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Highly Accessed Review

Recent advances in the diagnosis and treatment of hemophagocytic lymphohistiocytosis

Sebastian FN Bode1, Kai Lehmberg2, Andrea Maul-Pavicic1, Thomas Vraetz1, Gritta Janka2, Udo zur Stadt3 and Stephan Ehl1*

Author Affiliations

1 Centre of Chronic Immunodeficiency, University Medical Center Freiburg, D-79106 Freiburg, Germany

2 Department of Haematology and Oncology, Children's Hospital, University of Hamburg, D-20246 Hamburg, Germany

3 Center for Diagnostic, University Medical Center, Hamburg-Eppendorf, D-20251 Hamburg, Germany

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Arthritis Research & Therapy 2012, 14:213  doi:10.1186/ar3843

Published: 8 June 2012

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting high amounts of inflammatory cytokines. It is a frequent manifestation in patients with predisposing genetic defects, but can occur secondary to various infectious, malignant, and autoimmune triggers in patients without a known genetic predisposition. Clinical hallmarks are prolonged fever, cytopenias, hepatosplenomegaly, and neurological symptoms, but atypical variants presenting with signs of chronic immunodeficiency are increasingly recognized. Impaired secretion of perforin is a key feature in several genetic forms of the disease, but not required for disease pathogenesis. Despite progress in diagnostics and therapy, mortality of patients with severe HLH is still above 40%. Reference treatment is an etoposide-based protocol, but new approaches are currently explored. Key for a favorable prognosis is the rapid identification of an underlying genetic cause, which has been facilitated by recent immunological and genetic advances. In patients with predisposing genetic disease, hematopoietic stem cell transplantation is performed increasingly with reduced intensity conditioning regimes. Current research aims at a better understanding of disease pathogenesis and evaluation of more targeted approaches to therapy, including anti-cytokine antibodies and gene therapy.