Assessing the importance of interleukin-6 in COVID-19
Authors: Luke Y C Chen, Ryan L Hoiland, Sophie Stukas, Cheryl L Wellington, Mypinder S Sekhon
Journal: The Lancet Respiratory Medicine (2021)

The systematic review and meta-analysis of interleukin (IL)-6 in COVID-19, by Daniel Leisman and colleagues,1Leisman DE Ronner L Pinotti R et al.Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.Lancet Respir Med. 2020; 8: 1233-1244Summary Full Text Full Text PDF PubMed Scopus (590) Google Scholar provides a crucial comparison with other inflammatory syndromes, showing that IL-6 is more markedly elevated in conditions such as sepsis and acute respiratory distress syndrome (ARDS).1Leisman DE Ronner L Pinotti R et al.Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.Lancet Respir Med. 2020; 8: 1233-1244Summary Full Text Full Text PDF PubMed Scopus (590) Google Scholar We credit the authors for this key undertaking. However, we would like to raise two relevant considerations regarding aspects of the study design and the conceptualisation of hyperinflammatory syndromes in which IL-6 is elevated. First, in performing meta-analyses on retrospective studies, counting the same cohort of patients multiple times introduces replication. The authors include data on what they believe to be 1245 patients with COVID-19. However, of the 25 reports included, 17 contain patients treated at the same hospital during overlapping time periods (appendix pp 1–2). These patients were counted in the pooled analysis as many as four times. Taking the approach recommended by the Cochrane Handbook for Systematic Reviews of Interventions (section 4·6·1) and counting only one report from each centre (appendix pp 1–2, bolded studies), the number of patients would be 852. Furthermore, only studies available before April 14, 2020, were included in the analysis, and thus 23 of 25 studies were early reports from China. Subsequent studies from Europe and North America that show markedly elevated IL-6 concentrations in COVID-19 were excluded.2Stukas S Hoiland RL Cooper J et al.The association of inflammatory cytokines in the pulmonary pathophysiology of respiratory failure in critically ill patients with coronavirus disease 2019.Crit Care Explor. 2020; 2e0203Crossref PubMed Scopus (20) Google Scholar, 3Chen LYC Hoiland RL Stukas S Wellington CL Sekhon MS Confronting the controversy: Interleukin-6 and the COVID-19 cytokine storm syndrome.Eur Respir J. 2020; 562003006Crossref PubMed Scopus (156) Google Scholar Second, we believe that the manuscript misconstrues the significance of elevated IL-6 in COVID-19. Although IL-6 is often higher in other inflammatory conditions, this finding has limited bearing on the pathophysiology of immune misfiring in COVID-19. The association between initial IL-6 concentrations greater than 80 pg/mL and outcomes such as respiratory failure and death has been confirmed in numerous studies.3Chen LYC Hoiland RL Stukas S Wellington CL Sekhon MS Confronting the controversy: Interleukin-6 and the COVID-19 cytokine storm syndrome.Eur Respir J. 2020; 562003006Crossref PubMed Scopus (156) Google Scholar The authors omit any discussion of prognostic models, such as the ISARIC-4C,4Knight SR Ho A Pius R et al.Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score.BMJ. 2020; 370m3339Crossref PubMed Scopus (682) Google Scholar or COVID-19-associated hyperinflammatory syndrome,5Webb BJ Peltan ID Jensen P et al.Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.Lancet Rheumatol. 2020; 2: e754-e763Summary Full Text Full Text PDF PubMed Scopus (212) Google Scholar which highlight C-reactive protein and IL-6 as prognostic markers. Markedly elevated serum IL-6 concentrations are not a prerequisite for clinical response to IL-6 blockade. In approved disease indications such as multicentric Castleman disease and giant cell arteritis, median pretreatment IL-6 concentrations are only moderately elevated. Although preliminary results from randomised controlled trials of IL-6 blockade have been largely negative, other studies of immunomodulatory therapies examining both short-term and long-term outcomes are ongoing.6Parr JB Time to reassess tocilizumab's role in COVID-19 pneumonia.JAMA Intern Med. 2021; 181: 12-15Crossref PubMed Scopus (59) Google Scholar COVID-19 is a heterogeneous disease, with diverse manifestations of immune dysregulation ranging from cytokine storm, through so-called long-hauler syndrome, to multisystem inflammatory disorder in children. Serum IL-6 remains the best available biomarker for severity of COVID-19 and still holds great potential for guiding treatment of this disease. We declare no competing interests. LYCC is supported by the UBC Hematology Research Program. CLW is supported by grants from the Canadian Institutes for Health Research, Department of Defense, National Institutes of Health, Weston Brain Institute and Cure Alzheimer Fund. MSS is supported by the Vancouver Coastal Health Research Institute Clinician Scientist Award. Download .pdf (.19 MB) Help with pdf files Supplementary appendix Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromesThe description of a so-called cytokine storm in patients with COVID-19 has prompted consideration of anti-cytokine therapies, particularly interleukin-6 antagonists. However, direct systematic comparisons of COVID-19 with other critical illnesses associated with elevated cytokine concentrations have not been reported. In this Rapid Review, we report the results of a systematic review and meta-analysis of COVID-19 studies published or posted as preprints between Nov 1, 2019, and April 14, 2020, in which interleukin-6 concentrations in patients with severe or critical disease were recorded. Full-Text PDF Assessing the importance of interleukin-6 in COVID-19 – Authors' replyWe thank Luke Chen and colleagues for their interest in our study.1 With respect to potential double counting of participants—this is a valid criticism. Indeed some participants could have been double counted if they were treated at the same hospital in overlapping time periods. Among the identified studies, only small fractions of the study periods overlap. Nevertheless, we recalculated our primary analysis using only one study—whichever was largest—from each group with potentially overlapping cohorts (figure). Full-Text PDF