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

PLoS Med. 2021 Aug 12;18(8):e1003735. doi: 10.1371/journal.pmed.1003735. eCollection 2021 Aug.

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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Age Factors
  • Antigens, Viral / analysis
  • COVID-19 / diagnosis
  • COVID-19 / etiology
  • COVID-19 Serological Testing / methods*
  • COVID-19 Serological Testing / standards
  • Carrier State / diagnosis
  • Carrier State / virology
  • Humans
  • Nasopharynx / virology
  • Reagent Kits, Diagnostic
  • Reference Standards
  • SARS-CoV-2 / immunology
  • Sensitivity and Specificity
  • Viral Load

Substances

  • Antigens, Viral
  • Reagent Kits, Diagnostic

Grant support

The study was supported by the Ministry of Science, Research and Arts of the State of Baden-Wuerttemberg, Germany (no grant number; https://mwk.baden-wuerttemberg.de/de/startseite/) and internal funds from the Heidelberg University Hospital (no grant number; https://www.heidelberg-university-hospital.com/de/) to CMD. Further, this project was funded by United Kingdom (UK) aid from the British people (grant number: 300341-102; Foreign, Commonwealth & Development Office (FCMO), former UK Department of International Development (DFID); www.gov.uk/fcdo), and supported by a grant from the World Health Organization (WHO; no grant number; https://www.who.int) and a grant from Unitaid (grant number: 2019-32-FIND MDR; https://unitaid.org) to Foundation of New Diagnostics (FIND; JAS, SC, SO, AM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.