FDA has issued an alert to clinical labs and healthcare providers about the potential for COVID-19 antigen tests to deliver false positives after receiving reports from nursing homes and other settings.
The agency's Tuesday notice reminds users to follow the instructions, noting that improper storage and reading the results at the wrong time can lead to false results. At the same time, the agency said false positives could be an inevitable consequence of using tests with specificities below 100%. If a test with 98% specificity is used to screen a population in which 10% of people are infected, two out of every 10 positive results will be false.
The FDA's warning comes a day after The New York Times reported on a University of Arizona study raising concerns about the ability of a Quidel rapid antigen test to detect asymptomatic cases. The study found Quidel's test produced more false positives than positives confirmed by the gold standard PCR tests.
The potential for antigen tests to diagnose coronavirus infections at the point of care in 15 minutes has led the Trump administration and individual states to put the kits at the center of efforts to safely reopen the economy and protect nursing homes. BD and Quidel, leading suppliers of antigen cartridges and associated instruments, are shipping kits to 14,000 nursing homes, while Abbott has a deal with the Trump administration to provide 150 million of its card-based product.
When the Trump administration shared plans to provide Abbott BinaxNOW diagnostic tests to states for use in nursing homes, schools and other sites, it said antigen products are specific but may be less sensitive than laboratory-based nucleic acid tests. That would suggest false negatives are the biggest issue with antigen tests. Yet, FDA’s alert centers on reports of false positives.
FDA said it "is aware of reports of false positive results associated with antigen tests used in nursing homes and other settings." The agency did not name specific tests in the alert but the wording of its recommendations covers the card-type tests sold by Abbott and the instrument-based kits from BD and Quidel, notably when it discusses the need for proper handling of "the test cartridge/card."
The FDA recommendations also address the need to read the test at the specified time to cut the risk of false positives and false negatives. The instructions for use for the Abbott, BD and Quidel kits all stress that failure to adhere to certain timings can cause false results. FDA's recommendations also address the challenges associated with processing multiple specimens in batch mode and the need to minimize the risk of cross-contamination.
Even if tests are used correctly, any kit with a less than 100% specificity can deliver a large number of false positives when used to screen populations in which a pathogen has a low prevalence. FDA made that point in its alert, explaining how the false positive rate for a test with 98% specificity goes from 20% in a population with 10% prevalence to 96% in a population with 0.1% prevalence. Across the U.S., 7.1% of tested samples were positive in the latest CDC data.
The FDA alert comes a day after The New York Times reported on the use of Quidel’s antigen test by the University of Arizona. When used in samples from symptomatic patients, Quidel’s kit detected 80% of the infections found by PCR testing. However, the figure fell to 32% in samples taken from asymptomatic individuals.
While Quidel's Sofia SARS Antigen FIA test produced more false positives than PCR-confirmed positives in the study, the company's "intended use" document states that the diagnostic is for the detection of SARS-CoV-2 in individuals who are "suspected of COVID-19 by their healthcare provider within the first five days of the onset of symptoms."
Nonetheless, a Quidel spokesperson argued in an emailed statement that the "facts" of the New York Times story "actually show" that the company's antigen test performed "very well" in identifying infectious COVID-19 carriers among both symptomatic and asymptomatic individuals.
The Quidel spokesperson pointed out that the University of Arizona study has not been published yet in a peer-reviewed scientific journal. "The current confusion illustrates why complex scientific studies should never be publicly debated absent access to the full, peer-reviewed dataset," they added.
At the same time, the spokesperson noted that The New York Times reported the discrepancies between the Quidel antigen test and PCR "may have resulted from 'a good reason: [the people] were carrying too little of the coronavirus to spread it to others'" and that PCR tests "can pick up on harmless genetic fragments of the coronavirus that linger in the body for weeks after people have recovered."