Infectious Disease

IL-1 Inhibitors Related to a “Vital Discount” in COVID-19 Mortality

February 23, 2021

3 min read

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Cavalli reports on consulting fees from Sobi, Roche and Sanofi. In the study you will find all relevant financial information from all other authors.

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Interleukin-1 inhibitors have been linked to a “significant reduction” in mortality in patients hospitalized with COVID-19, respiratory failure and hyperinflammation, according to data published in The Lancet Rheumatology.

However, this association was not found with IL-6 inhibition, which was only effective in patients with “significantly high” C-reactive protein concentrations, the researchers found.

The patient has connected to an IV in a hospital bed

Interleukin-1 inhibitors have been reported to be linked to a “significant reduction” in mortality in patients hospitalized with COVID-19, respiratory failure and hyperinflammation. Source: Adobe Stock

“A subgroup of patients with severe COVID-19 develop a life-threatening hyperinflammatory response to the virus that is similar to the cytokine storm that develops after treatment with antigen receptor chimeric T cells or in macrophage activation syndrome with the release of interleukin (IL). 1, IL-6, IL-18 and interferon- “, wrote Dr. Giulio Cavalli of the Vita-Salute San Raffaele University in Milan, Italy, and colleagues. “To reduce the number of deaths in patients with COVID-19 and hyperinflammation, treatment with cytokine-blocking biologics has been suggested, with IL-6 and IL-1 being the most promising targets.”

“Currently, the overall evidence available speaks against the use of IL-6 inhibitors to treat COVID-19,” they added. “However, crucial questions regarding the role and therapeutic potential of IL-1 inhibition in COVID-19 remain open – in particular, whether IL-1 inhibition offers an advantage over standard management, whether IL-1 inhibition is more effective as IL-6 inhibition and how to identify those individuals who are most likely to benefit (or worsen) from treatment. “

To compare the effects of IL-1 and IL-6 inhibitors in patients with COVID-19, respiratory failure, and hyperinflammation, Cavalli and colleagues conducted a cohort study of people admitted to the San Raffaele Hospital. For this study, respiratory failure was defined as the ratio of partial pressure of oxygen to the amount of inhaled oxygen of 300 mm Hg or less. In the meantime, hyperinflammation has been identified based on a serum C-reactive protein concentration of 100 mg / l or more or a ferritin concentration of at least 900 ng / ml.

In total, the study included 392 patients who were enrolled between February 25, 2020 and May 20, 2020. Among these participants, 62 received the IL-1 inhibitor anakinra (Kineret, SOBI) while 55 received an IL-6 inhibitor – 29 received tocilizumab (Actemra, Genentech) and 26 were treated with sarilumab (Kevzara; Regeneron, Sanofi). A total of 275 received no interleukin inhibitors. The primary endpoint was survival, with a composite secondary endpoint of death or mechanical ventilation being an adverse clinical outcome.

All participants received a standard of care. The researchers used multivariable Cox regression analysis to compare the clinical outcomes between the interleukin treatment groups and to account for the baseline differences. They also used interaction tests to examine the likelihood of survival based on C-reactive protein or lactate dehydrogenase levels.

According to the researchers, the multivariate analysis found that patients who received IL-1 inhibitors had a significantly reduced risk of mortality (HR = 0.45; 95% CI, 0.204-0.99) compared to patients without interleukin inhibitors. However, patients in the IL-6 inhibitor group did not (HR = 0.9; 95% CI, 0.412-1.966). The multivariable analysis also showed that there was no difference in the risk of adverse clinical outcomes in patients treated with IL-1 (HR = 0.866; 95% CI, 0.482-1.553) or IL-6 (HR = 0.882; 95 % CI, 0.452-1.722) inhibitors compared to patients who did not receive interleukin therapy.

However, to increase the C-reactive protein concentrations, the participants treated with IL-6 inhibitors showed a significantly reduced risk of mortality (HR = 0.99; 95% CI, 0.981-0.999) and undesirable clinical results (HR = 0.987; 95)% CI , 0.979-0 * 995) compared with those without interleukin inhibitors.

With decreasing concentrations of serum lactate dehydrogenase, patients in both the IL-1 and IL-6 inhibitor groups had a reduced risk of mortality. At increasing concentrations, however, participants in both groups were associated with an increased risk of mortality (IL-1 HR = 1.009; 95% CI, 1.003-1.014 and IL-6 HR = 1.006; 95% CI, 1.001-1.011) and adverse clinical outcomes ( IL-1 HR = 1.006; 95% CI, 1.002-1.010 and IL-6 HR = 1.005; 95% CI, 1.001-1.010) compared to those who received no interleukin inhibitors.

“IL-1 inhibition, but not IL-6 inhibition, has been associated with a significant reduction in mortality in a large cohort of patients hospitalized with COVID-19 and hyperinflammation,” wrote Cavalli and colleagues. “IL-6 inhibition was only effective in a subset of patients with markedly high C-reactive protein concentrations, while both IL-1 and IL-6 inhibition were more effective in patients with low lactate dehydrogenase concentrations. The validation of these study results, in particular with regard to the effectiveness of IL-1 inhibition in COVID-19, requires controlled studies. “

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