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.

Fig 1. PRISMA flow diagram.

Based on Page et al. [297]. Ag-RDT, antigen rapid diagnostic test; IFU, instructions for use; sens., sensitivity; spec., specificity.

Fig 2. Methodological quality of the clinical accuracy studies: Risk of bias.

Proportion of studies with low, intermediate, high, or unclear risk of bias (percent).

Fig 3. Methodological quality of the clinical accuracy studies: Applicability.

Proportion of studies with low, intermediate, high, or unclear concerns regarding applicability (percent).

Fig 4. Bivariate analysis of 12 antigen rapid diagnostic tests.

Pooled sensitivity and specificity were calculated based on reported sample sizes, true positives, true negatives, false positives, and false negatives.

Fig 5. Univariate analysis of 3 antigen rapid diagnostic tests.

Pooled sensitivity and specificity were calculated based on reported sensitivity, specificity, and confidence intervals. SureScreen V, SureScreen Diagnostics COVID-19 Rapid Antigen Visual Read.

Fig 6. Pooled sensitivity by cycle threshold (Ct) values.

Low Ct values are the reverse transcription PCR semi-quantitative correlate for a high virus concentration.

Fig 7. Pooled sensitivity and specificity by instructions for use (IFU) conformity.

Fig 8. Pooled sensitivity and specificity by sample type.

AN, anterior nasal; MT, mid-turbinate; NP, nasopharyngeal; OP, oropharyngeal.

Fig 9. Pooled sensitivity and specificity by presence of symptoms and symptom duration.

Fig 10. Pooled sensitivity and specificity by age.