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Internal Medicine

Chikungunya

Acute disease, which results in fever, arthritis and skin rash, caused by an enveloped virus capable of replicating in mosquitoes.

Acute disease, which results in fever, arthritis and skin rash, caused by an enveloped virus capable of replicating in mosquitoes.


Epidemiology

Historically, CHIKV has been endemic in tropical and subtropical regions of sub-Saharan Africa and Southeast Asia, where two distinct CHIKV transmission cycles exist. CHIKV is maintained in a rural enzootic transmission cycle, which occurs between various forest or savannah Aedes (Stegomyia) mosquitoes and animal reservoirs, with nonhuman primates being the presumed major reservoir host

CHIKV Worldwide Prevalence
Dark green denotes countries with current or previous local transmission of CHIKV (as of July 2015) | CDC – https://www.cdc.gov/chikungunya/geo/index.html, Public Domain, https://commons.wikimedia.org/w/index.php?curid=51772486

Chikungunya virus (CHIKV):

CHIKV is a small (~70 nm in diameter), enveloped virus that is a member of the Old World Semliki Forest virus group of arthritogenic alphaviruses within the Togaviridae family
Transmission electron micrograph (TEM) depicting numerous Chikungunya virus particles
Transmission electron micrograph (TEM) depicting numerous Chikungunya virus particles, which are composed of a central dense core that is surrounded by a viral envelope. Each virion is approximately 50nm in diameter. | Cynthia Goldsmith – Centers for Disease Control and Prevention – http://phil.cdc.gov/PHIL_Images/17369/17369.tif, Public Domain, https://commons.wikimedia.org/w/index.php?curid=34743799

Transmission:

Transmission of CHIKV occurs mainly through the bite of an infected Aedes (subgenus Stegomyia) species of mosquito. However, maternal-fetal transmission can occur intrapartum, which results in high rates of infant morbidity
  • Enzootic sylvan transmission (animal-mosquito-human): Well established in Africa
    • Mediated by: Aedes africans, A. fancifer and wild primates
  • Urban cycle (human-mosquito-human transmission cycle): Found in Asia on occasional introduction into urban areas causing periodic outbreaks of CHIKV disease
    • Mediated by: Aedes aegypti or albopictus mosquitoes
Transmission cycle of CHIKV in Africa
Transmission cycle of CHIKV in Africa: Nonhuman primates, and possibly other wild animals, serve as reservoirs of the virus. Infected arboreal Aedes mosquitoes bite and infect humans. Infected humans, in turn, infect peridomestic Aedes aegypti, perpetuating the urban cycle of CHIKV transmission. | Thiboutot MM, Kannan S, Kawalekar OU, et al. Chikungunya: a potentially emerging epidemic? PLoS Negl Trop Dis 2010;4(4):e623

Pathogenesis

CHIKV-induced disease shares many similarities with illnesses caused by other arthritogenic alphaviruses, with some distinctions observed. After deposition into the bloodstream or skin through a bite of an infected mosquito, CHIKV replicates at the site of inoculation in fibroblasts and possibly macrophages. Despite triggering innate immune responses, the virus spreads via lymphatics into the bloodstream, allowing dissemination to several sites of replication, most commonly lymphoid organs (lymph nodes and spleen), skin, and especially tissues where prominent disease symptoms occur (muscle, peripheral joints, and tendons) but also in brain and liver in more severe cases. Replication of CHIKV in peripheral tissues results in remarkably high serum viral loads (>109 virus particles/ml; ref. 110). Such high-level viremia in humans is rare for most alphaviruses and allows CHIKV to be easily transmitted to mosquitoes via a bloodmeal.

Model of acute and chronic CHIKV pathogenesis
Model of acute and chronic CHIKV pathogenesis: Acute CHIKV infection begins with transmission of the virus via a bite of an infected mosquito to the skin, where it replicates in susceptible cells, including fibroblasts and macrophages. The virus disseminates through lymphatics and bloodstream to typical (solid) and atypical (hatched) sites of primary replication (indicated in blue). Acute infection elicits an inflammatory response in infected tissues, characterized by an extensive infiltration of mainly macrophages and monocytes, but also neutrophils, NK cells, and lymphocytes in target tissues (indicated in blue), and by elaboration of a number of proinflammatory chemokines and cytokines. Within arthroskeletal tissues, synovial hyperplasia begins. Viral replication and host immune responses cause myalgia and polyarthralgia in distal joints. Chronic CHIKV disease can persist for months or years after acute infection but is often limited to more distal joints. Chronic disease is likely mediated by persistent virus and inflammation. Possible sites of CHIKV persistence include endothelial cells in the liver and other organs, mononuclear cells in the spleen, macrophages within the synovial fluid and surrounding tissues, and satellite cells within the muscle (indicated in purple). Within the chronically infected joint, the continued presence of a subset of infiltrating cells (mainly macrophages, monocytes, and lymphocytes) and specific proinflammatory mediators (IL-6, IL-8, and MCP-1) within the synovial fluid likely contribute to prolonged inflammatory disease. Chronic joint pathology resembles that in rheumatoid arthritis, with significant hyperplasia and angiogenesis. This model is based on human and animal studies. | Silva, L. A., & Dermody, T. S. (2017). Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. The Journal of clinical investigation, 127(3), 737–749. https://doi.org/10.1172/JCI84417

Presentation

  • Incubation period: 2-12 days
  • Sudden onset of symptoms

Characteristic triad:

The vast majority of infected individuals develop chikungunya fever, an acute illness notable for rapid onset of fever, incapacitating polyarthralgia and arthritis, rash, myalgia, and headache
  1. Fever: Rises abruptly to 103-104°F and is accompanied by rigors
  2. Rash (4-8 days later): Itchy, transient maculopapular rash affecting the trunk and limbs
  3. Arthritis: Polyarticular arthralgia/arthritis, migratory and predominantly affects the small joints of hands, wrist, ankle and feet, with less involvement of larger joints. Appears suddenly and is often very severe in intensity and may continue for many months after illness

Other symptoms:

  • Headache (80% cases)
  • Fatigue, nausea, vomiting, muscle pain
  • Photophobia and retro-orbital pain

Complications (rare):

CHIKV disease is often self-limiting and has a low fatality rate (~0.1%), but manifestations of CHIKV infection that lead to acute and chronic disability have considerable implications, including a substantial impact on quality of life for infected patients as well as considerable economic and community consequences
  • Thrombocytopenia and shock
  • Encephalopathy
Typical and atypical manifestations of CHIKV disease in patients
Typical and atypical manifestations of CHIKV disease in patients | Silva, L. A., & Dermody, T. S. (2017). Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. The Journal of clinical investigation, 127(3), 737–749. https://doi.org/10.1172/JCI84417

Diagnosis

Diagnosis of CHIKV can be established or confirmed by detection of viral RNA with serology and/or reverse-transcription polymerase chain reaction (RT-PCR) depending on disease timeframe presentation.

CHIKV infection timeline regarding clinical manifestations, viral and antibody kinetics, and protocol for laboratory diagnosis
CHIKV infection timeline regarding clinical manifestations, viral and antibody kinetics, and protocol for laboratory diagnosis | Soto-Garita, C., Carrera, JP., López-Vergès, S. et al. Advances in Clinical Diagnosis and Management of Chikungunya Virus Infection. Curr Treat Options Infect Dis 10, 397–409 (2018). https://doi.org/10.1007/s40506-018-0172-x

Viral culture:

The gold standard for the diagnosis of Chikungunya fever is viral culture based on inoculation of mosquito cell cultures, mosquitoes, mammalian cell cultures, or mice. However, viral culture is seldom done in routine clinical practice as these facilities are not widely available in India. It has the advantage of detecting a wide range of viruses.

Molecular disagnosis:

  • RT-PCR
  • Real-time loop-mediated isothermal amplification (RT-LAMP)

Serodiagnosis:

Serodiagnostic methods for the detection of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against Chikungunya virus in acute and convalescent sera are used. IgM antibodies are detectable after a mean period of 2 days by ELISA immunofluorescent assay and they persist for periods ranging from several weeks to 3 months.. The IgG antibodies can be detected in convalescent samples and persists for years. Instances of persistence of IgM antibodies 18 months after disease onset in about 40% of symptomatic patients has also been described.
  • Enzyme-linked immunosorbent assay (ELISA)
  • Indirect immunofluorescent method
  • Hemagglutination inhibition
  • Neutralization techniques
Diagnostic criteria for chikungunya virus (CHIKV) fever | BSL3, biosafety level 3; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Ig, immunoglobulin; RT-PCR, reverse transcription-polymerase chain reaction. | Burt FJ, Rolph MS, Rulli NE, et al. Chikungunya: a re-emergingvirus. Lancet 2012; 379:662–71

Differential diagnosis:

  • Dengue fever: Acute CHIKV disease symptomatically resembles dengue fever. However, unlike dengue, a characteristic feature of CHIKV disease is recurring musculoskeletal disease primarily affecting the peripheral joints that can persist for months to years after acute infection

Management

Symptomatic treatment:

Treatment of Chikungunya fever is symptomatic and supportive.
  • Rest, adequate fluid intake
  • Paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDS): Symptom relief
  • Aspirin: Avoided due to effect on platelets
Treatment flowchart of the acute phase of chikungunya fever | MS, musculoskeletal; VAS, visual analogue scale. | Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia – SBR).

Subacute & chronic disease:

Chronic manifestations, including persistent or relapsing-remitting polyarthralgia, polyarthritis, and myalgia, have been found to respond adequately to hydroxychloroquine in combination with corticosteroids or other disease modifying anti-rheumatic drugs (DMARDs)
Treatment flowchart for subacute phase of chikungunya fever | MS, musculoskeletal; VAS, visual analogue scale; NSAID, nonsteroidal anti-inflammatory drug; HCQ, hydroxychloroquine. | Brazilian Society of Rheumatology.
Treatment flowchart of the chronic phase of chikungunya fever | MS, musculoskeletal; VAS, visual analogue scale; NSAID, nonsteroidal anti-inflammatory drug; CS, corticosteroid; HCQ, hydroxychloroquine; SSZ, sulfasalazine; CIJD, chronic inflammatory joint disease. | Brazilian Society of Rheumatology.

Prevention

Patients with Chikungunya fever should be advised to avoid being bitten by mosquitoes as the disease can be transmitted to others. Presently no commercial vaccine is available for Chikungunya fever in India, although some candidate vaccines are being tested in human beings.

Vector surveillance and control:

Educating the community and public health officials, vector control measures such as elimination of breeding sites and spraying of insecticides should be initiated at the individual and community levels as this can be rewarding. Vector surveillance and control is a key element in containing Chikungunya fever epidemics. Active involvement of community and public health authorities with regard to hygiene and mosquito control measures is essential to stand a chance in the war against the mosquitoes.
  • Integrated vector management: Reduce or interrupt transmission of disease

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