Elevated ferritin is associated with systemic inflammation, inflammasome activation and mortality in Acute Respiratory Distress Syndrome (ARDS)

Background: Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict response to immunomodulation. The role of hyperferritinaemia in ARDS from all-causes is unknown. Methods: Baseline plasma ferritin was measured in patients with ARDS from two randomised controlled trials of simvastatin (HARP-2; discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Logistic regression model with restricted cubic splines determined a ferritin threshold associated with 28-day mortality. Samples from HARP-2 were also analysed for inflammasome-associated inflammation. Results: Ferritin was measured in 511 patients from HARP-2 (95% enrolled) and 847 patients from ROSE (84% enrolled). In HARP-2, 144 patients (28%) had a ferritin >1360 ng/mL, which was associated with an increased 28-day mortality (OR 2.43, 95% CI 1.59-3.72). This hyperferritinaemic subgroup also had fewer ventilator-free days (median difference 16 days, p<0.001), longer ICU (3 days, 95% CI 0.01-5) and hospital stay (8 days, 95% CI 2-15). Similarly, the hyperferritinaemic group in ROSE had an increased 28-day mortality (OR 2.95, 95% CI 2.13-4.07) and had fewer ventilator-free days (median difference 14 days, p < 0.001). Ferritin primed inflammasome activation in macrophages in vitro, and inflammasome activation resulted in increased ferritin release. Conclusion: A ferritin concentration >1360 ng/mL identified ARDS patients with a higher mortality associated with inflammasome activation. These results provide support prospective trials targeting the ferritin-inflammasome axis in this subgroup of patients with ARDS.