Antigen Detection Tests for SARS-CoV-2: a systematic review and meta-analysis on real world data

Main Article Content

Matteo Riccò http://orcid.org/0000-0002-6525-2159
Silvia Ranzieri
Simona Peruzzi
Marina Valente
Federico Marchesi
Nicola Luigi Bragazzi
Davide Donelli
Federica Balzarini
Pietro Ferraro
Vincenza Gianfredi
Carlo Signorelli

Keywords

COVID-19, SARS-CoV-2, point-of-care diagnostics, rapid testing, real-world data, systematic review and meta-analysis

Abstract

Background and aim Rapid antigen detection (RAD) tests on nasopharyngeal specimens have been recently made available for SARS-CoV-2 infections, and early studies suggested their potential utilization as rapid screening and diagnostic testing. The present systematic review and meta-analysis was aimed to assess available evidence and to explore the reliability of antigenic tests in the management of the SARS-CoV-2 pandemic.


Materials and Methods. We reported our meta-analysis according to the PRISMA statement. We searched Pubmed, Embase, and pre-print archive medRxiv.og for eligible studies published up to November 5th, 2020. Raw data included true/false positive and negative tests, and the total number of tests. Sensitivity and specificity data were calculated for every study, and then pooled in a random-effects model. Heterogeneity was assessed using the I2 measure. Reporting bias was assessed by means of funnel plots and regression analysis.


Results. Based on 25 studies, we computed a pooled sensitivity of 72.8% (95%CI 62.4–81.3), a specificity of 99.4% (95%CI 99.0–99.7), with high heterogeneity and risk of reporting bias. More precisely, RAD tests exhibited higher sensitivity on samples with high viral load (i.e. <25 Cycle Threshold; 97.6%; 95%CI 94.1–99.0), compared to those with low viral load (≥25 Cycle Threshold; 43.6%; 95% 27.6-61.1).


Discussion. As the majority of collected reports were either cohort or case-control studies, deprived of preventive power analysis and often oversampling positive tests, overall performances may have been overestimated. Therefore, the massive referral to antigenic tests in place of RT-qPCR is currently questionable, and also their deployment as mass screening test may lead to intolerable share of missing diagnoses. On the other hand, RAD tests may find a significant role in primary care and in front-line settings (e.g. Emergency Departments). (www.actabiomedica.it)

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References

1. Guan W, Liang W, Zhao Y et al. Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis. Eur. Respir. J. 2020;55:2000547. doi: 10.1183/13993003.00547-2020
2. Huang C, Wang Y, Li X et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan , China. Lancet 2020;395:497-506. doi: 10.1016/S0140-6736(20)30183-5
3. Li Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N. Engl. J. Med. 2020;382:1199-1207. doi: 10.1056/NEJMoa2001316.
4. Riccò M; Ferraro P, Gualerzi G, et al. Point-of-Care diagnostic of SARS-CoV-2: knowledge, attitudes, and beliefs (KAP) of medical workforce in Italy. Acta Biomed 2020;91:57–67. doi: 10.23750/abm.v91i2.9573
5. European Centre for Diseases Prevention and Control (ECDC) An overview of the rapid test situation for COVID-19 diagnosis in the EU / EEA; Stockholm, 2020; available from: https://www.ecdc.europa.eu/en/publications-data/overview-rapid-test-situation-covid-19-diagnosis-eueea (accessed on November 12th, 2020)
6. Lippi G, Mattiuzzi C, Bovo C, Plebani M. Current laboratory diagnostics of coronavirus disease 2019 ( COVID-19). Acta Biomed. 2019;91:137–145. doi: 10.23750/abm.v91i2.9548
7. Tang YW, Schmitz JE, Persing DH, Stratton CW. The Laboratory Diagnosis of COVID-19 Infection: Current Issues and Challenges. J. Clin. Microbiol. 2020;58:e00512-20. doi: 10.1128/JCM.00512-20
8. Riccò M, Ferraro P, Gualerzi G et al. Point-of-Care Diagnostic Tests for Detecting SARS-CoV-2 Antibodies : A Systematic Review and Meta-Analysis of Real-World Data. J. Clin. Med. 2020;9:1515. doi: 10.3390/jcm9051515
9. Vashist SK. In Vitro Diagnostic Assays for COVID-19: Recent Advances and Emerging Trends. Diagnostics (Basel, Switzerland) 2020;10:202. doi: 10.3390/diagnostics10040202..
10. Cassaniti I, Novazzi F, Giardina F et al. Performance of VivaDiagTM COVID-19 IgM/IgG Rapid Test is inadequate for diagnosis of COVID-19 in acute patients referring to emergency room department. J. Med. Virol. 2020;92:1724-1727. doi: 10.1002/jmv.25800.
11. Xu R, Cui B, Duan X, Zhang P, Zhou X, Yuan Q. Saliva: potential diagnostic value and transmission of 2019-nCoV. Int. J. Oral Sci. 2020;12:11. doi: 10.1038/s41368-020-0080-z..
12. World Health Organization (WHO) Antigen-detection in the diagnosis of SARS-CoV-2 infection using rapid immunoassays; 2020; Available from: https://www.who.int/publications/i/item/antigen-detection-in-the-diagnosis-of-sars-cov-2infection-using-rapid-immunoassays; accessed on Novembre 12th, 2020
13. World Health Organization (WHO) Laboratory testing strategy recommendations for COVID-19: interim guidance, 22 March 2020; 2020; World Health Organization. available from https://apps.who.int/iris/handle/10665/331509, accessed on November 12th, 2020
14. Scohy A, Anantharajah A, Bodéus M, Kabamba-Mukadi B, Verroken A, Rodriguez-Villalobos H. Low performance of rapid antigen detection test as frontline testing for COVID-19 diagnosis. J. Clin. Virol. 2020;129:104455. doi: 10.1016/j.jcv.2020.104455.
15. Moher D, Liberati A, Tetzlaff J et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6:e1000097. doi: 10.1371/journal.pmed.1000100
16. Bizzaro N, Villalta D, Giavarina D, Tozzoli R. Are anti-nucleosome antibodies a better diagnostic marker than anti-dsDNA antibodies for systemic lupus erythematosus? A systematic review and a study of metanalysis. Autoimmun. Rev. 2012;12:97–106. doi: doi: 10.1016/j.autrev.2012.07.002
17. Herrera V, Hsu V, Adewale A et al. Testing Healthcare Workers Exposed to COVID19 using Rapid Author ’ s Affiliation : medRxiv 2020;2020.0812.20172726. doi: 10.1101/2020.08.12.20172726
18. Porte L, Legarraga P, Vollrath V, Aguilera X. Evaluation of a novel antigen-based rapid detection test for the diagnosis of SARS-CoV-2 in respiratory samples. Int J Infect Dis 2020;99:328-333. doi: 10.1016/j.ijid.2020.05.098
19. Young S, Taylor SN, Cammarata CL, et al. Clinical evaluation of BD Veritor SARS-CoV-2 point-of-care test performance compared to PCR-based testing and versus the Sofia 2 SARS Antigen point-of-care test. J Clin Microbiol 2020;59:e02338-20.. doi: 10.1128/JCM.02338-20
20. Veyrenche N, Bollore K, Pisoni A, et al. Diagnosis value of SARS-CoV-2 antigen/antibody combined testing using rapid diagnostic tests at hospital admission. medRxiv 2020; 2020.09.19.20197855. doi: 10.1101/2020.09.19.20197855
21. Cerutti F, Burdino E, Grazia M et al. Urgent need of rapid tests for SARS CoV-2 antigen detection: Evaluation of the SD-Biosensor antigen test for SARS-CoV-2. J. Clin. Virol. 2020;132: 104654. doi: 10.1016/j.jcv.2020.104654
22. Albert E, Torres I, Bueno F, et al. Field evaluation of a rapid antigen test (PanbioTM COVID-19 Ag Rapid Test 2 Device) for the diagnosis of COVID-19 in primary healthcare centers. medRxiv 2020;2020.10.16.20213850. doi: 10.1101/2020.10.16.20213850
23. Gremmels H, Winkel BMF, Schuurman R et al. Real-life validation of the Panbio COVID-19 Antigen Rapid Test (Abbott) in community-dwelling subjects with symptoms of potential SARS-CoV-2 infection. medRxiv 2020;2020.10.16.20214189. doi: 10.1101/2020.10.16.20214189
24. Van der Moeren N, Zwart VF, Lodder EB et al. Performance evaluation of a sars-cov-2 rapid antigentest: test performance in the community in the netherlands. medRxiv 2020;2020.10.19.20215202. doi: 10.1101/2020.10.19.20215202
25. Lindner AK, Nikolai O, Kausch F et al. Head-to-head comparison of SARS-CoV-2 antigen-detecting rapid test with self-collected anterior nasal swab versus professional- collected nasopharyngeal swab. medRxiv 2020;2020.10.26.20219600. doi: 10.1101/2020.10.26.20219600
26. Hirotsu Y, Maejima M, Shibusawa M, Nagakubo Y. Comparison of automated SARS-CoV-2 antigen test for COVID-19 infection with quantitative RT-PCR using 313 nasopharyngeal swabs, including from seven serially followed patients. Int J Infect Dis 2020;99:397–402. doi: 10.1016/j.ijid.2020.08.029
27. Krüger LJ, Gaeddert M, Köppel L et al. Evaluation of the accuracy , ease of use and limit of detection of novel , rapid , antigen- detecting point-of-care diagnostics for SARS-CoV-2. medRxiv 2020;2020.10.01.20203836. doi: 10.1101/2020.10.01.20203836
28. Lambert-Niclot S, Cuffel A, Le Pape S et al. Evaluation of a Rapid Diagnostic Assay for Detection of SARS-CoV-2 Antigen in Nasopharyngeal Swabs. J. Clin. Microbiol. 2020;58, e00977-20. doi: 10.1128/JCM.00977-20
29. Linares M, Pérez Tanoira R, Romanyk J et al. Panbio antigen rapid test is reliable to diagnose SARS-CoV-2 infection in the first 7 days after the onset of symptoms. medRxiv 2020, 2020.09.20.20198192. doi: 10.1101/2020.09.20.20198192
30. Liotti FM, Menchinelli G, Lalle E et al. Performance of a novel diagnostic assay for rapid SARS-CoV-2 antigen detection in nasopharynx samples. Clin. Microbiol. Infect. 2021;27:487-488. doi: 10.1016/j.cmi.2020.09.030.
31. Mertens P, De Vos N, Martiny D et al. Development and Potential Usefulness of the COVID-19 Ag Respi-Strip Diagnostic Assay in a Pandemic Context. Front. Med. 2020;7:225. doi: 10.3389/fmed.2020.00225.
32. Pekosz A, Cooper CK, Parvu V et al. Antigen-based testing but not real-time PCR correlates with SARS-CoV-2 virus culture. medRxiv 2020;2020.10.02.20205708. doi: 10.1101/2020.10.02.20205708
33. Porte L, Legarraga P, Iruretagoyena M et al. Rapid SARS-CoV-2 antigen detection by immunofluorescence – a new tool to detect infectivity. medRxiv 2020;2020.10.04.20206466. doi: 10.1101/2020.10.04.20206466
34. Freymond A, Segura M. Performance evaluation of the Simtomax ® CoronaCheck rapid diagnostic test. medRxiv 2020;2020.10.28.20219667. doi: 10.1101/2020.10.28.20219667
35. Alemany A, Baro B, Ouchi D et al. Analytical and Clinical Performance of the Panbio COVID-19 Antigen-Detecting Rapid Diagnostic Test Background. medRxiv 2020;2020.10.30.20223198. doi: 10.1101/2020.10.30.20223198
36. Courtellement L, Guinard J, Guillaume C et al. Real-life performance of a novel antigen detection test on nasopharyngeal specimens for SARS-CoV-2 infection diagnosis: a prospective study. medRxiv 2020;2020.10.28.20220657. doi: 10.1101/2020.10.28.20220657
37. Pilarowski G, Lebel P, Sunshine S et al. Performance characteristics of a rapid SARS-CoV-2 antigen detection assay at a public plaza testing site in San Francisco. medRxiv 2020;2020.11.02.20223891. doi: 10.1101/2020. 11.02.20223891
38. Gupta A, Khurana S, Das R et al. Rapid chromatographic immunoassay-based evaluation of COVID-19: A cross- sectional, diagnostic test accuracy study & its implications for COVID-19 management in India. Indian J Med Res Epub 2021;153:126-131. doi: 10.4103/ijmr.IJMR_3305_20
39. Nalumansi A, Lutalo T, Kayiwa J et al. Field Evaluation of the Performance of a SARS-CoV-2 Antigen Rapid Diagnostic Test in Uganda using Nasopharyngeal Samples. Int. J. Infect. Dis. 2020;104:282-286 doi: 10.1016/j.ijid.2020.10.073
40. Blairon L, Wilmet A, Beukinga I, Tré-hardy M. Implementation of rapid SARS-CoV-2 antigenic testing in a laboratory without access to molecular methods: Experiences of a general hospital. J Clin Virol. 2020;129:104472. doi: 10.1016/j.jcv.2020.104472.
41. Fenollar F, Bouam A, Ballouche M et al. Evaluation of the Panbio Covid-19 rapid antigen detection test device for the screening of patients with Covid-19. J. Clin. Virol. 2020, JCM.02589-20. doi: 10.1128/JCM.02589-20.
42. Dutta NK, Mazumdar K, Gordy JT. The Nucleocapsid Protein of SARS–CoV-2: a Target for Vaccine Development. J. Virol. 2020;94:e00647-20. doi: 10.1128/JVI.00647-20
43. World Health Organization (WHO) Assessment tool for laboratories implementing COVID-19 virus testing; 2020; Available from: https://www.who.int/publications/i/item/assessment-tool-for-laboratories-implementing-covid-19-virus-testing; accessed on November 12th, 2020.
44. Harrington A, Cox B, Snowdon J, et al. Comparison of Abbott ID Now and Abbott m2000 methods for the detection of SARS-CoV-2 from nasopharyngeal and nasal swabs from symptomatic patients. J. Clin. Microbiol. 2020;58:e00798-20. doi: 10.1128/JCM.00798-20.
45. Vandenberg O, Martiny D, Rochas O, van Belkum A, Kozlakidis Z. Considerations for diagnostic COVID-19 tests. Nat. Rev. Microbiol. 2021;19:171-183. doi: 10.1038/s41579-020-00461-z..
46. Lee CK, Cho CH, Woo MK, Nyeck AE, Lim CS, Kim WJ. Evaluation of Sofia fluorescent immunoassay analyzer for influenza A/B virus. J. Clin. Virol. 2012;55:239–243. doi: 10.1016/j.jcv.2012.07.008
47. Hurt AC, Alexander R, Hibbert J, Deed N, Barr IG. Performance of six influenza rapid tests in detecting human influenza in clinical specimens. J. Clin. Virol. 2007;39:132–135. doi: 10.1016/j.jcv.2007.03.002
48. Uyeki TM, Prasad R, Vukotich C et al. Low sensitivity of rapid diagnostic test for influenza. Clin. Infect. Dis. 2009; 48:e89-92. doi: 10.1086/597828.
49. Cui Z, Chang H, Wang H et al. Development of a rapid test kit for SARS-CoV-2: an example of product design. Bio-Design Manuf. 2020, epub ahead of print. doi: 10.1007/s42242-020-00075-7.
50. Miller AB. Fundamental issues in screening for cancer. In Cancer epidemiology and prevention. Second edition; Schottenfeld, D., Fraumeni, J., Eds.; Oxford University Press: New York, 1996.
51. Wilson J, Jungne G. Principles and practice of screening for disease; 1st ed.; World Health Organization: Geneva, 1968; Vol. 34;.
52. Salvatore P, Dawson P, Wadhwa A et al. Epidemiological Correlates of PCR Cycle Threshold Values in the Detection of SARS-CoV-2. Clin Infect Dis 2020;ciaa1469. doi: 10.1093/cid/ciaa1469.
53. Riva E, Sainaghi PP, Turriziani O, Antonelli G, Patti G. SARS-CoV-2 infection: diagnostic testing results occasionally require special attention. Emerg. Microbes Infect. 2020;9:1955–1957. doi: 10.1080/22221751.2020.1814165
54. Yanes-Lane M, Winters N, Fregonese F et al. Proportion of asymptomatic infection among COVID-19 positive persons and their transmission potential: A systematic review and meta-analysis. PLoS One 2020;15:e0241536. doi: 10.1371/journal.pone.0241536
55. Bellato V, Konishi T, Pellino G et al. Screening policies, preventive measures and in-hospital infection of COVID-19 in global surgical practices. J. Glob. Health 2020;10:020507. doi: 10.7189/jogh.10.020507
56. Mutti A. Occupational Medicine in the time of COVID-19. Med Lav 2020;111:83–86. doi: 10.23749/mdl.v111i2.9546
57. Woloshin S, Patel N; Kesselheim AS. False Negative Tests for SARS-CoV-2 Infection. N Eng J Med 2020, 383(6):e38. doi: 10.1056/NEJMp2015897
58. Patel U, Malik P, Mehta D, et al. Early epidemiological indicators, outcomes, and interventions of COVID-19 pandemic: A systematic review. J Glob Health 2020;10:020506. doi: 10.7189/jogh.10.020506.
59. Bourgonje, A.R.; Abdulle, A.E.; Timens, W.; Hillebrands, J.; Navis, G.J.; Gordijn, S.J.; et al. Angiotensin‐converting enzyme‐2 ( ACE2 ), SARS‐CoV ‐2 and pathophysiology of coronavirus disease 2019 ( COVID ‐19) . J. Pathol. 2020;251:228-248. doi: 10.1002/path.5471.
60. Fang Z, Zhang Y, Hang C, Ai J, Li S, Zhang W. Comparisons of viral shedding time of SARS-CoV-2 of different samples in ICU and non-ICU patients. J. Infect. 2020;81:147-178. doi: 10.1016/j.jinf.2020.03.013.
61. Azzi L, Carcano G, Gianfagna F et al. Saliva is a reliable tool to detect SARS-CoV-2. J. Infect. 2020;81:e45-e50. doi: 10.1016/j.jinf.2020.04.005.
62. Riccò M, Ranzieri S, Peruzzi S. et al. RT-qPCR assays based on saliva rather than on nasopharyngeal swabs are possible but should be interpreted with caution: Results from a systematic review and metaanalysis. Acta Biomed. 2020;91:e2020025. doi: 10.23750/abm.v91i3.10020.
63. Padoan A, Zuin S, Cosma C, Basso D, Plebani M, Bonfante F. Clinical performances of an ELISA for SARS-CoV-2 antibody assay and correlation with neutralization activity. Clin. Chim. Acta 2020;510:654–655. doi: 10.1016/j.cca.2020.08.024
64. Reusken CB, Buiting A, Bleeker-Rovers C et al. Rapid assessment of regional SARS-CoV-2 community transmission through a convenience sample of healthcare workers, the Netherlands, March 2020. Eurosurveillance 2020;25:2000334. doi: 10.2807/1560-7917.ES.2020.25.12.2000334.
65. To KKW, Tsang OTY, Leung WS et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect. Dis. 2020;20:565–574. doi: 10.1016/S1473-3099(20)30196-1.
66. Ceron JJ, Lamy E, Martinez-Subiela S et al. Use of Saliva for Diagnosis and Monitoring the SARS-CoV-2: A General Perspective. J. Clin. Med. 2020;9:1491. doi: 10.3390/jcm9051491
67. Hirotsu Y, Maejima M, Shibusawa M et al. Pooling RT-PCR test of SARS-CoV-2 for large cohort of “healthy” and infection-suspected patients: A prospective and consecutive study on 1,000 individuals. medRxiv 2020;2020.05.04.20088146. doi: 10.1101/2020.05.04.20088146
68. Chartrand C, Leeflang MMG, Minion J, Brewer T, Pai M. Review Accuracy of Rapid Influenza Diagnostic Tests. Ann. Intern. Med. 2012;156:500–511. doi: 10.7326/0003-4819-156-7-201204030-00403
69. Riccò M, Ranzieri S, Marchesi F. Rapid antigen tests for large-scale diagnostic campaigns: A case study from North-Eastern Italy. J Infect. 2021;82:e39-e40. doi: 10.1016/j.jinf.2021.01.011
70. Riccò M. A systematic review on rapid antigen test devices for SARS-CoV-2 in nursing homes: Useful, but handle with care. Enferm Infecc Microbiol Clin 2022;epub ahead of print. doi: 10.1016/j.eimc.2022.02.012