Hypereosinophilic syndrome

Hypereosinophilic Syndrome
Yoavanit Srivaro M.D.

Outline
• Historical Background
• Eosinophil:Morphology,Production,
Tissue Distribution
• Definition
• Pathogenesis
• Epidemiology
• Classification
• Clinical manifestation
• Diagnosis
• Treatment

Year Event
1846 1st observed by Wharton Jones
1879 1st named by Paul Ehrlich
1968 Term Hypereosinophilic syndrome coined
by Hardy and Anderson
1979 Diagnosis critierias for HES established by
Chusid and colleagues
1994 1st description of lymphocyte-variant
hypereosinophilia
1998 Identification of rearrangement of the
FGR1 gene
2001 WHO diagnostic criteria for HES and CEL
2001-2002 Succesful empiric treatment of HES pts
with imatinib
2002 Characteriation of the 1st PDGFR alpha
rearrangement
2003 Identification of the FIP1L1-PDGFR alpha

Eosinophil
• Morphology
• Production
• Tissue Distribution

Kita H. et al.Middleton's Allergy ; 8th edition. 2014. p. 265-79

Date of download: 12/28/2014 Copyright © 2014 McGraw-Hill Education. All rights reserved.
Transmission electron micrograph (×10,000) of an eosinophil showing the characteristic binucleate cell with specific granules containing an
electron dense core. The major contents of the cell are listed.
(Courtesy of Dr. A. Dewar, National Heart and Lung Institute.)
CLC, Charcot Leyden crystal; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPO, eosinophil peroxidase; GF, growth
factor; GM-CSF, granulocyte-monocyte colony-stimulating growth factor; HETE, hydroxyeicosatetraenoic acid; LT, leukotriene; MBP, major basic
protein; PAF, platelet-activating factor; PDGF, platelet-derived growth factor; PG, prostaglandin; PSGL, P-selectin glycoprotein ligand; TBX,
Legend:
From: Chapter 62. Eosinophils and Their Disorders
Williams Hematology, 8e, 2010

Eosinophil:Production
• Hematopoietic factors for eosinophil
production & differentiation
- IL-3
- IL-5
- GM-CSF

Ackerman SJ, Bochner BS. Mechanisms of eosinophilia in the pathogenesis of hypereosinophilic disorders.
Immunology and allergy clinics of North America. 2007;27(3):357-75.

Eosinophil:Tissue Distribution
• Primarily a tissue-dwelling cell
• In humans the tissue eosinophil-to-blood
ratio is about 100 : 1
• GI tract (but not the esophagus), regulated by
eotaxin-1
• Eosinophils also home into the thymus,
mammary gland, and uterus, also controlled
by eotaxin-1

Eosinophil:Tissue Distribution
• Mean bone marrow maturation& storage time is about
4.3 days
• Short half-life of 8 to 18 hrs (after enter the blood)
• Normal range of blood eosinophils is
0 to 500 cells/microliter
• Exhibits diurnal variation in humans
Lowest : morning
Highest : evening
• Tissue life span 2 to 5 days
• Cytokines increase eosinophil survival in vitro up to 14
days

Definition
Eosinophilia
Blood eosinophil count exceeding 500 cells/microliter
Severity of eosinophilia
• Mild eosinophilia 500 to 1,500 cells/microliter
• Moderate eosinophilia 1,500 to 5,000 cells/microliter
• Severe eosinophilia > 5,000 cells/microliter
Roufosse F, Weller PF. Practical approach to the patient with hypereosinophilia. The Journal of allergy and
clinical immunology. 2010;126(1):39-44.

Klion AD. et al.Middleton's Allergy ; 8th edition. 2014. p. 1205-23.

Definition
Diagnostic criteria for HES established by Chusid and
colleagues,1975
1.Peripheral blood eosinophilia (>1,500 cells/microliter)
for longer than 6 months
2.Evidence of eosinophil-related target organ damage
3.Exclusion of all other etiologies for eosinophilia
Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with
review of the literature. Medicine. 1975;54(1):1-27.

Definition
Contemporary consensus proposal on criteria and
classification of eosinophilic disorders and related
syndromes
1. Hypereosinophilia-absolute eosinophil count >1,500
cells/microlitr for 1 mo,checked on 2 occasions*
2. Evidence of eosinophil-mediated target organ
damage
3. Exclusion of all other potential causes of
hypereosinophilia
Valent P, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and
related syndromes. The Journal of allergy and clinical immunology. 2012;130(3):607-12.e9.

Definition
*Tissue hypereosinophilia can be identified in
addition to an elevated absolute eosinophil count
with tissue hypereosinophilia, defined as:
1. Eosinophils >20% of nucleated cells in bone
marrow
2. Extensive tissue infiltration of target organ by
histologic analysis
3. Histologic evidence of eosinophil degranulation
in a target tissue in the absence of eosinophils in
that target tissue

HE-related organ damage
Organ dysfunction
With
Marked tissue eosinophil
infiltrates
And/Or
Extensive deposition of
eosinophil-derived proteins
In the presence or absence
of marked tissue eosinophils
(1) Fibrosis (lung, heart,
digestive tract, skin, and others)
(2) Thrombosis with or without
thromboembolism
(3) Cutaneous (including
mucosal) erythema,
edema/angioedema, ulceration,
pruritus, and eczema
(4) Peripheral or central
neuropathy with chronic or
recurrent neurologic deficit
And 1 or
more of
the
following

Pathogenesis
• 2 Pathogenetically different conditions can
trigger eosinophil growth & accumulation
1) Intrinsic defect of eosinophil-committed
neoplastic progenitor cells
: mutations including those involving PDGFR
or FGFR1
2) overproduction of cytokines:IL-3 or IL-5
Valent P, Klion AD, Rosenwasser LJ, Arock M, Bochner BS, Butterfield JH, et al. ICON: Eosinophil Disorders.
The World Allergy Organization journal. 2012;5(12):174-81.

Pathogenesis
• Degree & pattern of organ involvement are governed
by 2 distinct factors.
1) Increased production and/or persistent
accumulation of (normal or neoplastic) eosinophils
2) Persistent activation of eosinophils

Pathogenesis
• Mediators &substances : from activated
eosinophils can cause
1) Tissue remodeling and/or tissue damage.
2) Activate platelets and endothelial cells
3) Alter the production/expression of
prothrombotic and antifibrinolytic substances
Tissue fibrosis and Thrombosis

Epidemiology
Surveillance, Epidemiology, and End Results
(SEER) database
• Prevalence of HES or chronic eosinophilic
leukemia in the United States is between 0.3
and 6.3 cases per 100,000 person-years
Crane MM, Chang CM, Kobayashi MG, Weller PF. Incidence of myeloproliferative hypereosinophilic
syndrome in the United States and an estimate of all hypereosinophilic syndrome incidence. J Allergy Clin
Immunol 2010;126: 179-81.

•SEER 17 area registries
•2001-2005
•131 incident cases
•78 males & 53 females
•Median age at dx :
52.5 years
Immunol 2010;126: 179-81.

•SEER 17 area registries
•2001-2005
•131 incident cases
•78males & 53 females
•Median age at dx :
52.5 years
Immunol 2010;126: 179-81.

Classification
Klion AD. et al.Middleton's Allergy ; 8th edition. 2014. p. 1205-23

Classification

Classification
Myeloproliferative forms of HES
• Mutation in hematopoietic multipotent
precursor cells: primary stimulation of the
eosinophilia
• Mutation-related gain-of-function kinase
specifically involved in the pathogenesis
(FIP1L1/PDGFR alpha-associated HES)
Simon HU, et al. Refining the definition of hypereosinophilic syndrome. The Journal of allergy and clinical
immunology. 2010;126(1):45-9.

Encodes
Highly conserved protein
involved in messenger
RNA processing
Encodes
•Receptor tyrosine kinase
•Platelet-derived growth
factor receptor alpha
Montgomery ND, et al. Diagnostic complexities of eosinophilia. Archives of pathology & laboratory
medicine. 2013;137(2):259-69.

•The 4q12 deletion removes
negative regulatory motifs
encoded to the exon 12 breakpoint
•Leading to constitutive activation of this receptor
:Receptor tyrosine kinase
:Platelet-derived growth factor receptor alpha
Montgomery ND, et al. Diagnostic complexities of eosinophilia. Archives of pathology & laboratory
medicine. 2013;137(2):259-69.

FIP1L1-PDGFRα enhances eosinophil development
by
Modifying the expression & activity of lineage-specific
transcription factors through Ras/MEK and p38MAPK cascades
Fukushima K,et al. FIP1L1-PDGFRalpha imposes eosinophil lineage commitment on hematopoietic
stem/progenitor cells. The Journal of biological chemistry. 2009;284(12):7719-32.

Classification
Myeloproliferative forms of HES
• Clinical
Hepatomegaly, Splenomegaly
• Laboratory
- Circulating myeloid precursors, Increased serum
vitamin B12 or Tryptase, Anemia, Thrombocytopenia
- Hematologic (myeloid fibrosis, left shift in maturation
of myeloidprecursors)
- And/or cytogenetic abnormalities suggestive of
myeloproliferative disease.
immunology. 2010;126(1):45-9.

Classification
Lymphocytic forms of HES
• Lymphocytes generate increased amounts of at least
1 eosinophil hematopoietin
- IL-3 and/or IL-5
- Primary cause of secondary polyclonal blood
hypereosinophilia
immunology. 2010;126(1):45-9.

Classification
Lymphocytic forms of HES
• Aberrant T cells are most often CD3−CD4+ orCD3+CD4−CD8−
• Typically present with dermatologic manifestations
• Elevated serum IgE & TARC (CCL17) levels
• Flow cytometry & T cell receptor rearrangement studies are
useful in confirming the dx
• Progression to T cell lymphomas occurs in fewer than 3% of
these pts

Classification
Overlap form of HES
Organ-restricted eosinophilic disorders
• Represent T cell–driven HES
• Eosinophilic pneumonia, eosinophilic intrinsic
asthma, CSS, Eosinophilic sinus disease,
Eosinophilic dermatitis,EGID
immunology. 2010;126(1):45-9.

Classification

Classification
Undefined forms of HES
Episodic angioedema with eosinophilia (Gleich’s syndrome)
• 1st described by Gerald Gleich and colleagues in 1984
• This 1st report described four pts (three males, one female) with
- Recurrent episodes of angioedema and/or urticaria
- 10% to 20% increase in body weight
- Fever (three patients)
- Hypereosinophilia
- Elevated IgM
- Leukocyte counts ( reach as high as 108,000 cells/microliter with
88% eosinophils.)
• These four pts were followed for a period of 2 to 17 years & none of them
developed organ involvement
Banerji A,et al. Cytokine-associated angioedema syndromes including episodic angioedema with eosinophilia
(Gleich's Syndrome). Immunology and allergy clinics of North America. 2006;26(4):769-81.

Classification
• Clinical presentation and diagnosis
- Recurrent episodes of
# angioedema, urticaria,pruritus ,fever,weight gain
# elevated serum IgM, oliguria, leukocytosis
with eosinophilia &eosinophil degranulation in the dermis
# an elevated IgE

Classification
• Clinical presentation and diagnosis
- Episodes usually occur every few weeks to months
- Complete resolution of symptoms between episodes
- Good prognosis with no visceral organ involvement

F.H. Hsieh / Ann Allergy Asthma Immunol 112 (2014) 484e488

Clinical manifestation
Ogbogu PU, et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics
and response to therapy. The Journal of allergy and clinical immunology. 2009;124(6):1319-25.e3.

Cardiac Disease
• Acute, necrotic stage
• Second stage of heart disease
• Later thrombotic & fibrotic stage

Cardiac Disease
Acute, necrotic stage
 Early weeks of illness
 Endocardial damage
 Myocardial infiltration with eosinophils &lymphocytes
 Myocardial necrosis
 Eosinophil degranulation & microabscesses
 Normal cardiac findings
 Prominent subungual and conjunctival splinter
hemorrhages.
 Elevations of serum troponin

Cardiac Disease
Second stage of heart disease
 Thrombus formation :ventricular endocardium
 Progressive scarring :entrapment of chordae
tendineae
- Mitral valve regurgitation
- Tricuspid valve regurgitation
 Endomyocardial fibrosis: restrictive
cardiomyopathy

Cardiac Disease
Later thrombotic & fibrotic stages
 Signs & Symptoms
- Dyspnea
- Chest pain
- Signs of LV&RV CHF
- Murmurs of atrioventricular valve regurgitation
- Cardiomegaly

Cardiac Disease
Later thrombotic & fibrotic stages
 Echocardiography & MRI
- Intracardiac thrombi
- Endomyocardial fibrosis
 Benefit from
- Medical tx for CHF
- Valve replacement

Neurologic Complication
• The first type
: Embolic strokes
• The second type
: Encephalopathy
: Upper motor neuron signs
• The third type
: Peripheral neuropathy

Moore PM, Harley JB, Fauci AS. Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Annals
of internal medicine. 1985;102(1):109-14.

• The first type
: Embolic strokes
• The second type
: Encephalopathy
• The third type

• The first type
: Embolic strokes
• The second type
: Encephalopathy
• The third type
Klion AD et al.Middleton's Allergy ; 8th edition. 2014. p. 1205-23.

Skin Manifestation
• Angioedema & urticaria
• Pruritic papules or nodules
• Cutaneous microthrombi or digital arteritis
• Mucosal ulcers & lymphomatoid papulosis

Skin Manifestation
• Angioedema & urticaria
- Benign courses without cardiac or neurologic
complications
- Not require corticosteroid therapy, or
respond to prednisone alone

Leiferman KM, Gleich GJ, Peters MS. Dermatologic manifestations of the hypereosinophilic syndromes.
Immunology and allergy clinics of North America. 2007;27(3):415-41.

Skin Manifestation
• Pruritic papules or nodules
Biopsies
• Perivascular infiltration with eosinophils
• Mild or moderate perivascular neutrophilic &
mononuclear infiltrates without vasculitis

Skin Manifestation
• Mucosal ulcers & lymphomatoid papulosis
- Refractory to therapy
- Ulcer:Mouth, nose, pharynx, penis,
esophagus, stomach & anus
- PDGFRA-positive disease

Respiratory Symptom
• Chronic, persistent,nonproductive cough
• Asthma
• Respiratory symptoms due to CHF
• Pulmonary emboli
• Eosinophilic lung infiltrates
• Pulmonary fibrosis with cardiac fibrosis

Gastrointestinal Symptom
• Eosinophilic gastritis
• Enterocolitis & colitis
• Hepatic involvement
- Chronic active hepatitis
- Focal hepatic lesions
- Eosinophilic cholangitis
- Budd-Chiari syndrome from hepatic vein
obstruction

Immunologic abnormalities
Elevated IgE
• Lymphoproliferative or episodic angioedema
variants of HES
• Better prognosis

Labaratory abnormalities
•Elevated vitamin B12
levels
•Abn LAP scores
•Cytogenetic
abnormalities
•Myelofibrosis, myeloid
dysplasia & basophilia
• Myeloproliferative
variant of HES
• Require cytotoxic
therapy
• Less likely to respond
to prednisolone

Myeloproliferative
variant

Lymphoproliferative
variant

Evaluate end
organ
involvement

Treatment
• Patients with eosinophilia without organ
involvement
- Benign course
- Require no therapy.
- Monitoring :serum troponin levels &
echocardiographic q 6-months

Treatment
• F/P-negative eosinophilic patients
- A trial course of prednisone (60 mg/day or 1
mg/kg/ day)

Treatment
• Patients with myeloproliferative variants of
HES (documented PDGFRA mutations)
- Imatinib 100 to 400 mg/day.
- Clinical & hematologic response within 2 to
4 weeks
- Newer tyrosine kinase inhibitors: nilotinib,
sorafenib, & dasatinib

Treatment
• Patients with other variants of HES with organ
involvement
Prednisone (1 mg/kg/day or 60 mg/day in adults)
If blood eosinophilia is suppressed
Tapered to an alternate-day schedule

Treatment
• Second line drug for PDGFRA-NEGATIVE HES
patients
1. Hydroxyurea
2. Interferon-α
3. Neutralizing anti-IL- 5 monoclonal
antibodies

Treatment
• Patients with aggressive disease that is
unresponsive to standard therapies
- Bone marrow transplantation

Treatment
• Marked valvular compromise Cardiac surgery
• Endomyocardial thrombosis Thrombectomy
• Endomyocardial fibrosis Endomyocardectomy

Result
18 of 161 patients (11%)
(FIP1L1-PDGFR alpha)
mutation—positive
29 of 168 patients (17%)
Aberrant or clonal T-cell
population.

FIG 2. Response to treatment. The bars represent response rates after 1 month of therapy

Corticosteroid monotherapy
induced complete or partial
responses at 1 month in 85%
(120/141)

Hydroxyurea monotherapy
induced complete responses at
1 month in 33% (6/18)

IFN-alpha monotherapy
induced complete responses at
1 month in 17% (2/12)

Anti IL-5 monotherapy induced
complete responses at 1 month
in 80% (12/15)

Imatinib monotherapy induced
complete responses at 1 month
in 65% (20/31)

68 Pts received
Imatinib
17 Pts
FP -positive 43 Pts
FP -negative
15 Pts
Complete
response
2 Pts
Non
response
6 +4Pts
Complete +Partial
response
33 Pts
Non
response

Summary
• Markedly increased blood eosinophilia
>1,500 cells/microliter
• Must first & foremost address 2 questions
1) Secondary to common and treatable
underlying condition?
2) Itself causing rapidly progressive damage?

Summary
• Serious complications of hypereosinophilia
:require urgent tx
1) Myocardial damage
2) Pulmonary involvement with hypoxia
3) Neurological involvement

Summary
• Failure to detect and underlying cause of
eosinophilia Diagnostic test to identify of
HES variant

Hypereosinophilic syndrome

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