The course of action for effective anti-cytokine treatment in COVID-19
Authors: Giulio Cavalli, Lorenzo Dagna
Journal: The Lancet Respiratory Medicine (2021)

Even in the aftermath of global anti-SARS-CoV-2 vaccination campaigns, safe and effective treatments to inhibit inflammation and reduce mortality continue to be needed for the substantial proportion of unvaccinated individuals at risk of developing severe COVID-19. The COV-AID trial, the results of which were reported by Jozefien Declercq and colleagues in The Lancet Respiratory Medicine, was a factorial, randomised controlled trial investigating interleukin (IL)-1 blockade (anakinra) and IL-6 blockade (tocilizumab or siltuximab) in patients with COVID-19, respiratory failure, and cytokine release syndrome.1Declercq J Van Damme KFA 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; (published online Oct 29.)https://doi.org/10.1016/S2213-2600(21)00377-5Google Scholar This trial was done between April 4 and Dec 6, 2020 in 16 Belgian hospitals and enrolled 342 patients. The primary outcome was time to clinical improvement (increase in 2 points from baseline status on a 6-point ordinal scale). Patients were randomly assigned in a 1:2 ratio to anakinra or standard-of-care treatment, and then 1:1:1 to siltuximab, tocilizumab, or standard of care. The trial showed near-identical times to clinical improvements across groups, indicating marginal or no added benefit for cytokine blockade in this setting. The use of a factorial design adds complexity to the interpretation of this data. The advantages of this design are the possibility to test multiple treatments simultaneously, while minimising the number of patients exclusively receiving standard of care. However, the dual randomisation strategy resulted in four treatment groups (no cytokine inhibitors; IL-1 inhibition, IL-6 inhibition; IL-1 and IL-6 inhibition combined) with disparities in allocation: notably, only 34 patients received anakinra alone, compared with 129 patients receiving IL-6 inhibitors alone. In addition, the power of factorial designs is influenced by potential interactions between treatments: it is increased by synergistic interaction and decreased by detrimental interaction.2Montgomery AA Peters TJ Little P Design, analysis and presentation of factorial randomised controlled trials.BMC Med Res Methodol. 2003; 3: 26Google Scholar The authors assumed a priori no interaction between IL-1 and IL-6 blockade; however, whether there is no interaction is debatable from a biologic standpoint as IL-1 is found upstream of IL-6 in inflammatory cascades: inhibiting IL-1 results in IL-6 inhibition, hence the two treatments are partially redundant.3Mantovani A Dinarello CA Molgora M Garlanda C Interleukin-1 and related cytokines in the regulation of inflammation and immunity.Immunity. 2019; 50: 778-795Google Scholar In addition, co-administration of anticytokine treatments is typically avoided on the basis of safety concerns. It is interesting to note that co-administration of IL-1 and IL-6 inhibitors was not associated with increased adverse events in COV-AID. However, it is possible that a safety signal did not emerge owing to the relatively small sample size, and the rationale for co-administration of IL-1 and IL-6 inhibitors remains a questionable one. The results of the COV-AID trial are partially at odds with available evidence. Previously, only observational studies had compared IL-1 and IL-6 inhibition in COVID-19 and found that anakinra was more effective.4Cavalli 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. 2021; 3: e253-e261Google Scholar Two controlled trials evaluated anakinra. The CORIMUNO trial enrolled patients with relatively mild disease and was prematurely interrupted because of assumed futility.5Tharaux P-L Pialoux G Pavot A et al.Effect 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: 295-304Google Scholar, 6Cavalli G Dagna L The right place for IL-1 inhibition in COVID-19.Lancet Respir Med. 2021; 9: 223-224Google Scholar Conversely, the large SAVE-MORE trial enrolled patients on the basis of biomarker profiling: using soluble urokinase plasminogen activator receptor (suPAR) as a proxy for IL-1 bioactivity, the investigators selected patients at high risk for clinical deterioration and observed dramatic reductions in mortality in patients receiving anakinra in addition to the standard of care (including dexamethasone).7Kyriazopoulou E Poulakou G Milionis H et al.Early treatment of COVID-19 pneumonia with anakinra guided by urokinase plasminogen receptor: a randomised trial.Nat Med. 2021; (published online Sept 3.)https://doi.org/10.1038/s41591-021-01499-zGoogle Scholar In contrast, IL-6 inhibition received much more attention: 27 trials were completed and included in a meta-analysis, which suggested an overall benefit of IL-6 blockade, probably driven by the large RECOVERY and REMAP-CAP trials.8Shankar-Hari M Vale CL Godolphin PJ et al.Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: meta-analysis.JAMA. 2021; 326: 499-518Google Scholar However, a clearly notable factor differentiating these trials from the COV-AID trial is the 28-day mortality in the standard-of-care group, which exceeded 25% compared with only 10% in the COV-AID trial.8Shankar-Hari M Vale CL Godolphin PJ et al.Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: meta-analysis.JAMA. 2021; 326: 499-518Google Scholar This low mortality in the COV-AID trial reflects historical trends, which make it ever more difficult to reveal incremental benefits in patients with COVID-19 treated with biologic agents in randomised trials. Of note, the COV-AID study was designed to reveal a large treatment effect; it was not designed to show moderate treatment effects. It is worth remembering that the moderate clinical effectiveness of dexamethasone, which contributed to saving innumerable lives, required a massive nationwide investigation to be revealed.9Group RC Horby P Lim WS et al.Dexamethasone in hospitalized patients with Covid-19 - preliminary report.N Engl J Med. 2020; 384: 693-704Google Scholar Thereby, writing off potential therapeutic options (ie, cytokine inhibitors) on the basis of the negative results of relatively small trials only powered to detect large clinical effects is not advisable. Two important messages can be taken from this investigation and instruct further use of cytokine inhibitors in COVID-19. First, this study adds to the zeitgeist that universal treatment of COVID-19 with cytokine inhibitors is neither a suitable nor a sustainable option. Consequently, patient selection is crucial, and the severity of the individual's inflammatory response is the main criterion for eligibility to treatment. Indeed, a patient-level meta-analysis indicated that the benefit of anakinra treatment in COVID-19 is maximum for patients with serum C-reactive protein concentrations greater than 100 mg/L,10Kyriazopoulou E Huet T Cavalli G 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-e697Google Scholar whereas the SAVE-MORE trial found that early identification of candidate patients with suPAR followed by treatment with anakinra resulted in a 55% relative decrease in mortality, which reached 80% for patients with cytokine storm. Screening of individuals on the basis of molecular taxonomy of inflammatory responses is not always practical. Still, it is a necessary and feasible leap to transition from blanket therapeutic attempts, which are bound to yield mixed or disappointing results, to refined and appropriate management strategies. GC and LD have received consulting fees and honoraria from manufacturers of IL-1 and IL-6 inhibitors Swedish Orphan Biovitrum, Novartis, Sanofi, Roche, outside of the submitted work. Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trialDrugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. Full-Text PDF