Abstract Rationale Inflammation in acute respiratory distress syndrome (ARDS) and COVID-19 causes disruption of the alveolar-capillary barrier and tissue damage, which has been associated with increased mortality. Elevated pro-inflammatory plasma biomarkers (specifically interleukin-6) levels reflect the degree of systemic inflammation, and are linked to severity of lung injury. Understanding the causal pathway between inflammation, interventions, and patient outcomes could improve clinical care. Objectives To assess IL-6 as a mediator of effective interventions in ARDS and COVID-19. Methods We leveraged individual patient data from five large randomized controlled trials. Interventions were imatinib, anakinra, low tidal volume ventilation, high positive end-expiratory pressure (PEEP), and simvastatin. We evaluated IL-6 as a mediator for the effectiveness of interventions on 28-day survival with joint modeling. Additionally, we analyzed the role of other pro-inflammatory markers (IL-8, TNFR1, and CRP). The association between IL-6 and mortality was meta-analyzed using a random effects model. Measurements and main results For 2563 patients, IL-6 measures were available at baseline and at least one other timepoint. IL-6 mediated the effects of imatinib, anakinra, and low tidal volume on mortality. Higher PEEP and simvastatin did not alter IL-6 trajectories. In all studies, there were associations between higher IL-6 concentrations and increased mortality over 28 days (pooled HR for a log10 unit increase = 4·83, 95% CI: 3·50 to 6·66). Conclusions . The mortality benefit by Anakinra and Imatinib in COVID-19 and low tidal volume ventilation in acute lung injury may operate through resolution of inflammation defined by a reduction in plasma IL-6 levels.
Kramer et al. (Fri,) studied this question.