The conundrum of interleukin-6 blockade in COVID-19
Authors: Corrado Campochiaro, Lorenzo Dagna
Journal: The Lancet Rheumatology (2020)

Since the very first cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were identified in China, patients with severe manifestations of COVID-19 have been shown to develop a hyperinflammatory syndrome resembling that seen in patients with either macrophage-activation syndrome or cytokine-release syndrome associated with chimeric antigen receptor T-cell therapy.1Mehta P McAuley DF Brown M Sanchez E Tattersall RS Manson JJ COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: 1033-1034Summary Full Text Full Text PDF PubMed Scopus (6768) Google Scholar As a result, in the absence of a specific antiviral treatment for SARS-CoV-2 infection, many therapeutic efforts have focused on use of immunosuppressive drugs targeting the potential mediators of this hyperinflammatory state.1Mehta P McAuley DF Brown M Sanchez E Tattersall RS Manson JJ COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: 1033-1034Summary Full Text Full Text PDF PubMed Scopus (6768) Google Scholar, 2Cavalli G De Luca G Campochiaro C et al.Interleukin 1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.Lancet Rheumatol. 2020; 2: e325-e331Summary Full Text Full Text PDF PubMed Scopus (769) Google Scholar, 3De Luca G Cavalli G Campochiaro C et al.GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study.Lancet Rheumatol. 2020; 2: e465-e473Summary Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 4Della-Torre E Campochiaro C Cavalli G et al.Targeting IL-1, IL-6 or GM-CSF in COVID-19.Ann Rheum Dis. 2020; (published online July 31.)https://doi.org/10.1136/annrheumdis-2020-218612Google Scholar Since interleukin (IL)-6 blocking agents have been effectively used for treating patients with hyperinflammatory states, and because increased amounts of IL-6 have been reported in patients with COVID-19, strategies aimed at inhibiting this cytokine have been rapidly attempted.1Mehta P McAuley DF Brown M Sanchez E Tattersall RS Manson JJ COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: 1033-1034Summary Full Text Full Text PDF PubMed Scopus (6768) Google Scholar, 5Campochiaro C Della-Torre E Cavalli G et al.Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study.Eur J Intern Med. 2020; 76: 43-49Summary Full Text Full Text PDF PubMed Scopus (321) Google Scholar, 6Guaraldi G Meschiari M Cozzi-Lepri A et al.Tocilizumab in patients with severe COVID-19: a retrospective cohort study.Lancet Rheumatol. 2020; 2: e474-e484Summary Full Text Full Text PDF PubMed Scopus (717) Google Scholar, 7Della-Torre E Campochiaro C Cavalli G et al.Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study.Ann Rheum Dis. 2020; (published online July 3.)https://doi.org/10.1136/annrheumdis-2020-218122Crossref Scopus (197) Google Scholar In The Lancet Rheumatology, Noa Biran and colleagues8Biran N Ip A Ahn J et al.Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study.Lancet Rheumatol. 2020; (https://doi.org/S2665-9913(20)30277-0 published online Aug 14.)Summary Full Text Full Text PDF PubMed Scopus (216) Google Scholar offer important real-life insight into the use of tocilizumab in the most critically ill population of mechanically ventilated patients admitted to the intensive care unit.9Zangrillo A Beretta L Scandroglio AM et al.Characteristics, treatment, outcomes and cause of death of invasively ventilated patients with COVID-19 ARDS in Milan, Italy.Crit Care Resusc. 2020; (published online April 23.)https://ccr.cicm.org.au/config/cicm-ccr/media/pdf/june-covid-19/oa2/ccr_-zangrillo128_sep_v10.pdfDate accessed: August 5, 2020Google Scholar They obtained data from a prospective observational database used by the Hackensack Meridian Health network of 13 hospitals in New Jersey, USA, and did a retrospective study to compare outcomes in patients who received tocilizumab with those who did not. They did a multivariable Cox regression analysis with propensity score matching to reduce confounding effects and found an association between exposure to tocilizumab and decreased hospital-related mortality (hazard ratio 0·64, 95% CI 0·47–0·87, p=0·0040). When analysing factors associated with reduced mortality in those who received tocilizumab, baseline C-reactive protein concentrations of 15 mg/dL or higher emerged as a clear cutoff, suggesting that IL-6 blockade exerts its best effects among patients with an overt inflammatory state. Moreover, Biran and colleagues did not note any increase in secondary infections, thus supporting the safety of tocilizumab in this setting. Although evidence that patients with hyperinflammation respond well to tocilizumab is not surprising, the negative results of randomised trials of tocilizumab (eg, the COVACTA trial; NCT04320615) are in apparent contradiction with the study by Biran and colleagues. Clearly, a retrospective observational study cannot be fully compared with a randomised trial because of the inherent limitations of a retrospective study that could affect the results. Indeed, although propensity score matching helped to better compare outcomes of patients, the presence of indication and sampling biases, together with a 10% rate of missing data, are limitations.8Biran N Ip A Ahn J et al.Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study.Lancet Rheumatol. 2020; (https://doi.org/S2665-9913(20)30277-0 published online Aug 14.)Summary Full Text Full Text PDF PubMed Scopus (216) Google Scholar Nonetheless, the COVACTA trial is not fully comparable, particularly with respect to the treatment scheme and inclusion criteria. In the COVACTA trial, investigators used a dose of tocilizumab of 8 mg/kg up to 800 mg and a second infusion was allowed in case of clinical worsening or absence of improvement, whereas in the study by Biran and colleagues a lower dose of tocilizumab (400 mg) was used in a one-time scheme, with a second dose permitted at the point of worsening oxygenation. Moreover, the inclusion criteria of the COVACTA trial required a definite diagnosis of COVID-19 pneumonia with an oxygen saturation of 93% or lower or a ratio of the arterial pressure of oxygen to fractional inspired oxygen less than 300 mm Hg, with no mention of the inflammatory status of the patients. The reduced dose in a more select population with inflammation might, therefore, be more effective in this setting. Observational studies are important in a rapidly evolving pandemic because they can offer clues for reshaping the design of future or ongoing randomised trials, and this is exactly what the study by Biran and colleagues adds. More than 6 months have passed since SARS-CoV-2 was first recognised as a new pathogen in the world, and several questions are still without answer. Have we correctly identified the right COVID-19 population for treatment with anti-inflammatory drugs? Are systemic inflammatory markers reliable enough for selecting patients with hyperinflammation? Do increased concentrations of a specific cytokine imply that its neutralisation will be effective in COVID-19? What is the degree of immunosuppression we are aiming for in SARS-CoV-2 infection? These and other questions are why we eagerly await results of ongoing international randomised trials. CC reports personal fees from Roche and Sobi, outside of the submitted work. LD reports personal fees from Roche, Sobi, and Sanofi, outside of the submitted work. Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational studyIn this observational study, patients with COVID-19 requiring ICU support who received tocilizumab had reduced mortality. Results of ongoing randomised controlled trials are awaited. Full-Text PDF