Combining rapid diagnostic tests to estimate primary and post-primary dengue immune status at the point of care

Abstract

Background Characterising dengue virus (DENV) infection history at the point of care is challenging as it relies on intensive laboratory techniques. We investigated how combining different rapid diagnostic tests (RDTs) can be used to accurately determine the primary and post-primary DENV immune status of reporting patients during diagnosis. Methods and findings Serum from cross-sectional surveys of acute suspected dengue patients in Indonesia (N:200) and Vietnam (N: 1,217) were assayed using dengue laboratory assays and RDTs. Using logistic regression modelling, we determined the probability of being DENV NS1, IgM and IgG RDT positive according to corresponding laboratory viremia, IgM and IgG ELISA metrics. Laboratory test thresholds for RDT positivity/negativity were calculated using Youden’s J index and were utilized to estimate the RDT outcomes in patients from the Philippines, where only data for viremia, IgM and IgG were available (N:28,326). Lastly, the probabilities of being primary or post-primary according to every outcome using all RDTs, by day of fever, were calculated. Combining NS1, IgM and IgG RDTs captured 94.6% (52/55) and 95.4% (104/109) of laboratory-confirmed primary and post-primary DENV cases, respectively, during the first 5 days of fever. Laboratory test predicted, and actual, RDT outcomes had high agreement (79.5% (159/200)). Among patients from the Philippines, different combinations of estimated RDT outcomes were indicative of post-primary and primary immune status. Overall, IgG RDT positive results were confirmatory of post-primary infections. In contrast, IgG RDT negative results were suggestive of both primary and post-primary infections on days 1–2 of fever, yet were confirmatory of primary infections on days 3–5 of fever. Conclusion We demonstrate how the primary and post-primary DENV immune status of reporting patients can be estimated at the point of care by combining NS1, IgM and IgG RDTs and considering the days since symptoms onset. This framework has the potential to strengthen surveillance operations and dengue prognosis, particularly in low resource settings.

Field evaluation of rapid diagnostic tests to determine dengue serostatus in Timor-Leste

“…This is consistent with assays having been developed for the diagnosis of dengue in patients with acute febrile illness and differentiation of primary vs. post-primary dengue (where concentrations of IgG are usually higher compared to those seen long after convalescence). Previous studies have found that some ELISAs which detect dengue IgG can also be insensitive, particularly in individuals who have lower titres of neutralising antibodies and/or where there is a monotypic antibody profile [ 22 , 23 ]. Importantly, the latter group of individuals are most likely to benefit most from vaccination but would be denied this if pre-vaccination screening was falsely negative.…”

Identification of prior dengue-naïve Dengvaxia recipients with an increased risk for symptomatic dengue during fever surveillance in the Philippines

“…After Dengvaxia recipients presented with symptoms compatible with dengue at any health facility in the Philippines ( 3 ), blood samples were collected and sent to RITM, the national reference laboratory, for diagnostic testing. Participants testing positive, using either DENV RT-PCR or Panbio dengue IgM-capture ELISA (Abbott, South Korea), were defined as laboratory-confirmed acute dengue cases, and participants testing negative using both tests were classified as non-acute dengue or other febrile illnesses ( 38 , 39 ). The day of symptom (fever) onset was designated as day 1.…”

Dengue vaccine development: challenges and prospects

“…Various RDTs have been tested and some have shown reasonable sensitivity and specificity [57]. Primary and postprimary DENV immune status of reporting patients can be estimated at the point of care by combining NS1, IgM, and IgG RDTs and considering the days since symptoms onset [58]. Dengue IgG RDTs and the Panbio ELISA exhibited favourable specificities (99-100%).…”