Case Presentation: A 19 year old male with no significant medical history presented to the emergency department with one week of fatigue and 2 days of jaundice. He noted new nosebleeds, new shortness of breath particularly when lying flat, abdominal distension, discomfort and constipation. He had no fever, no sore throat, no headache or dizziness, no nausea or vomiting.
Exam: Temperature 99.6F, heart rate 92, blood pressure 134/73, respiratory rate 97% on room air. Physical exam revealed an ill-appearing male with notable jaundice and scleral icterus. Dried blood was noted at the nares, his throat was without erythema or exudates. A systolic murmur was noted radiating to the right carotid and breath sounds were decreased at the bases bilaterally. Hepatosplenomegaly was easily appreciated and his abdomen was tender to palpation throughout with normal bowel sounds.
Lab data significant for white blood cell count 5.6 x 10^9/L, hemoglobin 11.4g/dL, platelets 99,000, AST 896 IU/L, ALT 303 IU/L, alkaline phosphatase 1023 IU/L, lipase 31 IU/L, albumin 2.5g/dL, total bilirubin 7.8mg/dL, direct bilirubin 5.0mg/dL, LDH 3385 IU/L, PT 17.1sec, INR 1.5, fibrinogen 85mg/dL, d-dimer 5676ng/mL, ferritin 60,000ng/mL, triglycerides 312mg/dL. Epstein-Barr Virus (EBV) studies were consistent with acute EBV infection. Abdominal ultrasound revealed hepatosplenomegaly and mild ascites.
Acute disseminated intravascular coagulation (DIC) was diagnosed based upon prolonged INR, elevated D-dimer and low fibrinogen. Cryoprecipitate transfusion was given. Due to hepatosplenomegaly, moderate pancytopenia, and very high ferritin level, EBV-related hemophagocytic lymphohistiocytosis (HLH) was suspected and Oncology was consulted. Bone marrow biopsy revealed prominent hemophagocytosis. Low NK cell activity and elevated soluble CD25 confirmed the diagnosis. The patient was started on etoposide and dexamethasone in accordance with the HLH-2004 guidelines. The patient’s DIC and liver failure resolved and he was discharged home with close follow-up with Oncology.
Discussion: HLH is a clinical syndrome characterized by over-activation of the immune system. Persistent stimulation of lymphocytes and histiocytes results in high levels of cytokines and a potentially fatal hyper-inflammatory state. Primary HLH is an inherited immune disorder. Secondary HLH occurs with immune activation in response to a trigger. Triggers include infection, metabolic disorders, primary immunodeficiencies, autoimmune or inflammatory disease, and malignancy. EBV infection, commonly known as the kissing disease, appears to be the triggering infection in this case.
Patients with HLH present with a triad of fever, splenomegaly, and cytopenia. Other laboratory findings include elevated ferritin, triglycerides, transaminases, bilirubin, and lactate dehydrogenase, and low fibrinogen.
Diagnosis comes from the HLH-2004 guideline and requires 5 of the following 8 criteria: 1. fever, 2. splenomegaly, 3. cytopenia, 4. hypertriglyceridemia and/or hypofibrinogenemia, 5. hemophagocytosis in bone marrow, spleen, lymph node, or liver, 6. low or absent NK cell activity, 7. hyperferritinemia, and 8. elevated soluble CD25 (soluble IL-2 receptor alpha).
Conclusions: HLH is a potentially fatal clinical syndrome with which hospitalists should be familiar. It is important to consider HLH when presented with the triad of fever, splenomegaly, and cytopenia, especially when hypertriglyceridemia, hypofibrinogenemia and hyperferritinemia are present.