Performance of Antigen Detection Tests for SARS-CoV-2: A Systematic Review and Meta-Analysis

Abstract

Coronavirus disease 2019 (COVID-19) initiated global health care challenges such as the necessity for new diagnostic tests. Diagnosis by real-time PCR remains the gold-standard method, yet economical and technical issues prohibit its use in points of care (POC) or for repetitive tests in populations. A lot of effort has been exerted in developing, using, and validating antigen-based tests (ATs). Since individual studies focus on few methodological aspects of ATs, a comparison of different tests is needed. Herein, we perform a systematic review and meta-analysis of data from articles in PubMed, medRxiv and bioRxiv. The bivariate method for meta-analysis of diagnostic tests pooling sensitivities and specificities was used. Most of the AT types for SARS-CoV-2 were lateral flow immunoassays (LFIA), fluorescence immunoassays (FIA), and chemiluminescence enzyme immunoassays (CLEIA). We identified 235 articles containing data from 220,049 individuals. All ATs using nasopharyngeal samples show better performance than those with throat saliva (72% compared to 40%). Moreover, the rapid methods LFIA and FIA show about 10% lower sensitivity compared to the laboratory-based CLEIA method (72% compared to 82%). In addition, rapid ATs show higher sensitivity in symptomatic patients compared to asymptomatic patients, suggesting that viral load is a crucial parameter for ATs performed in POCs. Finally, all methods perform with very high specificity, reaching around 99%. LFIA tests, though with moderate sensitivity, appear as the most attractive method for use in POCs and for performing seroprevalence studies.

Unmasking the ‘Asymptomatic’ COVID-19: A Nose Question

“…The accuracy of rapid antigen tests in at-risk groups, e.g., hospital workers, is limited and may produce false negatives with a greater potential to create or increase the severity of existing outbreaks [ 41 ]. Rapid antigen tests show higher sensitivity in symptomatic patients than in asymptomatic ones, suggesting that viral load is a crucial parameter for antigen-based tests performed at points of care [ 42 ]. Accordingly, the sensitivity of the rapid antigenic tests was lower in asymptomatics, as more than half were falsely negative (58.7%), compared to symptomatics (84.2%) [ 43 ].…”

Challenges in the Detection of SARS-CoV-2: Evolution of the Lateral Flow Immunoassay as a Valuable Tool for Viral Diagnosis

“…It has been determined that the time to detect the viral antigen with LFIA is in the first 7 days the patient develops symptoms because the highest viral load occurs in this period. Individuals with mild or asymptomatic symptoms or who exceed this time could have a low viral load [ 111 ]. In this disease period, LFIAs detect at least a Ct value < 25 (~100,000 RNA copies/mL), which is sufficiently accurate and helpful for mass population screening programs [ 112 , 113 ].…”

Clinical Added Value of SARS-CoV-2 Antigen Detection in Blood Samples

“…However, performing RT-PCR requires special equipment and trained laboratory staff, familiar with molecular techniques. Moreover, molecular tests are costly, time consuming in the absence of automation, and a long time-to-result was reported in the early months of the pandemic [ 4 , 5 ]. Thus, several rapid serological and antigenic diagnostic tests (RDTs), based on lateral flow immunoassay (LFIA) technology, have been developed to detect anti-SARS-CoV-2 antibodies from capillary blood or serum, or SARS-CoV-2 antigens from nasopharyngeal and nasal secretions and saliva.…”

“…Thus, several rapid serological and antigenic diagnostic tests (RDTs), based on lateral flow immunoassay (LFIA) technology, have been developed to detect anti-SARS-CoV-2 antibodies from capillary blood or serum, or SARS-CoV-2 antigens from nasopharyngeal and nasal secretions and saliva. They provide quick results, which are available in 15 minutes, and can be used for point-of care testing (POCT) [ 5 , 6 ]. This unprecedented sanitary crisis has led to a blooming of tests, with hundreds of antibody and antigen detection assays reported on the FIND website [ 7 ] either being in use or at some stage of development.…”

“…However, later generations of LFIA assays, such as the COVID-VIRO ® , revealed excellent sensitivity of 96.7% (CI, 93.5%−99.9%) as compared to RT-PCR [ 11 ] on NP samples. LFIA tests have played an important role in mitigating the effects of the global pandemic with SARS-CoV-2, due to their ability to rapidly detect infected individuals and stop further spread of the virus [ 5 ].…”