Case Presentation: A 29 year-old male (AP) with history of ALL presented with neutropenic fevers after receiving intrathecal methotrexate one day prior. AP was in consolidation phase of treatment with most recent bone marrow biopsy showing hypocellular marrow without evidence of leukemia. On admission, he was febrile to 102.9 degrees Fahrenheit with pancytopenia and ANC 460 with consolidation on CXR and respiratory viral panel positive for Enterovirus. AP was empirically treated with vancomycin, cefepime, azithromycin. After unremitting high grade fevers after 72 hours from admission, a CT chest was performed, showing upper lobe opacifications with the primary impression concerning for fungal process. The patient was subsequently broadened to voriconazole and meropenem. Repeat Blood cultures remained negative along with negative Fungitell and cryptococcal antigen. Despite improvement in ANC after administration of neupogen, his respiratory status continued to decline. On day 6 of admission, AP was placed on high flow oxygen with a paO2/FiO2 ratio 177. He was transferred to MICU for ARDS and underwent intubation. Urgent bronchoscopy revealed normal airways with serial bloodier lavages consistent with diffuse alveolar hemorrhage. Given development of ARDS and persistent fevers despite resolution of neutropenia, there was clinical suspicion for HLH. Ferritin was found to be 16000 w/ triglycerides 553. With cytopenia, known splenomegaly, persistent fevers, elevated ferritin and triglyceride level the patient had 5 of 8 clinical criteria for HLH per HLH-2004 protocol. Bone marrow biopsy revealed macrophages with hemophagocytosis with no blasts or leukemic cells. Soluble IL-2 and NK cell activity were sent out. AP was diagnosed with diffuse alveolar hemorrhage in the setting of HLH. The patient received pulse dose steroids and transitioned to dexamethasone 10 mg twice daily per HLH 04 protocol. After 48 hours with marked clinical improvement, he was successfully extubated to room air and discharged on a steroid taper.
Discussion: HLH is a disease of the immune system that is caused by an imbalance in activation of CD8+ T cells and Treg cells leading to hyperactive lymphocytes and macrophages with decreased NKC activity and increased T cell activity. Per HLH-2004 protocol the diagnostic criteria include fever, splenomegaly, hypertriglyceridemia, hyperferritinemia, cytopenia in 2 or more cell lines, hemophagocytosis in a bone marrow biopsy, decreased CD25 (NKC activity marker), and increased soluble IL-2R antibodies. HLH has historically been regarded as a pediatric disease, with a known list of predisposing genetic mutations. Recently there has been an increasing number of reports of cases in adults with underlying inflammatory processes, e.g. infectious, rheumatologic, and malignant. One recent study showed that as many as 1 in 100 adults with hematologic malignancies will develop HLH over the course of their disease.
Conclusions: We present a case of HLH causing diffuse alveolar hemorrhage in a young male with hematologic malignancy. HLH is a disease of dysregulation of the immune system. Its diagnosis depends on meeting 5 of the 8 criteria described above, currently under scrutiny as the disease has become increasingly recognized in adults. While more commonly a genetic disease presenting in children, adults can develop HLH in the setting of other inflammatory conditions, and should be in the differential in a cancer patient with unexplained persistent fevers.