Hemophagocytic lymphohistiocytosis: review of etiologies and management

George, Melissa R

Hemophagocytic lymphohistiocytosis pathophysiology of HLH. A rapid flow cytometric analysis of intracellular X-linked inhibitor of apoptosis protein (XIAP) has been developed for detection for X-linked lymphoproliferative disease and carrier state, which has also proven useful following bone marrow transplant to monitor reconstitution. 25, 26 A prospective evaluation of degranulation assays was found to be useful in the differential diagnosis of FHL. CD107 may serve as a useful surrogate marker for reduced or absent NK-cell and cytotoxic T-cell activity. Using an assay for surface upregulation of CD107a on NK-cells and cytotoxic T-lymphocytes in a large cohort of patients under evaluation for HLH, the vast majority of patients with FHL subtypes 3-5 and Griscelli syndrome (GS) type 2 or Chediak-Higashi syndrome (CHS) had abnormal resting NK-cell degranulation. NK-cell degranulation was found to be normal in the majority of patients with FHL type 2 and X-linked lymphoproliferative disease. Instead these patients were found to have diminished intracellular SAP (SLAM [signaling lymphocytic activation molecule]associated protein), XIAP, and perforin expression. Most patients with secondary HLH did not have abnormalities of NK-cell degranulation. Thus, degranulation assays may help speed the diagnosis of HLH and allow treatment to begin more rapidly. 27 Degranulation of CD107 may be associated with a specific type of FHL (FHL-5) in which missense mutations lead to decreased lymphocyte stability of syntaxin binding protein 2 (Munc18-2) and syntaxin 11. These proteins would normally be involved in regulating vesicle transport to the plasma membrane, which is key to the pathophysiology of HLH. 28 Flow cytometry for perforin staining in cytotoxic lymphocytes, including NK-cells, CD8+ T-cells, and CD56+ T-cells, seems to be useful as a quick and reliable marker for perforin gene mutations seen in HLH. In a study of eleven unrelated HLH patients and 19 family members, four of seven patients with FHL showed lack of intracellular perforin in all cytotoxic cell types, which corresponded to mutations in the perforin gene. The parents of these patients also had abnormal perforin staining, indicative of their carrier state for perforin mutations. Evaluation of cytotoxic T-cells from the other three patients with FHL demonstrated normal percentages of perforin staining cytotoxic T-cells. The four patients with