Abstract
Original language | English |
---|---|
Article number | CD013705 |
Journal | Cochrane Database of Systematic Reviews |
Volume | 2022 |
Issue number | 7 |
DOIs | |
Publication status | Published - 22 Jul 2022 |
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In: Cochrane Database of Systematic Reviews, Vol. 2022, No. 7, CD013705, 22.07.2022.
Research output: Contribution to journal › Review article › Academic › peer-review
TY - JOUR
T1 - Rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection
AU - Cochrane COVID-19 Diagnostic Test Accuracy Group
AU - Dinnes, Jacqueline
AU - Sharma, Pawana
AU - Berhane, Sarah
AU - van Wyk, Susanna S.
AU - Nyaaba, Nicholas
AU - Domen, Julie
AU - Taylor, Melissa
AU - Cunningham, Jane
AU - Davenport, Clare
AU - Dittrich, Sabine
AU - Emperador, Devy
AU - Hooft, Lotty
AU - Leeflang, Mariska M. G.
AU - McInnes, Matthew D. F.
AU - Spijker, René
AU - Verbakel, Jan Y.
AU - Takwoingi, Yemisi
AU - Taylor-Phillips, Sian
AU - van den Bruel, Ann
AU - Deeks, Jonathan J.
N1 - Funding Information: Funding: "partly supported by Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand through grant number R016034012" Funding Information: Funding: "financial support by DFG (German Research Foundation) within the funding programme Open Access Publizieren" Funding Information: Funding: "Open Access funding enabled and organized by Projekt DEAL. This work was supported in part by the German BMBF initiative “NaFoUniMedCovid19” (01KX2021), subproject B-FAST (to U.P. and O.T.K.), and by the Medical Faculty of the LMU München, Munich, Germany (to O.T. K.)" Funding Information: Author COI: one author reports grants from FIND and Ministry of Science, Research and Culture, State of Baden Wuerttemberg, Germany. Another author reports grants from DFID (recently replaced byFCMO), WHO and from Unitaid. Funding Information: Members of the Cochrane COVID-19 Diagnostic Test Accuracy Review Group include: the project team (Deeks JJ, Dinnes J, Takwoingi Y, Davenport C, Leeflang MMG, Spijker R, Hooft L, Van den Bruel A, McInnes MDF, Verbakel J, Emperador D, Dittrich S, Cunningham J); the systematic review teams for each review: Molecular, antigen, and antibody tests (Arevalo-Rodriguez I, Buitrago DC, Ciapponi A, Domen J, Dretzke J, Mateos M, Nyaaba N, Sharma P, Taylor M, Taylor-Phillips S, van Wyk S, Verbakel J) Signs and symptoms (Stuyf T, Domen J, Horn S) Routine laboratory markers (Yang B, Langendam M, Ochodo E, Guleid F, Holtman G, Verbakel J, Wang J, Stegeman I) Imaging tests (Salameh JP, McGrath TA, van der Pol CB, Frank RA, Prager R, Hare SS, Dennie C, Jenniskens K, Korevaar DA, Cohen JF, van de Wijgert J, Damen JAAG, Wang J); the project team (Deeks JJ, Dinnes J, Takwoingi Y, Davenport C, Leeflang MMG, Spijker R, Hooft L, Van den Bruel A, McInnes MDF, Verbakel J, Emperador D, Dittrich S, Cunningham J); the systematic review teams for each review: Molecular, antigen, and antibody tests (Arevalo-Rodriguez I, Buitrago DC, Ciapponi A, Domen J, Dretzke J, Mateos M, Nyaaba N, Sharma P, Taylor M, Taylor-Phillips S, van Wyk S, Verbakel J) Signs and symptoms (Stuyf T, Domen J, Horn S) Routine laboratory markers (Yang B, Langendam M, Ochodo E, Guleid F, Holtman G, Verbakel J, Wang J, Stegeman I) Imaging tests (Salameh JP, McGrath TA, van der Pol CB, Frank RA, Prager R, Hare SS, Dennie C, Jenniskens K, Korevaar DA, Cohen JF, van de Wijgert J, Damen JAAG, Wang J); Thanks to the wider team of systematic reviewers from the University of Birmingham, UK who assisted with title and abstract screening across the entire suite of reviews for the diagnosis of COVID-19 prior to the publication of the first iteration of this review. The editorial process for this review was managed by Cochrane's Evidence Production & Methods Directorate, Central Editorial Service in collaboration with Cochrane Infectious Diseases. The following people conducted the editorial process for this article: • Sign-off Editor (final editorial decision): Michael Brown, Cochrane Evidence Production and Methods Directorate • Managing Editor (selected peer reviewers, collated peer-reviewer comments, provided editorial guidance to authors, edited the article): Anne-Marie Stephani, Cochrane Central Editorial Service • Editorial Assistant (conducted editorial policy checks and supported editorial team): Leticia Rodrigues, Cochrane Central Editorial Service • Copy Editor (copy editing and production): Denise Mitchell; Cochrane Evidence Production and Methods Directorate, Copy Edit Service; • Peer-reviewers (provided comments and recommended an editorial decision): Professor Jim Huggett, National Measurement Laboratory, LGC Queens Road, Teddington, Middlesex (clinical review), Kristien Verdonck, Institute of Tropical Medicine Antwerp, Belgium (clinical review), Luis Rafael Moscote-Salazar, Colombian Clinical Research Group in Neurocritical Care, Colombia (consumer review), Robert Walton, Senior Fellow in General Practice, Cochrane UK (methods review), Robin Featherstone, Cochrane Central Editorial Service (search review). Toby Lasserson is a member of Cochrane Evidence Production and Methods Directorate and provided peer-review comments on this article, but was not otherwise involved in the editorial process or decision making for this article. The editorial base of Cochrane Infectious Diseases is funded by UK aid from the UK Government for the benefit of low- and middle-income countries (project number 300342-104). The views expressed do not necessarily reflect the UK Government’s official policies. The authors thank Dr Mia Schmidt-Hansen who was the Cochrane Diagnostic Test Accuracy (DTA) Contact Editor for this review; the clinical and methodological referees; the Cochrane DTA Editorial Team; and Anne Lawson who copy-edited the protocol. We would also like to thank all corresponding authors who provided additional information regarding their studies. Jonathan Deeks is a UK National Institute for Health and Care Research (NIHR) Senior Investigator Emeritus. Yemisi Takwoingi is supported by a NIHR Postdoctoral Fellowship. Jonathan Deeks, Jacqueline Dinnes, Yemisi Takwoingi, and Clare Davenport are supported by the NIHR Birmingham Biomedical Research Centre. Sian Taylor-Phillips is supported by an NIHR Career Development Fellowship. This paper presents independent research 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. Funding Information: Funding: "supported by the Méditerranée-Infection Foundation and the French Agence Nationale de la Recherche under reference Investissements d’Avenir Méditerranée Infection 10-IAHU-03 and Région Provence-Alpes-Côte d’Azur and European funding FEDER IHUBIOTK." Funding Information: Funding: "supported by the Ministry of Health of the Czech Republic - conceptual development of research organization Motol University Hospital, FNM" Funding Information: Funding: "this work was supported by the RD16/0025/0038 project as a part of the Plan Nacional Research+Development+Innovation (R+D+I) and co-financed by Instituto de Salud Carlos III - Sub-dirección General de Evaluación y Fondo Europeo de Desarrollo Regional; Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias [grant number PI16/01740; PI18/01861; CM 19/00160, COV20–00005])." Funding Information: Funding: "work was supported by the Health, Labour and Welfare Policy Research Grants, Research on Emerging and Re-emerging Infectious Diseases and Immunization [grant number 20HA2002]". Funding Information: Funding: "the study was supported by the Ministry of Science, Research and Arts of the State of Baden-Wuerttemberg, Germany and internal funds from the Heidelberg University Hospital and Funding Information: Funding: study was supported by FIND, Heidelberg University Hospital and Charité – University Hospital internal funds. Funding Information: Funding: "supported by the Promising IP Project Support Program funded by the Ministry of Trade Industry and Energy. And this study was supported by the Clinical Trial Support Program funded by the Ministry of Health and Warfare. Also, this study was supported by the Technological Innovation R&D Program funded by the Korea Health Industry Development Institute (KHIDI)." Funding Information: Funding: study was supported by FIND, Heidelberg University Hospital and Charité – University Hospital internal funds. Pfizer funded the clinical team in Liverpool, UK Funding Information: Funding: "this study was enabled by internal funding provided by UPMC Hospital System and the University of Pittsburgh" Funding Information: Funding: 'funded using internal operating funds of Alberta Precision Laboratories and Alberta Health Services. Test kits and instruments were paid for by the Public Health Agency of Canada.' Funding Information: Funding: "DR and IO acknowledge support from the NIHR Health Protection Research Unit in Behavioural Science and Evaluation at University of Bristol. SH is supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford in partnership with Public Health England (PHE)." Funding Information: Funding: "the PCR testing in this manuscript is funded by the UK Department for Health and Social Care (DHSC) as part of pillar 2 testing, in an award made directly to the University of Birmingham. The provision of LFD tests is funded by DHSC as part of a national student testing program, and funded directly to the University of Birmingham. DHSC have had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." Funding Information: Funding: "the report presents independent research funded by the NIHR, Wellcome Trust and the Department of Health." Funding Information: Funding: no financial support Funding Information: Funding: "study supported by funds to the Istituto Nazionale per le Malattie Infettive (INMI) Lazzaro Spallanzani IRCCS, Rome, Italy, from the Ministero della Salute (Ricer-ca Corrente, linea 1; COVID-2020-12371817), the European Commission e Horizon 2020 (EU project 101003544 e CoNVat; EU project 101003551 e EXSCALATE4CoV; EU project 12371675 e EXCALATE4CoV; EU project 101005075 e KRONO) and the European Virus Archive e GLOBAL (grants no. 653316 and no. 871029)." Funding Information: Funding: "partially funded by a call from the Department of Health of the Generali-tat de Catalunya, code 6-17, main researcher: Francesc Vidal" Funding Information: Funding: "study was supported by Foundation of Innovative New Diagnostics (FIND), Charité University Hospital internal funds, as well as a grant of the Ministry of Science, Research and the Arts of Baden-Württemberg, Germany" Funding Information: Funding: work is based on research funded in part by the German Federal Ministry of Education and Research through projects VARIPath (01KI2021) to VMC and NaFoUniMedCovid19 (BFAST, FKZ: 01KX2021) to the Charité Funding Information: Author COI: "the authors are supported by ANID Chile through Fondecyt grants" Funding Information: Funding: "funding for this study was provided by the University of California San Francisco, Program for Breakthrough Biomedical Research, which is partially funded by the Sandler Foundation, a private donor, the Chan Zuckerberg Initiative, and the National Institutes of Health [UM1AI069496]". Funding Information: Funding: "Open Access funding enabled and organized by Projekt DEAL. This work was supported in part by the German BMBF initiative “NaFoUniMedCovid19” (01KX2021), subproject Funding Information: Funding: "supported by Provincial Secretariat for Higher Education and Scientific Research grant" Funding Information: Funding: published version: "supported by Cooperative Agreement Number 1U60OE000103, funded by Centers for Disease Control and Prevention through the Association of Public Health Laboratories." Preprint: "funded by the MA Department of Public Health. The community testing site was funded by the Centers for Disease Control and Prevention Building and Enhancing Epidemiology, Laboratory and Health Information Systems Capacity in Massachusetts –Enhancing Detection COVID Supplement (Grant # 6 NU50CK000518-01-08). BinaxNOW kits were supplied as part of the federal allocation to state health departments." Funding Information: Funding: "part of this work was funded by the German Ministry of Health (Konsil-iarlabor für Coronaviren) to CD and VMC and by the German Ministry of Research through projects VARIPath (01KI2021)to VMC. This project was funded in part by the German Federal Ministry of Education and Research (Bundesministerium für Bildun-gund For-schung, BMBF) (NaFoUniMedCovid19 – B-FAST, EVIPAN, FKZ:01KX202)" Funding Information: Funding: "financially supported by the Indian Council of Medical Research, New Delhi (for the Regional Virus Research and Diagnostic Laboratory at the All India Institute of Medical Sciences, New Delhi)" Funding Information: University Hospital Charité -Universitätsmedizin Berlin as well as grants from UK Department of International Development (DFID, recently replaced by FCMO), grants from World Health Organization (WHO), grants from Unitaid to Foundation of New Diagnostics (FIND). The testing devices and all components were provided by the manufacturer. T.C.J. is in part funded through NIAID-NIH CEIRS." Funding Information: Funding: supported by the Geneva Centre for Emerging Viral Diseases Funding Information: The editorial base of Cochrane Infectious Diseases is funded by UK aid from the UK Government for the benefit of low-and middle-income countries (project number 300342-104). The views expressed do not necessarily reflect the UK Government’s official policies. Funding Information: Funding: no specific grant funding Funding Information: Funding: "supported by FIND, Heidelberg University Hospital and Charité University Hospital internal funds, Ministry of Science, Research and the Arts of Baden-Württemberg, Germany" Funding Information: Funding: "supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health (grant number 3U54HL143541-02S2) through the RADx-Tech program." Funding Information: Funding: "supported by Grants from Montpellier University Hospital and Montpellier University (MUSE)." Funding Information: Funding: funded by Certest Biotec S.L. (Zaragoza, Spain); Each manufacturer provided Pan-bio and CerTest devices. Funding Information: Jonathan Deeks is a UK National Institute for Health and Care Research (NIHR) Senior Investigator Emeritus. Yemisi Takwoingi is supported by a NIHR Postdoctoral Fellowship. Jonathan Deeks, Jacqueline Dinnes, Yemisi Takwoingi, and Clare Davenport are supported by the NIHR Birmingham Biomedical Research Centre. Sian Taylor-Phillips is supported by an NIHR Career Development Fellowship. This paper presents independent research 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. Funding Information: Funding: funded by the Dutch Ministry of Health, Welfare and Sports (VWS) Funding Information: Funding: "this work was supported by the RD16/0025/0038 project as a part of the Plan Na-cional Research + Development + Innovation (R+D+I) and co-financed by Instituto de Salud Carlos III - SubdirecciónGeneral de Evaluación y Fondo Europeo de Desarrollo Regional; In-stituto de Salud Carlos III (Fondo de Investigaciones Sanitarias (Grant NumbersPI16/01740, PI18/01861; CM 19/00160, COV20-00005)." Funding Information: Funding: "work was supported by LumiraDx Ltd, including funding of the journal’s Rapid Services fee" Funding Information: Funding: "Oswaldo Cruz Foundation (to RFQG and scholarships to CC, RA, LC, NC), The Brazilian National Council for Scientific and Technological Development (CNPq) (scholarships to AO, DM, SG), Coordination for the Improvement of Higher Education Personnel (CAPES) (scholarships to NA, JA), The Minas Gerais Research Funding Foundation (FAPEMIG) (scholarship to PF). EcoDi-agnostica for attending our request for donation of diagnostic kits under evaluation." Funding Information: Funding: "this study was supported by the University of California, San Francisco, the Chan Zuckerberg Biohub, the Chan Zuckerberg Initiative, the San Francisco Latino Task Force, the National Institute of Allergy and Infectious Diseases (grants T32 AI060530 to LR and F31AI150007 to SS), and a private donor." Funding Information: Funding: "supported by a specific Research Grant of the Spanish Society of Pediatrics (Asociacion Espanola de Pediatra). This study was funded by project PI20/00095, from the Instituto de Salud Carlos III (Ministry of Economy, Industry and Competitiveness), and cofounded by the European Regional Development Funds. CDG is funded by the Spanish Ministry of Science and Innovation—Instituto de Salud Carlos III and Fondos FEDER (Contrato Rio Hortega CM19/00015)." Funding Information: Funding: no funding statement reported; COVID-19 Ag Respi-Strip tests provided by Coris BioConcept. Funding Information: Funding: "this study is funded by fundraising of SSPH+ that includes funds of the Swiss Federal Office of Public Health and private funders, by Cantons of Switzerland, by institutional funds of the Universities and by the University of Zurich Foundation and the Federal Office of Public Health" Funding Information: Funding: "work is based on research funded in part by the German Federal Ministry of Education and Research through projects VARIPath (01KI2021) to VMC and NaFoUniMed-Covid19 (BFAST, FKZ: 01KX2021) to the Charité" Publisher Copyright: Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.
PY - 2022/7/22
Y1 - 2022/7/22
N2 - Background: Accurate rapid diagnostic tests for SARS-CoV-2 infection would be a useful tool to help manage the COVID-19 pandemic. Testing strategies that use rapid antigen tests to detect current infection have the potential to increase access to testing, speed detection of infection, and inform clinical and public health management decisions to reduce transmission. This is the second update of this review, which was first published in 2020. Objectives: To assess the diagnostic accuracy of rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups. Sources of heterogeneity investigated included setting and indication for testing, assay format, sample site, viral load, age, timing of test, and study design. Search methods: We searched the COVID-19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) on 08 March 2021. We included independent evaluations from national reference laboratories, FIND and the Diagnostics Global Health website. We did not apply language restrictions. Selection criteria: We included studies of people with either suspected SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen tests. We included evaluations of single applications of a test (one test result reported per person) and evaluations of serial testing (repeated antigen testing over time). Reference standards for presence or absence of infection were any laboratory-based molecular test (primarily reverse transcription polymerase chain reaction (RT-PCR)) or pre-pandemic respiratory sample. Data collection and analysis: We used standard screening procedures with three people. Two people independently carried out quality assessment (using the QUADAS-2 tool) and extracted study results. Other study characteristics were extracted by one review author and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test, and pooled data using the bivariate model. We investigated heterogeneity by including indicator variables in the random-effects logistic regression models. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status. Main results: We included 155 study cohorts (described in 166 study reports, with 24 as preprints). The main results relate to 152 evaluations of single test applications including 100,462 unique samples (16,822 with confirmed SARS-CoV-2). Studies were mainly conducted in Europe (101/152, 66%), and evaluated 49 different commercial antigen assays. Only 23 studies compared two or more brands of test. Risk of bias was high because of participant selection (40, 26%); interpretation of the index test (6, 4%); weaknesses in the reference standard for absence of infection (119, 78%); and participant flow and timing 41 (27%). Characteristics of participants (45, 30%) and index test delivery (47, 31%) differed from the way in which and in whom the test was intended to be used. Nearly all studies (91%) used a single RT-PCR result to define presence or absence of infection. The 152 studies of single test applications reported 228 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies, with consistently high specificities. Average sensitivity was higher in symptomatic (73.0%, 95% CI 69.3% to 76.4%; 109 evaluations; 50,574 samples, 11,662 cases) compared to asymptomatic participants (54.7%, 95% CI 47.7% to 61.6%; 50 evaluations; 40,956 samples, 2641 cases). Average sensitivity was higher in the first week after symptom onset (80.9%, 95% CI 76.9% to 84.4%; 30 evaluations, 2408 cases) than in the second week of symptoms (53.8%, 95% CI 48.0% to 59.6%; 40 evaluations, 1119 cases). For those who were asymptomatic at the time of testing, sensitivity was higher when an epidemiological exposure to SARS-CoV-2 was suspected (64.3%, 95% CI 54.6% to 73.0%; 16 evaluations; 7677 samples, 703 cases) compared to where COVID-19 testing was reported to be widely available to anyone on presentation for testing (49.6%, 95% CI 42.1% to 57.1%; 26 evaluations; 31,904 samples, 1758 cases). Average specificity was similarly high for symptomatic (99.1%) or asymptomatic (99.7%) participants. We observed a steady decline in summary sensitivities as measures of sample viral load decreased. Sensitivity varied between brands. When tests were used according to manufacturer instructions, average sensitivities by brand ranged from 34.3% to 91.3% in symptomatic participants (20 assays with eligible data) and from 28.6% to 77.8% for asymptomatic participants (12 assays). For symptomatic participants, summary sensitivities for seven assays were 80% or more (meeting acceptable criteria set by the World Health Organization (WHO)). The WHO acceptable performance criterion of 97% specificity was met by 17 of 20 assays when tests were used according to manufacturer instructions, 12 of which demonstrated specificities above 99%. For asymptomatic participants the sensitivities of only two assays approached but did not meet WHO acceptable performance standards in one study each; specificities for asymptomatic participants were in a similar range to those observed for symptomatic people. At 5% prevalence using summary data in symptomatic people during the first week after symptom onset, the positive predictive value (PPV) of 89% means that 1 in 10 positive results will be a false positive, and around 1 in 5 cases will be missed. At 0.5% prevalence using summary data for asymptomatic people, where testing was widely available and where epidemiological exposure to COVID-19 was suspected, resulting PPVs would be 38% to 52%, meaning that between 2 in 5 and 1 in 2 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed. Authors' conclusions: Antigen tests vary in sensitivity. In people with signs and symptoms of COVID-19, sensitivities are highest in the first week of illness when viral loads are higher. Assays that meet appropriate performance standards, such as those set by WHO, could replace laboratory-based RT-PCR when immediate decisions about patient care must be made, or where RT-PCR cannot be delivered in a timely manner. However, they are more suitable for use as triage to RT-PCR testing. The variable sensitivity of antigen tests means that people who test negative may still be infected. Many commercially available rapid antigen tests have not been evaluated in independent validation studies. Evidence for testing in asymptomatic cohorts has increased, however sensitivity is lower and there is a paucity of evidence for testing in different settings. Questions remain about the use of antigen test-based repeat testing strategies. Further research is needed to evaluate the effectiveness of screening programmes at reducing transmission of infection, whether mass screening or targeted approaches including schools, healthcare setting and traveller screening.
AB - Background: Accurate rapid diagnostic tests for SARS-CoV-2 infection would be a useful tool to help manage the COVID-19 pandemic. Testing strategies that use rapid antigen tests to detect current infection have the potential to increase access to testing, speed detection of infection, and inform clinical and public health management decisions to reduce transmission. This is the second update of this review, which was first published in 2020. Objectives: To assess the diagnostic accuracy of rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups. Sources of heterogeneity investigated included setting and indication for testing, assay format, sample site, viral load, age, timing of test, and study design. Search methods: We searched the COVID-19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) on 08 March 2021. We included independent evaluations from national reference laboratories, FIND and the Diagnostics Global Health website. We did not apply language restrictions. Selection criteria: We included studies of people with either suspected SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen tests. We included evaluations of single applications of a test (one test result reported per person) and evaluations of serial testing (repeated antigen testing over time). Reference standards for presence or absence of infection were any laboratory-based molecular test (primarily reverse transcription polymerase chain reaction (RT-PCR)) or pre-pandemic respiratory sample. Data collection and analysis: We used standard screening procedures with three people. Two people independently carried out quality assessment (using the QUADAS-2 tool) and extracted study results. Other study characteristics were extracted by one review author and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test, and pooled data using the bivariate model. We investigated heterogeneity by including indicator variables in the random-effects logistic regression models. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status. Main results: We included 155 study cohorts (described in 166 study reports, with 24 as preprints). The main results relate to 152 evaluations of single test applications including 100,462 unique samples (16,822 with confirmed SARS-CoV-2). Studies were mainly conducted in Europe (101/152, 66%), and evaluated 49 different commercial antigen assays. Only 23 studies compared two or more brands of test. Risk of bias was high because of participant selection (40, 26%); interpretation of the index test (6, 4%); weaknesses in the reference standard for absence of infection (119, 78%); and participant flow and timing 41 (27%). Characteristics of participants (45, 30%) and index test delivery (47, 31%) differed from the way in which and in whom the test was intended to be used. Nearly all studies (91%) used a single RT-PCR result to define presence or absence of infection. The 152 studies of single test applications reported 228 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies, with consistently high specificities. Average sensitivity was higher in symptomatic (73.0%, 95% CI 69.3% to 76.4%; 109 evaluations; 50,574 samples, 11,662 cases) compared to asymptomatic participants (54.7%, 95% CI 47.7% to 61.6%; 50 evaluations; 40,956 samples, 2641 cases). Average sensitivity was higher in the first week after symptom onset (80.9%, 95% CI 76.9% to 84.4%; 30 evaluations, 2408 cases) than in the second week of symptoms (53.8%, 95% CI 48.0% to 59.6%; 40 evaluations, 1119 cases). For those who were asymptomatic at the time of testing, sensitivity was higher when an epidemiological exposure to SARS-CoV-2 was suspected (64.3%, 95% CI 54.6% to 73.0%; 16 evaluations; 7677 samples, 703 cases) compared to where COVID-19 testing was reported to be widely available to anyone on presentation for testing (49.6%, 95% CI 42.1% to 57.1%; 26 evaluations; 31,904 samples, 1758 cases). Average specificity was similarly high for symptomatic (99.1%) or asymptomatic (99.7%) participants. We observed a steady decline in summary sensitivities as measures of sample viral load decreased. Sensitivity varied between brands. When tests were used according to manufacturer instructions, average sensitivities by brand ranged from 34.3% to 91.3% in symptomatic participants (20 assays with eligible data) and from 28.6% to 77.8% for asymptomatic participants (12 assays). For symptomatic participants, summary sensitivities for seven assays were 80% or more (meeting acceptable criteria set by the World Health Organization (WHO)). The WHO acceptable performance criterion of 97% specificity was met by 17 of 20 assays when tests were used according to manufacturer instructions, 12 of which demonstrated specificities above 99%. For asymptomatic participants the sensitivities of only two assays approached but did not meet WHO acceptable performance standards in one study each; specificities for asymptomatic participants were in a similar range to those observed for symptomatic people. At 5% prevalence using summary data in symptomatic people during the first week after symptom onset, the positive predictive value (PPV) of 89% means that 1 in 10 positive results will be a false positive, and around 1 in 5 cases will be missed. At 0.5% prevalence using summary data for asymptomatic people, where testing was widely available and where epidemiological exposure to COVID-19 was suspected, resulting PPVs would be 38% to 52%, meaning that between 2 in 5 and 1 in 2 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed. Authors' conclusions: Antigen tests vary in sensitivity. In people with signs and symptoms of COVID-19, sensitivities are highest in the first week of illness when viral loads are higher. Assays that meet appropriate performance standards, such as those set by WHO, could replace laboratory-based RT-PCR when immediate decisions about patient care must be made, or where RT-PCR cannot be delivered in a timely manner. However, they are more suitable for use as triage to RT-PCR testing. The variable sensitivity of antigen tests means that people who test negative may still be infected. Many commercially available rapid antigen tests have not been evaluated in independent validation studies. Evidence for testing in asymptomatic cohorts has increased, however sensitivity is lower and there is a paucity of evidence for testing in different settings. Questions remain about the use of antigen test-based repeat testing strategies. Further research is needed to evaluate the effectiveness of screening programmes at reducing transmission of infection, whether mass screening or targeted approaches including schools, healthcare setting and traveller screening.
UR - http://www.scopus.com/inward/record.url?scp=85134765538&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/14651858.CD013705.pub3
DO - https://doi.org/10.1002/14651858.CD013705.pub3
M3 - Review article
C2 - 35866452
SN - 1465-1858
VL - 2022
JO - Cochrane Database of Systematic Reviews
JF - Cochrane Database of Systematic Reviews
IS - 7
M1 - CD013705
ER -