Antibody tests for identification of current and past infection with SARS-CoV-2

Jon Deeks, Jacqueline Dinnes, Yemisi Takwoingi, Clare Davenport, René Spijker, Sian Taylor-Phillips, Ada Adriano, Sophie Beese, Janine Dretzke, Lavinia Ferrante di Ruffano, Isobel Harris, Malcolm Price, Sabine Dittrich, Devy Emperador, Lotty Hooft, Mariska M G Leeflang, Ann Van De Bruel, Matthew D F McInnes, T Stuyf, J DomenS Horn, B Yang, M Langendam, E Ochodo, F Guleid, G Holtman, J Verbakel, I Stegeman, JP Salameh , TA McGrath , CB van der Pol , RA Frank , R Prager , SS Hare , C Dennie , K Jenniskens, DA Korevaar , JF Cohen , J van de Wijgert, JAAG Damen , Ridhi Agarwal, Simon Baldwin, Sarah Berhane, Clare Herd, Caroline Kristunas, Laura Quinn, Barney Scholefield

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Abstract

Background: The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus and resulting COVID‐19 pandemic present important diagnostic challenges. Several diagnostic strategies are available to identify current infection, rule out infection, identify people in need of care escalation, or to test for past infection and immune response. Serology tests to detect the presence of antibodies to SARS‐CoV‐2 aim to identify previous SARS‐CoV‐2 infection, and may help to confirm the presence of current infection.

Objectives: To assess the diagnostic accuracy of antibody tests to determine if a person presenting in the community or in primary or secondary care has SARS‐CoV‐2 infection, or has previously had SARS‐CoV‐2 infection, and the accuracy of antibody tests for use in seroprevalence surveys.

Search methods: We undertook electronic searches in the Cochrane COVID‐19 Study Register and the COVID‐19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID‐19 publications. We did not apply any language restrictions. We conducted searches for this review iteration up to 27 April 2020.

Selection criteria: We included test accuracy studies of any design that evaluated antibody tests (including enzyme‐linked immunosorbent assays, chemiluminescence immunoassays, and lateral flow assays) in people suspected of current or previous SARS‐CoV‐2 infection, or where tests were used to screen for infection. We also included studies of people either known to have, or not to have SARS‐CoV‐2 infection. We included all reference standards to define the presence or absence of SARS‐CoV‐2 (including reverse transcription polymerase chain reaction tests (RT‐PCR) and clinical diagnostic criteria).

Data collection and analysis: We assessed possible bias and applicability of the studies using the QUADAS‐2 tool. We extracted 2x2 contingency table data and present sensitivity and specificity for each antibody (or combination of antibodies) using paired forest plots. We pooled data using random‐effects logistic regression where appropriate, stratifying by time since post‐symptom onset. We tabulated available data by test manufacturer. We have presented uncertainty in estimates of sensitivity and specificity using 95% confidence intervals (CIs).

Main results: We included 57 publications reporting on a total of 54 study cohorts with 15,976 samples, of which 8526 were from cases of SARS‐CoV‐2 infection. Studies were conducted in Asia (n = 38), Europe (n = 15), and the USA and China (n = 1). We identified data from 25 commercial tests and numerous in‐house assays, a small fraction of the 279 antibody assays listed by the Foundation for Innovative Diagnostics. More than half (n = 28) of the studies included were only available as preprints.

We had concerns about risk of bias and applicability. Common issues were use of multi‐group designs (n = 29), inclusion of only COVID‐19 cases (n = 19), lack of blinding of the index test (n = 49) and reference standard (n = 29), differential verification (n = 22), and the lack of clarity about participant numbers, characteristics and study exclusions (n = 47). Most studies (n = 44) only included people hospitalised due to suspected or confirmed COVID‐19 infection. There were no studies exclusively in asymptomatic participants. Two‐thirds of the studies (n = 33) defined COVID‐19 cases based on RT‐PCR results alone, ignoring the potential for false‐negative RT‐PCR results. We observed evidence of selective publication of study findings through omission of the identity of tests (n = 5).

We observed substantial heterogeneity in sensitivities of IgA, IgM and IgG antibodies, or combinations thereof, for results aggregated across different time periods post‐symptom onset (range 0% to 100% for all target antibodies). We thus based the main results of the review on the 38 studies that stratified results by time since symptom onset. The numbers of individuals contributing data within each study each week are small and are usually not based on tracking the same groups of patients over time.

Pooled results for IgG, IgM, IgA, total antibodies and IgG/IgM all showed low sensitivity during the first week since onset of symptoms (all less than 30.1%), rising in the second week and reaching their highest values in the third week. The combination of IgG/IgM had a sensitivity of 30.1% (95% CI 21.4 to 40.7) for 1 to 7 days, 72.2% (95% CI 63.5 to 79.5) for 8 to 14 days, 91.4% (95% CI 87.0 to 94.4) for 15 to 21 days. Estimates of accuracy beyond three weeks are based on smaller sample sizes and fewer studies. For 21 to 35 days, pooled sensitivities for IgG/IgM were 96.0% (95% CI 90.6 to 98.3). There are insufficient studies to estimate sensitivity of tests beyond 35 days post‐symptom onset. Summary specificities (provided in 35 studies) exceeded 98% for all target antibodies with confidence intervals no more than 2 percentage points wide. False‐positive results were more common where COVID‐19 had been suspected and ruled out, but numbers were small and the difference was within the range expected by chance.

Assuming a prevalence of 50%, a value considered possible in healthcare workers who have suffered respiratory symptoms, we would anticipate that 43 (28 to 65) would be missed and 7 (3 to 14) would be falsely positive in 1000 people undergoing IgG/IgM testing at days 15 to 21 post‐symptom onset. At a prevalence of 20%, a likely value in surveys in high‐risk settings, 17 (11 to 26) would be missed per 1000 people tested and 10 (5 to 22) would be falsely positive. At a lower prevalence of 5%, a likely value in national surveys, 4 (3 to 7) would be missed per 1000 tested, and 12 (6 to 27) would be falsely positive.

Analyses showed small differences in sensitivity between assay type, but methodological concerns and sparse data prevent comparisons between test brands.

Authors' conclusions: The sensitivity of antibody tests is too low in the first week since symptom onset to have a primary role for the diagnosis of COVID‐19, but they may still have a role complementing other testing in individuals presenting later, when RT‐PCR tests are negative, or are not done. Antibody tests are likely to have a useful role for detecting previous SARS‐CoV‐2 infection if used 15 or more days after the onset of symptoms. However, the duration of antibody rises is currently unknown, and we found very little data beyond 35 days post‐symptom onset. We are therefore uncertain about the utility of these tests for seroprevalence surveys for public health management purposes. Concerns about high risk of bias and applicability make it likely that the accuracy of tests when used in clinical care will be lower than reported in the included studies. Sensitivity has mainly been evaluated in hospitalised patients, so it is unclear whether the tests are able to detect lower antibody levels likely seen with milder and asymptomatic COVID‐19 disease.

The design, execution and reporting of studies of the accuracy of COVID‐19 tests requires considerable improvement. Studies must report data on sensitivity disaggregated by time since onset of symptoms. COVID‐19‐positive cases who are RT‐PCR‐negative should be included as well as those confirmed RT‐PCR, in accordance with the World Health Organization (WHO) and China National Health Commission of the People's Republic of China (CDC) case definitions. We were only able to obtain data from a small proportion of available tests, and action is needed to ensure that all results of test evaluations are available in the public domain to prevent selective reporting. This is a fast‐moving field and we plan ongoing updates of this living systematic review.
Original languageEnglish
Article numberCD013652
Number of pages310
JournalCochrane Library
Volume2020
Issue number6
DOIs
Publication statusPublished - 25 Jun 2020

Bibliographical note

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.

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. 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: NIHR, Oxford Biomedical Research Centre, the UK Government Department of Health and Social Care and grants from NIHR and the Medical Research Council Publication status: preprint (not peer reviewed) Source: medRxiv Study author COI: several authors declared relationships with companies for other work; funders were co-authors

Funded by Emergency Project from the Science & Technology Commission of Chongqing; Major National S&T program grant from Science & Technology Commission of China; Grant from the National Natural Science Foundation of China, Grant from the Science & Technology Commission of Yuzhong district, Chongqing. COI (reported or derived): study author employed by BioScience Co. LTD, Tianjin, China Publication status (source): preprint (not peer reviewed) (medRxiv) NOTE: Study author institution reported as BioScience Co. LTD, Tianjin, China (www.bioscience-tj.com/en/about.php)

Funding: National Natural Science Foundation of China and China Postdoctoral Science Foundation Publication status: peer–reviewed early online Source: academic journal Study author COI: study authors state no competing financial interests

Funding: Beijing Natural Science Foundation Publication status: published letter Source: academic journal Study author COI: none mentioned

Funding Information:
Funding: intramural funding from the National Institute of Allergy and Infectious Diseases Publication status: preprint (not peer-reviewed) Source: bioRxiv Study author COI: NR

Funding: OS lab is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62 IBEID), “TIMTAMDEN” ANR-14-CE14-0029, “CHIKV-Viro-Immuno” ANR-14-CE14-0015-01 and the Gilead HIV cure program. LG is supported by the French Ministry of Higher Education, Research and Innovation.ME lab is funded by Institut Pasteur, Labex IBEID (ANR-10-LABX-62-IBEID), Reacting, EU grant Recover, ANR Oh’ticks. HM received core grants from the G5 Institut Pasteur Program, the Milieu Intérieur Program (ANR-10-LABX-69-01) and INSERM. C.P. is supported by a fellowship from the Agence Nationale de Recherch-es sur le Sida et les Hépatites Virales (ANRS). SVDW lab is funded by Institut Pasteur, CNRS, Université de Paris, Santé publique France, Labex IBEID (ANR-10-LABX-62-IBEID), REACTing, EU grant Recover. Publication status: preprint Source: medRxiv Study author COI: PC is the founder and CSO of TheraVectys

Funding: funded by Chongqing Education Board “new coronavirus infection and prevention” emergency scientific research project

Funding: Danish National Biobank resource, supported by the Novo Nordisk Foundation Publication status: preprint (not peer reviewed) Source: medRxiv Study authorCOI: none declared

Funding: Guangdong Provincial Science and Technology Program, National Natural Science Funds of China, Shenzhen University and the National Science and Technology Major Project Publication status: preprint (not peer reviewed) Source: medRxiv Study author COI: none declared

Funded by National Natural Science Foundation of China; National Key Research and Development Program of China; and the China Postdoctoral Science Foundation. Wuhan Institute of Virology of Chinese Academy of Sciences and Zhuhai Lizhu Diagnostics Inc. for providing assistance in ELISA detection. Conflicts of interest: Zhuhai Lizhu Diagnostics Inc. acknowledged in Funding statement. Preprint (not peer reviewed): medRxiv

Funded by National Natural Science Foundation of China (81672079 to CZ and 31800147 to ZL), the Open Research Fund Program of the State Key Laboratory of Virology of China (2019KF001 to ZL), the Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai (PWR12018-05 to XL), and the Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai (PWZxq2017-15 to XL) No conflicts of interest declared Preprint (not peer reviewed): medRxiv

Supported by the National Natural Science Foundation, the China Postdoctoral Science Foundation (2019M664008), and the Wuhan Young and Middle-aged Medical Backbone Talents Training Project (Wuweitong [2019] 87th266)

Funded by Emergency Project from the Science & Technology Commission of Chongqing; The Major National S&T programme grant from Science & Technology Commission of China. No conflicts of interest reported; 1 author from BioScience Co. Ltd, Chongqing, China Preprint (not peer reviewed)

Funded by Emergency Project from the Science & Technology Commission of Chongqing; The Major National S&T programme grant from Science & Technology Commission of China No conflicts of interest declared; 1 study author from BioScience Co. Ltd, Chongqing, China Preprint paper (not peer reviewed)

Funding: China National Mega-Projects for Infectious Diseases and the Science and Technology Major Project of Xiamen Publication status: preprint Source:Pre print server (medRxiv) Study author COI: none declared

Funding: T.J. is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29030104), National Natural Science Fund (Grant No.: 31870731 and U1732109), the Fundamental Research Funds for the Central Universities (WK2070000108). TJ and XLM is supported by a COVID-19 special task grant supported by Chinese Academy of Science Clinical Research Hospital (Hefei) with Grant No. YD2070002017 and YD2070002001, respectively. M.H. is supported by the new medical science fund of USTC (WK2070000130). Publication status: preprint Source: preprint server: medRxiv Study author COI: 3 study authors are employees of Kangrun Biotech LTD (Guangzhou, 308 China). 4 study authors have jointly applied for a patent related to the Ab detecting kits.

No information provided on study author conflicts. Published as early release (not final). Report the following funding "Zoonoses Anticipation and Preparedness Initiative (project Innovative Medicines Initiative grant no. 115760), the Innovative Medicines Initiative; the European Commission, and partners of the European Federation of Pharmaceutical Industries and Associations"

Funding: this study was partly supported by the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of Hong Kong; the Theme-Based Research Scheme (T11/707/15) of the Research Grants Council, Hong Kong Special Administrative Region; Sanming Project of Medicine in Shenzhen, China (SZSM201911014); the High Level-Hospital Program, Health Commission of Guangdong Province, China; and donations from the Shaw Foundation Hong Kong, Richard Yu and Carol Yu, May Tam Mak Mei Yin, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, and the Hong Kong Hainan Commercial Association South China Microbiology Research Fund Publication status: published paper Source: Lancet Infectious Diseases Study author COI: declare they have none

Supported by the Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund. No conflicts of interest noted. Report from a medRxiv preprint (not peer reviewed)

Funding: this work is funded by National Natural Science Foundation of China (No. 81973990, 91643101), and Science Foundation of Huazhong University of Science and Technology (No. 2020kfyXGYJ100) Publication status: published in journal Source:Infectious Disease Society of America Study author COI: declare that they have none

Funding: this work was funded by the Special Project for Emergency Scientific and Technological Research on New Coronavirus Infection

Funding: supported by the National Natural Science Foundation of China, Jiangsu Provincial Medical Talent, Six talent peaks project of Jiangsu Province, Advanced health talent of six-one project of Jiangsu Province, Nanjing Medical Science and Technique Development Foundation Publication status: published paper Source: Emerging Microbes & Infections Study author COI: none was declared

Funding: supported by National Key Research and Development Program of China and Emergency Science and Technology Project of Hubei Province Publication status: Journal pre-proof Source: Journal of Infection Study author COI: none

Funded by National Science and Technology Major Project of China, Liaoning Province Natural Science Foundation Project, Liaoning Province Central Government's special project to guide local scientific and technological development, Guangdong Province Major key projects of indusTentative technology, Major Special Project of Construction Program of China Medical University in 2018 and 345 talent project of Shengjing Hospital of China Medical University No conflicts of interest noted Report from a preprint (not peer reviewed)

Supported by the Mega-Project for Infectious Disease from Minister of Science and Technology of the People’s Republic of China, China Natural Science Foundation for excellent scholars, Strategic Priority Research Program of the CAS, Youth innovation promotion association of CAS

Funding: The National Key Research and Development Program of China, and The National Science and Technology Major Project Publication status: preprint Source:preprint server (medRxiv) Study author COI: report no COI but 1 author from a company (Beijing Hot-gen Biotechnology Inc., Beijing)

Funding: research Grants from Beijing Science and Technology Commission, Bill & Melinda Gates Foundation, National Natural Science Foundation of China (NSFC) and the National Science and Technology Major Project Publication status: preprint Source: preprint server medRxiv Study author COI: no details but 3 authors are from 3 different companies (Any-Go Technology Co., Ltd, Beijing; AbMax Biotechnology Co., LTD, Beijing; Zhenge Biotechnology Co., LTD, Shanghai)

Work was supported by the grants from Sichuan Science and Technology Program (2020YFS0014 and 2020YFS0558), the Chinese Academy of Medical Sciences (2019-I2M-5-032) and Technology & Science & Technology Bureau of Chengdu (2020-YF05-00060-SN and 2020-YF05-00075-SN) Authors declare no COI present; 3 co-authors employed by Maccura Biotech

Sabine Dittrich: is employed by FIND with funding from DFID and Australian Aid. FIND is a global non-for profit product development partnership and WHO Diagnostic Collaboration Centre. It is FIND’s role to accelerate access to high quality diagnostic tools for low resource

Publisher Copyright:
Copyright © 2020 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

Keywords

  • Antibodies, Viral/blood
  • Antibody Specificity
  • Betacoronavirus/immunology
  • COVID-19
  • Coronavirus Infections/diagnosis
  • False Negative Reactions
  • False Positive Reactions
  • Humans
  • Immunoglobulin A/blood
  • Immunoglobulin G/blood
  • Immunoglobulin M/blood
  • Pandemics
  • Pneumonia, Viral/diagnosis
  • Reference Standards
  • Reverse Transcriptase Polymerase Chain Reaction/standards
  • SARS-CoV-2
  • Selection Bias
  • Sensitivity and Specificity
  • Serologic Tests/methods

ASJC Scopus subject areas

  • Pharmacology (medical)

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