Simpler virus testing approach could reduce unnecessary PCR tests in high-risk settings

The COVID-19 pandemic yielded important advances in testing for respiratory viruses, but it also exposed important unmet needs in screening to prevent the spread of infections in high-risk settings.

While PCR (polymerase chain reaction) tests are the gold standard for detecting viral infections, they remain a challenge for screening large numbers of people in places vulnerable to outbreak - such as health care centers and nursing homes - due to high costs and the fact that different tests are required for each virus.

A new Yale study, however, finds that an alternate strategy - using a nasal swab to screen for an antiviral protein produced by the body as a defense against infection - can be an effective method for ruling out respiratory infections, limiting PCR testing only to those most likely to be infected, at a fraction of the cost. 

The study was published online on June 20 in The Lancet eBiomedicine. 

By comparing the results from both PCR tests and screenings for the immunological biomarker in more than 1,000 people (including children and adults, some who had a viral infection, and some who did not), the researchers found that using the less-costly screening test would enable a 10-fold or greater reduction in the need for PCR tests.

This new approach, the findings suggest, may offer a valuable strategy for managing outbreaks and for routine screenings to prevent virus transmission in high-risk settings, said Ellen F. Foxman, an associate professor of laboratory medicine and immunobiology at Yale School of Medicine (YSM) and senior author of the study. 

"If you wanted to screen every person who walked through the door for every respiratory virus, it would be difficult and prohibitively expensive," said Foxman. "But we also know that in some settings with close quarters - like military settings, health care and rehab facilities, or assisted living centers - an infected person who might be asymptomatic can spread the infection to others, including people at high risk from getting very sick from the virus.

"So the question was, how do you triage testing in these settings? Most people aren't going to have viruses, so you don't want to do sophisticated, expensive tests for them. Ideally you want a simple, inexpensive test that allows you to say, 'OK, you don't have a virus, you can go on your way,' and then focus further testing on the people who need it." 

First authors of the study were Julien Amat, a postdoctoral associate in Foxman's lab, and Sarah Dudgeon, a Ph.D. student in the research group of Wade Schulz, an associate professor of laboratory medicine at Yale. The study also involved a team of other collaborators in Yale's Department of Laboratory Medicine.

For the study, the researchers drew on an observation made by Foxman's lab in 2017: Nasal swabs taken from patients with suspected respiratory infections revealed that among those testing positive for viruses with PCR tests, antiviral defenses had been activated. This, they concluded, might be useful to indicate the presence of a virus. 

In the current study, they focused on the protein CXCL10 (a cytokine produced in the nasal passage in response to multiple respiratory viruses) using 1,088 swab samples collected from COVID-19 screening tests or clinical settings in Yale New Haven Hospital. They then performed a series of analyses - including a comparison with test results from PCR tests conducted using the same swabs, and mathematical modeling to predict resource savings from using the test in different scenarios.

The biomarker performed well in predicting viral infections regardless of patient age, sex, or other demographics, Foxman said. 

What's more, the research team utilized electronic records to evaluate those instances when the results from biomarker screening and the PCR tests did not align (when, for instance, the biomarker test was negative, and the PCR test was positive), and discovered factors that might contribute to the mismatches.

For example, the biomarker screen was less likely to identify a viral infection in individuals who were taking certain immunosuppressive cancer drugs. Likewise, they found that among individuals who'd tested positive for viral infections with PCR tests, but for whom the viral loads were so low that they were barely detectable, the biomarker screening was less likely to produce a positive test.

Overall, the researchers found that the biomarker method, if used to screen populations with low virus prevalence (for instance, hospital staff workers exhibiting no symptoms of infection), screening would reduce the need for 92% of PCR tests. 

So you could do less than one-tenth of the PCR tests and still identify the people with viral infections. This strategy could have been useful during the early COVID-19 pandemic, when our hospital was sometimes testing 10,000 or more people per week." The researchers estimate that the cost of commercial PCR tests are roughly five to 15 times greater than the cost of biomarker tests. It's exciting to consider the possible applications."

Ellen F. Foxman, associate professor of laboratory medicine and immunobiology at Yale School of Medicine 

The study was funded by the inaugural competition of the Yale-New Haven Health System (YNHHS) Innovation Award, an initiative that supports YNHHS employees and Yale faculty working on promising ideas with potential for health care impact, and the National Institutes of Health. 

Other authors of the study are Julien A. R. Amat, a postdoctoral associate at YSM and member of the Foxman lab; Sarah N. Dudgeon, a Ph.D. candidate in the Schulz research group; Nagarjuna R. Cheemarla, a former postdoctoral associate at YSM; Timothy A. Watkins, a graduate student and member of the Foxman lab; Alex B. Green, a former resident at Yale New Haven Hospital who is now a fellow at the Children's Hospital of Philadelphia; H. Patrick Young, an associate research scientist in the Department of Laboratory Medicine; David R. Peaper, an associate professor of laboratory medicine at YSM; Marie L. Landry, professor of laboratory medicine and of medicine (infectious diseases) at YSM; and Wade Schulz, an associate professor of laboratory medicine at YSM.