Case Presentation:

A previously healthy 28–year–old female medical student presented with four days of high fevers (up to 39.9 C) and epigastric pain. In the past month, she completed an infectious disease rotation, then went camping with freshwater lake and cave exposure, without any noted bug bites or animal contact. On presentation, the patient was febrile to 39.4 C, tachycardic to 110s, tachypneic to 20s, jaundiced, had right upper quadrant tenderness to palpation with fingertip splenomegaly, slight pedal edema and cervical lymphadenopathy. Initial labs were notable for pancytopenia and presumed acute liver injury. Ultrasound revealed a normal liver and an enlarged 14cm spleen. Patient was admitted to telemetry with concern for a viral illness and started on intravenous fluids with multiple infectious studies sent. Patient clinically worsened requiring ICU transfer 3 days after admission for severe sepsis with disseminated intravascular coagulation. Her work up revealed positive heterophile agglutinins, positive Epstein Barr Virus (EBV) serologies, including positive EBV IgM, decreased fibrinogen and ferritin greater than 16,000 mg/L. Bone marrow biopsy showed increased histiocytes with numerous cells showing phagocytosis of red and white blood cells. The constellation of symptoms, laboratory abnormalities, and pathologic findings were consistent with EBV induced hemophagocytic lymphohistiocytosis (HLH). The patient was started on high dose dexamethasone, rituximab, and etoposide with improvement of her symptoms and subsequent discharge home 11 days after admission.

Discussion:

HLH is a rare syndrome of pathologic immune activation, more often seen in children than adults. In adults, it is rarely related to a primary genetic disorder and is usually secondary to malignancy, rheumatologic disorders, or, as in the case of our patient, infection. EBV is the most frequent infection associated with HLH. The diagnosis is made when five of the following eight criteria are met: fever > 38.5 C, splenomegaly, cytopenia in at least two cell lines, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis demonstrated in bone marrow, spleen, lymph node, or liver biopsy, low or absent natural killer cell activity, serum ferritin > 500 mg/L, and elevated sCD25. These diagnostic criteria do not encompass all of the clinical features of HLH, which can also include hepatic, neurologic, and skin manifestations. Liver injury is common and occurs in greater than 75% of patients. Neurologic symptoms are less common, occurring in approximately 30% of patients. Skin manifestations of HLH vary considerably and occur in 6–65% of patients.

Conclusions:

Hospitalists may find HLH is a challenging diagnosis to make because of its rarity, variable presentation, and non–specific findings. However, as HLH can be fatal, one must maintain a high index of suspicion in patients presenting with high fever, acute liver failure, and pancytopenia.