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An inflammatory signature may hold a clue to predicting both COVID-19 severity and poor clinical outcomes, researchers found.

A laboratory study that took serum samples of nearly 1,500 COVID-19 patients at hospital admission found that interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α levels predicted both COVID-19 severity and death, after adjusting for other laboratory inflammation markers, as well as hypoxia and disease severity, reported Sacha Gnjatic, PhD, of Icahn School of Medicine at Mount Sinai in New York City, and colleagues.

These patients were followed for up to 41 days after admission, and the authors validated their results in a smaller cohort of 231 patients, and published their findings in

They specifically noted that COVID-19-related cytokine response was different from the traditional cytokine storm tied to sepsis and in cancer patients treated with chimeric antigen receptor (CAR) T-cell therapy, with "sustained elevated cytokine levels over days and weeks, and relative absence of coordination between cytokines."

Thus, they proposed that serum IL-6 and TNF-α "should be considered in the management and treatment of patients with COVID-19 to stratify prospective clinical trials, guide resource allocation and inform therapeutic options."

Researchers explained their rationale, noting that in addition to viral damage, uncontrolled inflammation contributes to disease severity. Patients with severe COVID-19 generally have higher levels of C-reactive protein, ferritin, and D-dimer, high neutrophil-to-lymphocyte ratio, and increased levels of inflammatory cytokines and chemokines, they said.

While IL-6 inhibitors have shown mixed results in clinical studies, the authors noted TNF-α "is important in nearly all acute inflammatory reactions," and TNF-α blockade has been used in autoimmune diseases, and could be a potential therapeutic approach "to reduce organ damage in patients with COVID-19."

They also noted monoclonal antibodies targeting cytokines are currently in clinical trials, but given potential side effects, "there is an urgent need to identify biomarkers that can accurately predict which patients will deteriorate from an unchecked inflammatory response and help guide rational targeted immunomodulatory therapeutic strategies."

For their study, the authors examined data from 1,484 patients hospitalized with confirmed COVID-19 infection, from March 21 to April 28. Patients were followed from the day of hospitalization to the day of discharge or death. They measured serum levels for four pathogenic cytokines: IL-6, IL-8, TNF-α and IL-1β, to assess correlation between disease severity and survival.

Of the these patients, only 1,257 had a documented or presumptive positive test result for SARS-CoV-2, while the remaining 167 could not be confirmed. Patients were a median age of 60 to 63, more than half were men, and from 38% to 45% were Hispanic, and 22% to 28% were Black. The most common comorbidity was hypertension, in 33% to 40% of patients. Median time from first cytokine test to last follow-up was 8 days.

Of 1,317 patients with a documented or presumed positive SARS-CoV-2 test, 20% died, while of 167 that could not be confirmed, about 8% died.

In unadjusted analysis, IL-6, IL-8, and TNF-α were significantly elevated in COVID-19 patients versus healthy donors and CAR T-cell-treated patients with no cytokine release syndrome.

Examining demographics, men had higher levels of IL-6 than women, and levels of IL-6, IL-8, and TNF-α increased with age. In multi-regression models, chronic kidney disease was the only comorbidity significantly associated with elevated cytokine levels, with elevated TNF-α in patients with diabetes and hypertension explained by other variables, the authors said.

In order to look at the effect of medication and treatment on cytokine levels, they also examined a subset of 244 patients with more than one assay performed. They found patients treated with corticosteroids and remdesivir showed "a rapid and gradual reduction" in IL-6 over time, but there was no effect on TNF-α. Not surprisingly, dexamethasone had the highest reduction effect on IL-6.

The authors confirmed their findings that cytokine patterns are predictive of COVID-19 survival and mortality, as well as disease severity, in the validation cohort. They suggested confirming their findings in a prospective study, but added they hope to build a predictive model using high-dimensional assays in order to aid clinical decision-making.

"We think that these practices will bring cytokine measurements to standard of care in prognosticating and monitoring patients with COVID-19," they concluded.

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