key: cord-0943849-97kwep5w
authors: Wan, Zhenzhou; Zhao, Yongjuan; Lu, Renfei; Dong, Yajuan; Zhang, Chiyu
title: Rapid antigen detection alone may not be sufficient for early diagnosis and/or mass screening of COVID‐19
date: 2021-08-03
journal: J Med Virol
DOI: 10.1002/jmv.27236
sha: 58199f9e85f620e47803167bf62a641925ec0a6d
doc_id: 943849
cord_uid: 97kwep5w

Currently, COVID-19 pandemic is still severe, and the major challenge in the fight against this pandemic is how to early find pre-symptomatic and asymptomatic individuals and to eliminate silent transmission. Rapid antigen detection alone may not be sufficient for early diagnosis and/or mass screening of COVID-19, and direct probe-based RT-LAMP assay or other nucleic acid amplification (NAA)-based POCT strategies should be recommended to use alone or together with rapid antigen test in mass screening or community-based testing of SARS-CoV-2 This article is protected by copyright. All rights reserved.

Rapid antigen detection alone may not be sufficient for early diagnosis and/or mass screening of COVID-19

To the editor, (Table 1 ). [3] [4] [5] [6] [7] [8] [9] Two-thirds of these rapid antigen tests had overall sensitivities (30.8%-68.9%) below the WHO recommended standard of ≥80%. One rapid antigen test (COVID-VIRO®) showed an excellent sensitivity of >90% even for the samples with a low viral load (>32 C t values in RT-qPCR), 3 one (COVID-19 Ag ECO Test) had an overall sensitivity of 82.0%, 4 

Rapid Test) showed variable sensitivities (75.0%-100%) in three different investigations. [4] [5] [6] After excluding one study with very small samples size (n=44) that showed very high sensitivity (100%), 4 we recalculated the sensitivity of the Panbio™ Ag Test using the data from two different investigations, 5,6 and obtained a 76.3% (216/283) ( Table 1 ). In spite of having a significantly positive correlation of antigen testing with SARS-CoV-2 viral culture assays, 10 it is clear that the vast majority (6/7) of tested rapid antigen assays have substantially lower sensitivity than the WHO recommended standard, especially for asymptomatic cases. 6, 8 The low sensitivity of these antigen testing assays is mainly due to low detection capacity for samples with low viral load (<100 000 RNA copies/ml or C t < 30).

Therefore, it is of concern whether the antigen detection alone is sufficient for early diagnosis and/or mass screening of COVID-19 in the fight against the pandemic. The incubation phase represents the early stage of infection, during which the rapidly replicating virus is highly transmissible, but the viral load (or antigen level) might be relatively low (Figure 1 ). The major challenge for rapid antigen testing is that its low detection sensitivity for low viral load samples will miss a large proportion of presymptomatic and asymptomatic COVID-19 individuals during the incubation phase (Figure 1 ), and these missed SARS-CoV-2 carriers will enlarge the silent transmission chain. 1,2 Therefore, the vast majority of the rapid antigen testing alone should be cautiously recommended for early diagnosis and mass screening of COVID-19 because of its low sensitivity.

As a promising POCT technique, RT-LAMP has comparable detection sensitivity with RT-qPCR, but significantly shorter sample-to-result time (about 30 min vs. about 4 h for RT-qPCR), easier operation, and less dependent on sophisticated equipment. 11 In particular, we and other groups developed direct probe-based SARS-CoV-2 RT-LAMP assays that can detect clinical samples at a level of over 1000 copies/ml (unpublished data), 12 enabling the finding of most presymptomatic and asymptomatic COVID-19 individuals (Figure 1 ). Although RT-qPCR is considered as the golden standard for SARS-CoV-2 detection, high dependence on molecular laboratory (sophisticated equipment with professionals) and long sample-to-result time (about 4 h) limit its capacity in mass screening or community-based testing of SARS-CoV-2. As a good alternative, direct probe-based RT-LAMP assay or other nucleic acid amplification (NAA)based POCT strategies should be recommended to use alone or together with rapid antigen test in mass screening or community-based testing of SARS-CoV-2.

T A B L E 1 Sensitivities and specificities of nine rapid antigen testing assays for SARS-CoV-2 detection F I G U R E 1 SARS-CoV-2 viral load dynamics at upper respiratory tract during COVID-19. SARS-CoV-2 viral load at the upper respiratory tract varies largely during the course of COVID-19, and peaks within about 4 days after symptom onset (or about 2 weeks after initial infection in asymptomatic cases). Symptomatic and asymptomatic individuals share similar viral load dynamics during the course of COVID-19, which is divided into three phases, incubation/pre-symptom, acute, and recovery phases. SARS-CoV-2 viral load is substantially lower during incubation/ pre-symptom and recovery phases than the acute phase, and transmissible SARS-CoV-2 virus persists from initial infection up to about 10 days after symptom onset or two to three weeks since initial infection in asymptomatic cases

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