cells, macrophages, and dendritic cells → viremia
    • Endothelial cells are targeted by the virus, triggering the release of cytokines and chemokines and leading to:
      • Increased vascular permeability
      • Deregulated platelet aggregation → stimulated coagulation cascade (procoagulant state)
      • Clotting factors eventually become deficient → hemorrhage

Clinical presentation

  • Sudden onset of flu-like symptoms: 
    • Headache
    • Fever
    • Back pain and arthralgias
    • Abdominal pain
    • Nausea/vomiting
    • Facial flushing
    • Injected conjunctiva
    • Petechiae on the palate
  • Symptoms last up to 7 days:
    • Most often followed by recovery
    • Can progress to severe disease with hemorrhage (ecchymosis, epistaxis, gum bleeding, hematuria, melena, heavy menstrual bleeding)
    • Exaggerated proinflammatory cytokine response (“cytokine storm”) leads to hypotension, shock, and multiorgan failure.
  • Fatality rates in hospitalized patients range from 9%–50%.

Diagnosis and management

  • Diagnostic tests:
    • Diagnosis is based on physical findings and history of risk exposure.
    • RT-PCR
    • Serology (detection of specific immunoglobulins IgM and IgG using ELISA)
  • Additional laboratory tests:
    • CBC: thrombocytopenia, leukopenia
    • Hepatic panel: transaminitis, hyperbilirubinemia
    • ↑ PT/INR
    • In disseminated intravascular coagulation: ↑ fibrin-degradation products, ↓ fibrinogen
  • Treatment
    • Supportive:
      • Cardiorespiratory support
      • Fluid balance
      • Blood-product replacement
    • Ribavirin may offer some benefit.
    • No available vaccine
  • Prevention:
    • Avoiding contact with blood and body fluids of infected animals
    • Wearing insect repellants and protective clothing
    • Isolation of patients
    • Using PPE

Rift Valley Fever Virus

Etiology and epidemiology

  • Genus: Phlebovirus
  • RVF virus 
  • Associated disease: RVF (viral hemorrhagic fever)
  • Epidemiology:
    • Endemic areas:
      • East Africa
      • Sub-Saharan Africa
      • Madagascar
    • Commonly affects livestock, but humans are infected secondarily
Enveloped virions of Rift Valley fever virus Bunyavirus

Enveloped virions of the Rift Valley fever (RVF) virus are characterized by a negative or ambisense RNA genome composed of 3 single-stranded segments (designated L, M, and S):
These 3 RNA molecules are encapsidated by nucleoprotein (N), which shapes the nucleocapsid that interacts with the viral polymerase (L). Glycoproteins Gn and Gc are noted externally.

Image: “Enveloped virions of Rift Valley fever virus (RVFV)” by Eva Calvo-Pinilla et al. License: CC BY 4.0

Pathophysiology

  • Vector:
    • Mosquitoes: Females can transmit the virus to their eggs.
      • Aedes mosquito (primary vector)
      • Culex mosquito
    • Infected animals
  • Transmission:
    • Mosquito bites
    • Contact with blood or body fluids of infected animals 
  • Host risk factors
    • Living in rural areas
    • Sleeping outdoors at night
    • Herdsmen/farmers
    • Veterinarians
    • Butchers/slaughterhouse workers

Clinical presentation

  • RVF infection can cause either mild or severe illnesses in humans. 
    • Mild illness:
      • 90% of cases
      • Most patients have either a flu-like illness or no symptoms.
      • Recovery in 2 days to 1 week
    • Severe illness:
      • 8%–10% of cases
      • Eye disease: retinitis, lesions affecting the macula (50% will have permanent blindness)
      • Hemorrhagic fever (1% of cases): bleeding, liver impairment, hematemesis (carries a 50% mortality rate)
      • Encephalitis (1% of cases): headaches, coma, seizures (can lead to permanent neurological deficits)

Diagnosis and management

  • RT-PCR
  • Viral isolation in cell culture
  • Serology (IgM antibodies against the RVF virus)
  • Management
    • Most infections are self-limiting.
    • Supportive care
    • No FDA-approved treatments 
  • Prevention
    • No vaccines exist for prevention.
    • Avoid contact with the blood and body fluids of infected animals.
    • Mosquito avoidance:
      • Insect repellents
      • Mosquito nets
      • Protective clothing

La Crosse Virus

Etiology and epidemiology

  • Genus: Orthobunyavirus
  • La Crosse Virus: most pathogenic virus in the California encephalitis serogroup
  • Associated disease: La Crosse encephalitis (mosquito-borne arboviral disease) 
  • Epidemiology:
    • La Crosse virus: most common arbovirus causing CNS infections in children (North America)
    • Approximately 75% of cases in the pediatric population
    • In the US:
      • 30–120 cases of neuroinvasive diseases reported annually 
      • Most cases are reported in the summertime with a peak incidence between July and September.
      • Areas most affected: upper midwestern, mid-Atlantic, and southeastern states
ultrastructural morphology exhibited by numerous La Crosse virus Bunyavirales

Image showing the ultrastructural morphology exhibited by numerous La Crosse virus (LCV) particles

Image: “Image showing the ultrastructural morphology exhibited by numerous La Crosse virus (LCV) particles” by Dr. Erskine Palmer, USCDCP. License: Public Domain

Pathophysiology

  • Vector: the eastern tree hole mosquito, Aedes triseriatus
  • Reservoir: A. triseriatus (virus passed from a female mosquito to the eggs)
  • Hosts: Cycles of infection occur between mosquitoes and hosts (humans, squirrels, chipmunks, and other small mammals).
  • Transmission: mosquito bite
  • Pathophysiology
    • The virus is transmitted subcutaneously by a feeding mosquito.
    • Viral replication begins in the muscle adjacent to the site of penetration, eventually followed by viremia.
    • Dissemination to the reticuloendothelial system (lymph nodes, liver, spleen) occurs, and neuroinvasion may follow.

Clinical presentation

  • Incubation: 3–7 days
  • Many infected individuals are asymptomatic or present with a mild flu-like illness:
    • Headache
    • Nausea, vomiting
    • Fatigue, lethargy
  • Few infected individuals may develop severe neuroinvasive disease (most often children < 16 years of age): 
    • Encephalitis
    • Seizures
    • Aseptic meningitis
    • Paralysis 
    • Coma
    • Fatalities are rare.

Diagnosis and management

  • Suspect in patients presenting with typical symptoms in an endemic area.
  • Diagnostic tests:
    • IgM and neutralizing antibodies to the virus in serum or CSF using ELISA 
    • A 4-fold increase in antibody titer 
    • Determination of viral antigens or genomic sequences in tissue, blood, or CSF
  • Additional tests:
    • Brain CT scan is normal.
    • EEG abnormalities are common.
  • Treatment
    • Supportive
    • Usually self-limiting
    • No effective antiviral drugs
    • No vaccine available
  • Prevention
    • Mosquito avoidance:
      • Insect repellent 
      • Protective clothing
      • Avoid mosquito-infested areas

Comparison of Species

Table: Comparison of species
OrganismHantavirusCrimean-Congo hemorrhagic fever virusRift Valley fever virusLa Crosse virus
CharacteristicsSingle-stranded, enveloped, negative-sense RNA viruses
GenusHantavirus or OrthohantavirusNairovirusPhlebovirusOrthobunyvirus
TransmissionInhalation and direct contact with the urine and feces of infected miceContact with infected ticks (especially Hyalomma spp.)
  • Mosquito bites
  • Exposure to blood and body fluids of infected animals
Mosquito bites
Clinical presentation
  • Hantavirus pulmonary syndrome
  • Hemorrhagic fever with renal syndrome
Hemorrhagic fever
  • Hemorrhagic fever
  • Ocular disease
  • Encephalitis
Encephalitis
Diagnosis
  • RT-PCR
  • ELISA (antibodies)
  • RT-PCR
  • ELISA (antibodies)
  • RT-PCR
  • ELISA (antibodies)
  • ELISA (antibodies in serum or CSF)
  • RT-PCR
ManagementSupportive
  • Supportive
  • Ribavirin
SupportiveSupportive

Differential Diagnosis

  • Saint Louis encephalitis virus: a member of the genus, Flavivirus, and the cause of St. Louis encephalitis. Saint Louis encephalitis virus is a small, enveloped, positive-sense ssRNA virus transmitted by Culex mosquito species. Most infections are asymptomatic. Symptomatic individuals may have varied presentations with flu-like symptoms, aseptic meningitis, encephalitis, or meningoencephalitis. The diagnosis is confirmed with serology. There are no effective antiviral drugs; thus, the management is supportive. Prevention is aimed at local mosquito control and personal protection using insect repellents and protective clothing.
  • Yellow fever: a disease caused by the yellow fever virus, a single-stranded, positive-sense RNA virus of the genus, Flavivirus. 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. The diagnosis can be confirmed with serology and PCR. There are no antiviral drugs available to treat yellow fever; thus, the management is supportive. Prevention includes mosquito avoidance and vaccination.
  • Tick-borne encephalitis virus (TBEV): a positive-sense, single-stranded RNA virus of the genus, Flavivirus, causing encephalitis. Transmission primarily occurs via Ixodes ticks, and infections are common in Europe, Russia, and Asia. Most patients are asymptomatic; however, symptomatic individuals may experience a biphasic illness. After recovering from nonspecific symptoms, patients can develop neurologic manifestations such as meningitis, encephalitis, or meningoencephalitis. Serology or PCR can confirm the diagnosis. There are no effective antiviral drugs to treat TBEV infections. Management is supportive.
  • Dengue virus: is a small, positive-sense, ssRNA virus of the genus, Flavivirus. Transmission is via the bite of female Aedes mosquitoes. Most infections are asymptomatic. Symptomatic individuals may go through 3 stages, with severe manifestations occurring in those with previous infections. The febrile phase includes fever, headache and retro-orbital pain, myalgias and arthralgias (“breakbone” pain), and maculopapular rashes. The critical phase includes hemorrhage and shock. There is symptom resolution in the convalescent phase. Diagnosis is made based on the clinical findings, serology, antigen testing, or PCR. Management is supportive.

References

  1. Ayoade, F., Cordova, L. (2021) California Encephalitis. Medscape. Retrieved May 25, 2021, from https://emedicine.medscape.com/article/234159-overview#a6
  2. Barbosa, N., Concha, J., Dasilva, L. (2020). Bunyavirus. 10.1016/B978-0-12-818731-9.00037-9. 
  3. Centers for Disease Control and Prevention (2012). Hantavirus. Retrieved May 24, 2021, from https://www.cdc.gov/hantavirus/hps/transmission.html
  4. Chandy, S., Mathai, D. (2017). Globally emerging hantaviruses: An overview. Indian J Med Microbiol. 35(2), 165-175. https://pubmed.ncbi.nlm.nih.gov/28681802/
  5. Cennimo, D., Hale, Z. (2019). Hantavirus Pulmonary Syndrome. Medscape. Retrieved May 25, 2021, from https://emedicine.medscape.com/article/236425-overview
  6. Drebot, M.A., Jones, S., Grolla, A., Safronetz, D., Strong, J.E., Kobinger, G., Lindsay, R.L. (2015). Hantavirus pulmonary syndrome in Canada: An overview of clinical features, diagnostics, epidemiology, and prevention. Can Commun Dis Rep. 04;41(6), 124-131. https://pubmed.ncbi.nlm.nih.gov/29769944/
  7. Hjelle, B. (2021) Hantavirus cardiopulmonary syndrome. UpToDate. Retrieved May 25, 2021, from https://www.uptodate.com/contents/hantavirus-cardiopulmonary-syndrome
  8. Krause, A., Mirazimi, A. (2010). Molecular biology and pathogenesis of Crimean-Congo hemorrhagic virus. Medscape. Retrieved May 25, 2021, from https://www.medscape.com/viewarticle/729785_2
  9. Leblebicioglu, H. (2021). Crimean-Congo hemorrhagic fever. UpToDate. Retrieved May 25, 2021, from https://www.uptodate.com/contents/crimean-congo-hemorrhagic-fever
  10. Mustonen, J. (2021). Kidney involvement in Hantavirus infections. UpToDate. Retrieved May 25, 2021, from https://www.uptodate.com/contents/kidney-involvement-in-hantavirus-infections
  11. Pepin, M., Bouloy, M., Bird, B.H., Kemp, A., Paweska, J. (2010). Rift Valley fever virus (Bunyaviridae: Phlebovirus): An update on pathogenesis, molecular epidemiology, vectors, diagnostics, and prevention. Vet Res 41, 61.
  12. Petersen, L. (2021). Arthropod-borne encephalitides. UpToDate. Retrieved May 25, 2021, from https://www.uptodate.com/contents/arthropod-borne-encephalitides
  13. Riedel, S., & Hobden, J.A., & Miller, S., & Morse, S.A., & Mietzner, T.A., & Detrick, B., & Mitchell, T.G., & Sakanari, J.A., & Hotez, P., & Mejia, R. (Eds.) (2019). Arthropod-borne and rodent-borne viral diseases. Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28e. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2629&sectionid=217774914

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