Pediatric macrophage activation syndrome, recognizing the tip of the Iceberg

Eur J Rheumatol. 2020 Feb;7(Suppl1):S13-S20. doi: 10.5152/eurjrheum.2019.19150.


Macrophage activation syndrome (MAS) is the name given to secondary hemophagocytic lymphohistiocytosis (sHLH) associated with rheumatic diseases. Previously, MAS has been best studied in children with systemic juvenile idiopathic arthritis (sJIA), who are at high risk of developing MAS. MAS/sHLH is a cytokine storm that results in multi-organ system failure and is frequently fatal. Early diagnosis and treatment is critical for improving survival. Various diagnostic tools have been developed for identifying MAS in the setting of sJIA, as well as for all forms of MAS/sHLH. These are largely based on clinical (e.g., fever) and laboratory features (e.g., cytopenias). None are perfectly sensitive and specific, however, increasing awareness of this condition is also paramount in making the diagnosis. Rare familial forms of HLH can also be diagnosed based on homozygous mutation in genes largely involved in perforin-mediated cytolytic function of lymphocytes (natural killer cells and CD8 T cells). Intriguingly, heterozygous defects in these same genes are frequently identified in patients with sHLH and MAS. Decreased cytolytic function results in prolonged interaction of the lytic lymphocytes and their target antigen presenting cells, thus resulting in the pro-inflammatory cytokine storm believed responsible for the multi-organ failure. Novel cytokine-targeted therapies are currently being explored for a less toxic yet effective alternative to chemotherapeutic approaches to treating children with sHLH/MAS. As increased recognition and diagnosis of MAS is on the rise, an earlier and cytokine-targeted approach to therapy will likely save many lives of children with this disorder.