SARS-CoV-2 sensitivity limbo – How low can we go?

•SARS-CoV-2 rapid diagnostic tests are less sensitive than traditional RT-PCR assays.•SARS-CoV-2 rapid diagnostic tests may play a role in specific circumstances.•The context in which SARS-CoV-2 rapid diagnostic tests are utilized effectively requires critical thinking and further data. Since the beginning of the pandemic, molecular methods such as real-time RT-PCR have been used as references for severe acute respiratory syndrome (SARS-CoV-2) detection. With unprecedented demands for SARS-CoV-2 testing, and difficulties acquiring NAAT supplies, clinical laboratories are challenged with providing timely results. Rapid diagnostic tests (RDTs) are simple, rapid, and portable technologies that offer a potential solution to increase the diagnostic testing capacity. Recently, some RDTs have become licensed under emergency use authorization for SARS-CoV-2 detection in the laboratory or point-of-care settings (Food and Drug Administration (FDA), 2020Food and Drug Administration (FDA) In vitro diagnostic EUAs.2020https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/vitro-diagnostics-euasGoogle Scholar), but despite their high specificity, the applicability of RDTs has been hampered by poor clinical sensitivity, which often falls below the ideal target product profiles recommended by the World Health Organization (Dinnes et al., 2020Dinnes J. Deeks J.J. Adriano A. Berhane S. Davenport C. Dittrich S. et al.Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection.Cochrane Database Syst Rev. 2020; 8 (Aug 26. PMID: 32845525)CD013705https://doi.org/10.1002/14651858.CD013705Crossref PubMed Scopus (543) Google Scholar, World Health Organization (WHO), 2020aWorld Health Organization (WHO) Antigen-detection in the diagnosis of SARS-CoV-2 infection using rapid immunoassays. Interim guidance. 11 September.2020https://www.who.int/publications/i/item/antigen-detection-in-the-diagnosis-of-sars-cov-2infection-using-rapid-immunoassaysGoogle Scholar, World Health Organization (WHO), 2020bWorld Health Organization (WHO) COVID-19 Target product profiles for priority diagnostics to support response to the COVID-19 pandemic v.1.0. 29 September.2020Google Scholar). In a recent systematic review and meta-analysis (Dinnes et al., 2020Dinnes J. Deeks J.J. Adriano A. Berhane S. Davenport C. Dittrich S. et al.Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection.Cochrane Database Syst Rev. 2020; 8 (Aug 26. PMID: 32845525)CD013705https://doi.org/10.1002/14651858.CD013705Crossref PubMed Scopus (543) Google Scholar), the average pooled sensitivity of antigen-based RDTs was 56%, and values as low as 11.7% have been reported (Nagura-Ikeda et al., 2020Nagura-Ikeda M. Imai K. Tabata S. Miyoshi K. Murahara N. Mizuno T. et al.Clinical Evaluation of Self-Collected Saliva by Quantitative Reverse Transcription-PCR (RT-qPCR), Direct RT-qPCR, Reverse Transcription-Loop-Mediated Isothermal Amplification, and a Rapid Antigen Test To Diagnose COVID-19.J Clin Microbiol. 2020; 58 (Aug 24PMID: 32636214; PMCID: PMC7448663): e01438-20https://doi.org/10.1128/JCM.01438-20Crossref PubMed Scopus (253) Google Scholar). In contrast, a recent study in this journal by Porte et al., 2020Porte L. Legarraga P. Vollrath V. Aguilera X. Munita J.M. Araos R. et al.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 (Oct Epub 2020 Jun 1. PMID: 32497809; PMCID: PMC7263236): 328-333https://doi.org/10.1016/j.ijid.2020.05.098Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar described high clinical sensitivity of an antigen-based RDT at 93.9%. Given the wide variability in RDT sensitivity, careful consideration is needed on the generalizability and applicability of these findings. Traditionally, SARS-CoV-2 detection methods strive to achieve the highest sensitivity possible (LeBlanc et al., 2020LeBlanc J.J. Gubbay J.B. Li Y. Needle R. Arneson S.R. Marcino D. et al.COVID-19 Pandemic Diagnostics Investigation Team of the Canadian Public Health Laboratory Network (CPHLN) Respiratory Virus Working Group. Real-time PCR-based SARS-CoV-2 detection in Canadian laboratories.J Clin Virol. 2020; 128 (Jul Epub 2020 May 13. PMID: 32405254; PMCID: PMC7219382): 104433https://doi.org/10.1016/j.jcv.2020.104433Crossref PubMed Scopus (66) Google Scholar). From an individual diagnostic perspective, the decreased analytical sensitivity of RDTs (∼105 copies/mL vs. ∼103 copies/mL for NAATs) would likely only be relevant during a short period in the acute stage of illness, or late in disease (LeBlanc et al., 2020LeBlanc J.J. Gubbay J.B. Li Y. Needle R. Arneson S.R. Marcino D. et al.COVID-19 Pandemic Diagnostics Investigation Team of the Canadian Public Health Laboratory Network (CPHLN) Respiratory Virus Working Group. Real-time PCR-based SARS-CoV-2 detection in Canadian laboratories.J Clin Virol. 2020; 128 (Jul Epub 2020 May 13. PMID: 32405254; PMCID: PMC7219382): 104433https://doi.org/10.1016/j.jcv.2020.104433Crossref PubMed Scopus (66) Google Scholar, Wölfel et al., 2020Wölfel R. Corman V.M. Guggemos W. Seilmaier M. Zange S. Müller M.A. et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581 (May Epub 2020 Apr 1. PMID: 32235945): 465-469https://doi.org/10.1038/s41586-020-2196-xCrossref PubMed Scopus (4463) Google Scholar, Mina et al., 2020Mina M.J. Parker R. Larremore D.B. Rethinking Covid-19 Test Sensitivity - A Strategy for Containment.N Engl J Med. 2020; (Sep 30, Epub ahead of print. PMID: 32997903)https://doi.org/10.1056/NEJMp2025631Crossref PubMed Scopus (449) Google Scholar, Larremore et al., 2020Larremore D.B. Wilder B. Lester E. Shehata S. Burke J.M. Hay J.A. Tambe M. Mina M.J. Parker R. Test sensitivity is secondary to frequency and turnaround time for COVID-19 surveillance.medRxiv [Preprint]. 2020; (PMID: 32607516; PMCID: PMC7325181. Jun 27:2020.06.22.20136309)https://doi.org/10.1101/2020.06.22.20136309Crossref Scopus (0) Google Scholar). As individuals with resolving viral loads are less likely to be infective [i.e., high cycle thresholds (Ct values) in real-time RT-PCR], this situation may adequately be served by an RDT (Wölfel et al., 2020Wölfel R. Corman V.M. Guggemos W. Seilmaier M. Zange S. Müller M.A. et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581 (May Epub 2020 Apr 1. PMID: 32235945): 465-469https://doi.org/10.1038/s41586-020-2196-xCrossref PubMed Scopus (4463) Google Scholar, Mina et al., 2020Mina M.J. Parker R. Larremore D.B. Rethinking Covid-19 Test Sensitivity - A Strategy for Containment.N Engl J Med. 2020; (Sep 30, Epub ahead of print. PMID: 32997903)https://doi.org/10.1056/NEJMp2025631Crossref PubMed Scopus (449) Google Scholar, Larremore et al., 2020Larremore D.B. Wilder B. Lester E. Shehata S. Burke J.M. Hay J.A. Tambe M. Mina M.J. Parker R. Test sensitivity is secondary to frequency and turnaround time for COVID-19 surveillance.medRxiv [Preprint]. 2020; (PMID: 32607516; PMCID: PMC7325181. Jun 27:2020.06.22.20136309)https://doi.org/10.1101/2020.06.22.20136309Crossref Scopus (0) Google Scholar). However, on a population level, the identification of individuals with early or late disease would allow for more complete contact tracing and potentially lead to more case finding and interventions. In recent publications, an alternative strategy has been proposed that might overcome the poor sensitivity of RDTs by repeat testing of target populations over time, thereby increasing the probability of capturing individuals who fall into a period of high viral shedding (Mina et al., 2020Mina M.J. Parker R. Larremore D.B. Rethinking Covid-19 Test Sensitivity - A Strategy for Containment.N Engl J Med. 2020; (Sep 30, Epub ahead of print. PMID: 32997903)https://doi.org/10.1056/NEJMp2025631Crossref PubMed Scopus (449) Google Scholar, Larremore et al., 2020Larremore D.B. Wilder B. Lester E. Shehata S. Burke J.M. Hay J.A. Tambe M. Mina M.J. Parker R. Test sensitivity is secondary to frequency and turnaround time for COVID-19 surveillance.medRxiv [Preprint]. 2020; (PMID: 32607516; PMCID: PMC7325181. Jun 27:2020.06.22.20136309)https://doi.org/10.1101/2020.06.22.20136309Crossref Scopus (0) Google Scholar). To date, the feasibility of repeat testing using RDTs has been hampered by limitations such as scalability (with low throughput devices), human and material resource requirements, and acceptability of repeat collections with the authorized specimen types (e.g., nasopharyngeal swabs). Regardless of the challenges of RDT implementation, thorough validation is required with consideration for factors that are method-, virus-, host-, and context-dependent. With the above considerations in mind, key parameters that remain to be defined for repeat testing using RDTs is the minimal acceptable value for sensitivity, the optimal testing frequency in target populations, and for which population or setting RDTs would be of best benefit. If the goal is case-finding and containment, the sensitivity of an assay would logically influence the testing frequency, and ideally, should be targeted to ensure the maximal and accurate detection of SARS-CoV-2 in the target population. However, if capacity or resource limitations defines a certain testing frequency, high sensitivity becomes increasingly relevant. As these parameters have yet to be defined for RDTs, we find ourselves in a “sensitivity limbo,” asking not only “how low can we go?” for accurate SARS-CoV-2 detection, but also “how low should we go?” The authors declare that they have no conflicts of interest related to this manuscript. There was no funding for this manuscript.

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