Hemophagocyitic histiocytosis
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Transcript of Hemophagocyitic histiocytosis
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Case history
4 yr old boy with unexplained fever=1 month
Fever was high grade,intermittent associated with pallor.
O/E Severely anemic, jaundice with no
lymphadenopathy;
Hepatosplenomegaly, liver span of 11 cm,smooth in
consistency with regular margins & spleen 2 cm below
Left costal margin,ascites –ve;
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Investigations
Blood smear
Hb=5.8(hypc mic),RBC=3.6 mil/cmm,TLC=9200,DLC89%
L,10% N, platelet=90000,Retic count 8%
Serum LDH=1111 U/L
BM aspiration
Hypercellular,reactive
lymphocytosis,hemophagocytosis++
No evdince of leukemia,lymphoma
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cont.
CXR Unremarkable
Monospot test=-ve
S,ferriten=843 ng/ml
S,triglycerides=559 mg/dl
SBr= 2.5 mg/dl,
SGPT=91 u/l
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Hemophagocytic
SyndromeDR RAFIQULLAH KHANTMO PWA HMC
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Accumulation of antigen-processing cells
(macrophages).
uncontrolled hemophagocytosis and uncontrolled
activation (upregulation) of inflammatory cytokines .
Tissue infiltration by activated CD8 T lymphocytes and
activated macrophages as well as hypercytokinemia
are classic features.
phagocytic cells lack the two markers (Birbeck granules
and CD1a-positivity) characteristic of the cells found in
LCH.
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Cont.
1 case/million/yr
M:F1:1
FHLH <4 yr of age,
Secondary HLH>6 yrs.
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Types
A. Primary hemophagocytic syndrome OR Familial
hemophagocytic lymphohistiocytosis (FHLH), previously
called Familial erythrophagocytic lymphohistiocytosis
FEL
only inherited form(AR).
Specific genes involved with FEL include mutations of
perforin, Munc 13–4, and Syntaxin-11.
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Cont.
B. Infection-associated hemophagocytic syndrome
(IAHS), also called secondary hemophagocytic
lymphohistiocytosis.
Disseminated lesions that involve many organ systems.
Infiltration of the involved organ with activated
phagocytic macrophages and lymphocytes
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Infections Associated with
Hemophagocytic Syndrome
MYCOBACTERIAL
VIRAL
Epstein-Barr virus
HIV
Adenovirus
Cytomegalovirus
Dengue virus
Herpes simplex virus
Parvovirus B19
Varicella-zoster virus
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Cont.
FUNGAL
Candida albicans
Cryptococcus neoformans
Histoplasma capsulatum
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cont.
BACTERIAL
• Enteric gram-negative rods
• Babesia microti
• Brucella abortus
• Haemophilus influenzae
• Mycoplasma pneumoniae
• Staphylococcus aureus
• Streptococcus pneumoniae
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cont.
PARASITIC----
Leishmania donovani
RICKETTSIAL----
Coxiella brunetii
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Others
AUTOIMMUNE
JIA,
SLE,
IBD
MALIGNANCY ASSOCIATED
Lymphoma
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CLINICAL MANIFESTATIONS.
Fever,
maculopapular and/or petechial rash,
weight loss, and irritability.
FHLH also is characterized by severe immunodeficiency.
Swollen or hemorrhagic gums
Feeding problems (especially prominent in infants)
Abdominal pain, vomiting, diarrhea,
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Cont.
Physical examination reveals
Hepatosplenomegaly,
Lymphadenopathy,
Respiratory distress, and
Symptoms of CNS involvement
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Diagnostic Criteria for
Hemophagocytic
Lymphohistiocytosis
By fulfilling 1 or 2 of the following criteria
1. Molecular dx consistent with HLH(PRF mut,SAP mut) OR
2. Having 5 out of 8 of the following
i. Fever
ii. Spleenomegaly
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Cont.
iii. Cytopenia(affecting ~2 cell lineages,hb<9 g/dl,or <10
g/dl for infants < 4 weeks of
age,platelets<100000/ul,neut<1000/ul)
iv. Hypertriglyceridemia(>265mg/dl)&/or
hypofibrogenemia(<150 mg/dl)
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Cont.
V. Hemophagocytosis in BM,spleen or lymph nodes
without evidence of malignancy
VI. Low or absent NK cytotoxicity
VII. Hyperferritinemia(>500 ng/ml)
VIII. Elevated soluble CD25(IL-2R alpha chain;>2400 u/l)
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BM ASPIRATION
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Treatment of HLH
Medical Care;
The newest protocol, HLH-2004goals;to first achieve clinical
stability,then to cure with (BMT)
Patients may be classified into high-risk and low-risk
groupshigh-risk groups receiving the etoposide (i.e, VP-16)
regimens.
Patients at low risktreated with only cyclosporine and
corticosteroids +_IVIG
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Cont.
Initial therapyetoposide and dexamethasone for 8
weeks.
In the HLH-2004 protocol, cyclosporine is added in the
beginning.
Intrathecal methotrexate is used only with persistently
abnormal CSF or progressive neurologic symptoms
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Cont.
children with persistent no familial disease or familial
diseasecontinuation therapy with etoposide IV
infusions, dexamethasone pulses, and cyclosporine PO is
instituted at week 9 from the start treatment.
Alemtuzumabrefractory HLH
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Cont.
When a treatable infection cannot be documented an identical
chemotherapeutic approach, including etoposide, is
recommended.
A thorough evaluation for infection should be undertaken in
immunodeficient patients with hemophagocytosis.
Rarely, the same syndrome may be identified in conjunction with a
neoplasm (e.g., leukemia)treatment of the underlying disease
In some patients, interferon and intravenous immunoglobulin have
been effective.
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Cont.
Surgical Care
BMT is performed when a suitable donor can be found
and the patient is stable.
Life-threatening respiratory difficulty or uncontrolled
hypersplenismsplenectomy
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Prognosis
invariably fatal if not treated.
The median survival rate2-6 months without treatment
Success or failure of an allogeneic BMT is the most
important long-term prognostic factor
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Take home message
If an infant presents with fever, hepatosplenomegaly,
and cytopenia,HLH should be high in the differential
diagnosis.
Pediatricians, dermatologists, and neurologists should
especially take note because the presenting symptoms
of hemophagocytic lymphohistiocytosis are likely to
bring the patient into their offices.
Any suspicion warrants a referral to a pediatric
hematologic-oncologist who is equipped with the
necessary tools to make a rapid diagnosis.
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