hypereosinophilic syndrome

Hypereosinophilic Syndrome

Yoavanit Srivaro M.D.

Outline

• Historical Background

• Eosinophil:Morphology,Production,

Tissue Distribution

• Definition

• Pathogenesis

• Epidemiology

• Classification

• Clinical manifestation

• Diagnosis

• Treatment

Historical Background

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 ptswith imatinib

2002 Characteriation of the 1st PDGFR alpha rearrangement

2003 Identification of the FIP1L1-PDGFR alpha fusion as tx target of imatinib

Eosinophil

• Morphology

• Production

• Tissue Distribution

Eosinophil: Morphology

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, thromboxane; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor.

Legend:

From: Chapter 62. Eosinophils and Their Disorders

Williams Hematology, 8e, 2010

Eosinophil:Production

Eosinophil:Production

• Hematopoietic factors for eosinophilproduction & 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 degranulationin a target tissue in the absence of eosinophils in that target tissue


HE-related organ damage

Organ dysfunction With

Marked tissue eosinophilinfiltrates

And/OrExtensive 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 orrecurrent 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 eosinophilicleukemia 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 hypereosinophilicsyndrome 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


Classification

Myeloproliferative forms of HES

• Mutation in hematopoietic multipotentprecursor cells: primary stimulation of the eosinophilia

• Mutation-related gain-of-function kinasespecifically 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.


Classification


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


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


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


Classification


Classification

Undefined forms of HESEpisodic 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

Undefined forms of HES

Episodic angioedema with eosinophilia (Gleich’s syndrome)

• 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

Undefined forms of HES

Episodic angioedema with eosinophilia (Gleich’s syndrome)

• 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


Classification


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


Clinical manifestation

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 chordaetendineae

- 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


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

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 angioedemavariants of HES

• Better prognosis


Labaratory abnormalities


•Elevated vitamin B12 levels•Abn LAP scores•Cytogenetic abnormalities•Myelofibrosis, myeloid dysplasia & basophilia

• Myeloproliferativevariant of HES• Require cytotoxictherapy• Less likely to respond to prednisolone

Diagnosis


Myeloproliferativevariant


Lymphoproliferativevariant


Evaluate end organ

involvement

Treatment

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 monotherapyinduced complete or partialresponses at 1 month in 85% (120/141)



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



IFN-alpha monotherapyinduced 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 PtsNon

response

6 +4PtsComplete +Partial

response

33 PtsNon

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

Thank You

hypereosinophilic syndrome

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