Accuracy of novel antigen rapid diagnostics for SARS-CoV-2: A living systematic review and meta-analysis

Abstract

Background SARS-CoV-2 antigen rapid diagnostic tests (Ag-RDTs) are increasingly being integrated in testing strategies around the world. Studies of the Ag-RDTs have shown variable performance. In this systematic review and meta-analysis, we assessed the clinical accuracy (sensitivity and specificity) of commercially available Ag-RDTs. Methods and findings We registered the review on PROSPERO (registration number: CRD42020225140). We systematically searched multiple databases (PubMed, Web of Science Core Collection, medRvix, bioRvix, and FIND) for publications evaluating the accuracy of Ag-RDTs for SARS-CoV-2 up until 30 April 2021. Descriptive analyses of all studies were performed, and when more than 4 studies were available, a random-effects meta-analysis was used to estimate pooled sensitivity and specificity in comparison to reverse transcription polymerase chain reaction (RT-PCR) testing. We assessed heterogeneity by subgroup analyses, and rated study quality and risk of bias using the QUADAS-2 assessment tool. From a total of 14,254 articles, we included 133 analytical and clinical studies resulting in 214 clinical accuracy datasets with 112,323 samples. Across all meta-analyzed samples, the pooled Ag-RDT sensitivity and specificity were 71.2% (95% CI 68.2% to 74.0%) and 98.9% (95% CI 98.6% to 99.1%), respectively. Sensitivity increased to 76.3% (95% CI 73.1% to 79.2%) if analysis was restricted to studies that followed the Ag-RDT manufacturers’ instructions. LumiraDx showed the highest sensitivity, with 88.2% (95% CI 59.0% to 97.5%). Of instrument-free Ag-RDTs, Standard Q nasal performed best, with 80.2% sensitivity (95% CI 70.3% to 87.4%). Across all Ag-RDTs, sensitivity was markedly better on samples with lower RT-PCR cycle threshold (Ct) values, i.e., <20 (96.5%, 95% CI 92.6% to 98.4%) and <25 (95.8%, 95% CI 92.3% to 97.8%), in comparison to those with Ct ≥ 25 (50.7%, 95% CI 35.6% to 65.8%) and ≥30 (20.9%, 95% CI 12.5% to 32.8%). Testing in the first week from symptom onset resulted in substantially higher sensitivity (83.8%, 95% CI 76.3% to 89.2%) compared to testing after 1 week (61.5%, 95% CI 52.2% to 70.0%). The best Ag-RDT sensitivity was found with anterior nasal sampling (75.5%, 95% CI 70.4% to 79.9%), in comparison to other sample types (e.g., nasopharyngeal, 71.6%, 95% CI 68.1% to 74.9%), although CIs were overlapping. Concerns of bias were raised across all datasets, and financial support from the manufacturer was reported in 24.1% of datasets. Our analysis was limited by the included studies’ heterogeneity in design and reporting. Conclusions In this study we found that Ag-RDTs detect the vast majority of SARS-CoV-2-infected persons within the first week of symptom onset and those with high viral load. Thus, they can have high utility for diagnostic purposes in the early phase of disease, making them a valuable tool to fight the spread of SARS-CoV-2. Standardization in conduct and reporting of clinical accuracy studies would improve comparability and use of data.

Factors that Influence the Reported Sensitivity of Rapid Antigen Testing for SARS-CoV-2

“…In addition, our meta-analysis revealed that antigen test sensitivity [96.0% (95% CI: 90.0, 99.0)] was highest in SARS-CoV-2-positive individuals with an increased likelihood of being infectious at the time of testing (e.g., culture positive; Pekosz et al, 2021). Although specificity data were not extracted for every study included in this meta-analysis, SARS-CoV-2 antigen testing had high specificity as published previously (Brümmer et al, 2021). Experimental factors such as anatomical collection site, specimen storage conditions, analytical sensitivity of reference, and composition of the study population with respect to symptomology all varied across the field of studies included here.…”

“…As others have noted previously, a wide range of reported sensitivities has been documented for rapid antigen testing (Dinnes et al, 2020;Brümmer et al, 2021). The main objective of this meta-analysis was to explore possible causes of the high degree of heterogeneity of assay sensitivity estimates across different studies.…”

“…Rapid antigen-based lateral flow testing for SARS-CoV-2, as with influenza, has been implemented globally to achieve rapid accurate results for COVID-19 diagnosis (Peeling et al, 2021). Although the majority of antigen-based tests share a common mechanism for detection of SARS-CoV-2 protein, the reported sensitivities of both Food and Drug Administration (FDA) Emergency Use Authorization (EUA)-approved and non-EUA-approved antigen-based tests have varied greatly in the literature (Brümmer et al, 2021). Multiple meta-analyses and systematic reviews have reported large inter-study heterogeneity related to SARS-CoV-2 antigenbased testing (Dinnes et al, 2020;COVID-19 Scientific Advisory Group Rapid Evidence Report, 2020;Brümmer et al, 2021).…”

“…Although the majority of antigen-based tests share a common mechanism for detection of SARS-CoV-2 protein, the reported sensitivities of both Food and Drug Administration (FDA) Emergency Use Authorization (EUA)-approved and non-EUA-approved antigen-based tests have varied greatly in the literature (Brümmer et al, 2021). Multiple meta-analyses and systematic reviews have reported large inter-study heterogeneity related to SARS-CoV-2 antigenbased testing (Dinnes et al, 2020;COVID-19 Scientific Advisory Group Rapid Evidence Report, 2020;Brümmer et al, 2021). Although reliable antigen test performance coincides with a high specimen viral load (Brümmer et al, 2021), study heterogeneity could impact our conclusions about antigen test performance.…”

“…Multiple meta-analyses and systematic reviews have reported large inter-study heterogeneity related to SARS-CoV-2 antigenbased testing (Dinnes et al, 2020;COVID-19 Scientific Advisory Group Rapid Evidence Report, 2020;Brümmer et al, 2021). Although reliable antigen test performance coincides with a high specimen viral load (Brümmer et al, 2021), study heterogeneity could impact our conclusions about antigen test performance. Factors that could affect overall antigen test performance include analytical sensitivity (i.e., antibody/antigen binding affinity) of the assay, which likely varies for tests across manufacturers (Mina et al, 2020), biases occurring from the study design (e.g., blinding, test order, etc.…”