Recognition of hemophagocytic lymphohistiocytosis in sickle cell vaso-occlusive crises is a potentially lifesaving diagnosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare but aggressive and potentially life-threatening syndrome caused by a hyperinflammatory response leading to organ damage. It is characterized by fevers, cytopenias, hepatosplenomegaly, hyperferritinemia, hypertriglyceridemia and hemophagocytosis by activated macrophages. HLH can either be primary (inherited) or secondary. Primary HLH generally presents in infancy and is associated with mutations that affect cytotoxic Tcell or inflammasome function. Secondary HLH is thought to be more common and to be due to infection, hematologic malignancy, autoimmune disorders or drugs. Sickle cell anemia is caused by homozygous mutations of the beta(β)-globin gene in which the sixth amino acid, glutamic acid, is replaced by valine, producing a hydrophobic motif in deoxygenated hemoglobin S (HbS). Patients with sickle cell anemia suffer from complications of chronic hemolysis and recurrent vaso-occlusive crises (VOC). Patients who are compound heterozygotes for HbS and hemoglobin C also can suffer from VOC. HLH in sickle cell disease and related hemoglobinopathies has been described but is not well characterized and has been associated with mycobacterium avium-complex infection, malaria, transfusion and bone pain crises. HLH in sickle cell patients is under-recognized so the true incidence is not known. HLH is a fatal syndrome that requires a timely diagnosis in order to initiate life-saving therapy. The clinical and laboratory features of sickle cell VOC and HLH partially overlap, making the diagnosis of HLH difficult in these patients. Here we present 2 cases of HLH in sickle cell patients where timely diagnosis and treatment ultimately led to favorable outcomes. Patient 1 is a 35-year old African American female with a history of sickle cell anemia, chronic lower extremity ulcerations, prior admissions for acute chest syndrome, asthma and migraine who presented to our hospital with worsening of chronic lower extremity pain. Her lifetime transfusion history was approximately 23 units of red cells and her baseline ferritin was 442 ng/mL. She was admitted for treatment of presumptive VOC. While in hospital, she developed recurrent fevers that did not respond to broad-spectrum intravenous (IV) antibiotics. Blood cultures and work-up for infection were unrevealing. The patient deteriorated clinically and was transferred to the intensive care unit. She developed hypoxia and imaging showed diffuse lymphadenopathy. During her hospital stay she developed worsening transaminitis [alanine transaminase (ALT) and aspartate aminotransferase (AST)], coagulopathy, pancytopenia and acute kidney injury (AKI) requiring hemodialysis. She was transfused four units of packed red blood cells and underwent an exchange transfusion that did not change her clinical status. Human immunodeficiency virus (HIV), hepatitis A/B/C, cytomegalovirus (CMV) and parvovirus B19 serological tests were negative. Although initially negative for acute Epstein-Barr virus (EBV) infection, she ultimately had a mild transient viremia (263 copies/mL; normal < 200). Laboratory testing demonstrated hyperferritinemia (9597 ng/mL; normal 10-109), hypertriglyceridemia (340 mg/dL; normal 40-200), hypofibrinogenemia (70 mg/dL; normal 180-460), and an elevated soluble IL-2R (5250 pg/mL; normal 190-570). A bone marrow (BM) biopsy showed hemophagocytosis, histiocytosis and BM damage (Figure 1A). Based on these clinical parameters and pathological finding, a diagnosis of HLH was made. BM cultures and acid-fast bacilli stains were negative for bacteria, fungi and mycobacteria. Approximately one month after hospital admission and three weeks after the completion of the exchange transfusion, the patient was started on intravenous immunoglobulin (400 mg/kg