Indication - Coronavirus disease (COVID-19)
SARS CoV-2 antigen
RDT; Handheld or small benchtop instrument for POC use
First added in 2020
Diagnosis, Aid to diagnosis
To diagnose COVID-19 in settings where NAT is unavailable or where prolonged turnaround times preclude clinical utility; To aid in the diagnosis of COVID-19 in the early symptomatic phases of illness, or in asymptomatic individuals with known contact with a confirmed case.
Upper respiratory specimens (e.g. nasopharyngeal or nasal swab)
WHO prequalified or recommended products
WHO supporting documents
Antigen-detection in the diagnosis of SARS-CoV-2 infection using rapid immunoassays; Interim guidance (11 September 2020) https://www.who.int/publications/i/item/antigen-detection-in-the-diagnosis-of-sars-cov-2infection-using-rapid-immunoassays; Guidance on SARS CoV-2 testing is reviewed regularly based on available evidence. For up to date guidance, see: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance-publications?publicationtypes=f85a3610-b102-4287-a6df-f3bc0b2e9f7c
ICD11 code: RA01.1
Summary of evidence evaluation
The first field studies of these tests are now emerging. The studies show that whereas the specificity of the tests is generally very high (97–99%), their sensitivity may be compromised. Evaluations in different settings have shown that sensitivity varies among them. There are no convincing data of the sensitivity of these tests in asymptomatic people. Although high specificity suggests that positive results in symptomatic patients indicate SARS-Cov-2 infection, the poor and variable sensitivity indicates that negative test results do not rule out disease, and a second test is required before infection can be ruled out.
Summary of SAGE IVD deliberations
Several concerns were raised about the unreliable sensitivity of the SARS CoV-2 antigen tests as shown in the various studies conducted to date. However, the test was considered essential especially to provide access to testing in settings where RT-PCR is not available. Nonetheless, it should be listed with clear caveats. SAGE IVD also decided not to recommend the test for use in asymptomatic individuals without known close contact with confirmed cases, because of concerns about the variable sensitivity and lack of test performance data in these individuals. Other concerns expressed related to the rapidly evolving evidence base and ongoing updates to guidelines, and how these factors may affect the stated test purpose. It was decided that these concerns should also be included in the caveats to the test purpose for this test.
SAGE IVD recommendation
SAGE IVD recommended including the SARS-CoV-2 antigen test in the third EDL: • as a disease-specific IVD for use in community settings and health facilities without laboratories (EDL 3, Section I.b, Coronavirus disease (COVID-19)); • using an RDT format, handheld or small benchtop instrument for POC use; • to aid in the diagnosis of COVID-19 in settings where NAT is unavailable or where prolonged turnaround times preclude clinical utility; and • to aid in the diagnosis of COVID-19 in the early symptomatic phases of illness, or in asymptomatic individuals with known close contact with a confirmed case. The test was recommended for inclusion provided that the following caveats are clearly stated: • A negative test does not rule out infection and should not determine clinical care. • Listing was based on available evidence and interim WHO guidelines and is subject to change. • Regulatory oversight of the majority of commercially available tests was limited to emergency use authorizations at the time of listing.
Details of submission from 2020
Note: This submission was made in response to a call from WHO for late-breaker submissions for SARS-CoV-2 diagnostic tests. Disease condition and impact on patients COVID-19 is a result of infection caused by the SARS-CoV-2 virus. COVID-19 typically presents with flu-like symptoms of respiratory disease from mild to moderate to severe. The common symptoms at early onset include fever, cough, headache, myalgia and fatigue. More severe cases present with symptoms of pneumonia and acute respiratory distress syndrome (ARDS), including shortness of breath, confusion, low blood pressure, persistent pain or pressure in the chest, and lethargy. Diarrhoea and bloody sputum are indications of progressive severity, as are patchy shadows and ground-glass opacity observed in chest x-ray and tomography scans. Severe complications include sepsis, respiratory failure, heart failure and septic shock. COVID-19 infection presents a challenge for clinical diagnosis, as many infected (and infectious) patients may present as asymptomatic (1–4). Does the test meet a medical need? The clinical utility of SARS-CoV-2 infection testing lies in early identification and isolation of cases, but also in choosing the right therapeutic approach in a clinical picture that can mimic several other entities (5, 6). WHO guidance on the use of rapid antigen tests recommends use in settings where “NAT is unavailable or where prolonged turnaround times preclude clinical utility” (7). Given the generally lower sensitivity of these tests compared to reverse transcription PCR (RT-PCR), they should only be used to identify COVID-19 infection in patients who are within 5–7 days of the onset of symptoms. Identifying COVID-19 may also limit further diagnostic investigations for other etiologies and eventually limit antibiotic use for empiric treatment of assumed bacterial pneumonia (8). In health care settings, early identification of infected individuals (both patients and health care workers) can prevent unrecognized spread of the virus within an institution. Early identification allows for proper isolation of infected patients and appropriate use of personal protective equipment (PPE) for health care workers. How the test is used Given the typically high specificity of rapid antigen tests, a positive result is considered indicative of SARS-CoV-2 infection. However, the sensitivity of these tests is variable, and therefore a negative test cannot be taken to rule out the presence of infection (9). Negative tests should be confirmed by an RT-PCR test or by a repeat antigen test when RT-PCR is not available.
Public health relevance
Prevalence and socioeconomic impact SARS-CoV-2 infection was first observed in Wuhan Province, China, in December 2019 as a new form of respiratory infection. From there it rapidly spread around the world, resulting in almost 60 million reported cases by November and claiming the lives of more than 1.3 million people. The infection has placed health care systems under severe strain around the world and resulted in serious global economic hardship, as countries restricted the movement of their populations and the conduct of daily business activities. Age appears to play a significant role in morbidity and mortality risk for COVID-19 (8). As seen with SARS-CoV, there have been very few SARS-CoV-2 deaths reported for the paediatric population, in stark contrast to the 14.8% mortality rate observed for patients > 80 years and 8% mortality rate for patients 70–79 years (10–12).
WHO or other clinical guidelines relevant to the test
In September 2020, WHO released guidelines for the use of SARS-CoV-2 rapid antigen tests (7). The guidelines stated that “SARS-CoV-2 Ag-RDTs can be used to diagnose SARS-CoV-2 infection in a range of settings where NAAT is unavailable or where prolonged turnaround times preclude clinical utility provided that they meet minimum performance requirements of ≥80% sensitivity and ≥97% specificity compared to a NAAT reference assay.” Several scenarios were described for the appropriate use of these tests. National public health entities around the world have rapidly developed and published similar guidelines, including the US Centers for Disease Control and Prevention (CDC), European Centre for Disease Prevention and Control (ECDC), and Health Canada, to name only a very few.
Evidence for diagnostic accuracy
The most significant review to date is a Cochrane review published in May 2020 (9) that reported eight evaluations in five studies of five different rapid antigen tests. While specificity was found to be consistently high at an average of 98.9% (95% CI: 97.3–99.5), sensitivity varied widely across the studies from 0 to 94%, with an average of 56.2% (95% CI: 29.5–79.8). However, the authors had low confidence in the results because several studies were poorly designed or reported, and many tests were done without following the manufacturer’s instructions. The authors stressed the urgent need for further evaluations and stated their intention to update their review soon. The update was published after this application was submitted. A meta-analysis of commercial assays registered in Brazil (13) included only two antigen direct assays to date in April, and showed a sensitivity range of 70–86% and specificity of 95–97%. Several primary studies have been done to assess the performance of antigen tests for SARS CoV-2. A PubMed search yielded seven independent evaluation studies (14–20) and two manufacturer-sponsored studies (21–22). All of the assays evaluated in these studies were rapid point-of-care (POC) tests. No published studies were found for laboratory-based high-throughput automated SARS CoV-2 antigen tests. All studies reviewed made similar observations, namely that the tests evaluated showed consistently high specificity when compared to an RT-PCR test, and hence strong positive predictive value. However, the tests also showed variable sensitivity depending on the study population, meaning that their negative predictive values are unreliable. Sensitivities were typically higher in patients with high viral loads (low RT-PCR cycle threshold values), i.e. those in the first 5–10 days after onset of symptoms. These observations led to universally similar conclusions and recommendations that rapid antigen tests may be useful when testing patients within the first week after onset of symptoms, but not thereafter. Given that the first week after onset of symptoms (and a few days prior to the onset of symptoms) is the period when these patients are at their most infectious (high viral load), and given the ease of use, low cost and amenability of these tests to mass production and broad distribution, they have an important role to play in infection control despite their limited sensitivity. Many more infectious individuals will be identified because of broad availability than will be missed because of lower sensitivity. The key caveat would be that negative test results would need to be managed carefully, and different suggestions have been made to address this issue. For example, to diagnose disease, patients with a negative antigen test and clinically suspected infection or known prior exposure should be retested with the antigen test if a PCR test is not available; ideally the result should be confirmed with an RT-PCR test.
Evidence for clinical usefulness and impact
Although no primary studies or reviews were found that demonstrated the clinical utility of the SARS CoV-2 rapid antigen tests, several of the clinical accuracy studies touched on the utility of this test in their conclusions. For diagnostic purposes, these tests may be best suited for use as a first-line test in acute patients within a few days of the onset of symptoms due to the fact that sensitivity decreases significantly as viral load declines. Negative tests in patients suspected of COVID-19 infection or with known prior exposure should be confirmed with an RT-PCR test. This approach may reduce the use of more costly RT-PCR tests and, thus, the burden on laboratories where they are performed. The ease of use, relatively low cost (US$5 has been announced by two suppliers), and potential for mass production and wide distribution make this test a useful tool for broad-based, rapid identification of individuals infected with SARS CoV-2 in settings where RT-PCR may not be available as well as for screening in settings where the pretest probability of a positive result is low.
Evidence for economic impact and/or cost–effectiveness
No studies were found to demonstrate the cost–effectiveness of using rapid antigen tests for SARS-CoV-2.
Ethical issues, equity and human rights issues
No ethical issues were identified. Given that COVID-19 has disproportionately affected resource-constrained settings, the expanded availability of testing offered by the rapid antigen test may help to alleviate the disease burden in these populations (23, 24).
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