COVID-19 rapid antigen testing strategies require careful evaluation
Jacqueline Dinnes
Abstract
Throughout the Covid-19 pandemic, testing for SARS-CoV-2 to allow early identification and isolation of those likely to be infectious has been a cornerstone of public health strategies to interrupt transmission of infection. An early reliance on reverse transcription polymerase chain reaction (RT-PCR) to confirm infection in those showing ‘typical’ signs and symptoms associated with Covid-19 was quickly supplemented with the use of rapid antigen detection tests (RDTs), particularly as the use case scenarios for testing changed from a focus on containment to a situation where testing has a much wider role as part of efforts to ease societal restrictions [1Boehme C Hannay E Sampath R. SARS-CoV-2 testing for public health use: core principles and considerations for defined use settings.Lancet Global Health. 2021; 9 (e247-e9)Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. The need for specialist laboratory facilities and worldwide demand for reagents limited countries’ ability to quickly scale up RT-PCR testing [2Peeling RW Olliaro PL Boeras DI Fongwen N. Scaling up COVID-19 rapid antigen tests: promises and challenges.Lancet Infect Dis. 2021; Summary Full Text Full Text PDF PubMed Scopus (211) Google Scholar]. RDTs conversely, are less expensive, provide results significantly more quickly, and do not require the same technical expertise or specialist facilities making them attractive for wide scale deployment [1Boehme C Hannay E Sampath R. SARS-CoV-2 testing for public health use: core principles and considerations for defined use settings.Lancet Global Health. 2021; 9 (e247-e9)Summary Full Text Full Text PDF PubMed Scopus (19) Google Scholar]. The advantages of RDTs come at a cost of lower and more variable sensitivity. Rt-PCR (able to detect even the smallest amount of viral RNA) is highly sensitive for detection of SARS-CoV-2, but has been criticised for its continued detection of the virus long after an individual is likely to remain infectious [3Mina MJ Peto TE García-Fiñana M Semple MG Buchan IE. Clarifying the evidence on SARS-CoV-2 antigen rapid tests in public health responses to COVID-19.Lancet. 2021; Summary Full Text Full Text PDF PubMed Scopus (100) Google Scholar]. RDTs use antibodies to capture SARS-CoV-2 proteins and accuracy is strongly affected by viral load. Indeed, test manufacturers have typically validated RDTs for use in symptomatic populations during the first five to seven days after symptom onset when viral load is expected to be highest and, by corollary, individuals are more likely to be infectious. A Cochrane review has shown RDT sensitivity of 78% on average during the first week after onset of symptoms (based on 2,320 RT-PCR positive cases), however observed sensitivities varied considerably, in part because of differences between assays, but also likely to reflect differences in sample types and storage, the adequacy of sampling and test interpretation [4Dinnes J Deeks JJ Berhane S et al.Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection.Cochrane Database Syst Rev. 2021; 3 (Cd013705)Google Scholar]. The same review highlighted the need for more information about how well RDTs perform in those who do not show typical signs and symptoms of Covid-19, and the lack of evidence for mass testing of asymptomatic individuals with no epidemiological indication for testing, for example to allow return to work or school, facilitate travel, or allow resumption of mass gatherings [4Dinnes J Deeks JJ Berhane S et al.Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection.Cochrane Database Syst Rev. 2021; 3 (Cd013705)Google Scholar]. In this article of EBioMedicine [5Wagenhäuser I Knies K Rauschenberger V et al.Clinical performance evaluation of SARS-CoV-2 rapid antigen testing in point of care usage in comparison to RT-qPCR.EBioMedicine. 2021; 69https://doi.org/10.1016/j.ebiom.2021.103455Summary Full Text Full Text PDF PubMed Scopus (58) Google Scholar], Isabell Wagenhäuser and colleagues provide a significant contribution to the evidence base for targeted community-based screening with RDTs. The ‘community’ consisted of over 5000 participants at a tertiary care hospital facility including all admitted patients or those accompanying patients, and hospital employees with respiratory symptoms or close contact with confirmed cases. The observed sensitivity of the RDT testing strategy was low – 42% overall and rising only to 49% in those with a ‘typical’ Covid-19 symptom profile. Almost all false positive results (15/16) occurred in those with no or with atypical Covid-19 symptoms, so that nearly three quarters of positive RDT results in this group were falsely positive (positive predictive value of 29%). As expected, the tests performed better in those with higher viral load and the authors point to the ability of the tests to detect all samples from individuals who may be considered ‘super spreaders’ of infection (detecting all 8 samples with SARS-CoV-2 RNA copies/mL of 10^8 or above), a claim that is supported by empirical studies of transmission risks [6Marks M Millat-Martinez P Ouchi D et al.Transmission of COVID-19 in 282 clusters in Catalonia, Spain: a cohort study.Lancet Infect Dis. 2021; 21: 629-636Summary Full Text Full Text PDF PubMed Scopus (249) Google Scholar]. However, transmission of infection does not stop at any specific viral load cut-off but operates on a continuum, with transmission also occurring in those with much lower viral loads [6Marks M Millat-Martinez P Ouchi D et al.Transmission of COVID-19 in 282 clusters in Catalonia, Spain: a cohort study.Lancet Infect Dis. 2021; 21: 629-636Summary Full Text Full Text PDF PubMed Scopus (249) Google Scholar]. Considering samples with viral loads above the commonly advocated cut-off for ‘infectiousness’ of 106 RNA copies/mL [7Corman VM Haage VC Bleicker T et al.Comparison of seven commercial SARS-CoV-2 rapid point-of-care antigen tests: a single-centre laboratory evaluation study.Lancet Microbe. 2021; Summary Full Text Full Text PDF Scopus (211) Google Scholar], 6 of 32 likely infectious cases in this study were missed. Wagenhäuser and colleagues[5Wagenhäuser I Knies K Rauschenberger V et al.Clinical performance evaluation of SARS-CoV-2 rapid antigen testing in point of care usage in comparison to RT-qPCR.EBioMedicine. 2021; 69https://doi.org/10.1016/j.ebiom.2021.103455Summary Full Text Full Text PDF PubMed Scopus (58) Google Scholar] reported RDT sensitivity at the lower end of that observed in other recent large-scale studies of RDT testing strategies which also included large proportions of asymptomatic people [8Pollock NR Jacobs JR Tran K et al.Performance and implementation evaluation of the Abbott BinaxNOW rapid antigen test in a high-throughput drive-through community testing site in Massachusetts.J Clin Microbiol. 2021; 59 (e00083-21)Crossref Scopus (103) Google Scholar,9Jakobsen KK Jensen JS Todsen T et al.Detection of SARS-CoV-2 infection by rapid antigen test in comparison with RT-PCR in a public setting.medRxiv. 2021; (2021.01.22.21250042)Google Scholar], so what are the possible explanations? Between-assay variations in sensitivity and the use of possibly less sensitive oropharyngeal samples may well have contributed [10Tsang NNY So HC Ng KY Cowling BJ Leung GM Ip DKM. Diagnostic performance of different sampling approaches for SARS-CoV-2 RT-PCR testing: a systematic review and meta-analysis.Lancet Infect Dis. 2021; Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar], however the low prevalence of SARS-CoV-2 and differences in the case-mix of participants, particularly in terms of the distribution of viral loads are likely to be a driving factor. While this study applied a blanket testing policy regardless of indication for SARS-CoV-2 testing, studies conducted at freely available Covid-19 testing sites will include those sufficiently motivated to attend and a greater proportion of people with epidemiological indications for testing [8Pollock NR Jacobs JR Tran K et al.Performance and implementation evaluation of the Abbott BinaxNOW rapid antigen test in a high-throughput drive-through community testing site in Massachusetts.J Clin Microbiol. 2021; 59 (e00083-21)Crossref Scopus (103) Google Scholar,9Jakobsen KK Jensen JS Todsen T et al.Detection of SARS-CoV-2 infection by rapid antigen test in comparison with RT-PCR in a public setting.medRxiv. 2021; (2021.01.22.21250042)Google Scholar]. The study period also overlapped a strict lockdown with declining prevalence of infection, and consequently lower proportions of people with the highest viral loads. The ability of RDTs to quickly pick up the majority of individuals with high levels of virus is undeniable but these tests do still miss people who are likely to be infectious and also risk falsely classifying uninfected individuals as positive. RDTs alone cannot be relied on to prevent outbreaks but, used in combination with Covid-19 symptom profiles and as triage to RT-PCR, can be a useful component of strategies to allow routine hospital procedures to continue. This study clearly emphasises the need for careful evaluation of RDT testing strategies for any given use case scenario prior to widespread roll-out. JD was solely responsible for the writing of the commentary. The author declares no conflict of interest. The author is supported by the NIHR Birmingham Biomedical Research Centre. This paper presents independent work supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Clinical performance evaluation of SARS-CoV-2 rapid antigen testing in point of care usage in comparison to RT-qPCRBackground: Antigen rapid diagnostic tests (RDT) for SARS-CoV-2 are fast, broadly available, and inexpensive. Despite this, reliable clinical performance data from large field studies is sparse.Methods: In a prospective performance evaluation study, RDT from three manufacturers (NADAL®, Panbio™, MEDsan®, conducted on different samples) were compared to quantitative reverse transcription polymerase chain reaction (RT-qPCR) in 5 068 oropharyngeal swabs for detection of SARS-CoV-2 in a hospital setting. Full-Text PDF Open Access