Hemophagocytic Lymphohistiocytosis in Early Infancy- Pitfall of Differentiation between Hereditary and Infectious Reasons

Hemophagocytic Lymphohistiocytosis (HLH) is characterized by pathologic immune activation which occurs either as a familial disorder or as an acquired condition. The diagnosis of HLH requires the presence of five out of nine criteria: fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis in bone marrow, hyperferritinemia, low or absent natural killer cell activity and high level of soluble interleukin-2 receptor.

Here we present a 6-month-old girl with parents from Southern Italy. She suffered from hepatosplenomegaly and a recurrent high fever for 3 months' duration. On admission, she showed neurological symptoms including irritability and neck stiffness. Blood analysis revealed bicytopenia, namely anemia and thrombocytopenia. The first bone marrow aspirate was indicative for neither malignancies nor HLH. At this time, additional investigations indicated macrophage activation syndrome with elevated ferritin value (11.741ng/ml), soluble interleukin-2 receptor (CD25) levels (16.018U/ml), hypertriglyceridemia (582mg/dl) supportive of the diagnosis of HLH. Because of the worsening of her clinical condition, a second bone marrow aspirate and biopsy was performed 5 days later when the child became pancytopenic. The second bone marrow aspirate still did not show morphological signs of HLH, but microorganisms were detected in at least one macrophage, which were consecutively diagnosed as Leishmania amastigotes within macrophages by positive Leishmanial polymerase chain reaction from bone marrow specimen. Consistent with the diagnosis of visceral Leishmaniasis Amphotericin B (liposomal) therapy was initiated which resulted in dramatic resolution of fever, splenomegaly, ferritin levels, and recovery of blood counts within 96 hours.

Familial hemophagocytic lymphohistiocytosis (FHL) manifests as acute illness with prolonged fever, cytopenias and hepatosplenomegaly. Onset typically occurs within the first months of life. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months. Acquired HLH is typically associated with T-/NK-cell lymphomas and autoimmune diseases but also with infections including EBV, malaria and Leishmaniasis. Even in non-endemic areas, our case of vertically transmitted Leishmaniasis highlights the importance of recognizing infectious etiologies of HLH compared with hereditary forms of HLH in early infancy to initiate appropriate therapy to prevent life-threatening complications.