HLH/MAS

Hemophagocytic lymphohistiocytosis / macrophage activation syndrome (HLH/MAS) is a rare, systemic hyperinflammatory syndrome, with high risk for severe morbidity and death.

People with HLH/MAS may carry genetic variants that modulate cytolytic functions, lymphocyte survival, and inflammasome activation and/or have predisposing conditions such as congenital immunodeficiency diseases, autoimmune rheumatic diseases, or hematologic malignancies. They may also have recent exposure to an acute trigger, such as an infection.

The pathogenic mechanism underlying HLH/MAS involves a sustained activation of natural killer cells, CD8+ T cells, and macrophages, resulting in excessive cytokine secretion (“cytokine storm”).

Historically, HLH/MAS has been classified as being either “primary (genetically inherited) HLH” or “secondary (acquired) HLH,” the latter of which has been referred to as “MAS” in the context of underlying autoimmune rheumatic diseases. However, it is now known that multiple factors may combine to trigger HLH/MAS, causing the consensus to start shifting toward considering the disease as a continuum.

Whom does HLH/MAS affect?

HLH/MAS affects both adults and children, with genetically driven forms of HLH/MAS most prevalent in the latter.

Why is HLH/MAS diagnosis commonly delayed or misdiagnosed?

In addition to the rare prevalence and a general lack of awareness of this disease among clinicians, HLH/MAS clinical manifestations are non-specific and can be mistaken for signs of other cytokine storm syndromes, such as sepsis and systemic juvenile idiopathic arthritis flares.

What does the clinical presentation of HLH/MAS involve?

Early signs include recurrent fevers, lymphadenopathy, organomegaly, rash, and arthralgias. These can progress with unexpected rapidity and severity, which is why early diagnosis and rapid treatment initiation are crucial to minimize the risk of severe morbidity and mortality. People with severe HLH/MAS have symptoms including edema, purpura, dyspnea, diarrhea, diffuse bleeding, icterus, and an overall sepsis-like appearance.