Severe Secondary Hemophagocytic Lymphohistiocytosis Triggered by Chronic Active Epstein - Barr Virus Infection

Case Report

Ann Hematol Oncol. 2016; 3(8): 1105.

Severe Secondary Hemophagocytic Lymphohistiocytosis Triggered by Chronic Active Epstein - Barr Virus Infection

Khoury J¹*, Alhalabi O¹, Haberichter K², Ogunleye F², Fennell T² and Jaiyesimi I³

¹Department of Internal Medicine, William Beaumont Hospital, USA

²Department of Pathology, William Beaumont Hospital, USA

³Department of Hematology and Oncology, William Beaumont Hospital, USA

*Corresponding author: John Khoury, Department of Internal Medicine, William Beaumont Hospital, 3601 W 13 Mile Rd, Royal Oak, MI 48073, USA

Received: June 13, 2016; Accepted: September 03, 2016; Published: September 06, 2016


Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and rare syndrome caused by pathologic activation of the immune system. It is classified into primary HLH, which is familial, and secondary HLH, which is acquired and associated with infections, malignancy and rheumatologic disorders. Here, we report a case of a 43-year-old male who presented with fever, elevated liver enzymes, hemolytic anemia and thrombocytopenia. The patient developed multiorgan failure and was transferred to the intensive care unit. Serological testing confirmed a previous Epstein–Barr virus (EBV) infection with positive EBV DNA in the blood detected by polymerase chain reaction (PCR). Further infectious workup from a nasopharyngeal swab was positive for rhinovirus detected by PCR. A diagnosis of HLH was established based on a bone marrow biopsy and the patient was started on induction therapy with intravenous dexamethasone and etoposide as part of the HLH-94 protocol. The patient gradually responded to therapy with full recovery after prolonged hospitalization

Keywords: Hemophagocytic lymphohistiocytosis; Chronic active EBV infection; HLH-94 protocol

Case Presentation

A 43-year-old Caucasian male who had splenectomy in his childhood due to idiopathic thrombocytopenic purpura (ITP) presented with jaundice and dark urine. The patient also reported flu like symptoms for a few days preceding his presentation to the hospital. He had no history of intravenous illicit drug use, alcohol use or liver disease. Shortly after being admitted, the patient became febrile (38°C) and tachycardic. He had scleral icterus with generalized jaundice and an unremarkable abdominal examination. Laboratory investigations revealed a white blood cell count of 30.0x103 cells/ mL (normal range: 3.5-10.1x103 cells/mL) with an absolute neutrophil count of 24.9x103 cells/mL (normal range: 1.6-7.2x103 cells/mL), hemoglobin of 11.8 g/dL (normal range: 13.5-17.0 g/dL), platelets 63x103 cells/mL (normal range: 150-400x103 cells/mL), alkaline phosphatase 77 U/L (normal range: 30-110 U/L), asparate aminotransferase (AST) 141 U/L (normal range: 10-37 U/L), alanine aminotransferase (ALT) 50 U/L (normal range: 9-47 U/L), total bilirubin 16.6 mg/dL (normal range: 0.3-1.2 mg/dL) with a direct bilirubin of 4.9 mg/dL (normal range: 0.0-0.3 mg/dL) at this point in time broad spectrum antibiotics were started for suspected sepsis. Other laboratory values included lactate dehydrogenase (LDH) 5238 U/L (normal range: 100-238 U/L), haptoglobin <8 mg/dL (normal range: 40-240 mg/dL), fibrinogen 412 mg/dL (normal range: 175-400 mg/dL) and a positive direct antiglobulin test (DAT). A peripheral blood smear did not show spherocytes, blasts or microangiopathic changes. Serologic studies were positive for EBV-IgG and nuclear antigen, while EBV-IgM and early antigen were negative. EBV DNA was detected in the blood by PCR. Other laboratory studies for viral and bacterial infections including blood cultures, hepatitis A, B and C, cytomegalovirus (CMV), mycoplasma, influenza A and B, HIV, adenovirus, parvovirus B19, human metapneumovirus, respiratory syncytial virus (RSV), and parainfluenza virus were negative. Nasopharyngeal swab polymerase chain reaction (PCR) testing for a broad panel of respiratory viruses was positive for rhinovirus. Other laboratory screening tests for antinuclear antibodies, rheumatoid factor, paroxysmal nocturnal hemoglobinuria and serum cryoglobulin were negative. On the third day of admission, the patient’s hemoglobin dropped to 4.1 g/dL. He was started on IV Dexamethasone and IVIG for presumptive autoimmune anemia and thrombocytopenia (Evans Syndrome). The patient was transferred to the intensive care unit for close monitoring. His platelets count improved, however despite multiple transfusions his hemoglobin continued to drop with a nadir of 3.0 g/dL. The patient continued to have persistent fever between 38°C and 39.5°C. He eventually developed multiorgan failure, which required mechanical ventilation and continuous renal replacement therapy (CRRT) support. To evaluate the underlying cause of the progressive anemia and thrombocytopenia the patient underwent a bone marrow biopsy which showed a hypercellular marrow with activated hemophagocytic macrophages (Figure 1). Flow cytometry on the bone marrow aspirate was negative for hematolymphoid malignancy. Further laboratory tests revealed a ferritin level of 62171 ng/dL (normal range: 14-338 ng/dL), triglycerides of 1310 mg/dL (normal range: 30-149 mg/dL) and a soluble CD25 (soluble IL-2 receptor alpha) level of 819 U/mL (normal range: 1033 U/mL or less). A diagnosis of HLH was made and subsequently the patient was started on IV Etoposide according to the HLH-94 protocol. MRI of the brain and CSF studies were negative for CNS involvement. Cyclosporine was not given due to impaired kidney function and the risk of developing posterior reversible encephalopathy syndrome (PRES). The patient also received Pneumocystis jiroveci pneumonia prophylaxis with trimethoprim-sulfamethoxazole throughout therapy. He responded gradually to therapy and was successfully extubated after 13 days of mechanical ventilation. Kidney and liver functions slowly recovered and his blood counts stabilized. He was discharged to the rehabilitation ward 52 days after admission. On the day of discharge his white blood cell count was 4.0x103 cells/mL, hemoglobin 8.1 g/dL, platelets 481x103 cells/mL, ferritin 3822 ng/ dL, triglyceride 169 mg/dL and liver function tests were normal. The patient has normal functional status 3 years after presentation. Follow up laboratory tests have shown normal blood counts in addition to normal kidney and liver function. Figure 2 illustrates the trend for pertinent laboratory values throughout the hospital stay.