Prelude to the perfect storm: the many triggers of secondary hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is an increasingly recognized disorder of immune hyperactivity that often leads to multiorgan failure and death. In adults, HLH is usually triggered by infection, malignancy, or an autoimmune/autoinflammatory disorder that precipitates a destructive cytokine storm. Treatment aims to deescalate the hyperimmunity by treating the triggers while interfering with the immune pathways that cause the morbidity. We summarize what is known about this devastating disorder while adding insights gleaned from our review of the literature coupled with our own experiences. For example, we recognized that 1) more than one trigger may coexist in the same patient, 2) there is a predilection for HLH in lymphoma patients, particularly in the presence of Epstein-Barr virus infection, 3) aspartate transaminase elevation exceeds that of alanine transaminase, and 4) encephalopathy is underrecognized. These and other observations may assist the readers in identifying HLH, distinguishing its clinical presentation from that of its triggers, and thoroughly assessing all possible triggers rather than anchoring on the first diagnosed.