Macrophage Activation Syndrome in Kawasaki Disease: Insights from a Systematic Literature Review on Diagnosis, Clinical Features, and Treatment.

Abstract

Background: Macrophage activation syndrome (MAS) is a hyperinflammatory and potentially fatal complication associated with rheumatologic disorders. In Kawasaki disease (KD), MAS is a rare and poorly described condition, making its differentiation from a severe, treatment-resistant presentation of KD particularly challenging.

Objective: We aimed to describe MAS in KD by analyzing its epidemiological, clinical, and laboratory characteristics, complications, therapeutic strategies, and outcomes.

Methods: A comprehensive literature review of PubMed, Embase, Scopus, and Cochrane Library was conducted to identify English-language studies on KD complicated by MAS, including case reports and case series, until 15 November 2024.

Results: A total of 176 pediatric patients (60 females; median age 4 years, range 0.13-17) from 48 articles were included. MAS occurred after or simultaneously with KD diagnosis in 174/176 cases (99%). Common features included fever (100%), splenomegaly (49.4%), and hyperferritinemia (98.2%). Cardiac involvement was reported in 37% of children. The HLH-2004 criteria were met in 63% of cases, while the 2016 Ravelli criteria for MAS complicating systemic juvenile idiopathic arthritis were met in 94%. Treatment included additional doses of IVIG (36.2%), GCs (82.8%), cyclosporine A (28.7%), and biologics (13.8%), with complete MAS resolution in 93% of cases.

Conclusions: MAS in KD is a rare but severe complication, with overlapping features that make its differentiation from severe and resistant KD challenging. Persistent fever despite initial IVIG administration, along with splenomegaly and hyperferritinemia, emerge as key warning signs. Ravelli criteria provide stronger diagnostic support compared to the HLH-2004 criteria. Moreover, MAS is associated with increased cardiac involvement.