Chikungunya Virus

Chikungunya virus belongs to the Alphavirus genus and causes a viral infection characterized by fever and joint pain. The arthropod-borne (arbovirus) virus is transmitted by mosquitoes (commonly Aedes albopictus and Aedes aegypti). Symptoms usually appear within 1 week of infection. Additional manifestations of chikungunya virus may include muscle pain, headache, maculopapular rash, and lymphadenopathy. Most infected individuals recover, but chronic arthritis may develop. Treatment is aimed at relieving symptoms. The disease is prevented by mosquito avoidance, use of insect repellent, and protective clothing.

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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.

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

General Characteristics

Basic features

Chikungunya virus:

  • Togaviridae family
  • Alphavirus genus
  • Genome:
    • Positive-sense, single-stranded RNA
    • Size: 11.8 kb
  • Properties:
    • Enveloped
    • Lipid-bilayer envelope has viral-encoded glycoproteins, which mediate cell attachment and entry: 
      • E1: consists of fusion peptides, which dissociate from E2 in low pH and facilitate the release of nucleocapsids into the host cytoplasm
      • E2: binds to cellular receptors, resulting in receptor-mediated endocytosis
    • Small, icosahedral capsid

Epidemiology

Geographic distribution:

  • Frequent outbreaks:
    • Africa
    • Southeast Asia 
  • Indian subcontinent
  • South America and islands of the Caribbean
  • United States:
    • Cases reported from travelers to the above areas
    • Local transmission noted in Florida, Puerto Rico, and the United States Virgin Islands

Pathogenesis

Vectors

  • Mosquitoes of the Aedes genus
  • Major vectors (also transmit Zika virus and dengue virus):
    • A. aegypti 
    • A. albopictus

Reservoirs

  • Humans
  • Primates: The virus is seen in Africa and maintained in the sylvatic cycle (e.g., wild primates, monkeys, and mosquitoes).

Transmission

  • Transmitted from mosquitoes to humans
  • Vertical transmission (rare)
  • Blood transfusion (rare)
Life cycle of Chikungunya virus

The life cycle of the chikungunya virus in Africa showing the interconnection between the sylvatic cycle, involving primates and mosquitoes, and the urban cycle, involving humans and mosquitoes.

Image: “Life cycle of Chikungunya virus” by Michelle M Thiboutot et al. License: CC BY 4.0

Host risk factors

  • Proximity to mosquito breeding sites
  • Severe disease can occur in:
    • Newborns 
    • Adults ≥ 65 years of age
    • Individuals with underlying conditions such as diabetes or cardiovascular disease

Pathophysiology

  • Chikungunya virus is introduced to the human skin and bloodstream via a mosquito bite.
  • Viral replication occurs in the dermal fibroblasts, then the bloodstream:
    • The virus directly invades and replicates within the joints and muscles.
    • ↑ In proinflammatory cytokines and inflammatory cells
  • Dissemination to and invasion of other organs may occur:
    • Liver (endothelial cells)
    • Brain (endothelial and epithelial cells)
    • Lymphoid tissue (lymph nodes and spleen)
  • Chronic joint disease is seen in up to 60% of patients and caused by:
    • Persistent viral replication
    • Continued immune response to remaining RNA 
    • Autoimmunity

Clinical Presentation

Neonatal infection

Infection of newborns is seen within 1 week of delivery. Signs and symptoms include:

  • Fever
  • Poor feeding
  • Edema
  • Rash
  • Thrombocytopenia
  • Neurologic disease (meningoencephalitis)

Infection of children and adults

The incubation period is 3–7 days. Symptoms of chikungunya fever appear within 1 week of infection and include:

  • High-grade fever 
  • Debilitating arthralgia and arthritis:
    • Bilateral and symmetric
    • Polyarticular: commonly involves the small joints of the hands, wrists, and ankles
    • Patients are often in a flexed posture due to pain.
    • The development of chronic arthritis increases in those ≥ 45 years of age and/or with preexisting osteoarthritis.
  • Headache
  • Muscle pain
  • Maculopapular rash (extremities and trunk)
  • Conjunctivitis
  • Lymphadenopathy

Severe symptoms may occur in those with risk factors:

  • Encephalitis 
  • Myocarditis
  • Hepatitis
  • Renal failure
  • Hemorrhage

Diagnosis

Diagnostics

  • Clinical history: fever, joint pain, and relevant exposure (i.e., travel to or living in an endemic area)
  • Confirmatory tests:
    • Serology via ELISA or indirect fluorescent antibody (IFA):
      • IgM noted by the 5th day of symptom onset and may persist up to 3 months
      • IgG noted by 2 weeks after symptom onset
    • RT-PCR of chikungunya virus RNA
    • Viral culture

Additional tests

Because the symptom complexes are similar and patients may be coinfected with more than 1 virus, the CDC and WHO recommend testing for chikungunya, dengue, and Zika viruses in patients presenting with suspicious symptoms.

CBC:

  • Lymphopenia
  • Thrombocytopenia

Other findings:

  • ↑ Hepatic transaminases
  • ↑ Creatinine

Management

Acute disease

Treatment of chikungunya fever is symptomatic:

  • Analgesia:
    • Acetaminophen for pain and fever
    • Avoid NSAIDs and aspirin until dengue fever is ruled out (due to bleeding risk).
  • Hydration

Rash spontaneously resolves and symptoms generally improve within 1 month.

Post-acute disease

  • Symptoms may persist or relapse, especially joint pain.
  • Analgesics such as acetaminophen and/or NSAIDs can be used.
  • For severe synovitis and continued elevation of inflammatory markers, a short course of glucocorticoids can be given.
  • For symptoms ≥ 3 months, disease-modifying antirheumatic drugs (DMARDs) such as methotrexate and sulfasalazine can be given.

Prevention

Avoid mosquito breeding areas by environment control (i.e., no standing water in containers) and use personal protection:

  • Insect repellent
  • Wear protective clothing.
  • Sleep under a mosquito net.

Comparisons of Species

Chikungunya virus and the equine encephalitis virus belong to the Alphavirus genus and are major etiologies of encephalitis in the United States.

Table: Comparison of chikungunya virus and equine encephalitis virus
OrganismChikungunya virusEquine encephalitis virus
Family Togaviridae
Genus Alphavirus
Characteristics
  • Enveloped, icosahedral capsid
  • Positive sense
  • ssRNA
Transmission Mosquito
Clinical
  • Fever
  • Headache
  • Arthritis
  • Rash
  • Fever
  • Headache
  • Nausea/vomiting
  • Severe: encephalitis
Diagnosis
  • Serology
  • RT-PCR
Management
  • Symptomatic
  • Control of joint pain
Supportive
Prevention
  • Mosquito avoidance
  • Insect repellent
  • Protective clothing
  • Mosquito net

Differential Diagnosis

Conditions mimicking acute chikungunya fever, have a similar symptom complex, and belong to the Flaviridae family and Flavivirus genus:

  • Dengue virus: a small, positive-sense, single-stranded RNA virus transmitted to humans by the bite of a female Aedes mosquito. Most infections are asymptomatic. Symptomatic individuals may progress through different stages. The febrile phase includes fever, headache, retro-orbital pain, myalgias, arthralgias, and maculopapular rash. More severe manifestations of capillary leakage, hemorrhage, and shock may occur in the critical phase. Resolution of signs and symptoms occur in the convalescent phase. Diagnostic tests include serology, antigen testing, or PCR. Management is supportive.  
  • Zika virus: a positive-sense, single-stranded RNA virus most commonly transmitted by an A. aegypti mosquito. The virus can also be transmitted sexually and transplacentally. Most infected patients are asymptomatic, but some may present with low-grade fever, pruritic rash, and conjunctivitis. Congenital Zika syndrome is a transplacental, fetal infection, which manifests with ocular defects, microcephaly, spasticity, and seizures. The diagnosis is made either by RT-PCR or serology. Treatment is mostly supportive. Prevention includes control of the mosquito population with insect repellent, and protective clothing. 

Conditions presenting as chronic arthritis:

  • Seronegative rheumatoid arthritis: inflammatory arthritis in 3 or more joints, which lasts for > 6 weeks. Rheumatoid factor and anti-cyclic citrullinated peptide tests are negative and could present similarly to chikungunya infection. Serology and history (including travel) distinguish seronegative rheumatoid arthritis from chikungunya infection.
  • Reactive arthritis: arthritis occurring concomitantly with or after an extraarticular infection. Characteristics include asymmetric oligoarthritis (often involving the lower extremities), enthesitis, back pain, and dactylitis. Diagnosis is made by history (GI or urinary infection is often noted) and ruling out other arthritis etiologies with laboratory work-up and imaging.

References:

  1. Centers for Disease Control and Prevention. (2019). Chikungunya virus. https://www.cdc.gov/chikungunya/
  2. Gibney, K.B., Fischer, M., Prince, H.E., et al. (2011). Chikungunya fever in the United States: a fifteen-year review of cases. Clin Infect Dis. 52(5):e121–6. http://reference.medscape.com/medline/abstract/21242326
  3. Miner, J., Lenschow, D., Wilson, M. (2021). Chikungunya fever: treatment and prevention. UpToDate. Retrieved May 22, 2021, from https://www.uptodate.com/contents/chikungunya-fever-treatment-and-prevention
  4. Natesan, S., Chandrasekar, P. (2019). Chikungunya virus. Medscape. Retrieved May 22, 2021, from https://emedicine.medscape.com/article/2225687-overview
  5. Staples, J.E., Breiman, R.F., Powers, A.M. (2009). Chikungunya fever: an epidemiological review of a re-emerging infectious disease. Clin Infect Dis. 49(6):942–8. http://reference.medscape.com/medline/abstract/19663604
  6. Schwartz, O., Albert, M. (2010). Biology and pathogenesis of chikungunya virus. Nat Rev Microbiol 8, 491–500. https://doi.org/10.1038/nrmicro2368
  7. Thiboutot, M.M., et al. (2010). Chikungunya: A Potentially Emerging Epidemic? PLoS Negl Trop Dis 4(4): e623. https://doi.org/10.1371/journal.pntd.0000623
  8. Wilson, M., Lenschow, D., Miner, J. (2020). Chikungunya fever: Epidemiology, clinical manifestations and diagnosis. UpToDate. Retrieved May 22, 2021, from https://www.uptodate.com/contents/chikungunya-fever-epidemiology-clinical-manifestations-and-diagnosis

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