Download 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
 Associated with Immune Deficiencies –
Chediak-Higashi Syndrome, Griscelli
syndrome, x-linked proliferative
syndrome
 Onset of disease usually <1 year of age
Classification
 Acquired
 Infections
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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
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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)
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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
Normal Function
NK cell/CTL
Target cell
Target Cell

Activated NK cell/CTL
Increased IFN-g
Apoptosis of Target Cell
Activate Macrophages for
phagocytosis
NK cell/CTL
Target Cell
Activated NK
Cell/CTL
Target Cell
↑ INF-g
Apoptosis
Activate Macrophages
↑↑ CYTOKINES
Persistence of target cells
↑ NK/CTL Proliferation
Cytokines
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Fever – IL-1, IL-6
Cytopenia
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Hemophagocytosis
Hematopoiesis suppression via: IFN–g, TNF-a, IL-B
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IL-1B activation of plasminogen
DIC from elevated IFN-g, TNF-a
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IFN-g  cholestasis, Fas/Fas-ligand  apoptosis
Elevated Ferritin - Increased IL-1B, secreted by
macrophages
HyperTG - TNF-a inhibition of lipoprotein lipase
Coagulopathy
Liver Dysfunction
Renal Failure - Elevated IL-6
Elevated CD25 – secreted from activated T-lymphocytes
Prognosis
 Mortality 22-59%
 Prognostic Factors predicting death
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>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-/chemotherapy
Treatment
 EBV-associated
 EBV-specific antiviral therapy not
effective
 Immunomodulatory
 TNF-a blockade, infliximab
 Emerging therapies: anti-IL-1, antiCD25, 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.