The Role of Antigen Rapid Diagnostic Test in COVID-19 Diagnosis

1. INTRODUCTION

Coronavirus disease 2019, COVID-19, emerged from the Wuhan province of China at the end of 2019 [1], and the World Health Organization (WHO) declared it as a pandemic on March 11^th, 2020 [2]. To combat the pandemic, Tedros Adhanom Ghebreyesusm, the Director-General of WHO, appealed to countries to perform extensive testing [3]. Rapid identification and isolation of patients were needed for curbing the spread of COVID-19 [1]. The gene sequence of SARS-CoV-2, which was responsible for COVID-19, was published in January 2020 [4].

Most of the tests that were developed to detect SARS-CoV-2 relied on viral RNA amplification. The tests typically use polymerase chain reaction (PCR) to detect viral RNA. These molecular tests are highly sensitive and specific. Reverse transcription-quantitative PCR (RT-qPCR) through nasopharyngeal swabs, throat swabs, or saliva is considered the gold standard for the diagnosis of COVID-19 [5]. Most of these tests require robust laboratory infrastructure and highly skilled laboratory personnel. The test results are usually available within 2 hours but may extend up to 7 days due to obvious reasons [6]. This led to the need for highly sensitive immunological diagnostic methods, which detect on-site viral antigens in clinical specimens that would help in early and accurate diagnosis of COVID-19 [7].

Ag-RDTs diagnose SARS-CoV-2 active infection by the detection of viral proteins in different types of specimens. These are lateral flow, single-use, rapid tests that are processed or visually read using a small compact device [4]. Ag-RDTs can be performed in various settings, including off-laboratory, by following the manufacturer’s instructions and the result can be achieved within 15-20 min. These tests can be carried out at a much faster rate and are also cheaper for extensive implementation [4]. Even though these rapid tests are very specific, they are not as sensitive as molecular assays [4]. Despite having lesser sensitivity than molecular tests, Ag-RDT appears beneficial in guiding patient management at the point of care and also for random screening or re-testing; this helps in making timely public health decisions in order to curb the transmission of the virus [8].

Table 1 shows some of the available COVID-19 Ag-RDTs made available by different manufacturers, their sensitivity & specificity, and specimens on which these tests can be performed. As of March 2021, the rapid tests that received US Food and Drug Administration (FDA) Emergency Use Authorization (EUA) is shown in Table (2) [9].

Even though the Ag-RDTs approved by WHO or US FDA for emergency use show a consistent performance constant, the independent Ag-RDTs evaluation carried out by the foundation for innovative new diagnostics (FIND) showed that their performance differs in different countries based on the assessment panel and the viral load in the study samples [4, 10].

Several Ag-RDT studies have been conducted globally. Lambert-Niclot et al. reported a sensitivity of 50% with COVID-19 Ag Respi-Strip (Coris) compared to RT-PCR. They stated that the test was more sensitive to high viral loads and can be used within a few days of the onset of symptoms [7]. Whereas a study from Belgium reported that Coris COVID-19 Ag Respi-Strip rapid test showed a higher antigen detection rate that correlates with higher viral loads, but this study also suggested that the test’s low sensitivity precludes its use as the first-line test for COVID-19 [11]. Mak et al. in China, evaluated the performance of BIOCREDIT COVID-19 Ag test with RT-PCR for SARS-CoV2. According to them, the rapid test detected between 11.1% and 45.7% of RT-PCR-positive samples. They suggested the use of the rapid test as an additional test to RT-PCR [12]. Another study by Kruttgen et al. compared the Ag-RDTs to RT-PCR kit and concluded that the sensitivity and specificity of the antigen assay are lower than the PCR assay. Nevertheless, they concluded that rapid antigen testing is a quick and easy-to-use approach that permits individuals who are contagious for SARS-CoV-2 to be separated from less or non-contagious individuals [13]. A field study by Albert et al. [14] found Panbio^TM COVID-19 Ag-RDT to perform well in primary health centers for the early diagnosis of COVID-19. Notably, their data indicated that patients with RT-PCR-proven Ag-RDT negative for COVID-19 are highly doubtful to be infectious. They reported that false-negative Ag-RDT results may be uncertain from a public health perspective, but a diagnostic approach that missed the RT-PCR confirmation of negative Ag-RDT tests in non-hospitalized patients might reduce laboratory workloads when there is a shortage of RT-PCR tests [14]. Some other field studies on Rapid Antigen tests are summarized in Table 3.

A study in Spain reported the overall sensitivity of 48.1% with the Panbio^TM COVID-19 Ag-RDT for the identification of SARS-CoV-2-infected individuals among asymptomatic close contacts of confirmed COVID-19 cases [15], which was similar to the data published by Linares et al. (54.5%) [16], Fenollar et al. (45.4%) [17], Bulilete et al. (59.0%) [18]. Porte et al. [19] evaluated the fluorescence immunochromatographic SARS-CoV-2 antigen test (Bioeasy Biotechnology Co., Shenzhen, China) during the first weeks of the outbreak in Chile, through oropharyngeal and nasopharyngeal swabs from suspected COVID-19 patients. They concluded that Ag-RDT carried on samples during the first week of symptoms and with high viral loads showed high sensitivity and specificity. They also proposed the use of Ag-RDT as an important tool for the early diagnosis of SARS-CoV-2, particularly when the molecular assays are limited [19]. A study from Thailand reported that SARS-CoV-2 Ag-RDT (StandardTM Q COVID-19 Ag kit) showed similar sensitivity (98.33%; 95% CI, 91.06-99.96%) and specificity (98.73%; 95% CI, 97.06-99.59%) with the RT-PCR assay. They suggested the use of Ag-RDT as a screening test, mainly in highly prevalent regions [20]. Many rapid antigen tests currently lack robust analytical sensitivity data when compared to reverse transcription-quantitative PCR (qRT-PCR). Perchetti et al. used SARS-CoV-2-positive samples to assess the analytical sensitivity of the Abbott BinaxNOW COVID-19 Ag card, and they noticed that BinaxNOW COVID-19 Ag card was roughly equivalent to a generic qRT-PCR cycle threshold (CT) value of 29 to 30 [21]. Another study by Eshghifar et al. reported that rapid antigen tests have low analytical and clinical sensitivity for identifying asymptomatic patients (low viral load). As a result, they proposed that the analytical sensitivity of rapid antigen tests be thoroughly assessed before being used in clinical settings [22].

CONCLUSION

To ensure proper patient management and public health action, countries need to maintain a balance between benefits and risk outcomes of rapid Ag-RDT. When the affordability and validity of the diagnostic assay are involved, no assay can show 100% correct results. More research is needed to better understand the validity of rapid Ag-RDTs in various settings and to know how often and when to use these tests. This would support testing strategies and health policies and would disrupt the transmission of disease. However, antigen rapid diagnostic tests can play a supporting role in the management of the COVID-19 pandemic.

REFERENCES