Hemophagocytic lymphohistiocytosis: do we have a solution for TMI (too much inflammation)?

Abstract

Hemophagocytic lymphohistiocytosis (HLH) and the related HLH-spectrum disorders macrophage activation syndrome, macrophage activation-like syndrome, and treatment-associated immune-effector-cell-associated HLH-like syndrome are extreme forms of too much inflammation (TMI). Adult patients with HLH associated with hematologic malignancies have a 70% to 80% mortality rate due to delayed diagnosis, prolonged immunosuppression with associated secondary infections, and disease recurrence. In recent years, educational efforts and epidemiological evolution have increased diagnostic awareness. This has been catalyzed by the COVID-19 pandemic, the first approved anti-interferon gamma antibody for primary relapsed/refractory HLH, advancements in the treatment of posttransplant graft-versus-host disease, and the broad availability of T-cell-engaging therapeutics. These truly challenging-to-diagnose entities under the cytokine storm umbrella confer TMI, causing multiorgan dysfunction and early death. Novel prognostic models, differential diagnosis with the help of advanced diagnostic algorithms, preemptive therapeutic interventions, and more individualized cytokine-directed treatment options have moved this previously neglected area in adult hematology to the forefront of the hematologist's daily practice.