ArticleEClinicalMedicine2026
Real-world clinical outcomes of macrophage activation-like syndrome and hyperferritinemia in sepsis: a retrospective database analysis.
Article in EClinicalMedicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Macrophage activation-like syndrome (MALS) is characterized by hyperferritinemia, yet its clinical course in real-world practice and the prognostic and clinical significance of varying ferritin levels have not been fully defined. The aim of this study was to characterize the epidemiology and clinical outcomes associated with sepsis and MALS. Methods: We performed a retrospective analysis of the TriNetX database, identifying sepsis patients with MALS and ferritin level ≥4420 ng/mL within 3 days of diagnosis; patients with sepsis and ferritin <4420 ng/mL were classified as no-MALS. Primary outcomes were 28-day and 90-day all-cause mortality, and secondary outcomes included need for endotracheal intubation, intensive care unit (ICU) admission, continuous renal replacement therapy (CRRT), and vasopressors. We performed subgroup analyses according to age, immune suppression status, and bacteremia and assessed varying ferritin cutoff values (2000, 3000, 4420, 6000, and 10,000 ng/mL) for MALS diagnosis against study outcomes. We also performed an exploratory analysis assessing survival among patients with MALS treated with anakinra. We performed propensity score matching using nearest-neighbor matching and used hazard ratios (HRs) with 95% confidence intervals (CIs) to report results. Findings: From January 2017 to January 2025, 10,169 patients met criteria for MALS and 214,338 were classified as no-MALS. After 1:1 propensity score matching, both cohorts included 10,168 matched patients. MALS was associated with higher 28-day (HR: 2.73) and 90-day (HR: 2.49) mortality and increased need for intubation (Day 28: HR: 2.04; Day 90: HR: 2.00), ICU admission (Day 28: HR: 1.86; Day 90: HR: 1.78), CRRT (Day 28: HR: 2.19; Day 90: HR: 2.16), and vasopressors (Day 28: HR: 1.80; Day 90: HR: 1.73). In subgroup analyses, patients aged ≥65 years, those with bacteremia, and immunocompromised patients had worse 28-day and 90-day outcomes. Mortality increased with higher ferritin cutoff values at day 28 (thresholds [ng/mL]: 2000 [HR: 2.44]; 3000 [HR: 2.57]; 6000 [HR: 2.94]; 10,000 [HR: 3.05]) and day 90 (thresholds [ng/mL]: 2000 [HR: 2.21]; 3000 [HR: 2.36]; 6000 [HR: 2.60]; 10,000 [HR: 2.67]), with similar trends for secondary outcomes. Anakinra was not associated with improved survival at day 14 or day 28. Interpretation: In patients with sepsis, MALS was associated with worse 28- and 90-day outcomes compared to patients with no-MALS. Increasing ferritin cutoff values, even below the current diagnostic threshold for MALS diagnosis, were associated with worse primary and secondary outcomes. These findings support the need for systematic ferritin measurement in patients with sepsis for earlier risk stratification and clinical decision-making. Funding: None.
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