Case Presentation: A 31 year old male with no significant past medical history presented with recurrent fevers, nausea, vomiting and headaches.  He denied travel outside the U.S, camping, or hiking.  Temperature was 103F associated with tachycardia. Physical examination was unremarkable except for mild scleral icterus.Initial labs showed transaminitis, hyperbilirubinemia, leukocytosis, thrombocytopenia, and elevated ferritin > 12,000 ng/ml. He was started on empiric antibiotics (ceftriaxone and piperacillin-tazobactam) for possible sepsis due to acute cholangitis. Right upper quadrant ultrasound revealed no bile duct abnormalities. CT scan revealed hepatosplenomegaly.  Other etiologies to explain the fever and transaminitis (CMV, HSV, HIV, acute viral hepatitis panel, and auto-immune panel) were negative. However, EBV IGM antibodies were positive. MRCP performed was suggestive of hepatitis but did not reveal any duct abnormalities. His predominant lymphocytosis and otherwise unremarkable workup, raised the question of Hemophagocyticlymphohistiocytosis (HLH)/macrophage activation syndrome. Liver and bone marrow biopsies were performed. Bone marrow biopsy revealed atypical lymphoctyes and the specimen was sent to Barnes Jewish Hospital where findings were consistent with HLH.  Liver biopsy revealed extensive infiltrates of lymphohistiocytic cells involving the portal areas, central veins, and sinusoids. These biopsy findings along with fever, splenomegaly, cytopenia, and elevated ferritin led to the diagnosis of HLH.  The patient was treated with corticosteroids with excellent clinical response.

Discussion: HLH is an aggressive histiocytic disorder of excessive immune activation from alteration of signaling between innate and adaptive immune responses. It is common in infants but can occur in adults.  It is either inherited or sporadic both of which are triggered by immune activation such as infections (commonly viral) and immunomodulatory conditions such as malignancy, HIV, and rheumatologic disorders. Common diagnostic criteria include molecular identification of gene mutations or at least 5 of the following criteria: fever, splenomegaly, cytopenias, hypertriglyceridemia, hemophagocytosis in tissues, low NK cell activity, ferritin> 500ng/ml and high soluble CD25. Serum Ferritin levels > 10000 ng/ml is highly sensitive and specific of HLH. Malignancy-associated HLH tend to have poor prognosis. High clinical suspicion is necessary to avoid life-threatening delays in treatment. Treatment is targeted at the underlying cause but commonly includes immunosuppressants and chemotherapeutics such as dexamethasone and etoposide.  The mortality of HLH is high but treatment with standardized protocols increases long term survivability.

Conclusions: The importance of this case is to indicate that, timely diagnosis of HLH and initiation of appropriate treatment  can have excellent prognosis with improved survival rates.