Eosinophils and hypereosinophilic syndrome

Eosinophil and
Hypereosinophilc
syndrome
22th January 2021
Nattasasi Suchamalawong, MD.
Pediatric Allergy and Immunology Unit,
King Chulalongkorn Memorial Hospital

Outline
Biology of eosinophil
Definition of eosinophilic disorder
Etiology of reactive eosinophilia
Hyperosinophilic syndrome
Overlap of Hypereosinophilic syndrome
Guideline for investigation
Treatment
Quiz

Eosinophil lineage
Kita H et al.Middleton’s Allergy; 9th edition, 2019
O’Sullivan JA, Bochner BS. Eosinophils and eosinophila associated diseases: an update. J Allergy Clin Immunol 2018;141:505–17.
Eosinophils are granulocytes : develop in the bone marrow in
response to IL-5, with a minor role for IL-3, GM-CSF and IL-33.
IL-5 : mediates the release of mature eosinophils into the
bloodstream from where they migrate into tissues .
pre–granulocyte-macrophage progenitor
granulocyte-macrophage progenitors eosinophil lineage–committed progenitors
mature resting eosinophils

Clinic Rev Allerg Immunol (2016) 50:125–139
Eosinophilic positioning in
the immune system
pluripotent stem cells
progenitor
eosinophil
Activated eosinophils
Complex proinflammatory effects:
- direct cytotoxic against tissues
microorganisms
promote thrombosis, fibrosis and
angiogenesis, tissue remodeling,
platelet and endothelial cells activation.
Blanchard and Rothenberg, Adv Immunol. 2009 ; 101: 81–121
Signaling pathway leading from binding of IL-5
- The transcriptional activation in the cell nucleus via the
Ras-Raf1-MEK-ERK pathway.
- The β subunit of the receptor is also able to activate
JAK2-STAT1pathway.

Giuseppe A. Ramirez et al. BioMed Research International Volume 2018, Article ID 9095275, 28 pages
Functional characterization
of eosinophil granules.
major basic protein (MBP)
Eosinophil cationic protein (ECP)
Eosinophil peroxidase (EPX)
Eosinophil-derived neurotoxin (EDN)

LANZKOWSKY’S MANUAL OF PEDIATRIC HEMATOLOGY AND ONCOLOGY, chapter 13 , 2016
Mechanism of eosinophil production in
bone marrow, release in circulation
and migration in tissue

eosinophil recruitment
into the tissue
• Selectin → interaction between eosinophil
and endothelial cell
• Integrin
• ẞ1 (VCA4)
• ẞ2 (CD18 family)
• ɑ4ẞ7 (B7) binding MAdCAM at laminar
propria, lymph nodes and payer’s patch
Marc E. Rothenberg. Allergy Clin Immunol 2004;113:11-28
Eotaxin, a selective chemokine regulating eosinophil migration,
Binds to the eosinophilic chemokine receptor CCR3
Which leads to further upregulation of cytokines
Including IL-3, IL-5, and IL-13
Sara Naramore. JPGN Volume 67, Number 3, September 2018

Liai w et al.Clinic Rev Allerg Immunol (2016) 50:125–139
Cellular features of eosinophils

Cellular structure, receptors, and mediators of eosinophils
Nicola L. Diny, Eosinophils in Autoimmune Diseases, Front. Immunol, 2017
1
2

Proinflammatory role of
eosinophils
Eosinophil : pleiotropic cells that respond to a
variety of triggers. eosinophil granule
constituents are toxic to a variety of tissues
major basic proteins (MBP-1& MBP-2)
matrix composed of
eosinophil cationic protein (ECP),
eosinophil-derived neurotoxin (EDN) and
eosinophil peroxidase (EPO).
extracellular deposition of MBP and ECP in the
small bowel : correlation between the level of
eosinophils and disease severity.
Marc E. Rothenberg. Allergy Clin Immunol 2004;113:11-28
Chen E. Rosenberg ,Marc E. Rothenberg. Middleton. Edition 9th.2020

Cytotoxic granules in eosinophil
function major basic
proteins (MBP)
eosinophil cationic
protein (ECP)
eosinophil
peroxidase (EPO)
eosinophil-derived
neurotoxin (EDN),
Cytotoxic effect
on epithelium
✓ ✓ ✓ -
Antiviral and
ribonucleus activity
- ✓ - ✓
Toxic pores ✓ - - -
Increase smooth
muscle activity
✓ - - -
Chen E. Rosenberg ,Marc E. Rothenberg. Middleton. Edition 9th.2019

Biology of Eosinophilia
• Normal mean eosinophil count in the circulating blood is 350-500/mm3. (3- 5 % of WBC )
• Not present in other human tissues exception of the thymus, spleen, lymph nodes,
uterus, and gastrointestinal tract
• Eosinophils are several hundredfold more abundant in tissues than in blood
• mild diurnal variation (trough: morning, peak: night) (fluctuation of circulating
adrenocorticosteroid levels)
• Stress, fever, most bacterial and viral infections → suppress blood eosinophil levels
• Growth factors are IL-5, GM-CSF, and IL-3
Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019
BM storage time 4.3 Days
Half-life 8-18 hours in Blood
Tissue life span several weeks
(2-5 days depend on tissue site)

Definition of eosinophilia
The severity of eosinophilia is graded according to the presence of their absolute
number in the circulating
▪Blood eosinophilia : > 500 cells per microliter
▪Hypereosinophilia (HE) : ≥ 1500 cells per microliter
on two consecutive occasions (interval > 1 month)
▪ Mild eosinophilia: 500-1500 cell/mm3
▪ Moderate eosinophilia: 1500-5000 cell/mm3
▪ Severe eosinophilia: > 5000 cell/mm3.

LEIFERMAN AND PETERS. J ALLERGY CLIN IMMUNOL PRACT SEPTEMBER/OCTOBER 2018
Definition
of eosinophilia

Leru P M.eosinophillic disorders. Clin Transl Allergy (2019) 9:36

developing and tropical countries
European และ developed countries

developing and tropical countries
European
developed countries
Allergic Disorders
• Allergic rhinitis
Nasal eosinophilia indicator of clinical response INS
• Atopic dermatitis
lack peripheral eosinophilia, although dermal deposition of
eosinophil granule proteins(MBP) , disease activity correlates
with eosinophil granule proteins in blood and urine.
• Chronic sinusitis
In adult, chronic sinusitis correlates with blood
eosinophilia and indicated extensive disease.
• Asthma
blood & sputum eosinophilia is advent of biologics
targeting.
• Nasal polyposis or sinusitis is accompanied by marked
systemic eosinophilia, eosinophilic granulomatosis with
polyangiitis (EGPA) should be considered.

Medication-related
eosinophilia
IL-2–stimulated production of IL-5.
: Eosinophilic myocarditis and biventricular
thrombosis
Urine eosinophils are best detected in fresh urine using
Hansel stain, which is more sensitive than Wright stain
Chronic, persistent neuropathy & myalgia
- Eosinophilia-myalgia syndrome : ingestion L-tryptophan
contaminated.
- Toxic oil syndrome : ingestion of edible oil adulterated
with denatured rapeseed oil.

Infectious diseases
ELISA serology is useful in detecting strongyloidiasis
even when fecal examinations are unrevealing.

Infectious diseases
British Journal of Haematology, 2017, 176, 553–572
Infectious diseases associated with eosinophilia*.
fungal
helminth

Skin and Subcutaneous tissue
• Wells syndrome ( eosinophilic cellulitis) – painful pruritic ,recurrent swelling on the extremities
with associated bacterial cellulitis (often manifestation of EGPA,HES)
• Kimura disease ( large subcutaneous masses ) VS Angiolymphoid Hyperplasia with Eosinophilia
(violaceous firm nodule smaller and more superficial )
• Angioedema with eosinophilia
- Gleich Syndrome : episodic , recurrent episodes of angioedema, urticaria, pruritis, fever,
weight gain, elevated IgM
- Nonepisodic angioedema with eosinophilia (NEAE) : extremities , Asian young woman
• Eosinophilic panniculitis - associated with leukocytoclastic vasculitis and erythema nodosum
• Eosinophilic pustular folliculitis( Ofuji disease) – mixed eosinophilic and neutrophilic infiltrates

Cutaneous manifestations demonstrating
extracellular eosinophil granule protein deposition
and patterns of eosinophil involvement

Histopathological patterns with eosinophil-related inflammation
in different cutaneous compartments

Pulmonary eosinophilia
lower respiratory tract eosinophilic disease
most common causes of noninfectious pulmonary
infiltrates
- Acute eosinophilic pneumonia (AEP)
Acute presentation fever >5-7 day
Rapid progressive respiratory failure
Diffuse alveolar / mixed alveolar interstitial infiltrate
Eo >25% of BAL fluid
Absence of parasitic, fungal and other infection
Prompt & Complete response to corticosteroids
- Chronic eosinophilic pneumonia
- Allergic Bronchopulmonary Aspergillosis (ABPA)
- history of asthma, pulmonary infiltrates,
mucoid impaction, peripheral eosinophilia,
central cylindrical Bronchiectasis, elevate IgE ,
SIgG and SIgE to aspergillus antigen

Eosinophilic Granulomatosis With polyangiitis (EGPA)
▪ Churg Strauss Syndrome
▪ Rare ANCA-associated vasculitis ( incidence 0.9 – 2.4 per million)
▪ Eosinophil-rich granulomatous inflammation and small to medium-size vessel vasculitis associated with
bronchial asthma and eosinophilia or sinusitis.
▪Histopathology : necrotizing small vessel vasculitis accompanied by eosinophil infiltrates and perivascular and
extravascular granulomas.
▪Mean Age =49-59 yr (Female>Male (1.2:1)
▪Almost all patients (>90%) have a history of bronchial asthma, and the duration from onset of asthma to
diagnosis of EGPA is median 5–9 years.
Connective tissue disease

Classification EGPA
1984 1990 2012
All 3 criteria must be met for a diagnosis of EGPA.
At least 4 of the 6 criteria are required to classify vasculitis as EGPA.
J ALLERGY CLIN IMMUNOL PRACT VOLUME 6, NUMBER 5 SEPTEMBER/OCTOBER 2018
1951
Churg and Strauss
Necrotizing vasculitis of small- medium vessel
eosinophil infiltration around vessels and
Tissues and extravascular granulomas

Connective tissue disease
1951
1984
1990
2017

EGPA : triphasic illness
1.prodromal phase : allergic rhinitis, sinusitis, and asthma in adulthood , Nasal polyp 61%
2.second phase : blood eosinophilia and eosinophilic tissue infiltration
3.third phase : potentially life-threatening vasculitis , multiple organs involvement (Eosinophilic
pneumonitis , mononeuritis multiplex)
Lab Features • Eosinophilia (>1000 cells/microliter)- 80% ,
Elevate ESR, CRP
ANCA +ve anti myeloperoxidase 30-47% (MPO-ANCA)
Treatment : Glucocorticoids , Mepolizumab (anti IL – 5 antibody)
if Failure: cyclophosphamide + prednisolone
Prognosis : Poor if Myocardial involvement 39% mortality >> Heart failure
Eosinophilic Granulomatosis With polyangiitis (EGPA)

Reactive causes of eosinophilia.

Causes of eosinophilia.
Primary (clonal) eosinophilia
Idiopathic eosinophilia

Hypereosinophilic Syndrome (HES)
Clinical manifestations of HES
: Extremely varied
nonspecific constitutional symptoms to
life-threatening endomyocardial fibrosis and
thromboembolic disease.
Lymphoid variant : dermatologic manifestations
Myeloid variant : cardiac complications
PDGFRA gene abnormalities
Most are diagnosed between 20-50 years of age,
although HES does occur in elderly and children.
Hypereosinophilia (HE)

Incidence of HES
- Prevalence of HES or chronic eosinophilic
leukemia in the United States is between
0.3-6.3 cases/100,000 person-years
- 10-15% of patients with HES have primary
myeloid HES = lymphoid-variant HES
J Allergy Clin Immunol. 2010 July ; 126(1): 179–181
Frequency distribution of diagnoses in a cohort of 302 subjects
referred for evaluation of unexplained hypereosinophilia.
Amy D. Klion, American Society of Hematology, 2015

Organ involvement in Hypereosinophilic Syndrome
M-HES : more likely to cardiac complication
L-HES : prone to dermatological manifestation
M-HES
L-HES Prognosis : mean survival was 9 mo, and
3-year survival rate was 12%
Poor prognosis :
- steroid-resistant primary myeloid neoplasms
- extremely high leukocyte counts (> 100,000/uL)
- presence of peripheral myeloblasts.

HES with
major organ
involvement
Cardiac
Dermatologic
Respiratory tract
Gastrointestinal tract
Neurologic
Major cause of morbidity and mortality
myocarditis, pericarditis, myocardial ischemia divided 3 stage
- Acute stage : normal cardiac finding , elevated serum troponin
- Thrombus stage : damaged endothelial surfaces of the heart, and
progressive scarring >> entrapment of chordae tendineae
- Fibrotic stage : sign of CHF effective evaluation : Echocardiogram ,MRI
Most common presentation : angioedema , urticaria , erythematous,
pruritic papules or nodules and Well syndrome
2nd most common ; including cough, wheezing, dyspnea, chest pain.
pulmonary emboli, eosinophilic pleural effusion, eosinophilic lung infiltrate
involve one or multiple segments of the intestinal tract
Biopsy : Eosinophilic infiltration and/or deposition of eosinophil
granule proteins
thromboembolic events, encephalopathy, and peripheral neuropathy
first sign of HES : Transient ischemic attacks

Jason Gotlib et al. The American Society of Hematology 2014
Major cause of morbidity and mortality
Most common
2nd most common

Variants of hypereosinophilic
syndrome (HES).
 Vitamin B12 ,tryptase
splenomegaly,
myelofibrosis, anemia,
thrombocytopenia,
myeloid dysplasia
FIP1L1/PDGFRA gene
Male predominatly
dermatologic manifestation :
angioedema urticaria
Serum IgE and TARC (CCL17)
who do not fall
into any of the
categories
-asymptomatic
-no evidence of a 2nd cause
or myeloid neoplasm
-Cyclic angioedema &
eosinophilia
HES associated with definite
diagnosis ; IBD,EOE

Amy D. Klion,American Society of Hematology, 2015

The American Society of Hematology, 2018

WHO revied 2016 classification of eosinophilic disorder
SHOMALI AND GOTLIB. WHO eosinophil disorder .Am J Hematol. 2019;94:1149–1166.

Molecular genetic abnormalities in myeloid/lymphoid neoplasms
associated with eosinophilia

WHO revied 2016 classification of eosinophilic disorder
Chronic eosinophilic leukemia –Not otherwise specified

Giuseppe A. Ramirez et al. BioMed Research International Volume 2018, Article ID 9095275, 28 pages

main subtypes of" primary (neoplastic)
hypereosinophilic syndromes

Suggested investigations to evaluate cause of eosinophilia
Allergic
Dermatological
Infectious
Gastrointestinal

Suggested investigations to evaluate cause of eosinophilia
Connective tissue disorder
Vasculitis
Respiratory
Lymphoma , malignancy

Diagnostic approaches to categorize
hypereosinophilic syndrome
Organ involvement
F.H. Hsieh et al.Mechanisms of Disease for the Clinician Hypereosinophilic syndrome,
Ann Allergy Asthma Immunol 112 (2014)

Testing algorithm for possible hematological
neoplasms with clonal eosinophilia

Treatment of
hypereosinophilic syndromes
Presumed HES
Clinically stable HES
Glucocorticoid-resistant HES
1 mg/kg of prednisone
cardiac involvement: add on steroid PDGFR-negative HES
1st line therapy : steroid
2nd line therapy : Hydroxyurea , IFN-

Khoury P, Klion et al. Allergy 2016;71(6):803–10.
Prospective study and retrospective study
Methods: Subjects with FIP1L1-PDGFRA-myeloid neoplasm (FP; n =16),
PDGFRA-negative HES with ≥4 criteria suggestive of a myeloid neoplasm (MHES; n =13)
steroid-refractory PDGFRA-negative HES with <4 myeloid criteria (SR; n = 16)
Primary outcome : AEC <1.5 × 109/L at 1 month and improvement of clinical symptoms.
Clinical, molecular, and bone marrow responses to imatinib
Results: Overall, imatinib response rates were 100% in the FP group (n = 16),
54% in the MHES group (n = 13) and 0% in the SR group (n = 16).
The presence of ≥ 4 myeloid features was the sole predictor of response.
After ≥ 18 months in complete remission, imatinib was tapered and discontinued in 8 FP and 1 MHES subjects.
Seven subjects (6 FP, 1 MHES) remain in remission off therapy for a median of 29 months (range 14-36).
imatinib therapy
300-400 mg daily ≥ 1 mo

Khoury P, Klion et al. Allergy 2016;71(6):803–10.
Imatinib response rates differ between group
PDGFRA-associated (FP)
myeloid (MHES) groups
corticosteroid nonresponder (SR),
prospective retrospective
AEC AEC AEC
Clinical features of MHES predict imatinib response in PDGFRA-negative HES.

Eosinophil-targeted therapy:
Novel biologics : target eosinophils, including mepolizumab, reslizumab, and benralizumab
PDGFR-negative HES patients : higher doses Mepolizumab (750 mg IV monthly) in have
shown promising results.
Severe eosinophilic asthma : Mepolizumab 100 mg subcutaneously , reslizumab and benralizumab
EGPA : Mepolizumab 300 mg subcutaneously.
life-threatening refractory hypereosinophilic syndrome : high dose mepolizumab (300 -750 mg)
severe hypereosinophilic syndrome : Benralizumab (anti–IL-5R) ;suppression of peripheral
eosinophilia and symptomatic improvement over 48 weeks
Fei Li Kuang. Med Clin N Am 104 (2020) 1–14

Advances treatment in eosinophilic diseases
KLION AND ROTHENBERG.J ALLERGY CLIN IMMUNOL DECEMBER 2019.
1
2

Kuang FL et al. J Allergy Clin Immunol Pract 2018;6(5):1518–27.e5.
Pretreatment serum IL-5 levels in 19 subjects with
active disease, categorized by response to mepolizumab.
A: Schematic of clinical decision making and
determination of response to mepolizumab.
Numbers and percentages of
HES subjects by response
Mepolizumab response by clinical subtype
Retrospective study
35 HES subjects treated with mepolizumab 750 mg SC monthly
55 HES subjects on conventional therapy: steroid

Kuang FL et al. J Allergy Clin Immunol Pract 2018;6(5):1518–27.e5.
Subjects managed with mepolizumab monotherapy had
fewer disease flares than HES subjects on conventional
therapies or mepolizumab-treated HES subjects requiring
additional HES therapies.
Conclusion
-Mepolizumab is an effective and well-tolerated therapy for HES.
-Primary benefit of treatment is the reduction of comorbidity due to discontinuation or reduction of
conventional HES therapies.
-high-dose mepolizumab was a safe and effective salvage therapy for severe, treatment-refractory HES.

Kuang FL et al. Benralizumab for PDGFRA-negative hypereosinophilic syndrome. N Engl J Med 2019;380(14):1336–46.
Method : randomized, double-blind, placebo-controlled
Study in PDGFRA-negative HES 20 symptomatic patients
Treatment group : Benralizumab 30 mg SC q 4 weeks for 12 weeks
Placebo group : every 4 weeks for 12 weeks (open triangles).
Until wk 13 : all the patients received 30 mg of benralizumab q 4
weeks
- All Patients continued to receive stable therapy (drugs or dietary
changes) for HES
Assessment : absolute eosinophil counts at week 13
Result : effect in benralizumab group than placebo group (9/10
patients vs. 3/10 patients (P=0.02) reduction of at least 50% in
the absolute eosinophil count at week 12.
showed suppression of peripheral eosinophilia and symptomatic
improvement over 48 weeks in 74%
Conclusion : patients with PDGFRA-negative HES who received
Benralizumab for 12 weeks had lower absolute eosinophil
counts and sustained for 48 weeks (74%)

Kuang F L and Klion A D, JAllergyClin Immunol Pract 2017;5:1502-9
Treatment in Hypereosinophilic Syndrome

The American Society of Hematology, 2018
Treatment in Hypereosinophilic Syndrome

M-HES
Summary

M-HES
L-HES
CEL-NOS
Summary

1. Eosinophilic granulomatosis with polyangiitis may include which of the following features?
a. An antecedent history of asthma
b. Multiorgan eosinophilic infiltration
c. High-grade peripheral eosinophilia
d. The presence of antineutrophil cytoplasmic antibodies
e. All of the above
2. Which is not a typical finding in myeloid-variant hypereosinophilic syndromes?
a. Elevated vitamin B12 levels
b. Clonal expansion of aberrant lymphocytes expressing IL-5
c. FIP1L1/PDGFRA gene rearrangement
d. Elevated serum tryptase
e. Splenomegaly
Quiz

3. Which of the following fungal diseases are often associated with eosinophilia?
a. Candidiasis
b. Aspergillosis
c. Coccidioidomycosis
d. B and C
e. All of the above
4. A 35-years old immigrant from Cameroon presents with asymptomatic marked eosinophilia. She arrived in
the United States more than 10 years ago and has not been back to Africa. Which of the following parasites is
the most likely cause of her eosinophilia?
a. Ascaris lumbricoides
b. Hookworm
c. Strongyloides stercoralis
d. Giardia lamblia
e. Blastocystis hominis
Quiz

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