Macrophage Activation Syndrome in Children: Update on Diagnosis and Treatment

Abstract

Macrophage activation syndrome (MAS) is potentially fatal; so, early diagnosis and timely treatment are essential. However, detecting MAS is sometimes challenging because its principal features can be observed in other pediatric diseases that cause severe inflammation. Cytokine storm due to immune dysregulation represents the clinical and laboratory features of MAS that are included in the diagnostic criteria. Most cases of MAS occur as an underlying condition worsens and progresses. Therefore, a patient with autoimmune or autoinflammatory disease who shows unexplained clinical deterioration despite appropriate management should be considered at high risk for MAS (i.e., occult MAS). The basic principles of treatment are control of triggering factors, supportive care, and relief of hyperinflammation. Systemic steroids and cyclosporine A are frequently used as a first-line treatment. For the treatment of refractory MAS, cytokine-specific biologic agents such as anakinra have recently become preferred over traditional immunosuppressive agents such as etoposide. MAS might be underrecognized in pediatric patients with infectious and inflammatory diseases due to its diverse clinical presentations. Clinical suspicion of MAS is of the utmost importance for early recognition of the disease.

Keywords: children; diagnosis; macrophage activation syndrome; review; treatment.

Figure 3

Therapeutic plan for treating MAS in children [10,24,71,72,73,74,75]. ^a Many institutions, especially in the United States, use anakinra instead of CSA as initial combination therapy with IVMP. MAS, macrophage activation syndrome; HLH, hemophagocytic lymphohistiocytosis; HLH-2004, HLH-2004 diagnostic criteria; 2016 MAS, 2016 classification criteria for MAS complicating sJIA; HScore, hemophagocytic syndrome diagnostic score; sIL-2R, soluble interleukin-2 receptor; NK, natural killer; BM, bone marrow; IVMP, intravenous methylprednisolone; CSA, cyclosporine A; IVIG, intravenous immunoglobulin; R/O, rule out; IL, interleukin; EBV, Epstein–Barr virus; IFN, interferon; JAK, Janus kinase.

Figure 1

Threshold model [32,33]. MAS, macrophage activation syndrome.

Figure 2

Occult MAS in actual practice [20,58,59]. MAS, macrophage activation syndrome; sJIA, systemic juvenile idiopathic arthritis; KD, Kawasaki disease; COVID-19, coronavirus disease 2019; MIS-C, multisystem inflammatory syndrome in children; sJIA/MAS, sJIA complicated with MAS; KD/MAS, KD complicated with MAS; MIS-C/MAS, MIS-C complicated with MAS.