Hemophagocytic Syndromes

Maggie Davis HovdaMorning Report10/30/2009

Hemophagocytosis

Pathologic finding of activated macrophages engulfing erythrocytes, leukocytes, platelets, and their precursors

Healthsystem.virginia.edu

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

Classification

Acquired Infections

Viral: Herpes viruses, esp EBV, CMV Bacterial Fungal Protozoal

Malignancy Lymphoma

Rheumatologic Disease

Incidence

Primary HLH 1/50,000 live births in a retrospective

review in Sweden Male:Female 1:1

Presentation Clinical

Fever, Splenomegaly – most common Other: Hepatomegaly, LAD, jaundice, rash CNS involvement: encephalitis, meningismus,

seizure

Labs Cytopenias Elevated triglycerides Elevated Ferritin Decreased Fibrinogen

Differential Diagnosis

Severe Sepsis Acute Leukemia TTP

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

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

Pathophysiology

Genetic mechanisms for primary HLH known

Mechanism of acquired HLH unknown

From Uptodate.com

Target cellNK cell/CTL

Apoptosis of Target Cell

Increased IFN-g

Activate Macrophages for phagocytosis

Target Cell Activated NK cell/CTL

Normal Function

Target CellNK cell/CTL

Target CellActivated NK Cell/CTL

Apoptosis

Persistence of target cells ↑ NK/CTL Proliferation

↑ INF-g

Activate Macrophages

↑↑ CYTOKINES

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

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

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

Treatment Steroids + Etoposide + Cyclosporine A Other considerations

ATG IVIG

Bone Marrow Transplant Familial Disease Non-familial: only if fail immuno-/chemo- therapy

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

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.