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COVID-19 Severity Biomarker Candidates Revealed in RNA Sequencing Study

SARS-CoV-2 SEM NIAID

NEW YORK — Changes in blood RNA levels reflecting increased neutrophil activity and decreased T cell activity could serve as biomarkers for COVID-19 severity, a new RNA sequencing-based study has found.

There have been more than 357 million global cases of COVID-19, which can range from largely asymptomatic to flu-like to severe, but there is no way to predict which patients might have those various outcomes.

Researchers from George Washington University sequenced whole-blood RNA from COVID-19 patients exhibiting a range of symptoms. As they reported in PLOS One, they found hundreds of genes that were differentially expressed between COVID-19 patients and healthy individuals as well as genes that were differentially expressed between COVID-19 patients with mild and severe symptoms. Increased symptom severity was linked to an increase in neutrophil activity and a decrease in T cell activity.

These changes, the researchers said, could potentially act as biomarkers to predict which patients might have more severe disease and need more aggressive treatment. "This test could prove very valuable during the pandemic, especially as variants continue to spread and doctors need to be confident in identifying the problem and providing effective treatment," senior author Timothy McCaffrey, professor of medicine at GW, said in a statement.

He and his colleagues analyzed whole-blood samples from 38 patients with COVID-19. Seven patients were PCR-positive for SARS-CoV-2 but were admitted to the hospital for other reasons and had no or mild symptoms; seven patients were PCR-positive for SARS-CoV-2 and had symptoms consistent with COVID-19 but did not need to be intubated or treated with vasopressors; and 24 patients had severe disease as they were PCR-positive for SARS-CoV-2 and either needed to be intubated or treated with vasopressors or died.

By comparing the transcriptomes of the COVID-19 patients to a set of healthy individuals, the researchers identified 758 genes that were differentially expressed. In particular, transcripts with increased expression tended to be involved in the innate immune response, while those with decreased expression were involved in the adaptive immune response, T cells, and TOR signaling.

The researchers further compared the transcriptomes of patients with mild COVID-19 to those with severe disease to again uncover differentially expressed genes, especially a marked increased expression of neutrophil RNAs and decreased expression of T cell-related transcripts. The expression of neutrophil defensin 1, or DEFA1, was especially increased.

Additionally, CD15+ neutrophils were present in increased abundance in COVID-19 patients and, after controlling for their boosted numbers, exhibited about a fivefold higher elastase activity per cell. This increase in elastase activity in CD15+ neutrophils was further associated with disease severity, as it was even higher among patients who needed vasopressor treatment.

The findings suggested to the researchers that increased neutrophil and decreased T cell activity were associated with COVID-19 severity. Drawing off that, they further said that blood DEFA1 RNA levels and neutrophil elastase activity could be biomarkers of host immunity following COVID-19 infection and potentially help predict disease severity.

"Beyond the current pandemic, our technique would be able to detect any infection with a high degree of accuracy," McCaffrey said. "That has applications for all sorts of conditions wherein doctors diagnosing patients need to quickly rule in or rule out whether they are dealing with an infection or something else."

If further testing indicates their approach is effective, McCaffrey and his colleagues plan to seek an Emergency Use Authorization from the US Food and Drug Administration, though they noted that could take months.

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