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Eosinophils and hypereosinophilic syndrome

Eosinophils and hypereosinophilic syndrome

Presented by Nattasasi Suchamalawong, MD.

January22, 2021

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Eosinophils and hypereosinophilic syndrome

  1. 1. Eosinophil and Hypereosinophilc syndrome 22th January 2021 Nattasasi Suchamalawong, MD. Pediatric Allergy and Immunology Unit, King Chulalongkorn Memorial Hospital
  2. 2. Outline Biology of eosinophil Definition of eosinophilic disorder Etiology of reactive eosinophilia Hyperosinophilic syndrome Overlap of Hypereosinophilic syndrome Guideline for investigation Treatment Quiz
  3. 3. Biology of Eosinophil
  4. 4. 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
  5. 5. 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.
  6. 6. 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)
  7. 7. 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
  8. 8. 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
  9. 9. Liai w et al.Clinic Rev Allerg Immunol (2016) 50:125–139 Cellular features of eosinophils
  10. 10. Cellular structure, receptors, and mediators of eosinophils Nicola L. Diny, Eosinophils in Autoimmune Diseases, Front. Immunol, 2017 1 2 Kita H et al.Middleton’s Allergy; 9th edition, 2019
  11. 11. 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
  12. 12. 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
  13. 13. 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 LANZKOWSKY’S MANUAL OF PEDIATRIC HEMATOLOGY AND ONCOLOGY, chapter 13 , 2016 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)
  14. 14. Definition and Classification
  15. 15. 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. Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019 LANZKOWSKY’S MANUAL OF PEDIATRIC HEMATOLOGY AND ONCOLOGY, chapter 13 , 2016
  16. 16. LEIFERMAN AND PETERS. J ALLERGY CLIN IMMUNOL PRACT SEPTEMBER/OCTOBER 2018 Definition of eosinophilia
  17. 17. Leru P M.eosinophillic disorders. Clin Transl Allergy (2019) 9:36
  18. 18. Reactive eosinophilia
  19. 19. Leru P M.eosinophillic disorders. Clin Transl Allergy (2019) 9:36 developing and tropical countries European และ developed countries
  20. 20. developing and tropical countries European developed countries Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019 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.
  21. 21. 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. Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019
  22. 22. Infectious diseases Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019 ELISA serology is useful in detecting strongyloidiasis even when fecal examinations are unrevealing.
  23. 23. Infectious diseases British Journal of Haematology, 2017, 176, 553–572 Infectious diseases associated with eosinophilia*. fungal helminth
  24. 24. 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 Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019
  25. 25. Cutaneous manifestations demonstrating extracellular eosinophil granule protein deposition and patterns of eosinophil involvement LEIFERMAN AND PETERS. J ALLERGY CLIN IMMUNOL PRACT SEPTEMBER/OCTOBER 2018
  26. 26. Histopathological patterns with eosinophil-related inflammation in different cutaneous compartments LEIFERMAN AND PETERS. J ALLERGY CLIN IMMUNOL PRACT SEPTEMBER/OCTOBER 2018
  27. 27. Pulmonary eosinophilia Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019 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
  28. 28. 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
  29. 29. 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
  30. 30. Connective tissue disease Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019 1951 1984 1990 2017
  31. 31. 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)
  32. 32. British Journal of Haematology, 2017, 176, 553–572 Reactive causes of eosinophilia.
  33. 33. British Journal of Haematology, 2017, 176, 553–572 Reactive causes of eosinophilia.
  34. 34. British Journal of Haematology, 2017, 176, 553–572 Causes of eosinophilia. Primary (clonal) eosinophilia Idiopathic eosinophilia
  35. 35. Hypereosinophilic syndrome
  36. 36. 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) Leru P M.eosinophillic disorders. Clin Transl Allergy (2019) 9:36 Kita H et al.Middleton’s Allergy; 9th edition, 2019
  37. 37. 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
  38. 38. Organ involvement in Hypereosinophilic Syndrome M-HES : more likely to cardiac complication L-HES : prone to dermatological manifestation Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019 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.
  39. 39. Organ involvement in Hypereosinophilic Syndrome 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 Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019 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
  40. 40. Organ involvement in Hypereosinophilic Syndrome Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019 Jason Gotlib et al. The American Society of Hematology 2014 Major cause of morbidity and mortality Most common 2nd most common
  41. 41. Variants of hypereosinophilic syndrome (HES). Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019  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
  42. 42. Amy D. Klion,American Society of Hematology, 2015
  43. 43. The American Society of Hematology, 2018
  44. 44. WHO revied 2016 classification of eosinophilic disorder SHOMALI AND GOTLIB. WHO eosinophil disorder .Am J Hematol. 2019;94:1149–1166.
  45. 45. Molecular genetic abnormalities in myeloid/lymphoid neoplasms associated with eosinophilia SHOMALI AND GOTLIB. WHO eosinophil disorder .Am J Hematol. 2019;94:1149–1166.
  46. 46. SHOMALI AND GOTLIB. WHO eosinophil disorder .Am J Hematol. 2019;94:1149–1166. WHO revied 2016 classification of eosinophilic disorder Chronic eosinophilic leukemia –Not otherwise specified
  47. 47. Giuseppe A. Ramirez et al. BioMed Research International Volume 2018, Article ID 9095275, 28 pages
  48. 48. main subtypes of" primary (neoplastic) hypereosinophilic syndromes Leru P M.eosinophillic disorders. Clin Transl Allergy (2019) 9:36
  49. 49. Suggested investigations to evaluate cause of eosinophilia British Journal of Haematology, 2017, 176, 553–572 Allergic Dermatological Infectious Gastrointestinal
  50. 50. Suggested investigations to evaluate cause of eosinophilia British Journal of Haematology, 2017, 176, 553–572 Connective tissue disorder Vasculitis Respiratory Lymphoma , malignancy
  51. 51. 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)
  52. 52. Testing algorithm for possible hematological neoplasms with clonal eosinophilia British Journal of Haematology, 2017, 176, 553–572
  53. 53. Kilon AD.et al. Middleton’s Allergy; 9th edition, 2019 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-
  54. 54. 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
  55. 55. 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.
  56. 56. 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
  57. 57. Advances treatment in eosinophilic diseases KLION AND ROTHENBERG.J ALLERGY CLIN IMMUNOL DECEMBER 2019. 1 2
  58. 58. 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
  59. 59. 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.
  60. 60. 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%)
  61. 61. Kuang F L and Klion A D, JAllergyClin Immunol Pract 2017;5:1502-9 Treatment in Hypereosinophilic Syndrome
  62. 62. The American Society of Hematology, 2018 Treatment in Hypereosinophilic Syndrome
  63. 63. SHOMALI AND GOTLIB. WHO eosinophil disorder .Am J Hematol. 2019;94:1149–1166. M-HES Summary
  64. 64. SHOMALI AND GOTLIB. WHO eosinophil disorder .Am J Hematol. 2019;94:1149–1166. M-HES L-HES CEL-NOS Summary
  65. 65. 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
  66. 66. 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
  67. 67. Thank you for your attention

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