Hemophagocytic Lymphohistiocytosis: Advances in Pathophysiology, Diagnosis, and Treatment

Abstract

emophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening disorder characterized by immune dysregulation, overwhelming immune activation, and inflammation. HLH has been categorized as primary or familial HLH (FHLH), when there is a family history of HLH or known underlying genetic defects. Reactive or secondary HLH occurs in the setting of infection or underlying rhematologic disorders or malignancy. HLH occurring in a setting of rheumatologic illness is commonly referred to as macrophage activation syndrome (MAS). Most patients with FHLH have defects in lymphocyte cytotoxicity, leading to ineffective infection control and immune dysregulation resulting in massive activation and expansion of cytotoxic T cells and macrophages. This immune activation results in marked elevation of inflammatory cytokines, including interferon (IFN)-g, interleukin (IL)-1, IL-6, and IL-10, and an ensuing extreme hyperinflammatory state. Clinically, patients with FHLH or secondary HLH typically present with high-grade fever, progressive cytopenias, liver dysfunction, coagulopathy, and variable degrees of neurologic symptoms. Depending on the predominant organ system involved in HLH, patients may be seen by different clinical subspecialists. Initial manifestations of HLH may include fulminant hepatic failure or isolated neurologic involvement presenting with seizures and altered sensorium. Over the last decade, research on the genetics and pathophysiology of HLH has greatly improved our understanding of this condition. Importantly, increasing awareness and availability of better treatment options have improved the prognosis of HLH from a fatal disorder to a treatable condition with good long-term survival. In this review, we present recent advances in genetic and pathophysiological research, rapid diagnostic modalities, and clinical management of HLH.