Is targeting one cytokine better than another in treating COVID-19?

While it has been clear from early on in the COVID-19 pandemic that some severe cases are characterised by a hyperinflammatory state, targeting the cytokines involved in that inflammation has proven to be remarkably complicated. Now, new research shows that inhibition of IL-1, but not of IL-6, is associated with a reduction in mortality in most patients, while IL-6 inhibition does have an effect in certain subsets.

Trials of IL-6 inhibition with tocilizumab and sarilumab, and of IL-1 inhibition with anakinra, have offered up conflicting and often disappointing results. The new trial, led by Dr Giulio Cavalli of IRCCS San Raffaele Scientific Institute in Milan, is the first to compare the efficacy of the two approaches. The results were published in The Lancet Rheumatology.

The study included 392 patients admitted to the hospital with COVID-19, respiratory insufficiency, and hyperinflammation, defined as serum C-reactive protein concentration of at least 100 mg/L or ferritin concentration of 900 ng/mL or more. Of those, 62 received anakinra, and 55 received one of the two IL-6 inhibitors (29 received tocilizumab, 26 received sarilumab).

Compared to patients who received no interleukin inhibitor, those receiving IL-1 inhibition had a significantly reduced risk of death, with a hazard ratio of 0.450 (95% CI, 0.204-0.990; p = .047). Those treated with IL-6 inhibition, however, saw no such benefit (HR 0.900, 95% CI, 0.412-1.966; p = .79).

IL-6 inhibition did offer a mortality benefit, however, with increasing C-reactive protein levels, compared to patients who did not receive any interleukin inhibition. Both types of cytokine inhibition improved mortality outcomes with decreasing concentrations of serum lactate dehydrogenase.

The authors noted that IL-1 is found upstream of IL-6 in inflammatory cascades, and decreases in IL-6 concentration typically follow effective IL-1 inhibition. “Such a hierarchical association might account for the more robust clinical benefit of IL-1 inhibition observed in our investigation,” the authors wrote. “The current analysis reveals new information about the profile of the optimal candidates for treatment with interleukin inhibitors, which might aid clinical decision making and instruct further study design.”

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