key: cord-0814399-k7zaawih
authors: Farina, Nicola; Dagna, Lorenzo
title: Interleukin 6 inhibition in severe COVID-19: another piece of the puzzle
date: 2022-04-25
journal: Eur J Intern Med
DOI: 10.1016/j.ejim.2022.04.018
sha: ac42c248d718876227004fcb78d22b2f531ede20
doc_id: 814399
cord_uid: k7zaawih

nan

More than two years have passed since the beginning of the coronavirus disease 2019 (COVID- 19) pandemic. Extensive efforts have been invested into better understanding the pathogenesis of this disease and developing the ideal pharmacological approach (1). However, severe COVID-19 still remains a therapeutic challenge. Since the very beginning of the pandemic, a detrimental inflammatory response was implicated as the major driver of the significant morbidity and mortality that characterizes patients with critical COVID-19 (2) . As targeted anti-viral medications were lacking, different anti-inflammatory strategies were studied to stop the progression of tissue damage and respiratory failure (3, 4) . In light of their remarkable anti-inflammatory properties, monoclonal antibodies targeting interleukin (IL)-6 (5) intuitively posed as agents of choice in these difficult-totreat patients, also because this cytokine was found to be elevated in patients with severe COVID- 19 (1,6). However, the first studies on monoclonal antibodies blocking the IL-6 pathway, many of which were also published in this Journal, showed mixed results (2, (7) (8) (9) . Later, the first randomized studies that were designed to address this issue paradoxically contributed to uncertainty: three studies did not find that IL-16 was associated to a significant clinical benefit in patients with variable degrees of disease severity (10) (11) (12) . Intriguingly, one study even hinted at a possible ominous effect in terms of survival in patients treated with tocilizumab (13) . On the other hand, the larger RECOVERY trial showed that tocilizumab was able to decrease both mortality and the need for mechanical ventilation in severely ill patients with COVID-19 (14) . As a result of this latter observation, IL-6 blocking agents were approved for the treatment of patients with severe COVID-19 (15). Differences in study samples, disease severity, and duration of follow-up have been regarded as possibly responsible for such discrepant results. Also, the timing of those treatments with regards to the different clinical phases of COVID-19 might have contributed to make the potential beneficial effects of IL-6 blockade less evident (16) (17) (18) (19) . Once these issues were made clear, the need for accurate and comprehensive re-analysis of the generated data became glaring.

Indeed, one meta-analysis of randomized clinical trials did show that IL-6 inhibition had, in fact, a beneficial effect on survival in patients with severe COVID-19 (20) . However, this study analyzed aggregate data from each study without considering individual patient information. On the contrary, meta-analyses of raw individual patient data from each analyzed study are more reliable, since different durations of follow-up, sample sizes, and outcomes can be evaluated separately. Hence, more definitive conclusions may be drawn from such studies.

In their work published in this issue of the Journal (21), Tasoudis and colleagues present the first meta-analysis on IL-6 inhibition in COVID-19 based on individual patient data. Tasoudis et al retrieved and analyzed data about more than 7,000 individual patients with COVID-19 from nine different randomized clinical trials. The Authors then confirmed the remarkable therapeutic potential of IL-6 inhibition, which was associated with a reduction of mortality that has been estimated to be up to 25%. A 26% reduction of the likelihood of need for mechanical ventilation and a 28% increase in the probability of discharge from hospital were also found in patients treated with monoclonal antibodies targeting IL-6. Furthermore, the Authors found that the beneficial effect of IL-6 inhibition was even more pronounced in those studies in which a greater proportion of patients received corticosteroids as a concomitant medication. Finally, there was a tendency to a greater improvement associated with IL-6 inhibition in older patients with severe COVID-19.

In summary, Tasoudis and colleagues were able to identify by means of their analysis a beneficial impact of pharmacological blockade of IL-6 in patients with COVID-19. Very importantly, this study gives new insights about the apparent discrepancies between the findings of previous clinical trials, as the overall therapeutic effect of IL-6 inhibition isas highlighted by the elegant design of their meta-analysisclear-cut.

More than two years since the beginning of the pandemic, the role of IL-6 inhibition in severe COVID-19 finally seems to be clearer. The initial findings suggesting this approach as an effective treatment for severe cases of COVID-19 have beenat lastconfirmed, and pharmacological blockade of IL-6 now represents a significant therapeutic option in this scenario.

Repurposing of Biologic and Targeted Synthetic Anti-Rheumatic Drugs in COVID-19 and Hyper-Inflammation: A Comprehensive Review of Available and Emerging Evidence at the Peak of the Pandemic

Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study

COVID-19: Pharmacology and kinetics of viral clearance

More evidences on which biologic and which pathway is key in severecritical COVID-19 pneumonia" by Ferraccioli

Tocilizumab for the treatment of immunerelated adverse events: a systematic literature review and a multicentre case series

Detectable Serum Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load (RNAemia) Is Closely Correlated With Drastically Elevated Interleukin 6 Level in Critically Ill Patients With Coronavirus Disease

Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in

Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia

Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19

Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

The right place for IL-1 inhibition in COVID-19

Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study

Respiratory Impairment Predicts Response to IL-1 and IL-6 Blockade in COVID-19 Patients With Severe Pneumonia and Hyper-Inflammation

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis

Interleukin-6 inhibitors reduce mortality in coronavirus disease-2019: An individual patient data meta-analysis from randomized controlled trials