Diagnostic accuracy of serological tests for the diagnosis of Chikungunya virus infection: A systematic review and meta-analysis

Abstract

Background Chikungunya virus (CHIKV) causes febrile illnesses and has always been misdiagnosed as other viral infections, such as dengue and Zika; thus, a laboratory test is needed. Serological tests are commonly used to diagnose CHIKV infection, but their accuracy is questionable due to varying degrees of reported sensitivities and specificities. Herein, we conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of serological tests currently available for CHIKV. Methodology and principal findings A literature search was performed in PubMed, CINAHL Complete, and Scopus databases from the 1st December 2020 until 22nd April 2021. Studies reporting sensitivity and specificity of serological tests against CHIKV that used whole blood, serum, or plasma were included. QUADAS-2 tool was used to assess the risk of bias and applicability, while R software was used for statistical analyses. Thirty-five studies were included in this meta-analysis; 72 index test data were extracted and analysed. Rapid and ELISA-based antigen tests had a pooled sensitivity of 85.8% and 82.2%, respectively, and a pooled specificity of 96.1% and 96.0%, respectively. According to our meta-analysis, antigen detection tests serve as a good diagnostic test for acute-phase samples. The IgM detection tests had more than 90% diagnostic accuracy for ELISA-based tests, immunofluorescence assays, in-house developed tests, and samples collected after seven days of symptom onset. Conversely, low sensitivity was found for the IgM rapid test (42.3%), commercial test (78.6%), and for samples collected less than seven of symptom onset (26.2%). Although IgM antibodies start to develop on day 2 of CHIKV infection, our meta-analysis revealed that the IgM detection test is not recommended for acute-phase samples. The diagnostic performance of the IgG detection tests was more than 93% regardless of the test formats and whether the test was commercially available or developed in-house. The use of samples collected after seven days of symptom onset for the IgG detection test suggests that IgG antibodies can be detected in the convalescent-phase samples. Additionally, we evaluated commercial IgM and IgG tests for CHIKV and found that ELISA-based and IFA commercial tests manufactured by Euroimmun (Lübeck, Germany), Abcam (Cambridge, UK), and Inbios (Seattle, WA) had diagnostic accuracy of above 90%, which was similar to the manufacturers’ claim. Conclusion Based on our meta-analysis, antigen or antibody-based serological tests can be used to diagnose CHIKV reliably, depending on the time of sample collection. The antigen detection tests serve as a good diagnostic test for samples collected during the acute phase (≤7 days post symptom onset) of CHIKV infection. Likewise, IgM and IgG detection tests can be used for samples collected in the convalescent phase (>7 days post symptom onset). In correlation to the clinical presentation of the patients, the combination of the IgM and IgG tests can differentiate recent and past infections.

Development and evaluation of recombinant E2 protein based IgM capture enzyme-linked immunosorbent assay (ELISA) and double antigen sandwich ELISA for detection of antibodies to Chikungunya virus

“…However, a sensitivity of 60.0% and 52.5%, a specificity of 96.2% and 96.8%, and an accuracy of 89.8% and 88.9% were obtained for the Mac-ELISA and Das-ELISA, respectively, when compared to a CHIKV qRT-PCR method. These results are consistent with results reported for similar assays such as ELISAbased methods and IIFT commercial tests manufactured by Euroimmun (Lu ¨beck, Germany) [9]. In this study, the serum samples obtained for evaluation were all from patients in acute phase (day 1-11 after onset of illness), IgM and total antibodies were detected by Mac-ELISA and Das-ELISA respectively from less than 30% (7/22) serum samples collected within 3 days after onset of illness, while the detection rate of qRT-PCR was 100%.…”

“…Early detection, immediate response, and followed epidemiological evaluation will provide the best opportunity to prevent the potential establishment of the CHIKV in a new area. Limited by the short viremia duration, RT-PCR based viral RNA detection methods are only applicable for samples obtained at acute phase of the illness, usually less than 5 days after onset of illness, serological methods are therefore important and highly demanded for case finding and risk assessment [8,9]. ELISAs for detection of virus specific antibodies have a number of advantages compared to other traditional serological tests, such as immunofluorescence assay and virus neutralization tests.…”

“…Laboratory diagnosis is generally to detect virus, viral RNA, or virus-specific IgM antibodies in serum or plasma collected within the first 5 days after onset, after which the CHIKV-specific antibody detection assay is a sensitive test [ 7 , 8 ]. A variety of commercially available or in-house used CHIKV antibodies detection assays were reported, but the availability and assessments of the performance have been limited [ 8 , 9 ]. Some were developed based on inactivated CHIKV particle [ 10 ], which is generally unfavorable for long-term storage, especially in areas with only sporadic case reports.…”

Histopathological and immunological characteristics of placentas infected with chikungunya virus

“…The serology was performed to analyze the presence of anti-CHIKV antibodies. Usually, IgM antibody is detected during the acute phase (≤7 days post symptom onset) of CHIKV infection, indicating recent infection; however could persist up to 3 months ( Andrew et al, 2022 ). IgG antibodies are used to indicate late infection, since these antibodies are detected mainly in samples of convalescent phase (>7 days post symptom onset; Andrew et al, 2022 ).…”

“…Usually, IgM antibody is detected during the acute phase (≤7 days post symptom onset) of CHIKV infection, indicating recent infection; however could persist up to 3 months ( Andrew et al, 2022 ). IgG antibodies are used to indicate late infection, since these antibodies are detected mainly in samples of convalescent phase (>7 days post symptom onset; Andrew et al, 2022 ). For example, the serum of case 2 was collected at delivery and evidenced the presence of IgG antibodies only, displaying a late infection, during the first trimester of gestation.…”