Antigen Tests

Elon Musk recently tweeted that he was tested four times in the same day.  Two tests were positive, and two tests were negative.  How can this be? 

Mr. Musk was tested with the BD Veritor Plus rapid antigen test for SARS-CoV-2.  BD Veritor is one of several SARS-CoV-2 antigen tests made available in the United States by an Emergency Use Authorization (EUA) with the FDA.  While PCR tests have some limitations, antigen tests are fraught with many more challenges that bring their results into question.  

First the good news.  Antigen tests are cheap, plentiful, and rapid, usually providing results in 15 minutes or less.  And, with one exception, all antigen tests can be performed in laboratories operating under a CLIA Certificate of Waiver, meaning that they can be performed by personnel with very little education in laboratory science.

So what’s the bad news?  I see three major problems with antigen tests: the test process, the lack of amplification, and poor sensitivity.

The antigen tests from different vendors all follow, with minor variations, the same process.  A sample is collected on a swab, usually from the back of the nose (nasopharynx), and the swab is placed in an incubation well on the test device.  A few drops of reagent containing antibodies against the target (in this case, the SARS-CoV-2 virus capsule) are added.  If the antibodies bind to the target, a signal is sent to the test system.  This signal is usually a color change.  The whole process is very much like a home urine pregnancy test.  

Well, what could go wrong with that?  Strong lines are easy to see, but what about faint lines?  Where is the cut-off between positive and negative?  Some vendors include a reader calibrated to take the guesswork out of reading results, but you begin to see the problem.  The test system introduces an element of subjectivity and operator technique that varies from tester to tester, and these variations impact test results.  Recall that most of these tests are intended to be performed by personnel with very little training in laboratory medicine.  

This process lacks the amplification step of PCR.  That means when the swab is scraped against the back of the nose, what rubs off is all that you have for the test.  If you happened to not scrap off enough virus in an infected person, too bad—the test will be negative.

And that brings me to the final problem with antigen tests: low sensitivity.  According to the FDA submissions by BD, the antigen test used on Mr. Musk has a sensitivity that may be as low as 67%.  What does that mean?  Sensitivity of 67% means that one out of every three infected patients tests negative with the system. That’s right: wrong answers one-third of the time! And that is in the best of circumstances, using data that the manufacturer chose to submit to the FDA. These tests are not always used in the best of circumstances; remember, the test is approved for use by personnel with very little education in laboratory science.

BD makes the following statement in its submission to the FDA: “Negative test results do not preclude infection and should not be used as the sole basis for treatment or other patient management decisions, including infection control decisions, particularly in the presence of clinical signs and symptoms consistent with COVID-19, or in those who have been in contact with the virus. It is recommended that these results be confirmed by a molecular testing method, if necessary, for patient management.” Mr. Musk’s experience is not surprising.

My colleague says she has a Magic 8–Ball on her desk that is a lot like an antigen test: it’s cheap, plentiful and rapid. And, she says, it gives about as many correct answers. I agree.