Anakinra To Prevent Respiratory Failure In COVID-19

Abstract

Introduction The management of pneumonia caused by SARS-CoV-2 should rely on early recognition of the risk for progression to severe respiratory failure (SRF) and its prevention. We investigated if early suPAR (soluble urokinase plasminogen activator receptor)-guided anakinra treatment could prevent COVID-19-assocated SRF. Methods In this open-label prospective trial, 130 patients admitted with SARS-CoV-2 pneumonia SARS-CoV-2 and suPAR levels ≥6 μg/l were assigned to subcutaneous anakinra 100mg once daily for 10 days. The primary outcome was the incidence of SRF at day 14. Secondary outcomes were 30-day mortality, changes in sequential organ failure assessment (SOFA) score, of cytokine-stimulation pattern and of circulating inflammatory mediators. Equal number of propensity score-matched comparators for comorbidities, severity on admission and standard-of care (SOC) were studied. Results The incidence of SRF was 22.3% (95% CI, 16.0-30.2%) among anakinra-treated patients and 59.2% (95% CI, 50.6-67.3%; P: 4.6 x 10-8) among SOC comparators (hazard ratio, 0.30; 95%CI, 0.20-0.46). 30-day mortality was 11.5% (95% CI, 7.1-18.2%) and 22.3% (95% CI, 16.0-30.2%) respectively (hazard ratio 0.49; 95% CI 0.25-0.97%; P: 0.041). Anakinra treatment was associated with decrease in SOFA score and in circulating interleukin (IL)-6, sCD163 and sIL2-R; the serum IL-10/IL-6 ratio on day 7 was inversely associated with the change in SOFA score. Duration of stay at the intensive care unit and at hospital was shortened compared to the SOC group; the cost of hospitalization was decreased. Conclusions Early suPAR-guided anakinra treatment is associated with decrease of the risk for SRF and restoration of the pro- /anti-inflammatory balance.

Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19

“…A significant association was not observed in a retrospective study of 57 treated patients (aHR 0.79, 95% CI 0.44 to 1.42), 27 while an association was observed in a prospective study of 130 patients (aHR 0.49, 95% CI 0.26 to 0.91). 28 A significant unadjusted association was also observed in a further study of 52 patients treated with anakinra (HR 0.30, 95% CI 0.12 to 0.71). 29 RRs were calculated from four studies totalling 424 participants.…”

Targeting of the NLRP3 Inflammasome for early COVID-19

“…Also shown in Figure 1 are significantly elevated levels of tumor necrosis factor alpha (TNFα), IL-10 and urokinase plasminogen activator receptor (uPAR). Plasma uPAR is elevated in COVID-19 patients and levels positively correlate with poor outcomes (Kyriazopoulou et al 2020).…”

“…For example, high doses of anakinra reduces deaths as well as number of days in the hospital (Cauchois et al 2020, Cavalli et al 2020, Huet et al 2020). Anakinra has also been administered in less severe hospitalized patients and resulted in similar reduction in disease (Kyriazopoulou et al 2020). Since anakinra blocks the IL-1 Receptor, the efficacy of anakinra may be due to reducing IL-1α or IL-1β.…”

SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release

“…Repurposing FDA-approved drugs that inhibit inflammatory cytokines or GSDMD, the final mediator of both cytokine release and inflammatory death, are worth continuing to assess in controlled clinical trials. Although anti-IL-1β (canakinumab) did not meet its endpoint for efficacy in hospitalized hypoxic COVID-19 patients (Novartis press release, 11/06/2020), an unpublished manuscript of a randomized control trial of anakinra (IL-1RA) in patients with SARS-CoV-2 pneumonia showed a highly significant reduction in the development of severe respiratory failure and overall clinical severity ( 53 ). The possible efficacy of antagonizing IL-1 implicates GSDMD activation in severe COVID-19 disease since IL-1 secretion depends heavily on GSDMD pore formation.…”