Exploring a Phenotype of COVID-19-Associated Hyperinflammation


An observational study in the United Kingdom supports the concepts of a hyperinflammation phenotype for severe COVID-19 cases and could help guide risk assessment, precision medicine, and trial design.

Patients with a phenotype of COVID-19-associated hyperinflammation could be at greater risk of poor clinical outcomes, including the need for escalated respiratory support and death, according to a new observational study, published in The Lancet Rheumatology.

Investigators from the United Kingdom used C-reactive protein (greater than 150 mg/L or doubling within 24 hours from greater than 50 mg/L) and ferritin values (greater than 1500 µg/L) to define the phenotype, which they referred to as COV-HI.

The study was led by Jessica Manson, PhD, department of rheumatology, University College London Hospitals NHS Trust and Colin Crooks, PhD, Nottingham Digestive Diseases Center.

“Our work builds on, and contributes to, the evidence enabling risk prediction models for people with COVID-19,” the authors wrote.

The study involved 269 patients admitted to University College London Hospitals and Newcastle upon Tyne Hospitals between March 1 and March 31. Overall, 90 patients (33%) met the COV-HI criteria at admission, and mortality was higher among them (36 [40%] of 90 patients) than those who didn’t meet the COV-HI criteria at admission (46 [26%] of 179). Those who met the criteria also had a greater risk of next-day death or need for escalated respiratory support from supplemental oxygen to non-invasive ventilation or intubation (combined endpoint; hazard ratio 2·24 [95% CI 1·62—2·87]). These poor clinical outcomes among patients with COV-HI were seen despite a lower median age (66 years versus 71) and a lower Charlson Comorbidity Index score 1 [0–2] vs 2 [0–3]) than those without COV-HI.

Among the study participants, 91 patients (34%) were not eligible for escalation of respiratory support based on their treatment plans. Ineligible patients who met COV-HI criteria had a higher mortality (68%) than those who were eligible for escalated care (29%). Possible explanations for this difference could include increased frailty or comorbidities among those who were ineligible for escalated care or improved outcomes due to escalated care among those eligible.

“In clinical practice, it would be easy to flag patients with the COV-HI phenotype who, for example, would require close monitoring for the need to escalate to a critical care environment,” an associated comment by Kiran Reddy, department of anaesthesiology and intensive care medicine at Children’s University Hospital in Dublin, Ireland, and colleagues said. “It is worth noting, however, that the definition of hyperinflammation was arbitrarily defined by the authors, potentially introducing confirmation bias, and it would be useful to see these findings reproduced in independent cohorts.”

The study identified hyperinflammation as uncontrolled, self-perpetuating and tissue-damaging inflammatory activity marked by C-reactive protein and ferritin values. A larger study could help answer whether there are subtypes of hyperinflammatory disease caused by COVID-19 with different biomarker thresholds.

“The presence of markers of hyperinflammation in this study was associated with the need for escalation of respiratory support and the risk of death in people with COVID-19,” the study authors wrote. “These findings support the concept that a high-risk inflammatory phenotype (COV-HI) exists and might be associated with increased mortality. The COV-HI criteria need to be validated in a larger cohort but have the potential to be developed as an easy bedside risk assessment tool and could be important for patient stratification and optimal trial design.”

Hyperinflammation has been a key focus of research in the fight against COVID-19. Recent studies have explored the use of interleukin-6 inhibitors to treat critically ill COVID-19 patients with cytokine release syndrome. Aakriti Gupta, MD, a cardiologist at New York’s Columbia University Irving Medical Center, recently told Contagion® about her firsthand experience treating patients experiencing hyperinflammation.

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