Approach
Clinical suspicion in a patient with suggestive symptoms and potential exposure to mosquito bites is key for the diagnosis.
Confirmed chikungunya infection requires the presence of symptoms plus a history of visiting or residing in an area with reported transmission of chikungunya virus within the past 15 days, and a positive test such as:[47]
Viral culture to detect virus in first 3 days of illness
RT-PCR to detect viral RNA in first 8 days of illness
Serology to detect IgM and neutralizing antibodies that develop toward the end of the first week of illness onset.
Chikungunya virus infection is a notifiable disease in the US and some other countries. It is important to differentiate from dengue fever and Zika virus infection as presentation is similar, although coinfection is possible.
Clinical manifestations
The incubation period ranges between 1 and 12 days, but the majority of cases present 2 to 4 days after a mosquito bite. A travel history (to an endemic area within the 15 days prior to onset of infection) and questions about outdoor exposure may offer clues to the diagnosis.
The presentation is usually abrupt with high fever and chills. Occasionally, patients may not develop fever. In those cases, prominent arthralgia is usually reported.
Arthralgias and arthritis are very common.[18] They tend to affect the appendicular, rather than the axial, skeleton. The distal joints are most commonly affected: ankles, wrists, feet, and hands. The involvement is usually polyarticular and symmetric. The pain may be associated with morning stiffness and may improve with modest activity, but worsen with aggressive movements. Backache and headache may affect up to two-thirds of patients. Some patients may present with neuropathic-type pain.[48]
A nonspecific rash can occur in up to 50% of those affected.[18] The rash is maculopapular, nonpruritic and of global distribution. Diffuse erythoderma is also described. Other presentations including vesicular and purpuric lesions have been described, although less often. Centrofacial hyperpigmentation and ulcers in skin folds may also be present, as well as aphthous ulcers. Pruritus is common. Edema of face and extremities has also been described.
Neurologic (e.g., meningitis, meningoencephalitis), ocular, or hemorrhagic manifestations are unusual. Patients at the extremes of age or those with extensive comorbid illness, including chronic rheumatologic conditions, are more likely to develop a severe course.[49][50]
The most feared manifestation of infection is chronic arthritis, which can last for years and can be crippling. This chronic form of the disease is usually polyarticular. Symptoms can resemble rheumatoid arthritis (arthritis on 3 or more joints, symmetric arthritis, arthritis of the hands, radiologic erosions, and even positive rheumatoid factor) or seronegative spondyloarthropathy (chronic low back pain, limitation of lumbar spine mobility, sacroilitis), and, in many cases, patients with chronic infection may fulfill American College of Rheumatology criteria for these conditions.[4] In other cases, undifferentiated polyarthritis may occur. The symptoms can be continuous or relapsing. Frequently, the symptoms considerably affect quality of life, preventing normal activities and work.[51][52] The relative frequency of these manifestations is highly variable, ranging between 14% and 87%.[53]
Comorbid illnesses do not predispose people to infection; however, those affected tend to develop more severe clinical presentation.[39] Patients with chronic medical conditions such as diabetes mellitus or chronic organ failure tend to have worse outcomes. Lethal cases have been reported.[18][50]
Routine laboratory testing
Patients may develop lymphopenia, thrombocytopenia, transaminitis, and hypocalcemia. Initial testing could include complete blood count with differential, liver function tests, a basic metabolic panel, erythrocyte sedimentation rate, and C-reactive protein. However, results of the initial tests are nonspecific and not helpful in narrowing down the differential diagnosis.
Laboratory confirmatory diagnosis
Laboratory diagnosis is usually by detection of serum antibodies; however, viral nucleic acid detection or cultures can also be used.[47]
In the US, the most common method of confirmatory diagnosis is by detection of immunoglobulin M (IgM) by enzyme-linked immunosorbent assay or immunofluorescence assays. Testing is available commercially and via the CDC.[47] IgM antibodies are detectable toward the end of the first week of illness and disappear after 3 months or so. IgG is better detected by immunochromatography. If IgG is used to confirm the diagnosis, a fourfold elevation of the titers between acute illness and convalescence is expected. IgG antibodies tend to last for years. A positive IgM antibody result should be confirmed by neutralizing antibody testing.[47]
The reliability and quality of laboratories involved in serologic testing are important considerations. A study has shown that, among 30 international laboratories, only 6 provided valid results, with many of them being unable to detect IgM antibodies properly.[54]
Real-time reverse transcription polymerase chain reaction (RT-PCR) can detect the virus faster than serologic samples (viremia is quite prominent when symptoms appear). This test is reliable, fully automated and can quantify the viral burden; however, it is more expensive and less commonly available. A real-time loop-mediated isothermal amplification (RT-LAMP) is another nucleic acid detection method that has proven useful for rapid diagnosis. In the US, the Food and Drug Administration has issued an Emergency Use Authorization for the Trioplex RT-PCR assay. The assay allows physicians to determine whether a patient is infected with chikungunya, Zika, or dengue virus in one test rather than having to order 3 separate tests, allowing for more rapid diagnosis.[55] Availability of commercial tests depends on location; it is only available in qualified laboratories and is not available in US hospitals or other primary care settings.
Chikungunya virus can be isolated by inoculation in mice or by inoculation in mosquito or mammalian cell lines (including HeLa and Vero cells); however, this method requires a biosafety level 3 laboratory and the results take longer, so they are not the preferred method of detection.
An ideal diagnostic test would be highly specific and sensitive, able to be processed at the bedside without supplementary equipment, inexpensive, and rapid. This ideal test is still not available.[54][56][57]
Additional testing
In patients with meningitis or meningoencephalitis, the cerebrospinal fluid will show typical findings of aseptic compromise of the meninges, including mild pleocytosis with predominance of mononuclear cells, elevated protein, and normal to mildly low glucose.
Magnetic resonance imaging of the brain may show hyperintensity in the temporal lobes and insular cortex or periventricular enhancement in cases of encephalitis, meningeal enhancement in cases of meningitis, and multiple hyperintense lesions in T2 and fluid-attenuated inversion recovery (FLAIR) in cases of acute demyelinating encephalomyelitis.
Electroencephalogram may show generalized electrical activity in cases of encephalopathy.
Electromyogram and nerve conduction studies may reveal generalized motor axonal neuropathy in cases of myeloradiculitis.[58][59]
Rheumatologic radiologic imaging during the acute phase of illness does not contribute to the diagnosis, except maybe to rule out other conditions. In chronic cases, tendinitis, joint effusions, bony erosions, and marrow edema have been reported. The destructive changes resemble rheumatoid arthritis.[60][61]
Placental histologic examination can also be performed on the placenta of an infected mother. This is not routinely done, as diagnosis in both mother and newborn can be done via serology; however, it may be considered in the settings of low-weight newborns, congenital abnormalities, or stillbirths.
Differential diagnosis
It is important to differentiate between chikungunya, dengue, and Zika virus infection, as they can all produce similar symptoms, particularly during the acute phase. The World Health Organization has produced a tool to help physicians differentiate between these three diseases.[62]
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