Case Presentation: A 26-year-old man with history of virally undetectable HIV, presented with 3 weeks of intermittent fevers and night sweats associated with chills, non-productive cough and generalized weakness, but denied weight loss. Vital signs revealed fever of 101.3F, tachycardia (pulse 118 bpm) and hypotension (blood pressure 95/61 mmHg). Physical exam revealed cervical and axillary lymphadenopathy (LAD) and clear lungs on auscultation. Laboratory investigation showed pancytopenia (WBC 1.68 K/uL with atypical lymphocytes, Hemoglobin 8.5 g/dL and Platelets 65 K/uL), elevated C-reactive protein 210 mg/L, hyponatremia 127 mmol/L, hypoalbuminemia 3.0 g/dL and transaminitis (AST 181 U/L and ALT 98 U/L). Blood smear showed rare immature myeloid cells. CT chest/abdomen/pelvis showed splenomegaly and LAD (supraclavicular, mediastinal and retroperitoneal). He developed acute hypoxic respiratory failure and presumed septic shock, requiring intubation and ICU transfer for vasopressor support and was started empirically on Vancomycin and Cefepime. Additional labs showed hypertriglyceridemia (423 mg/dL), elevated lactate dehydrogenase (LDH) 508 U/L, markedly elevated ferritin (18,019 ug/L) and soluble CD-25 (9, 342 U/ml). Despite persistent fevers, blood cultures remained negative. QuantiFERON®-TB test was negative for tuberculosis. Epstein-Barr virus (EBV) nuclear antigen and IgG antibody were positive. Bone marrow biopsy revealed EBV positive classical Hodgkin’s Lymphoma (cHL). Given constellation of clinical and laboratory findings, a concurrent diagnosis of Hemophagocytic Lymphohistioscytosis (HLH) was made. Antibiotics were discontinued and he was started on Dexamethasone and induction chemotherapy with improvement in symptoms.
Discussion: HLH is a rare and deadly syndrome in which an aberrant, severe hyperinflammatory state develops.(1) With an incidence of approximately 1.2 cases per 1 million individuals per year, if left untreated it carries a mortality rate of 24%. HLH can be characterized as primary (genetic) or secondary (sHLH). sHLH is typically due to viral infections (most commonly EBV), autoimmune disease, drugs or malignancy (most commonly lymphoma).(2) The presentation of HLH is variable and non-specific but often mimics septic shock due to its association with multi-organ failure.(1) Our patient presented with classic B-cell symptoms, cytopenias and diffuse LAD which warranted bone marrow biopsy that confirmed cHL. HLH investigation was pursued given presumed septic shock without source. The presence of fever, splenomegaly, cytopenias in ≥2 cell lines, elevated soluble CD-25 ≥ 2,400 U/mL, ferritin level ≥ 500 ug/L and hypertriglyceridemia ≥ 265 mg/dL, fulfilled five of the eight 2004-HLH criteria required for diagnosis. The associated hyponatremia, hypoalbuminemia, transaminitis and elevated LDH were all supportive. While the EBV serology was suggestive of past infection, it can be reactivated in the setting of acute disease, and coupled with underlying cHL, were likely the potential triggers for HLH in our patient.The prompt diagnosis of HLH in our case led to early initiation of corticosteroids and induction chemotherapy for underlying malignancy, both factors which portend a better prognosis.
Conclusions: HLH should be considered in the differential diagnosis for any patient presenting with unexplained cytopenias and protracted fevers. Early diagnosis of both HLH and its underlying trigger is critical to decrease associated morbidity and mortality.