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;

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

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

Hemophagocytic

SyndromeDR RAFIQULLAH KHANTMO PWA HMC

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.

Cont.

1 case/million/yr

M:F1:1

FHLH <4 yr of age,

Secondary HLH>6 yrs.

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.

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

Infections Associated with

Hemophagocytic Syndrome

MYCOBACTERIAL

VIRAL

Epstein-Barr virus

HIV

Adenovirus

Cytomegalovirus

Dengue virus

Herpes simplex virus

Parvovirus B19

Varicella-zoster virus

Cont.

FUNGAL

Candida albicans

Cryptococcus neoformans

Histoplasma capsulatum

cont.

BACTERIAL

• Enteric gram-negative rods

• Babesia microti

• Brucella abortus

• Haemophilus influenzae

• Mycoplasma pneumoniae

• Staphylococcus aureus

• Streptococcus pneumoniae

cont.

PARASITIC----

Leishmania donovani

RICKETTSIAL----

Coxiella brunetii

Others

AUTOIMMUNE

JIA,

SLE,

IBD

MALIGNANCY ASSOCIATED

Lymphoma

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,

Cont.

Physical examination reveals

Hepatosplenomegaly,

Lymphadenopathy,

Respiratory distress, and

Symptoms of CNS involvement

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

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)

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)

BM ASPIRATION

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

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

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

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.

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

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

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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