Anakinra dampens cytokine hyperinflammation in COVID-19

Tuesday, 12 May 2020

The biological DMARD anakinra (Kineret) may have a role in treating critically ill COVID-19 patients when there is a shortage of ventilators, according to Italian researchers.

The interleukin (IL)-1 receptor antagonist was associated with improved survival and reduced markers of inflammation when used at high doses in patients with acute respiratory distress syndrome and hyperinflammation, they report in a retrospective study Lancet Rheumatology.

They say the drug was used as a stop-gap emergency measure for critically ill patients at the San Raffaele Hospital, Milan at a time when there was a shortage of ICU beds for mechanical ventilation.

The patients selected for anakinra use had ARD and hyperinflammation as defined as an increase in either the serum inflammation marker C-reactive protein (CRP ≥100 mg/L) or ferritin (≥900 ng/mL), or both. They were being managed with  non-invasive ventilation with CPAP but were not being treated with steroids or other anti-inflammatory drugs.

An initial attempt to use subcutaneous lower doses of anakinra was abandoned when there was little effect on CRP levels. At the height of the pandemic in March 2020, 29 patients at the hospital received high-dose intravenous anakinra (10mg/kg a day).

At 21 days, anakinra treatment was associated with reductions in serum CRP and progressive improvements in respiratory function in 21 (72%) patients. Five (17%) patients were on mechanical ventilation and three (10%) died.

In a control group of 16 patients who received  standard treatment, eight (50%) showed respiratory improvement at 21 days; one (6%) patient was on mechanical ventilation and seven (44%) died.

Overall, at 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (p=0·009).

Mechanical ventilation-free survival was 72% in the anakinra group versus 50% in the standard treatment group (p=0·15).

Bacteraemia occurred in four (14%) of the patients receiving high-dose anakinra and two (13%) of 16 patients receiving standard treatment.

The study investigators said the ani-cytokine effect of anakinra as approved in CAR T-cell therapy may also be of benefit for patients with COVID-19 disease when health services are overwhelmed.

“This effect allowed us to postpone or avoid intubation in most patients. Treatment was well tolerated, and discontinuation was not followed by relapses in systemic inflammation or respiratory dysfunction,” they noted.

Compared to other anti-cytokine treatments, anakinra has an excellent safety record and its short half life allows prompt discontinuation, making it a controllable off-label treatment to dampen detrimental inflammation, they added.

“Of note, previous studies indicated that IL-1 inhibition might also limit endothelial dysfunction, which has a role in the development of coagulopathy in COVID-19,” they wrote.

The positive findings from the retrospective study should be confirmed in a larger prospective  trial, the study authors suggested.

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