Extreme differences in SARS-CoV-2 Omicron viral loads among specimen types drives poor performance of nasal rapid antigen tests for detecting presumably pre-infectious and infectious individuals, predicting improved performance of combination specimen antigen tests

BackgroundIn a recent household-transmission study of SARS-CoV-2, we found extreme differences in SARS-CoV-2 viral loads among paired saliva, anterior-nares swab (ANS) and oropharyngeal swab specimens collected from the same timepoint. We hypothesized these differences may hinder low-analytical-sensitivity assays (including antigen rapid diagnostic tests, Ag-RDTs) using a single specimen type (e.g., ANS) from reliably detecting infected and infectious individuals. MethodsWe evaluated a daily at-home ANS Ag-RDT (Quidel QuickVue) in a cross-sectional analysis of 228 individuals and in a longitudinal analysis (throughout infection) of 17 individuals enrolled early in the course of infection. Ag-RDT results were compared to RT-qPCR results and high, presumably infectious viral loads (in each, or any, specimen type). ResultsThe ANS Ag-RDT correctly detected only 44% of timepoints from infected individuals on cross-sectional analysis, and in this population had an inferred limit of detection of 7.6x106 copies/mL. From the longitudinal cohort, daily Ag-RDT clinical sensitivity was very low (<3%) during the early, pre-infectious period of the infection. Further, the Ag-RDT detected [&le;]63% of presumably infectious timepoints. The poor observed clinical sensitivity of the Ag-RDT was similar to what was predicted based on quantitative ANS viral loads and the inferred limit of detection of the ANS Ag-RDT being evaluated, indicating high-quality self-sampling. ConclusionNasal Ag-RDTs, even when used daily, can miss individuals infected with the Omicron variant and even those presumably infectious. Evaluations of Ag-RDT detection of infected or infectious individuals should be compared with a composite (multi-specimen) infection status to correctly assess performance. Key pointsNasal-swab rapid antigen tests have low analytical sensitivity and the sampling of only the nasal cavity hinders their ability to detect infected individuals, including those with high and presumably infectious viral loads in throat or saliva specimens.