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Hemophagocytic Syndromes

Hemophagocytic Syndromes. Maggie Davis Hovda Morning Report 10/30/2009. Hemophagocytosis. Pathologic finding of activated macrophages engulfing erythrocytes, leukocytes, platelets, and their precursors. Healthsystem.virginia.edu. Classification. Primary Familial/Genetic

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Hemophagocytic Syndromes

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  1. Hemophagocytic Syndromes Maggie Davis Hovda Morning Report 10/30/2009

  2. Hemophagocytosis • Pathologic finding of activated macrophages engulfing erythrocytes, leukocytes, platelets, and their precursors Healthsystem.virginia.edu

  3. Classification • Primary • Familial/Genetic • Associated with Immune Deficiencies – Chediak-Higashi Syndrome, Griscelli syndrome, x-linked proliferative syndrome • Onset of disease usually <1 year of age

  4. Classification • Acquired • Infections • Viral: Herpes viruses, esp EBV, CMV • Bacterial • Fungal • Protozoal • Malignancy • Lymphoma • Rheumatologic Disease

  5. Incidence • Primary HLH • 1/50,000 live births in a retrospective review in Sweden • Male:Female 1:1

  6. Presentation • Clinical • Fever, Splenomegaly – most common • Other: Hepatomegaly, LAD, jaundice, rash • CNS involvement: encephalitis, meningismus, seizure • Labs • Cytopenias • Elevated triglycerides • Elevated Ferritin • Decreased Fibrinogen

  7. Differential Diagnosis • Severe Sepsis • Acute Leukemia • TTP

  8. Work-up • Bacterial: Bl Cx, U Cx, CXR • Viral pathogens: EBV, CMV, parvo, HIV, HHV-6 • Fungal Cx and serology • Eval for lymphoproliferative DO – pan scan, BM bx • Recent Travel or animal exposure – eval for Leishmaniasis, brucellosis, rickettsioses, malaria • HIV +: serum crypto ag, primary or reactivation toxo

  9. Diagnostic Criteria • Known Genetic Defect • Clinical and Laboratory (5/8) • Fever • Splenomegaly • Cytopenia in ≥ 2 cell lines • Hypertriglyceridemia and/or hypofibrinogenemia • Elevated Ferritin • Elevated CD25 • Decreased or absent NK-cell activity • Hemophagocytosis in bone marrow, CSF, or LN

  10. Pathophysiology • Genetic mechanisms for primary HLH known • Mechanism of acquired HLH unknown From Uptodate.com

  11. Normal Function NK cell/CTL Target cell Target Cell  Activated NK cell/CTL Increased IFN-g Apoptosis of Target Cell Activate Macrophages for phagocytosis

  12. NK cell/CTL Target Cell Activated NK Cell/CTL Target Cell ↑ INF-g Activate Macrophages Apoptosis ↑↑ CYTOKINES Persistence of target cells ↑ NK/CTL Proliferation

  13. Cytokines • Fever – IL-1, IL-6 • Cytopenia • Hemophagocytosis • Hematopoiesis suppression via: IFN–g, TNF-a, IL-B • Elevated Ferritin - Increased IL-1B, secreted by macrophages • HyperTG - TNF-a inhibition of lipoprotein lipase • Coagulopathy • IL-1B activation of plasminogen • DIC from elevated IFN-g, TNF-a • Liver Dysfunction • IFN-g  cholestasis, Fas/Fas-ligand  apoptosis • Renal Failure - Elevated IL-6 • Elevated CD25 – secreted from activated T-lymphocytes

  14. Prognosis • Mortality 22-59% • Prognostic Factors predicting death • >30 yo • Underlying disease process • Hb <10 • Platelet <100 k • Ferritin > 500 ug/l • Bili or alk phos elevation

  15. Our Patient: HIV and EBV • HIV • HIV reported with severely low and normal CD4 counts in HIV + pts • Implicated as inciting infection • EBV • Usually targets B-lympho’s, but in HLH targets T-lympho’s • Associated with elevated peripheral blood levels • More common in Asian countries

  16. Treatment • Steroids + Etoposide + Cyclosporine A • Other considerations • ATG • IVIG • Bone Marrow Transplant • Familial Disease • Non-familial: only if fail immuno-/chemo- therapy

  17. Treatment • EBV-associated • EBV-specific antiviral therapy not effective • Immunomodulatory • TNF-a blockade, infliximab • Emerging therapies: anti-IL-1, anti-CD25, anti-CD 20, IFN-a

  18. References • Doyle, T., Bhagani, S., Cwynarski, k. Haemophagocytic syndrome and HIV. Current Opinion in Infectious Diseases. 2009, 22:1-6. • Arceci, R. When T cells and macrophages do not talk: the hemophagocytic syndromes. Current Opinion in Hematology. 2008, 15:359-367. • Janka, G. Hemophagocytic Syndromes. Blood Reviews. 2007, 21:245-253. • Creput, C. et al. Understanding organ dysfunction in hemophagocytic lymphohistiocytosis. Intensive Care Medicine. 2008, 34:1177-1187. • Fisman, D. Hemophagocytic Syndromes and Infection. Emerging Infectious Diseases. 2000, 601-608.

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