Adult Onset of Hemophagocytic Syndrome: Report of 13 Cases from a Single Institution.

Hemophagocytic syndrome (HLH) is a rare disorder usually of early infancy characterized by fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia and hemophagocytosis. Impaired natural killer activity has been demonstrated in these patients (pts). The persistent antigen driven T-cell activation results in the hyperproduction of cytokines and secondary tissue damage caused by macrophages’ activation. Mutations in the perforin 1 gene (PRF1) are known and may be considered the most frequent genetic defect underlying familial HLH. Two distinct forms of HLH are recognized: familial (autosomal recessive disorder) and secondary (in association with systemic infection, underlying malignancy or autoimmune disorder). The diagnosis of adult HLH is often overlooked because of its rarity and heterogeneous clinical presentation.

Aim, patients and methods: to clarify common clinical characteristics and underlying disease, we describe 13 cases (M/F 7/6, median age 64, range 31–71) fulfilling the diagnostic criteria for HLH, according to guidelines of the histiocyte society, admitted to our Institution since February 2003.

Results: at presentation 12/13 pts had fever, 9/13 splenomegaly, 13/13 cytopenia, 11/13 hypertriglyceridemia and/or hypofibrinogenemia, 8/13 histological hemophagocytosis. Median hemoglobin level was 8.6 g/dl (range 7.7–11.7), platelets 25 x10⁹/L (4–166), ANC 0.76 x10⁹/L (0.09–17.1); ferritin > 40000 mg/L (1687->40000). In 9/13 pts an underlying disease was diagnosed: 2 autoimmune haemolytic anemia [AHA], 1 Still disease, 1 Castleman disease, 4 Non-Hodgkin lymphoma (2 diffuse large B cell, 1 anaplastic null lymphoma, 1 peripheral unspecified T cell lymphoma, 1 small B-lymphocyte lymphoma). Both B-cell lymphoma had marked accompanying Tcell infiltration. Twelve pts were screened for viral infection, which was positive in 5/12 (41.7%). In 4 of 9 evaluated pts HHV8 DNA was detected, in three of whom without any other manifestation of infection. In 2/3 pts the viral load, determined by real time PCR for orf26, showed an extremely high number of viral copies. Two of the 11 evaluated pts were positive for CMV-DNA (1 Tcell lymphoma, 1 AHA); 3/6 pts had detectable EBV-DNA (1 Castleman, 2 AHA). Three of 3 pts studied, showed low NK activity, using K562 cells as target or perforin expression (two without concomitant haematological disease, one pts with a small B-lymphocyte lymphoma). In spite of aggressive treatment (steroid, immunoglobulin, rituximab, cyclosporine A), eleven of 13 pts died of multiorgan failure few days after diagnosis (median survival of 9 days range 2–24); two patients are still alive (one without underlying haematological disease and one with diffuse large B cell lymphoma), after steroid therapy and anthracycline containing chemotherapy respectively.

Conclusion: HLH in adults is a not-uncommon disorder often associated with systemic viral infection, underlying malignancy or autoimmune disorder. Mutations in the perforin 1 gene (PRF1) or acquired abnormal perforin or NK function may have a pathogenic role. Its earlier recognition by haematologists in the setting of unexplained pancytopenia may allow more effective treatment of this highly fatal disease.