Widening the Differential: a Case of Hemophagocytic Lymphohistiocytosis Disguised as a Fever of Unknown Origin

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is an under recognized, aggressive inflammatory disease characterized by excessive activity of histiocytes and lymphocytes. According to the HLH-2004 guidelines, five of the following eight criteria must be met to diagnose HLH: fever >38.5¡ã C, splenomegaly; cytopenias affecting ¡Ý two cell lines; hypertriglyceridemia/hypofibrinogenemia; evidence of hemophagocytosis in the bone marrow, spleen or lymph nodes; hyperferritinemia; low NK cell activity; or high levels of soluble CD25. Once a diagnosis of HLH is established, investigations for infectious, malignant or autoimmune etiologies must be pursued. We report a case of fever of unknown origin (FUO) that presented multiple times prior to the diagnosis of HLH, which was determined to be secondary to ALK-positive anaplastic large cell lymphoma (ALK-ALCL). This case highlights the importance of searching for an alternative diagnosis in cases of FUO when initial workup is unrevealing. Case: A 38 year old man with no significant past medical history initially presented with fever and abdominal pain. He subsequently had an appendectomy that revealed minimal inflammation in the appendix. He presented again with continued fever, but a definitive diagnosis was not made. Upon his third admission due to recurrent fevers, he was found to have hepatosplenomegaly, and was diagnosed with atypical mononucleosis secondary to Epstein-Barr virus. He presented a fourth time with recurrent fevers and respiratory distress. His exam was significant for bilateral rhonchi, hepatosplenomegaly and a truncal rash. An extensive workup revealed a ferritin of 3681 ng/ml and triglycerides of 310 mg/dL. Five of the eight criteria for HLH were met with fever, splenomegaly, anemia with thrombocytopenia, hypertriglyceridemia, and elevated ferritin. He was ultimately diagnosed with ALK-positive anaplastic large cell lymphoma via lymph node biopsy and underwent CHOP-E chemotherapy. Discussion: HLH is a rare condition that is challenging to diagnose because it presents with common clinical signs. HLH can mimic septic shock due to severe systemic inflammation and can quickly progress to organ failure; therefore a high index of suspicion is required to diagnose HLH. New scoring systems, such as the 2016 bone marrow (BM) score, can assist the clinician in early detection of HLH. Furthermore, simultaneous investigation into the etiology of HLH must be pursued. ALK-ALCL is a common etiology of HLH in pediatrics, but remains extremely rare in adults. Our patient¡¯s diagnosis of HLH secondary to ALK-ALCL that presented multiple times with fever highlights the importance of considering HLH when identifying etiologies of fever of unknown origin.