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

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

14. 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

15. 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

16. 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

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

18. 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

19. 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.