Editor’s note: The following statement from Brian Metzger, MD, on the current state of COVID-19 serology testing was originally published on the Travis County Medical Society’s website. As of April 14, the U.S. Food and Drug Administration (FDA) has granted emergency use authorization (EUA) to four antibody tests for the detection of SARS-CoV-2. It is best to check the FDA website for the latest serological tests with an EUA. The opinions expressed are those of the author, not of the Texas Medical Association.
Over the past few weeks, I have grown increasingly concerned about the current offering of serology testing for SARS-CoV-2, the virus responsible for COVID-19. Given the lack of clear guidance surrounding the issues of serology testing, particularly given the unique issues around the SARS-CoV-2 pandemic, I feel compelled to write this message.
With the use of a blood sample, serology testing can identify antibodies produced against the virus. Serology testing is different from molecular testing (such as PCR), which is used to diagnose active infection by detection of segments of viral RNA, typically via a nasopharyngeal swab. In the near future, serology testing will be utilized several ways:
- to help determine the prevalence of SARS-CoV-2 in the population,
- to identify individuals in the community who are immune,
- to help delineate the phase of the infection (recent past vs. distant past),
- to identify donors for therapeutic plasma, and
- possibly to help with return to work decisions.
Serology testing can identify whether antibodies are being made, and in addition, which type of antibodies. The most common serology testing involves identification of IgM and IgG antibodies. IgM is the first antibody made following infection. Therefore, soon after infection, only IgM will be present at detectable levels. This is followed several days later by production of IgG antibodies. At this next phase, both IgM and IgG will be present at detectable levels. IgM antibody production will then begin to wane, leaving IgG as the only detectable antibody. What we know about SARS-CoV-2 serology testing so far is that approximately 50% of patients are seropositive for IgM by day 7 after symptom onset. Approximately 85% of patients are seropositive for IgM and approximately 50% are positive for IgG by day 14 after symptom onset. Serology testing should never be used to make a diagnosis of active COVID-19 since antibody production is not present at detectable levels until several days (often more than a week) after the onset of symptoms. Only molecular testing should be used to make the diagnosis of active COVID-19.
Serology testing is currently in development. As of April 14th, the U.S. Food and Drug Administration (FDA) has granted emergency use authorization (EUA) to one antibody test for the detection of SARS-CoV-2. Yes … one. Anyone who is marketing you a serology test that is claiming to be FDA approved might be doing so illegally.
Serology testing will play a key role in multiple aspects of the pandemic. This is particularly why serology testing must be as accurately as possible. Development of accurate, reliable, and validated serology testing is more laborious than development of molecular testing. Unfortunately, the FDA made the decision several weeks ago to allow unvalidated serology tests to be sold in the U.S. without first undergoing a review of their data. The vast majority of these tests are point of care (POC). The FDA had minimal requirements for companies to sell these tests. The FDA required those who are offering these tests to disclose: 1) the test has not been reviewed by the FDA; 2) negative results do not rule out SARS-CoV-2 infection, particularly in those who have been in contact with the virus, and follow-up testing with a molecular diagnostic should be considered to rule out infection in these individuals; 3) positive results may be due to past or present infection with non-SARS-CoV-2 coronavirus strains, such as coronavirus HKU1, NL63, OC43, or 229E; and 4) results from antibody testing should not be used as the sole basis to diagnose or exclude SARS-CoV-2 infection or to inform infection status. Those disclosures alone should make you pause before offering serology testing at this time.
The FDA required these disclosures in order to warn physicians offering the test and patients receiving the test that the results have not been reviewed by the agency, and therefore may be unreliable. How inaccurate are some of these tests? Both Spain and the UK have made public that the POC serology testing they had purchased were inaccurate, and the tests were returned to the manufacturer. A negative result may be a result of that particular test being insensitive to detecting SARS-CoV-2 antibodies. A positive result may be a result of the presence of cross-reactivity with antibodies to more common, non-SARS-CoV-2 strains of coronavirus. A false negative result can be a missed opportunity to make a diagnosis. A false positive result can be disastrous, since the patients will leave the test counseling thinking that they are no longer susceptible to SARS-CoV-2 infection, possibly resulting in discontinuation of social distancing measures and other means of protecting themselves from infection.
Serology testing that proceeds through the FDA emergency review authorization will be more reliable since there will have at least been a review of their data, including the sensitivity and specificity of the test. Ideally, testing data would not only be reviewed by the FDA, but would also undergo further validation by independent labs using a real world setting. The good news is that there will be several serology tests that will complete the FDA EUA process over the next few weeks.
One other item to consider is the current low prevalence of SARS-CoV-2 in most areas. The current prevalence of patients who have had SARS-CoV-2 remains very low in Austin. As of April 14, there have been 900 cases identified in Travis County. Even if one assumed that the actual prevalence of SARS-CoV-2 infections in Travis County were 10 times the reported number, we would not yet have a county-wide prevalence of 1%. This means that, even a relatively accurate test with a high specificity may result in as many false positives as true positives in the current low prevalence setting of Travis County.
Serology testing will play a significant role in the COVID-19 pandemic. However, that role is not now … and not with current, largely unreviewed, serology testing.
The issues surrounding COVID-19 are numerous, with a degree of complexity not previously seen in our lifetime. I could not ask for a better medical community to fight against COVID-19 than the one in Travis County. Thank you for your time.
Brian Metzger, MD is a member of the Austin Public Health COVID-19 Expert Advisory Panel and the infectious disease consultant to the Travis County Medical Society ED/EMS Advisory Committee. He practices at Austin Infectious Disease Consultants.