Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Childhood Inflammatory Disorders: Diagnosis and Management

Abstract

Macrophage activation syndrome (MAS), a form of secondary hemophagocytic lymphohistiocytosis, is a frequently fatal complication of a variety of pediatric inflammatory disorders. MAS has been most commonly associated with systemic juvenile idiopathic arthritis (sJIA), as approximately 10% of children with sJIA develop fulminant MAS, with another 30-40% exhibiting a more subclinical form of the disease. Children with other rheumatologic conditions such as systemic lupus erythematosus and Kawasaki disease are also at risk for MAS. Moreover, MAS also complicates various genetic autoinflammatory disorders such as gain of function mutations in the cytosolic inflammasome NLRC4, pediatric hematologic malignancies (e.g., T-cell lymphoma), and primary immunodeficiencies characterized by immune dysregulation. Disease-specific and broadly inclusive diagnostic criteria have been developed to facilitate the diagnosis of MAS. Recently, simple screening tools such as the serum ferritin to erythrocyte sedimentation rate ratio have been proposed. Early diagnosis and rapid initiation of immunosuppression are essential for the effective management of MAS. With a better understanding of the pathophysiology of MAS and the advent of novel therapeutics, a broad immunosuppressive approach to treatment is giving way to targeted anti-cytokine therapies. These treatments include agents that block interleukin-1 (IL-1), IL-6, IL-18, interferon-γ, as well as inhibitors of downstream targets of cytokine signaling (e.g., Janus kinases). Increased early recognition of MAS among pediatric inflammatory disorders combined with the use of effective and less toxic cytokine-targeted therapies should lower the mortality of this frequently fatal disorder.

Fig. 1

The spectrum of HLH- and MAS-related diseases. The cytokine storm characterized by FHL, acquired HLH, and MAS can be considered a final common pathway that results from impaired cytotoxicity, baseline immune activation, or a combination of both of these factors. CHS Chediak-Higashi syndrome, FHL familial hemophagocytic lymphohistiocytosis, GS Griscelli syndrome, HLH hemophagocytic lymphohistiocytosis, HPS Hermansky-Pudlak syndrome type 2, IA-HLH infection-associated HLH, IC-HLH immune-compromised HLH, IFNγ interferon gamma, IL interleukin, MA-HLH malignancy-associated HLH, MAS macrophage activation syndrome, R-HLH rheumatologic HLH, stim stimulation, TNF tumor necrosis factor

Fig. 2

Exponential increase in the number of publications per year cited in PubMed on MAS, HLH, and cytokine storm. CSS cytokine storm syndrome, HLH hemophagocytic lymphohistiocytosis, MAS macrophage activation syndrome

Fig. 3

Suggested treatment algorithm for patients with HLH and MAS spectrum diseases. The depicted treatment algorithm is based on expert opinion and currently available data, which are limited. Decisions about treatment are the responsibility of the treating clinician and should always be tailored to individual clinical circumstances. *Anakinra, cyclosporine, glucocorticoids, and IVIG can be used alone or in combination. If anakinra monotherapy is employed, lack of response within 24–48 h suggests the need for additional immunosuppression, particularly high-dose glucocorticoids. ATG anti-thymocyte globulin, FHL familial hemophagocytic lymphohistiocytosis, HLH hemophagocytic lymphohistiocytosis, HSCT hematopoietic stem-cell transplant, IVIG intravenous immunoglobulin, MAS macrophage activation syndrome