Accuracy of rapid point-of-care antigen-based diagnostics for SARS-CoV-2: an updated systematic review and meta-analysis with meta regression analyzing influencing factors

Abstract

Background Comprehensive information about the accuracy of antigen rapid diagnostic tests (Ag-RDTs) for SARS-CoV-2 is essential to guide public health decision makers in choosing the best tests and testing policies. In August 2021, we published a systematic review and meta-analysis about the accuracy of Ag-RDTs. We now update this work and analyze the factors influencing test sensitivity in further detail. 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 until August 31, 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 with reverse transcription polymerase chain reaction (RT-PCR) testing as a reference. To evaluate factors influencing test sensitivity, we performed 3 different analyses using multivariate mixed-effects meta-regression models. We included 194 studies with 221,878 Ag-RDTs performed. Overall, the pooled estimates of Ag-RDT sensitivity and specificity were 72.0% (95% confidence interval [CI] 69.8 to 74.2) and 98.9% (95% CI 98.6 to 99.1), respectively. When manufacturer instructions were followed, sensitivity increased to 76.4% (95%CI 73.8 to 78.8). Sensitivity was markedly better on samples with lower RT-PCR cycle threshold (Ct) values (sensitivity of 97.9% [95% CI 96.9 to 98.9] and 90.6% [95% CI 88.3 to 93.0] for Ct-values <20 and <25, compared to 54.4% [95% CI 47.3 to 61.5] and 18.7% [95% CI 13.9 to 23.4] for Ct-values ≥25 and ≥30) and was estimated to increase by 2.9 percentage points (95% CI 1.7 to 4.0) for every unit decrease in mean Ct-value when adjusting for testing procedure and patients symptom status. Concordantly, we found the mean Ct-value to be lower for true positive (22.2 [95% CI 21.5 to 22.8]) compared to false negative (30.4 [95% CI 29.7 to 31.1]) results. Testing in the first week from symptom onset resulted in substantially higher sensitivity (81.9% [95% CI 77.7 to 85.5]) compared to testing after 1 week (51.8%, 95% CI 41.5 to 61.9). Similarly, sensitivity was higher in symptomatic (76.2% [95% CI 73.3 to 78.9]) compared to asymptomatic (56.8% [95% CI 50.9 to 62.4]) persons. However, both effects were mainly driven by the Ct-value of the sample. With regards to sample type, highest sensitivity was found for nasopharyngeal (NP) and combined NP/oropharyngeal samples (70.8% [95% CI 68.3 to 73.2]), as well as in anterior nasal/mid-turbinate samples (77.3% [95% CI 73.0 to 81.0]). Conclusion Ag-RDTs detect most of the individuals infected with SARS-CoV-2, and almost all when high viral loads are present (>90%). With viral load, as estimated by Ct-value, being the most influential factor on their sensitivity, they are especially useful to detect persons with high viral load who are most likely to transmit the virus. To further quantify the effects of other factors influencing test sensitivity, standardization of clinical accuracy studies and access to patient level Ct-values and duration of symptoms are needed.

Diagnostic accuracy of thirteen COVID‐19 (SARS‐CoV‐2) rapid antigen self‐tests with very high sensitivity approved for home use in Australia

“…This would be particularly true for low‐risk asymptomatic individuals who are fully vaccinated, with no history of close contacts or other risk factors for COVID‐19. A review and meta‐analysis of a large number of international independent studies showed the pooled sensitivity and specificity values for RATs from asymptomatic samples to be 56.8% and 99.1% respectively 6 . Using the metrics from this meta‐analysis would produce positive predictive values that are considerably lower than those we have calculated.…”

“…A review and meta-analysis of a large number of international independent studies showed the pooled sensitivity and specificity values for RATs from asymptomatic samples to be 56.8% and 99.1% respectively. 6 Using the metrics from this meta-analysis would produce positive predictive values that are considerably lower than those we have calculated. This would suggest that the metrics provided by the manufacturers are likely to be over-estimates.…”

COVID‐19 rapid antigen tests approved for self‐testing in Australia: published diagnostic test accuracy studies and manufacturer‐supplied information. A systematic review

“…29 Our findings are similar to those of earlier systematic reviews, which found that the sensitivity of RATs varied substantially but that their specificity was consistently high. 2,30 The 2022 Cochrane review identified two studies that compared the effect of who interpreted RAT results on estimated sensitivity; each found that it was lower when interpreted by participants rather than by a medical practitioner. 2 Other factors that can vary substantially between studies, including study design, participant characteristics, and test setting and conduct, can also influence estimated sensitivity.…”

“…Consequently, indirect (between-study) comparisons of test performance are difficult to interpret. 2,30 However, it is not clear on the TGA website that the sensitivity values listed are derived from different studies and should not be directly compared. It might be assumed that a "high sensitivity" test is more accurate than one with "acceptable sensitivity".…”