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Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by fever, hepatosplenomegaly, pancytopenia, and infiltration of vital organs by non-Langerhans histiocytes and is rapidly fatal without early diagnosis and institution of therapy. Immune dysregulation is thought to be responsible for the disease.Extensive immune evaluation was performed on 13 consecutive patients diagnosed with HLH over a 4-year period to characterize existing immunologic abnormalities in order to improve early diagnosis. Evaluation included quantitative immunoglobulins, immunophenotyping, mitogen-induced lymphoproliferation. natural killer (NK) cell function, and cytotoxic T cell lymphocytolysis (CTL).Immunoglobulin levels showed no consistent abnormality. Immunophenotyping showed an absolute decrease in number of B cells but normal numbers and proportional distribution of T cell subsets and NK cells. Most patients demonstrated decreased proliferative responses to mitogens (10/13) and severely decreased to absent T cell cytoloxicity (11/12) and NK cytotoxic function (13/13).Our results show that while humoral immunity is essentially intact, cellular immune function is significantly impaired in the vast majority of patients with HLH. The coincident finding of profoundly decreased T cell cytotoxicity along with absent NK cytotoxicity suggests that patients with active HLH may have global cytotoxic dysfunction. Since the majority of our patients were studied prior to starting therapy, we feel that these findings reflect the pathophysiologic process and are not therapy related. Unclear from the present work is whether these findings represent primary or secondary dysfunction. We conclude from these studies that profoundly decreased CTL function and absence of NK cell function are characteristic immunologic features of HLH and may serve as additional laboratory data, in conjunction with currently proposed diagnostic guidelines, to support a diagnosis of HLH.