Paediatric macrophage activation syndrome: clinical features and outcomes across diverse aetiologies.

OBJECTIVES

To characterize clinical features and outcomes of paediatric macrophage activation syndrome (MAS) and examine associations with immune-regulatory genetic variation.

METHODS

This retrospective study included 120 children with MAS. Clinical, laboratory and outcome data were analysed. A subgroup underwent genetic testing for Hemophagocytic Lymphohistiocytosis (HLH)-related variants. Multivariable logistic regression identified factors associated with outcomes.

RESULTS

Aetiologies included multisystem inflammatory syndrome in children (MIS-C) (36.7%), systemic juvenile idiopathic arthritis (sJIA) (26.7%), infection-triggered MAS (23.3%), other rheumatologic diseases (10.8%) and lymphoma (2.5%). Intensive care unit (ICU) admission and acute organ failure occurred in 60% and 45%, and mortality was 17.5%. Compared with sJIA, non-sJIA had higher ICU admission (72.7% vs 25.0%, P = 0.02) and mortality (21.6% vs 6.3%, P = 0.04), whereas recurrence was more common in sJIA (28.1% vs 9.1%, P = 0.04). Stratified analyses (MIS-C, other MAS and sJIA) showed higher ICU admission in MIS-C and other MAS, highest mortality in other MAS and highest recurrence in sJIA, with rates of 77.3%, 68.2% and 25.0% (P < 0.001), 6.8%, 36.4% and 6.3% (P < 0.001), and 2.3%, 15.9% and 28.1% (P = 0.01), respectively. Among tested patients, 22.4% carried HLH-related variants. Variant positivity was independently associated with higher ferritin, younger MAS onset, recurrence, acute organ dysfunction and sJIA aetiology. Higher peak ferritin predicted mortality (OR 2.01) and reduced remission off therapy (OR 0.70), whereas sJIA aetiology was associated with lower mortality (OR 0.21).

CONCLUSION

Paediatric MAS is aetiologically heterogeneous, with inflammatory burden and organ dysfunction driving poor outcomes. Immune-regulatory variants are linked to severe or relapsing disease, supporting phenotype-guided stratification.