Safety and efficacy of interleukin-1 antagonists in hospitalized patients with COVID-19

Abstract

the ongoing pandemic of coronavirus disease-2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection still represents a major public health concern. Severe COVID-19 is characterized by systemic hyper-inflammation, cytokine storm and rapid progression to respiratory failure and acute respiratory distress syndrome (ARDS). [[1]McGonagle D. Sharif K. O'Regan A. Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease.Autoimmun Rev. 2020; 19102537Crossref Scopus (963) Google Scholar] Major inflammatory cytokines, such as interleukin (IL)−6, IL-8, tumor necrosis factor (TNF)-α and IL-1, have been shown to be predictors of disease severity and mortality, therefore, it was relatively early proposed that they should represent both prognostic biomarkers, but also treatment targets in COVID-19. Therefore, there has been a vivid and ongoing discussion regarding the role of antirheumatic drugs targeting various stages of the inflammatory cascade in COVID-19. Concerning the role of IL-1 blockers, former meta-analyses of observational studies resulted in enthusiasm about the promising role of anakinra, for the reduction of COVID-19 related mortality, [[2]Kyriazopoulou E. Huet T. Cavalli G. Gori A. Kyprianou M. Pickkers P. et al.Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.Lancet Rheumatol. 2021; 3: e690-e697Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar,[3]Barkas F. Filippas-Ntekouan S. Kosmidou M. Liberopoulos E. Liontos A. Milionis H. Anakinra in hospitalized non-intubated patients with coronavirus disease 2019: a Systematic review and meta-analysis.Rheumatology (Oxford). 2021; 60: 5527-5537Crossref PubMed Scopus (11) Google Scholar] while data concerning the role of canakinumab was limited. Thus, we sought to perform an updated systematic review and meta-analysis of relevant randomized controlled trials, in order to evaluate the safety and efficacy of IL-1 blockers in patients with severe COVID-19. The present systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our protocol has been registered at the PROSPERO database (CRD42022324746). We searched PubMed, Cochrane Library, clinicaltrials.gov, European Union (EU) Clinical Trials Register and medrxiv.gov databases from inception to 1st April 2022 for randomized controlled trials (RCTs) enrolling hospitalized adult subjects with documented SARS-CoV-2 infection, assigned either to an IL-1 antagonist (either anakinra or canakinumab) or control (placebo or active comparator). Our exclusion criteria were a. observational studies, b. case series or case reports and c. studies performed in the pediatric population. Complete search strategy is provided in supplementary appendix (supplementary table 1). We set as primary efficacy outcome the death in the context of SARS-CoV-2 infection. We set as secondary efficacy outcome the need for invasive mechanical ventilation (IMV) or initiation of extracorporeal membrane oxygenation (ECMO) and the composite of non-invasive mechanical ventilation or initiation of high-flow oxygen (HFO). We also assessed major safety outcomes, with emphasis on secondary bacterial infections (bacterial sepsis and septic shock), neutropenia and transaminasemia. After de-duplication and assessment of eligible studies at title and abstract level for potential inclusion in our systematic review, two independent reviewers (A.D. and D.P.) extracted the data of interest from the eligible report. Differences were calculated with the use of risk ratio (RR), with 95% confidence interval (CI), after implementation of the Mantel-Haenszel (M-H) random effects formula. Statistical heterogeneity among studies was assessed by using I2 statistics. All analyses were performed at the 0.05 significance level, while they were undertaken with RevMan 5.3 software. Two independent reviewers (A.D. and D.P.) assessed the quality of the included RCTs, by using the Revised Cochrane risk of bias tool for randomized trials (RoB 2.0) for the primary efficacy outcome. Discrepancies between reviewers were solved by discussion, consensus, or arbitration by a third senior reviewer (D.M). Study selection process is depicted in the corresponding flow diagram (online supplementary material). Seven RCTs were finally included in the present systematic review and meta-analysis [4Caricchio R. Abbate A. Gordeev I. Meng J. Hsue P.Y. Neogi T. et al.Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: a Randomized Clinical Trial.JAMA. 2021; 326: 230-239Crossref PubMed Scopus (86) Google Scholar, 5Cremer P.C. Sheng C.C. Sahoo D. Dugar S. Prada R.A. Wang K.M. et al._the Three C study group. Double-blind randomized proof of-concept trial of canakinumab in patients with COVID-19 associated cardiac injury and heightened inflammation.Eur Heart J Open. 2021; 43: 1055-1063Google Scholar, 6CORIMUNO-19 Collaborative groupEffect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial.Lancet Respir Med. 2021; 9: 295-304Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 7Declercq J. Van Damme K.F.A. De Leeuw E. Maes B. Bosteels C. Tavernier S.J. 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: 1427-1438Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 8Kyriazopoulou E. Poulakou G. Milionis H. Metallidis S. Adamis G. Tsiakos K. et al.Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial.Nat Med. 2021; 27: 1752-1760Crossref PubMed Scopus (156) Google Scholar, 9Kharazmi A.B. Moradi O. Haghighi M. Kouchek M. Manafi-Rasi A. Raoufi M. et al.A randomized controlled clinical trial on efficacy and safety of anakinra in patients with severe COVID-19.Immun Inflamm Dis. 2022; 10: 201-208Crossref PubMed Scopus (10) Google Scholar, 10Derde L.P. The REMAP-CAP InvestigatorsEffectiveness of tocilizumab, sarilumab, and anakinra for critically ill patients with COVID-19. The REMAP-CAP COVID-19 immune modulation therapy domain randomized clinical trial.medRxiv. 2021; https://doi.org/10.1101/2021.06.18.21259133Crossref Scopus (0) Google Scholar]. Two trials assessed the efficacy and safety of canakinumab, [[4]Caricchio R. Abbate A. Gordeev I. Meng J. Hsue P.Y. Neogi T. et al.Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: a Randomized Clinical Trial.JAMA. 2021; 326: 230-239Crossref PubMed Scopus (86) Google Scholar,[5]Cremer P.C. Sheng C.C. Sahoo D. Dugar S. Prada R.A. Wang K.M. et al._the Three C study group. Double-blind randomized proof of-concept trial of canakinumab in patients with COVID-19 associated cardiac injury and heightened inflammation.Eur Heart J Open. 2021; 43: 1055-1063Google Scholar] while the rest five evaluated the efficacy and safety of anakinra, compared to control or active comparator, in patients with COVID-19 [6CORIMUNO-19 Collaborative groupEffect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial.Lancet Respir Med. 2021; 9: 295-304Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 7Declercq J. Van Damme K.F.A. De Leeuw E. Maes B. Bosteels C. Tavernier S.J. 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: 1427-1438Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 8Kyriazopoulou E. Poulakou G. Milionis H. Metallidis S. Adamis G. Tsiakos K. et al.Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial.Nat Med. 2021; 27: 1752-1760Crossref PubMed Scopus (156) Google Scholar, 9Kharazmi A.B. Moradi O. Haghighi M. Kouchek M. Manafi-Rasi A. Raoufi M. et al.A randomized controlled clinical trial on efficacy and safety of anakinra in patients with severe COVID-19.Immun Inflamm Dis. 2022; 10: 201-208Crossref PubMed Scopus (10) Google Scholar, 10Derde L.P. The REMAP-CAP InvestigatorsEffectiveness of tocilizumab, sarilumab, and anakinra for critically ill patients with COVID-19. The REMAP-CAP COVID-19 immune modulation therapy domain randomized clinical trial.medRxiv. 2021; https://doi.org/10.1101/2021.06.18.21259133Crossref Scopus (0) Google Scholar]. Therefore, we pooled data from seven trials in a total of 2120 enrolled subjects. A detailed description of enrolled trials is provided in the online supplementary material. Administration of IL-1 antagonists failed to produce a decrease in the risk for COVID-19 death (RR = 0.93, 95% CI; 0.70 – 1.22, I2 = 28%, p = 0.22), for COVID-19 related IMV (RR = 1.05, 95% CI; 0.77 – 1.42, I2 = 41%, p = 0.13) and for the composite outcome of non-invasive mechanical ventilation or HFO initiation (RR = 1.03, 95% CI; 0.65 – 1.62, I2 = 0%, p = 0.9). No significant difference between the two treatment options was documented for all three comparisons. Data are shown in Fig. 1 (panels A-C). Regarding safety outcomes of interest, IL-1 blockers did not result in an increase in the risk for bacterial sepsis (RR = 1.82, 95% CI; 0.83 – 3.99, I2 = 0%, p = 0.14), for bacterial septic shock (RR = 1.27, 95% CI; 0.29 – 5.45, I2 = 65%, p = 0.75), for neutropenia (RR = 4.58, 95% CI; 0.83 – 25.39, I2 = 0%, p = 0.08), for anemia (RR = 0.75, 95% CI; 0.53 – 1.06, I2 = 0%, p = 0.11), for thrombocytopenia (RR = 0.91, 95% CI; 0.30 – 2.71, I2 = 0%, p = 0.86), for transaminasemia (RR = 2.64, 95% CI; 0.22 – 31.16, I2 = 70%, p = 0.44) and for acute kidney injury or acute renal failure (RR = 0.71, 95% CI; 0.38 – 1.34, I2 = 0%, p = 0.3) [online supplementary material]. Overall risk of bias across the selected trials is considered as low. In the present updated meta-analysis of relevant RCTs we demonstrated that IL-1 antagonists do not exert any significant effect on “hard” outcomes in COVID-19, such as in-hospital mortality, need for invasive mechanical ventilation and requirement for non-invasive mechanical ventilation. Of note, neither anakinra nor canakinumab provide any significant effect on the above-mentioned surrogate endpoints. However, utilization of IL-1 antagonists in hospitalized patients with severe COVID-19 seems to be relatively safe, across a number of safety endpoints, including bacterial sepsis and septic shock, cytopenia, acute kidney injury and transaminasemia. The results of our meta-analysis are opposite to those of relevant meta-analyses of observational studies, [[2]Kyriazopoulou E. Huet T. Cavalli G. Gori A. Kyprianou M. Pickkers P. et al.Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.Lancet Rheumatol. 2021; 3: e690-e697Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar,[3]Barkas F. Filippas-Ntekouan S. Kosmidou M. Liberopoulos E. Liontos A. Milionis H. Anakinra in hospitalized non-intubated patients with coronavirus disease 2019: a Systematic review and meta-analysis.Rheumatology (Oxford). 2021; 60: 5527-5537Crossref PubMed Scopus (11) Google Scholar] strongly supporting the use of anakinra in patients with severe COVID-19. In specific, Kyriazopoulou et al. [[2]Kyriazopoulou E. Huet T. Cavalli G. Gori A. Kyprianou M. Pickkers P. et al.Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.Lancet Rheumatol. 2021; 3: e690-e697Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar] have formerly shown that anakinra led to an impressive reduction in the odds for COVID-19 related death by 68%, regardless of comorbidities, ferritin concentrations, or the baseline PaO2/FiO2 ratio. However, authors documented the synergistic effect of anakinra and dexamethasone on mortality benefit, [[2]Kyriazopoulou E. Huet T. Cavalli G. Gori A. Kyprianou M. Pickkers P. et al.Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.Lancet Rheumatol. 2021; 3: e690-e697Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar] while, no significant effect was shown when anakinra was administered without dexamethasone. Similar results were generated by Barkas et al. [[3]Barkas F. Filippas-Ntekouan S. Kosmidou M. Liberopoulos E. Liontos A. Milionis H. Anakinra in hospitalized non-intubated patients with coronavirus disease 2019: a Systematic review and meta-analysis.Rheumatology (Oxford). 2021; 60: 5527-5537Crossref PubMed Scopus (11) Google Scholar], who showed in their meta-analysis of observational studies that anakinra decreased the odds for mortality by 68% and the odds for IMV by 62%, compared to standard of care, while, no significant increase in the odds for major adverse events, such as secondary bacteremia or liver dysfunction, was documented. [[3]Barkas F. Filippas-Ntekouan S. Kosmidou M. Liberopoulos E. Liontos A. Milionis H. Anakinra in hospitalized non-intubated patients with coronavirus disease 2019: a Systematic review and meta-analysis.Rheumatology (Oxford). 2021; 60: 5527-5537Crossref PubMed Scopus (11) Google Scholar] We consider as major strengths of our meta-analysis the fact that included only RCTs, which are considered as the highest level of evidence, after a thorough and meticulous searching in medical databases and gray literature sources. However, we recognize as main limitation of the present meta-analysis the lack of access to individual participant data, which could permit us to conduct subgroup analyses for the assessed outcomes, according to baseline characteristics of specific interest, such as co-morbidities, pharmacotherapy, or status of prior vaccination. In addition, the results of the present meta-analysis cannot be generalized to newer SARS-CoV-2 variants, such as the omicron variant. To sum up, in the present updated meta-analysis of relevant RCTs, we failed to document any treatment benefit with IL-1 blockers in hospitalized patients with COVID-19, as added to standard of care, despite being a safe treatment option. Current evidence does not support their administration in patients with severe COVID-19. Athina Dimosiari and Demosthenes Makris conceived and designed the study. Athina Dimosiari and Dimitrios Patoulias performed literature searching and data extraction. Athina Dimosiari and Dimitrios Patoulias performed the analyses of retrieved data. Athina Dimosiari, Dimitrios Patoulias and Ioannis Pantazopoulos wrote the first draft. Epaminondas Zakynthinos and Demosthenes Makris critically revised the manuscript. All authors agree to its submission for publication.