IL-1, IL-6 Inhibition in Patients With COVID-19 and Hyperinflammation Assessed

patient in ICU with mechanical ventilation
Researchers compared IL-1 and IL-6 inhibition vs standard management in hospitalized patients with COVID-19, respiratory insufficiency, and hyperinflammation.

In patients with COVID-19 hospitalized with respiratory insufficiency and hyperinflammation, interleukin (IL)-1 inhibition, but not IL-6 inhibition, may be associated with a significant reduction in mortality, according to study results published in Lancet Rheumatology.

Some patients with COVID-19 develop a maladaptive, systemic, life-threatening hyperinflammatory response to SARS-CoV-2, which is associated with a poor prognosis. Although IL inhibitors have been used as treatment in COVID-19, little is known about the comparative effectiveness of the different IL inhibitors in this population.

Researchers sought to compare the effectiveness of IL-1 inhibition (with anakinra) and IL-6 inhibition (with tocilizumab or sarilumab) in patients with severe COVID-19 and hyperinflammation.

The cohort study was conducted at San Raffaele Hospital in Milan, Italy. Participants who were admitted to the hospital with respiratory insufficiency, defined as the ratio of partial pressure of oxygen to the fraction of inspired oxygen of 300 mmHg or less, and hyperinflammation, defined as serum C-reactive protein (CRP) concentration of 100 mg/L or more or ferritin concentration of 900 ng/mL or more, were included in the study. The primary study endpoint was survival. Secondary endpoints included a composite of death or mechanical ventilation (an adverse clinical outcome). Clinical outcomes were compared using multivariable Cox regression analysis.

A total of 392 study participants were enrolled in the study between February 25, 2020, and May 20, 2020. Among them, 275 participants did not receive treatment with any IL inhibitors, 62 received the IL-1 inhibitor anakinra, and 55 received an IL-6 inhibitor (29 received tocilizumab and 26 received sarilumab). All patients also received standard care. Compared with individuals who did not receive treatment with any IL inhibitors, those who received IL-inhibitor treatment were younger, presented with higher lactate dehydrogenase (LDH) concentrations at baseline, and received noninvasive mechanical ventilation more frequently.

According to multivariable analysis, patients who received treatment with the IL-1 inhibitor anakinra had a significantly reduced risk for mortality compared with those who did not receive treatment with IL inhibitors (hazard ratio [HR], 0.450; 95% CI, 0.204-0.990; P =.047); however, patients who received treatment with IL-6 inhibitors did not have a reduced mortality risk (HR, 0.900; 95% CI, 0.412-1.966; P =.79). Further, no difference in risk for adverse clinical outcomes was reported among patients who received IL-1 inhibition (HR, 0.866; 95% CI, 0.482-1.553; P =.63) and those who received IL-6 inhibition (HR, 0.882; 95% CI, 0.452-1.722; P =.71) compared with those who did not receive IL inhibitors.

Regarding elevated CRP concentrations, study participants who received IL-6 inhibitors exhibited a significantly reduced risk for mortality (HR, 0.990; 95% CI, 0.981-0.999;

P =.031) and adverse clinical outcomes (HR, 0.987; 95% CI, 0.979-0.995; P =.0021) compared with those who did not receive treatment with IL inhibitors. Regarding decreasing serum LDH levels, study participants who received treatment with the IL-1 inhibitor and those who received treatment with IL-6 inhibitors had a decreased risk for mortality. In contrast, increasing LDH concentrations in patients who received IL inhibition were associated with an increased risk for mortality (HR, 1.009; 95% CI, 1.003-1.014; P =.0011 with IL-1 inhibition and HR, 1.006; 95% CI, 1.001-1.011; P =.028 with IL-6 inhibition), as well as with an adverse clinical outcome (HR, 1.006; 95% CI, 1.002-1.010; P =.0031 with IL-1 inhibition and HR, 1.005; 95% CI, 1.001-1.010; P =.016 with IL-6 inhibition), compared with patients who did not receive IL inhibition.

Limitations included those inherent with observational studies, limited available data on certain variables with prognostic relevance in COVID-19, and the risk for potential confounding.

Overall, although IL-1 inhibition, but not IL-6 inhibition, was associated with significantly lower rates of mortality in hospitalized patients with severe COVID-19, IL-6 inhibition was effective in a subgroup of patients with high CRP concentrations. In addition, both the IL-1 and IL-6 inhibitors were effective in patients with low concentrations of LDH. However, the researchers concluded, “Validation of these study findings, particularly concerning the efficacy of IL-1 inhibition in COVID-19, requires controlled investigations.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Cavalli G, Larcher A, Tomelleri A, et al. Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study. Lancet Rheumatol. Published online February 3, 2021. doi:10.1016/S2665-9913(21)00012-6