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

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).

Figure 1.

The process of studies retrieval and inclusion adopted in the present systematic review and meta-analysis. A total of 25 studies with 29 estimates were retrieved.

Figure 2.

Forest plot representing the estimated specificity of SARS-CoV-2 antigen-based studies. Pooled specificity was 99.4% (95%CI 99.0–99.7), with considerable heterogeneity (I2 81%), and a significant difference between FIA (98.9%, 95%CI 97.7 – 99.4) and ICT based estimates (99.7%, 95%CI 99.1 – 99.9; chi squared test p value < 0.001). Note: A = Coris Bioconcept - COVID-19 Ag Respi-Strip; B = SD Biosensor - STANDARD F COVID-19 Ag FIA; C = Bioeasy Biotechnology Co. - Bioeasy 2019-Novel Coronavirus (2019-nCoV) Fluorescence Antigen Rapid Test Kit; D = BD Life Sciences – Veritor Plus System; E = Fujirebio Inc – Lumipulse G; F = Quidel Corporation – SOFIA SARS ANTIGEN FIA; G = Abbot Diagnostics - Panbio COVID-19 Ag Rapid Test device; H = Abbot Diagnostics - BinaxNow COVID-19 Ag Card; I = AAZ – COVID-Viro; L = SD Biosensor - STANDARD Q COVID-19 Ag.

Figure 3.

Forest plot representing the estimated sensitivity of SARS-CoV-2 antigen-based studies. Pooled sensitivity was 72.8% (95%CI 62.4–81.3), being not significantly greater in FIA based studies (i.e. 75.3%, 95%CI 58.4-86.9) than in ICT based studies (72.3%; 95%CI 58.6-83.2). Heterogeneity was substantial (I2, 97%), for both groups (i.e. I2, 95% in ICT studies, I2 = 96% in FIA studies). Note: A = Coris Bioconcept - COVID-19 Ag Respi-Strip; B = SD Biosensor - STANDARD F COVID-19 Ag FIA; C = Bioeasy Biotechnology Co. - Bioeasy 2019-Novel Coronavirus (2019-nCoV) Fluorescence Antigen Rapid Test Kit; D = BD Life Sciences – Veritor Plus System; E = Fujirebio Inc – Lumipulse G; F = Quidel Corporation – SOFIA SARS ANTIGEN FIA; G = Abbot Diagnostics - Panbio COVID-19 Ag Rapid Test device; H = Abbot Diagnostics - BinaxNow COVID-19 Ag Card; I = AAZ – COVID-Viro; L = SD Biosensor - STANDARD Q COVID-19 Ag.

Figure 4.

Forest plot representing the estimated sensitivity of SARS-CoV-2 antigen-based studies by cycle threshold value, i.e. CT < 25 (left) vs. CT ≥ 25 (right). Pooled sensitivity was 97.6% (95%CI 94.1–99.0) for studies with higher viral load (CT < 25), compared to 43.6% (95% 27.6-61.1) in studies with lower viral load (CT ≥ 25). Heterogeneity was substantial, for both sub-analyses (i.e. I2 80% for samples with high viral load vs. I2 95% in samples with low viral load). Note: Note: A = Coris Bioconcept - COVID-19 Ag Respi-Strip; B = SD Biosensor - STANDARD F COVID-19 Ag FIA; C = Bioeasy Biotechnology Co. - Bioeasy 2019-Novel Coronavirus (2019-nCoV) Fluorescence Antigen Rapid Test Kit; D = BD Life Sciences – Veritor Plus System; F = Quidel Corporation – SOFIA SARS ANTIGEN FIA; G = Abbot Diagnostics - Panbio COVID-19 Ag Rapid Test device; L = SD Biosensor - STANDARD Q COVID-19 Ag.

Figure 5.

Funnel plots for Sensitivity (a), and Specificity (b) of studies included in the metanalysis. Visual inspection suggested a significant asymmetry for all analyses, with subsequent reporting bias. However, regression analysis dismissed a significant reporting bias for overall analysis of sensitivity (t = -0.0329, df = 27, p-value = 0.974), but not for specificity (t = 3.504, df = 27, p-value = 0.002).

Figure 6.

Radial plots for Sensitivity (a), and Specificity (b) of studies included in the metanalysis. Visual inspection suggested the seemingly random distribution of included studies on both sides of the regression line for sensitivity, but not for specificity.

Figure 7.

Forrest plot representing the pooled diagnostic odds ratio (DOR) of antigen-based tests for SARS-CoV-2. A substantial heterogeneity in reported studies was identified (I2 76.3%, Cochran’s Q: 118.145 (df=28, p < 0.001)).

Figure 8.

Summary Receiver Operated Characteristics (sROC) curves for antigen tests for SARS-CoV-2 RNA. The small but noticeable differences between estimates from a random-effect model (AUC = 0.844) and a fixed-effect model (AUC = 0.867) are consistent with the hypothesis of a threshold effect in diagnostic performances of assessed tests.