Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection

Jacqueline Dinnes, Jonathan J Deeks, Sarah Berhane, Melissa Taylor, Ada Adriano, Clare Davenport, Sabine Dittrich, Devy Emperador, Yemisi Takwoingi, Jane Cunningham, Sophie Beese, Julie Domen, Janine Dretzke, Lavinia Ferrante di Ruffano, Isobel M Harris, Malcolm J Price, Sian Taylor-Phillips, Lotty Hooft, Mariska Mg Leeflang, Matthew Df McInnesRené Spijker, Ann Van den Bruel, Cochrane COVID-19 Diagnostic Test Accuracy Group

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Abstract

Background: Accurate rapid diagnostic tests for SARS-CoV-2 infection could contribute to clinical and public health strategies to manage the COVID-19 pandemic. Point-of-care antigen and molecular tests to detect current infection could increase access to testing and early confirmation of cases, and expediate clinical and public health management decisions that may reduce transmission.

Objectives: To assess the diagnostic accuracy of point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups.

Search methods: Electronic searches of the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) were undertaken on 30 Sept 2020. We checked repositories of COVID-19 publications and included independent evaluations from national reference laboratories, the Foundation for Innovative New Diagnostics and the Diagnostics Global Health website to 16 Nov 2020. 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 or molecular tests suitable for a point-of-care setting (minimal equipment, sample preparation, and biosafety requirements, with results within two hours of sample collection). We included all reference standards that define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction (RT-PCR) tests and established diagnostic criteria).

Data collection and analysis: Studies were screened independently in duplicate with disagreements resolved by discussion with a third author. Study characteristics were extracted by one author and checked by a second; extraction of study results and assessments of risk of bias and applicability (made using the QUADAS-2 tool) were undertaken independently in duplicate. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and pooled data using the bivariate model separately for antigen and molecular-based tests. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status.

Main results: Seventy-eight study cohorts were included (described in 64 study reports, including 20 pre-prints), reporting results for 24,087 samples (7,415 with confirmed SARS-CoV-2). Studies were mainly from Europe (n = 39) or North America (n = 20), and evaluated 16 antigen and five molecular assays. We considered risk of bias to be high in 29 (37%) studies because of participant selection; in 66 (85%) because of weaknesses in the reference standard for absence of infection; and in 29 (37%) for participant flow and timing. Studies of antigen tests were of a higher methodological quality compared to studies of molecular tests, particularly regarding the risk of bias for participant selection and the index test. Characteristics of participants in 35 (45%) studies differed from those in whom the test was intended to be used and the delivery of the index test in 39 (50%) studies differed from the way in which the test was intended to be used. Nearly all studies (97%) defined the presence or absence of SARS-CoV-2 based on a single RT-PCR result, and none included participants meeting case definitions for probable COVID-19.
Antigen tests. Forty-eight studies reported 58 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies. There were differences between symptomatic (72.0%, 95% CI 63.7% to 79.0%; 37 evaluations; 15530 samples, 4410 cases) and asymptomatic participants (58.1%, 95% CI 40.2% to 74.1%; 12 evaluations; 1581 samples, 295 cases). Average sensitivity was higher in the first week after symptom onset (78.3%, 95% CI 71.1% to 84.1%; 26 evaluations; 5769 samples, 2320 cases) than in the second week of symptoms (51.0%, 95% CI 40.8% to 61.0%; 22 evaluations; 935 samples, 692 cases). Sensitivity was high in those with cycle threshold (Ct) values on PCR ≤25 (94.5%, 95% CI 91.0% to 96.7%; 36 evaluations; 2613 cases) compared to those with Ct values >25 (40.7%, 95% CI 31.8% to 50.3%; 36 evaluations; 2632 cases). Sensitivity varied between brands. Using data from instructions for use (IFU) compliant evaluations in symptomatic participants, summary sensitivities ranged from 34.1% (95% CI 29.7% to 38.8%; Coris Bioconcept) to 88.1% (95% CI 84.2% to 91.1%; SD Biosensor STANDARD Q). Average specificities were high in symptomatic and asymptomatic participants, and for most brands (overall summary specificity 99.6%, 95% CI 99.0% to 99.8%). At 5% prevalence using data for the most sensitive assays in symptomatic people (SD Biosensor STANDARD Q and Abbott Panbio), positive predictive values (PPVs) of 84% to 90% mean that between 1 in 10 and 1 in 6 positive results will be a false positive, and between 1 in 4 and 1 in 8 cases will be missed. At 0.5% prevalence applying the same tests in asymptomatic people would result in PPVs of 11% to 28% meaning that between 7 in 10 and 9 in 10 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed. No studies assessed the accuracy of repeated lateral flow testing or self-testing. Rapid molecular assays. Thirty studies reported 33 evaluations of five different rapid molecular tests. Sensitivities varied according to test brand. Most of the data relate to the ID NOW and Xpert Xpress assays. Using data from evaluations following the manufacturer’s instructions for use, the average sensitivity of ID NOW was 73.0% (95% CI 66.8% to 78.4%) and average specificity 99.7% (95% CI 98.7% to 99.9%; 4 evaluations; 812 samples, 222 cases). For Xpert Xpress, the average sensitivity was 100% (95% CI 88.1% to 100%) and average specificity 97.2% (95% CI 89.4% to 99.3%; 2 evaluations; 100 samples, 29 cases). Insufficient data were available to investigate the effect of symptom status or time after symptom onset.

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. The assays shown to meet appropriate criteria, such as WHO's priority target product profiles for COVID-19 diagnostics (‘acceptable’ sensitivity ≥ 80% and specificity ≥ 97%), can be considered as a replacement for laboratory-based RT-PCR when immediate decisions about patient care must be made, or where RT-PCR cannot be delivered in a timely manner. Positive predictive values suggest that confirmatory testing of those with positive results may be considered in low prevalence settings. Due to the variable sensitivity of antigen tests, people who test negative may still be infected. Evidence for testing in asymptomatic cohorts was limited. Test accuracy studies cannot adequately assess the ability of antigen tests to differentiate those who are infectious and require isolation from those who pose no risk, as there is no reference standard for infectiousness. A small number of molecular tests showed high accuracy and may be suitable alternatives to RT-PCR. However, further evaluations of the tests in settings as they are intended to be used are required to fully establish performance in practice. Several important studies in asymptomatic individuals have been reported since the close of our search and will be incorporated at the next update of this review. Comparative studies of antigen tests in their intended use settings and according to test operator (including self-testing) are required.

Original languageEnglish
Article numberCD013705
Number of pages412
JournalCochrane Database of Systematic Reviews
Volume2021
Issue number3
Early online date24 Mar 2021
DOIs
Publication statusPublished - 24 Mar 2021

Bibliographical note

Funding Information:
Funding: this research was supported by grants from National Key R&D Program of China (2016YFA0502204); Chongqing Health Commission COVID-19 Project (2020ZX01).

Funding Information:
Funding: This study was partly supported by Consultancy Services for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance, and the Theme-Based Research Scheme (T11/707/15) of the Research Grants Council, the donations of Richard Yu and Carol Yu, the Shaw Foundation Hong Kong Michael Seak-Kan Tong, May Tam Mak Mei Yin Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy, and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, the Jessie & George Ho Charitable Foundation, Perfect Shape Medical Limited, and Kai Chong Tong.

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 Wellcome Trust (Senior Research Fellowship to RKG WT108082AIA and PhD Research Fellowship to DAC; Principal Research Fellowship 210688/Z/18/Z to PJL), Addenbrooke’s Charitable Trust to PJL, National Institute of Health Research (NIHR) Cambridge BRC

Funding Information:
Funding: No funding statement reported; COVID-19 Ag Respi-Strip tests provided by Coris BioConcept.

Funding Information:
Author COI: Pre-print - Dr. Besser reports personal fees from STAGO, personal fees from Novar-tis, personal fees from Cosmopharma, personal fees from Werfen, personal fees from Agios, grants from Mitsubishi Pharma, outside the submitted work; RKG reports fees from ad hoc consulting from ViiV, Gilead and UMOVIS.

Funding Information:
Funding: RKG is funded by Wellcome Senior Fellowship In Clinical Science award no WT108082AIA

Funding Information:
Jonathan Deeks is a UK National Institute for Health Research (NIHR) Senior Investigator Emeritus. Yemisi Takwoingi is supported by a NIHR Postdoctoral Fellowship. Jonathan Deeks, Jacqueline Dinnes, Yemisi Takwoingi, Clare Davenport and Malcolm Price 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: 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: Study was 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:
Funding: funded in part by the National Mega Project on Major Infectious Disease Prevention (2017ZX10103005-007) and by the Cepheid Investigator-Initiated Study award (Cepheid-IIS-2020-005).

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, Emperador D, Dittrich S, Cunningham J); the systematic review teams for each review: Molecular, antigen, and antibody tests (Adriano A, Arevalo-Rodriguez I, Beese S, Buitrago DC, Ciapponi A, Domen J, Dretzke J, Ferrante di Ruffano L, Harris I, Mateos M, Price M, Taylor M, Taylor-Phillips S) 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 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 (Agarwal R, Baldwin S, Berhane S, Herd C, Kristunas C, Quinn L, Scholefield B). the project team (Deeks JJ, Dinnes J, Takwoingi Y, Davenport C, Leeflang MMG, Spijker R, Hooft L, Van den Bruel A, McInnes MDF, Emperador D, Dittrich S, Cunningham J); the systematic review teams for each review: Molecular, antigen, and antibody tests (Adriano A, Arevalo-Rodriguez I, Beese S, Buitrago DC, Ciapponi A, Domen J, Dretzke J, Ferrante di Ruffano L, Harris I, Mateos M, Price M, Taylor M, Taylor-Phillips S) 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 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 (Agarwal R, Baldwin S, Berhane S, Herd C, Kristunas C, Quinn L, Scholefield B). The editorial process for this review was managed by Cochrane's Editorial and Methods Department Central Editorial Service in collaboration with Cochrane Infectious Diseases. We thank Helen Wakeford, Anne-Marie Stephani and Deirdre Walshe for their comments and editorial management. We thank Liz Bickerdike for comments on the Abstract. We thank Robin Featherstone and Douglas M Salzwedel for comments on the search and Mike Brown and Paul Garner for sign-off comments. We thank Denise Mitchell for her efforts in copy-editing this review. Thank you also to peer referees Kristien Verdonck, David Sinclair and Jim Hugget, consumer referees Brian Duncan and Ceri Dare, methodological referees Mia Schmidt-Hansen and Jo Leonardi-Bee, for their insights. 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, and colleagues at both the Norwegian Insititute of Public Health and the EPPI-Centre who provided updates from their COVID-19 living evidence maps. Jonathan Deeks is a UK National Institute for Health Research (NIHR) Senior Investigator Emeritus. Yemisi Takwoingi is supported by a NIHR Postdoctoral Fellowship. Jonathan Deeks, Jacqueline Dinnes, Yemisi Takwoingi, Clare Davenport and Malcolm Price 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: The study is funded, in part, by a Bill and Melinda Gates Foundation Award (INV-017872) to E25Bio, Inc. EN is funded by Tu-s University DISC Seed Grant. MLN is supported by a FAPESP grant (#2020/04836-0) and is a CNPq Research Fellow. AFV is supported by a FAPESP Fellow grant (#18/17647-0). GRFC is supported by a FAPESP Fellow grant (#20/07419-0). BHGAM 798 is supported by a FAPESP Scholarship (#19/06572-2).

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:
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: supported by Grants from Montpellier University Hospital and Montpelli-er University (MUSE).

Funding Information:
Funding: not stated; presume funded by test manufacturer (see COI statement)

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:
Author COI: CT, RS, MS, MK, T-KH, SDM, K-YFL, JB, and AO are employees of DnaNudge. CT is the coinventor of the DnaNudge CovidNudge system and is named on the patent for the method and apparatus for analysing biological specimens on the DnaNudge platform (US Patent No: US 10 093 965.B2).16 LSPM has consulted for bioMerieux (2013–20), DNAelectronics (2015), Dairy Crest (2017– 18), Pfizer (2018–20), and Umovis Lab (2020), received speaker fees from Profile Pharma (2018), received research grants from the UK National Institute for Health Research (NIHR; 2013–2019), Leo Pharma (2016), and CW+ Charity (2018–19), and received educational support from Eumedica (2016–17). NM has received speaker fees from Beyer (2016) and Pfizer (2019), and received educational support from Eumedica (2016) and Baxter (2017). MMG and GC are partly supported by the NIHR Imperial Biomedical Research Centre. GC is an NIHR research professor and investigator within the NIHR London in-vitro diagnostic co-operative. All other authors declare no competing interests.

Funding Information:
Funding: Supported by the National Institute for Health Research (NIHR) Imperial NHS Trust Biomedical Research Centre (London, UK). Part of this work was supported by the NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at Oxford University (Oxford, UK) in partnership with Public Health England (grant HPRU-2012-10041). DnaNudge supplied the test cartridges and NudgeBox processing units.

Publisher Copyright:
Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

Keywords

  • Adult
  • Antigens, Viral/analysis
  • Asymptomatic Infections
  • Bias
  • COVID-19 Nucleic Acid Testing
  • COVID-19 Serological Testing/methods
  • COVID-19/diagnosis
  • Child
  • Cohort Studies
  • False Negative Reactions
  • False Positive Reactions
  • Humans
  • Molecular Diagnostic Techniques/methods
  • Point-of-Care Systems
  • Predictive Value of Tests
  • Reference Standards
  • SARS-CoV-2/immunology
  • Sensitivity and Specificity

ASJC Scopus subject areas

  • Pharmacology (medical)

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