Interleukin-6 as an Effective Intermediate Endpoint in Critical Illness: An Individual Patient Data Meta-analysis of Randomized Controlled Trials

Abstract Title: Interleukin-6 as an effective intermediate endpoint in critical illness: an individual patient datameta-analysis of five randomized controlled trials. Authors Lina Kramer, Carolyn Calfee, Danny McAuley, Jurjan Aman, Evangelos J. Giamarellos-Bourboulis, Martijn W. Heymans, Lieuwe D.J. BosRationale Acute respiratory distress syndrome (ARDS) affects around 10% of patients acutely admittedto the intensive care unit (ICU) and has a 40% fatality rate. ARDS rates spiked during theCOVID-19 pandemic. Clinical trials have investigated the effectiveness of variousinterventions targeted, but it remains unclear what underlying mechanisms link effectiveinterventions. Resolution of inflammation could be a key intermediate disease state towardsrecovery and thereby function as a surrogate in early phase studies and evaluation oftreatment efficiency in individual patients. We hypothesized that interleukin-6 (IL-6) is amediator of therapeutic efficacy in patients with ARDS and COVID-19. Methods This is an individual patient meta-analysis of clinical and biological data from fiverandomized controlled trials (RCTs). Patients were included if they had plasma IL-6 measuresavailable at baseline and at least one additional time point. The endpoints for therapeuticefficacy were survival after ICU admission to day 28 and 90. We used joint modeling, combining mixed effects models for intervention effects over time on IL-6 with time-to-eventmodels for the effects of interventions and IL-6 on the risk of death. Obtained estimates forthe association between the risk of death and IL-6 values were meta-analyzed. Results In all studies, IL-6 was strongly associated with the risk of death up to day 28 (pooledestimate: HR = 4.95; 95%-CI [3.16–7.39]) and 90 (pooled estimate: HR = 3.06; 95%-CI[1.33–7.02]). Interventions that reduced mortality also reduced IL-6 concentrations, which inturn reduced the risk of death, both for immunomodulators: Anakinra (SAVE-MORE) andImatinib (COUNTER-COVID) in COVID-19 as well for the use of low tidal volume inARDS (ARMA). Conclusion IL-6 seems to be an effective intermediate endpoint for therapeutic efficacy in critically illpatients. Resolution of systemic hyperinflammation is an important therapeutic target toimprove patient outcomes. Figure: joint model estimates for the association between IL-6 and the hazard of death.