Background: The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the subsequent COVID-19 pandemic underscored significant challenges in diagnostics. Effective diagnostic strategies are crucial not only for identifying current infections and ruling them out but also for determining the necessity for escalated care, and for assessing past infections and immune responses. Point-of-care (POC) antigen and molecular tests designed to detect active SARS-CoV-2 infections have emerged as a promising approach. These rapid diagnostic tools offer the potential for quicker detection and isolation of confirmed cases compared to traditional laboratory-based methods, which is vital in curbing transmission within households and across communities.
Objectives: The primary objective is to rigorously evaluate the diagnostic accuracy of point-of-care antigen and molecular tests. This assessment aims to determine their effectiveness in identifying current SARS-CoV-2 infection in individuals presenting in community settings or within primary and secondary healthcare environments. Understanding the reliability of these tests is paramount for their effective implementation in managing public health crises and improving patient care.
Search Methods: To gather comprehensive evidence, a thorough electronic search was conducted on May 25, 2020. The search encompassed the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is consistently updated with the latest published articles from PubMed and Embase, as well as preprints from medRxiv and bioRxiv. Additionally, various repositories of COVID-19 publications were examined to ensure no relevant studies were missed. Notably, no language restrictions were applied, broadening the scope of the search to include global research efforts.
Selection Criteria: The study selection process focused on research involving individuals suspected of having a current SARS-CoV-2 infection. This included studies on individuals known to have, or not to have, SARS-CoV-2 infection, and scenarios where tests were utilized for infection screening. The review included diagnostic accuracy studies of any design that evaluated antigen or molecular tests specifically designed for point-of-care use. Key criteria for point-of-care suitability included minimal equipment needs, simplified sample preparation, reduced biosafety requirements, and the ability to deliver results within two hours of sample collection. All reference standards used to define the presence or absence of SARS-CoV-2 were considered, including reverse transcription polymerase chain reaction (RT-PCR) tests and established clinical diagnostic criteria.
Data Collection and Analysis: Study selection and data extraction followed a rigorous, dual-reviewer process to ensure accuracy and minimize bias. Two independent reviewers screened studies and resolved any discrepancies through discussion, involving a third reviewer when necessary. One reviewer independently extracted study characteristics, which were then meticulously checked by a second reviewer. Crucially, two reviewers independently extracted 2×2 contingency table data, essential for calculating diagnostic accuracy metrics, and assessed the risk of bias and applicability of the included studies using the QUADAS-2 tool, a recognized standard for quality assessment of diagnostic accuracy studies. The primary outcomes, sensitivity and specificity, along with their 95% confidence intervals (CIs), were presented for each test using paired forest plots for visual comparison. Data were pooled using the bivariate hierarchical model, applied separately for antigen and molecular-based tests. Simplifications were implemented in cases where data were limited by the number of available studies. Furthermore, available data were systematically tabulated by test manufacturer to provide a clear overview of test performance across different commercial products.
Main Results: The review incorporated 22 publications, representing 18 distinct study cohorts and a total of 3198 unique samples. Among these samples, 1775 were confirmed to have SARS-CoV-2 infection, reflecting a substantial dataset for analysis. Geographically, the studies were conducted across diverse locations: ten in North America, two in South America, four in Europe, one in China, and one international study, enhancing the generalizability of the findings. The analysis included data for eight commercial tests—four antigen and four molecular—along with one in-house antigen test, providing a comprehensive assessment of available point-of-care technologies. It is important to note that five of the included studies were available only as preprints at the time of the review, highlighting the rapidly evolving nature of research during the pandemic. Quality assessment revealed that no study was at low risk of bias across all quality domains, and concerns about the applicability of results were noted across all studies. Patient selection was judged to be at high risk of bias in 50% of studies due to deliberate over-sampling of confirmed COVID-19 cases and unclear in 7 out of 18 studies due to reporting inadequacies. A significant majority, 16 studies (89%), relied solely on a single negative RT-PCR to confirm the absence of COVID-19 infection, which carries the risk of missing true infections. Information on blinding of index tests (n = 11) and participant exclusions from analyses (n = 10) was frequently lacking, further impacting the robustness of the findings. Notably, no significant differences in methodological quality were observed between evaluations of antigen and molecular tests. The sensitivity of antigen tests varied widely across studies, ranging from 0% to 94%, with an average sensitivity of 56.2% (95% CI 29.5% to 79.8%) and a high average specificity of 99.5% (95% CI 98.1% to 99.9%). These figures are based on 8 evaluations in 5 studies encompassing 943 samples. Data for individual antigen tests remained limited, with no more than two studies available for any single test. Rapid molecular assays demonstrated more consistent sensitivity, ranging from 68% to 100%, with a higher average sensitivity of 95.2% (95% CI 86.7% to 98.3%) and a specificity of 98.9% (95% CI 97.3% to 99.5%). These results are based on 13 evaluations in 11 studies with 2255 samples. Predictive values were also calculated based on a hypothetical cohort of 1000 people with suspected COVID-19 infection, assuming a prevalence of 10%. This scenario yielded 105 positive test results, including 10 false positives (positive predictive value of 90%), and 895 negative results, including 5 false negatives (negative predictive value of 99%). Analysis of individual tests focused on pooled results for ID NOW (Abbott Laboratories) (5 evaluations) and Xpert Xpress (Cepheid Inc) (6 evaluations). The summary sensitivity for the Xpert Xpress assay (99.4%, 95% CI 98.0% to 99.8%) was significantly higher, exceeding that of ID NOW (76.8%, (95% CI 72.9% to 80.3%) by 22.6 percentage points (95% CI 18.8 to 26.3). Conversely, the specificity of Xpert Xpress (96.8%, 95% CI 90.6% to 99.0%) was marginally lower than ID NOW (99.6%, 95% CI 98.4% to 99.9%), with a difference of -2.8% (95% CI -6.4 to 0.8).
Authors’ Conclusions: This review provides an analysis of early-stage evaluations of point-of-care tests for SARS-CoV-2 infection, primarily based on remnant laboratory samples. The current findings have limited immediate applicability due to uncertainties about test performance in real-world clinical settings and variations related to COVID-19 symptoms, symptom duration, and use in asymptomatic individuals. While rapid tests hold promise for guiding RT-PCR triage and enabling earlier detection in positive cases, the existing evidence is not yet robust enough to definitively determine their clinical utility. There is an urgent need for prospective and comparative evaluations of rapid COVID-19 infection tests in clinically relevant settings. Future studies should prioritize recruiting consecutive series of eligible participants, encompassing both symptomatic individuals seeking testing and asymptomatic individuals potentially exposed to confirmed cases. Clear documentation of symptomatic status and the time elapsed since symptom onset or exposure is essential. Point-of-care tests must be performed on samples strictly according to manufacturer instructions and conducted at the point of care to ensure accurate and reliable results. All future research reports in this field should adhere to the Standards for Reporting of Diagnostic Accuracy (STARD) guideline to enhance the quality and transparency of evidence.
