Biomarker analysis reveals clues to COVID-19 disease severity

Predicting disease severity from a SARS-CoV-2 infection has been an elusive but critical need in addressing the COVID-19 pandemic, as some patients experience mild symptoms while others develop fatal complications. As scientists try to determine what contributes to infection levels and mortality, several medical signs are providing potential answers.

The Neutrophil Monitoring Laboratory and the Immunological Monitoring Laboratory at the Frederick National Laboratory for Cancer Research (FNL) have been working with the National Institute of Allergy and Infectious Diseases (NIAID) since 2020 to find these answers as part of a large NIAID COVID-19 Consortium.

“Our body’s own immune and inflammatory responses to SARS-CoV-2 appear to contribute to disease severity,” said Douglas Kuhns, Ph.D., head of both FNL laboratories involved in the biomarker study for the consortium. “Measurement of these responses, particularly those that may be overly exuberant, may provide some insight into areas of therapeutic intervention.”

Some immune hormone levels point to severe disease

The laboratories analyzed levels of 66 biological markers, or biomarkers, in biospecimens collected from 175 patients with COVID-19 ranging from mild to critical disease severity as well as healthy volunteers. Their analysis of more than 1,400 samples revealed 12 immune hormones that, when elevated, were independently associated with mortality.

12 biomarkers found associated with mortality:

CCL2, IL-15, soluble ST2 ST2, NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10

The dataset provides a basis for additional studies being performed on this cohort of patients with COVID-19. Correlations between multiple biomarker levels versus patient co-morbidities, therapies, among other endpoints are still being mined to determine if additional insights can be extracted from this extensive dataset. So far, the work at FNL has contributed to a study in CellPress and another in JCI Insight.

Ongoing NIAID collaboration prompted move into COVID-19 work

For several years, the Neutrophil Monitoring Laboratory and the Immunological Monitoring Laboratory have been measuring cytokine profiles in patients with various immune deficiencies for investigators in the Laboratory of Clinical Immunology and Microbiology and Laboratory of Infectious Diseases within NIAID.

“Our previous experience in biomarker analyses and close collaborations with the NIAID investigators provided the impetus for the expansion of our work scope into this project,” Kuhns said.

Kuhns’ laboratories processed samples and used 10 different multiplex assays. The laboratory teams tracked control samples and compiled data into a single database merged with the vast clinical data associated with each patient. Many of the samples exceeded the working range of a given plate and had to be repeated at increased dilution.

“A major problem was a limited sample volume, so much effort went into coordinating multiple plates in a single day to minimize sample waste and avoid multiple cycles of freeze-thaw,” Kuhns said.

Kuhns said they are continuing the research with more recent COVID-19 samples from a validation cohort from New Jersey and samples from a cohort of Italian children with multi-system inflammatory syndrome. They are also collaborating with investigators in the National Institutes of Health to measure even more extensive cytokine/biomarker panels in paired plasma and lung samples from patients with COVID-19.

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