Is Cytokine Blockade an Effective Therapeutic Strategy for COVID-19?

Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells.
Can blockade of the interleukin-1 or IL-6 pathways shorten the time to clinical improvement in patients with COVID-19 or hypoxic respiratory failure?

Researchers found that agents targeting IL-1 and IL-6 failed to truncate time to clinical improvement in patients exhibiting COVID-19, hypoxic respiratory failure, decreased Systematic Organ Failure Assessment (SOFA) score, and low baseline mortality risk. These were among the findings of a study published in the Lancet Respiratory Medicine.

In the current prospective, randomized-controlled trial, Belgian researchers assigned 112 patients to IL-1 blockade and 230 patients to no IL-1 blockade, as well as assigning 227 patients to IL-6 blockade and 115 to no IL-6 blockade. Of the 342 patients included in the study, 77% were male, the median age was 65 years, and the median SOFA score was 3.

During the first randomization, participants received no IL-1 blockade or were administered subcutaneous anakinra once daily (100 mg) for 28 days or until discharge. During a second randomization, participants received either no IL-6 blockade or were administered a single dose of siltuximab (11 mg/kg) intravenously or a single dose of tocilizumab (8 mg/kg) intravenously.

The median time to clinical improvement was 12 days in the IL-1 blockade arm vs 12 days in the no IL-1 blockade arm, whereas this measure was 11 days vs 12 days in the IL-6 blockade and no blockade arms, respectively. In total, 55 patients died during the course of the trial, but there was no observed differences among treatment groups. Severe adverse events and infections were comparable among treatment groups.

The current trial does not buoy the blocking of IL-1 or IL-6 in COVID-19 patients, although the researchers cite the need for more research to assess whether biomarkers could identify responders. “Although IL-6 blockade in combination with corticosteroids might be beneficial in the most severely ill patients, it seems less effective when used early in the disease course or in populations with low to moderate mortality,” stated the authors.

The results of the current study are contrary to similar studies. “Our results are clearly at odds with data from the platform trials REMAP-CAP and RECOVERY, despite the fact that patient severity categories and timing of intervention were largely similar,” the investigators noted.

The investigators also said that bigger studies or meta-analyses that reflect individual patient characteristics are needed to determine which patient subsets are at risk of increase death and may derive benefit from cytokine blockade.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Declercq J, Van Damme KF, De Leeuw E, et al. Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-aid): a factorial, randomised, controlled trial. Lancet Respir Med. 2021;9(12):1427-1438. doi:10.1016/S2213-2600(21)00377-5