eosinophilic gastrointestinal disorders (part i)
TRANSCRIPT
Outline
• Introduction
• Epidemiology
• Classification
• Gastrointestinal Eosinophils Under Homeostatic Healthy States
• Clinical Evaluation
• Eosinophilic Esophagitis
Eosinophilic Esophagitis Outline
• Definition
• Etiology
• Pathogenesis
• Clinical feature
• Diagnostic studies
• Treatment
• Prognosis
Introduction
• Disorders that selectively affect GI tract
• Eosinophil-rich inflammation in the absence of known causes for eosinophilia
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Epidemiology(1)
• EoE is a global health problem now reported in
- Australia - Japan
- Brazil - Spain
- England - Switzerland
- Italy - Israel
Shitrit AB, Reinus C, Zeides S, et al. Eosinophilic esophagitis. Isr Med Assoc J 2006;8:587.
Epidemiology(4)
Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. The New England journal of medicine. 2004;351(9):940-1.
Epidemiology(3)
• 0.4% (~4 : 1000) prevalence of EoE in a random sample of Swedish adults.
• EoE occurred in about 1 : 1000 children in the Cincinnati metropolitan area over a 10-year period.
Ronkainen J, Talley NJ, Aro P, et al. Prevalence of eosinophilia and eosinophilic esophagitis inadults in the community: a random population based study (Kalixanda). Gastroenterology 2006;130:A575
Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med 2004;351:940-1.
Gastrointestinal Eosinophils Under Homeostatic Healthy States
• Eosinophils are present at low levels in numerous tissues
• In biopsy and autopsy specimens, organs that normally demonstrate tissue eosinophils at substantial levels are
- GI tract - Lymph nodes
- Spleen - Thymus
DeBrosse CW, Case JW, Putnam PE, Collins MH, Rothenberg ME. Quantity and distribution of eosinophils in the gastrointestinal tract of children. Pediatric and developmental pathology : the official journal of the
Society for Pediatric Pathology and the Paediatric Pathology Society. 2006;9(3):210-8.
Gastrointestinal Eosinophils Under Homeostatic Healthy States
• Eosinophils throughout the GI tract of conventional healthy mice : normally present in the lamina propria of the stomach, small intestine, cecum, and colon.
• Eosinophils are not normally present in Peyerpatches or intraepithelial locations.
• Eosinophils are frequently infiltrate in Peyerpatches regions in EGID.
Mishra A, Hogan SP, Lee JJ, et al. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J ClinInvest 1999;103: 1719-27
Rothenberg ME, Mishra A, Collins MH, et al. Pathogenesis and clinical features of eosinophilic esophagitis. J Allergy ClinImmunol 2001;108:891-4.
DeBrosse CW, Case JW, Putnam PE, Collins MH, Rothenberg ME. Quantity and distribution of eosinophils in the gastrointestinal tract of children. Pediatric and developmental pathology : the official journal of the
Society for Pediatric Pathology and the Paediatric Pathology Society. 2006;9(3):210-8.
Kita H. et al.Middleton's Allergy ; 8th edition. 2014. p. 265-279
PROINFLAMMATORY ROLE OF EOSINOPHILS
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
Kita H. et al.Middleton's Allergy ; 8th edition. 2014. p. 265-279
MBP, EPX, and ECP have cytotoxic effects on
epithelium at concentrations similar to those in biologic fluids from patients with
eosinophilia
Kita H. et al.Middleton's Allergy ; 8th edition. 2014. p. 265-279
MBP triggers degranulation of mast cells
and basophils.
Kita H. et al.Middleton's Allergy ; 8th edition. 2014. p. 265-279
Eosinophil-mediated damage is caused by • Toxic hydrogen peroxide and halide acids generated by EPX • Superoxide generated by the respiratory burst oxidase enzyme pathway in eosinophils
Proinflammatory Role of Eosinophils
• Triggering of eosinophils by engagement of receptors for cytokines, immunoglobulins, and complement can lead to the generation of a wide range of inflammatory cytokines
Yousefi S, Gold JA, Andina N, Lee JJ, Kelly AM, Kozlowski E, et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nature medicine. 2008;14(9):949-53.
Proinflammatory Role of Eosinophils
• TGF-β is linked with epithelial growth, fibrosis, and tissue remodeling.
• Eosinophils express MHC class II molecules and relevant costimulatory molecules (CD28, CD40, CD80 [B7-1], CD86
• Eosinophils secrete cytokines capable of promoting lymphocyte proliferation , activation &Th1 or Th2 polarization (IL-2, -4, -6, -12, -10).
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Clinical Evaluation
• Pts with EGID present with a variety of clinical problems, most often
-Failure to Thrive -Abdominal pain
-Irritability -Gastric dysmotility
-Vomiting -Diarrhea
-Dysphagia -Microcytic anemia
-Hypoproteinemia
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Clinical Evaluation
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
•Blood eosinophilcounts are generally in the normal range in most pts• Above-normal levels can distinguish pts with active versus inactive EoE
Evaluation for Hypereosinophilic syndrome
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.
Evaluation for Hypereosinophilic syndrome
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.
Evaluation for Hypereosinophilic syndrome
*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
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.
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
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.
Evaluation for Hypereosinophilic syndrome
• Pts with EGID, the diagnosis of HES should always be considered, especially if they develop extra-GI manifestations .
• Thus, additional diagnostic testing for HES should be considered.
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Evaluation for Hypereosinophilic syndrome
• Pts with marked eosinophilia are at risk for the development of cardiac disease.
• Routine surveillance of the cardiorespiratorysystem is warranted.
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Eosinophilic Esophagitis Outline
• Defnition
• Etiology
• Pathogenesis
• Clinical feature
• Diagnostic studies
• Treatment
• Prognosis
Definition
• “Eosinophilic esophagitis represents a chronic, immune/antigen mediated, esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation”
Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. The Journal of allergy and clinical immunology.
2011;128(1):3-20.e6; quiz 1-2.
Etiology
• Food allergen and aeroallergen sensitization
• Genetics
• Cytokine (IL-5) , Chemokine(Eotaxin-3)
• Immune dysregulation
Esophageal eosinophilic inflammation is mechanistically linked to pulmonary inflammation, on the basis of the induction of experimental EoE by repeated delivery of specific allergens to the lung of mice.
Mishra A, Hogan SP, Brandt EB, et al. An etiological role for aeroallergens and eosinophils in experimental esophagitis. J Clin Invest 2001; 107:83-90.
Fogg MI, Ruchelli E, Spergel JM. Pollen and eosinophilic esophagitis. The Journal of allergy and clinical immunology. 2003;112(4):796-7.
Genetics
• 3 Basic approach
1) Mendelian disorder
2) Candidate gene identification
3) Genome wide association study
Rothenberg ME. Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis. Gastroenterology. 2015.
Rothenberg ME. Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis. Gastroenterology. 2015.
Thymic stromal lymphopoeitin (TSLP) protein
• GWAS, genotyping 351 patients with EoE and 3104 healthy controls and evaluating 550,000 common variants.
• On chromosome 5q22, a single locus spanning the TSLP and WD repeat domain 36 (WDR36) genes showed a significant association with EoE.
Rothenberg ME, Spergel JM, Sherrill JD, Annaiah K, Martin LJ, Cianferoni A, et al. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nature genetics. 2010;42(4):289-91.
Thymic stromal lymphopoeitin (TSLP) protein
• TSLP has a known role in processes germane to EoE
1. Polarization of Th2 immunity
2. Induction of eotaxins
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Etiology
• Food allergen and aeroallergen sensitization
• Genetics
• Cytokine (IL-5) , Chemokine(Eotaxin-3)
Blanchard C, Wang N, Stringer KF, et al. Eotaxin-3 and a uniquely conserved gene expression profile in eosinophilicesophagitis. J Clin Invest 2006;116:536-47.
Pathogenesis
• Activation of epithelial inflammatory pathways (production of eotaxin-3 [encoded by CCL26]).
Rothenberg ME. Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis. Gastroenterology. 2015.
Pathogenesis
• Activation of epithelial inflammatory pathways (production of eotaxin-3 [encoded by CCL26]).
• Impaired barrier function (mediated by loss of desmoglein-1).
Rothenberg ME. Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis. Gastroenterology. 2015.
Pathogenesis
• Activation of epithelial inflammatory pathways (production of eotaxin-3 [encoded by CCL26]).
• Impaired barrier function (mediated by loss of desmoglein-1).
• Increased production and/or activity of transforming growth factor-b.
Rothenberg ME. Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis. Gastroenterology. 2015.
Pathogenesis
• Activation of epithelial inflammatory pathways (production of eotaxin-3 [encoded by CCL26]).
• Impaired barrier function (mediated by loss of desmoglein-1).
• Increased production and/or activity of transforming growth factor-b.
• Induction of allergic inflammation by eosinophils and mast cells.
Rothenberg ME. Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis. Gastroenterology. 2015.
Rothenberg ME. Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis. Gastroenterology. 2015.
Rothenberg ME. Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis. Gastroenterology. 2015.
Clinical feature(1)
Yan BM, Shaffer EA. Eosinophilic esophagitis: a newly established cause of dysphagia. World journal of gastroenterology : WJG. 2006;12(15):2328-34.
Clinical feature(2)
Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. The New England journal of medicine. 2004;351(9):940-1.
Remedios M, Campbell C, Jones DM, Kerlin P. Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointestinal endoscopy. 2006;63(1):3-12.
Remedios M, Campbell C, Jones DM, Kerlin P. Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointestinal endoscopy. 2006;63(1):3-12.
Study of 26 adult patients with EoE, all had dysphagia, 11 had food impaction.
Diagnostic Studies
• Esophageal ultrasound
• Radiographic and Endoscopic Studies
• Histology
• Allergy Evaluation
Esophageal ultrasound
• Dysfunctional muscularis mucosa.
• Providing a possible explanation for the impaired esophageal dysmotility.
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Esophageal ultrasound
C. Endosonographic image (20 MHz catheter probe) showing thick-wall esophagus with prominent mucosa/submucosa layer and narrow lumen.
Fox VL, Nurko S, Furuta GT. Eosinophilic esophagitis: it's not just kid's stuff. Gastrointestinal endoscopy. 2002;56(2):260-70.
Radiographic and Endoscopic Studies
• Strictures
• Mucosal rings
• Ulcerations
• Whitish papules
• Polyps
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Radiographic studies
Figure 2. Radiographic and endoscopic studies from an 18-year-old female with history of asthma, eczema, and long-standing obstructive dysphagia beginning in early childhood. A.Barium esophagram showing a small caliber esophagus
Fox VL, Nurko S, Furuta GT. Eosinophilic esophagitis: it's not just kid's stuff. Gastrointestinal endoscopy. 2002;56(2):260-70.
Endoscopic Studies
Fox VL, Nurko S, Furuta GT. Eosinophilic esophagitis: it's not just kid's stuff. Gastrointestinal endoscopy. 2002;56(2):260-70.
Endoscopic Studies
Fox VL. Eosinophilic esophagitis: endoscopic findings. Gastrointestinal endoscopy clinics of North America. 2008;18(1):45-57; viii.
Endoscopic Studies
Fox VL. Eosinophilic esophagitis: endoscopic findings. Gastrointestinal endoscopy clinics of North America. 2008;18(1):45-57; viii.
Endoscopic Studies
Fox VL. Eosinophilic esophagitis: endoscopic findings. Gastrointestinal endoscopy clinics of North America. 2008;18(1):45-57; viii.
Endoscopic Studies
A) mucosal edema, concentric ring, linear furrow B) linear furrow, white exudates C) corrugated appearance, linear shearing
Fox VL. Eosinophilic esophagitis: endoscopic findings. Gastrointestinal endoscopy clinics of North America. 2008;18(1):45-57; viii.
Histology
Collins MH. Histopathologic features of eosinophilic esophagitis. Gastrointestinal endoscopy clinics of North America. 2008;18(1):59-71; viii-ix.
Histology
Collins MH. Histopathologic features of eosinophilic esophagitis. Gastrointestinal endoscopy clinics of North America. 2008;18(1):59-71; viii-ix.
Histology
Collins MH. Histopathologic features of eosinophilic esophagitis. Gastrointestinal endoscopy clinics of North America. 2008;18(1):59-71; viii-ix.
Histology
Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):1342-63.
Histology
Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):1342-63.
Histology
Collins MH. Histopathologic features of eosinophilic esophagitis. Gastrointestinal endoscopy clinics of North America. 2008;18(1):59-71; viii-ix.
Histology
Collins MH. Histopathologic features of eosinophilic esophagitis. Gastrointestinal endoscopy clinics of North America. 2008;18(1):59-71; viii-ix.
Histology
Collins MH. Histopathologic features of eosinophilic esophagitis. Gastrointestinal endoscopy clinics of North America. 2008;18(1):59-71; viii-ix.
Histology
Collins MH. Histopathologic features of eosinophilic esophagitis. Gastrointestinal endoscopy clinics of North America. 2008;18(1):59-71; viii-ix.
Histology
Collins MH. Histopathologic features of eosinophilic esophagitis. Gastrointestinal endoscopy clinics of North America. 2008;18(1):59-71; viii-ix.
Allergy Evaluation
• Peripheral blood eosinophil count
• Food allergen and Aeroallergen sensitization - Skin-prick tests
- Allergen-specific IgE in serum
- Delayed skin patch testing
: Food protein sensitization
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Allergy Evaluation
• Peripheral blood eosinophil count
- There was a significant amount of variability in the defining level for “peripheral eosinophilia”
-Range of eosinophils reported as abnormal ranged from greater than 350 eosinophils
per mm3 to greater than 800 eosinophils per
mm3).
Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):1342-63.
Allergy Evaluation
• Peripheral blood eosinophil count
• One study demonstrated that persistent blood eosinophilia correlated with persistent dysphagia.
• In another study, the degree of elevation of serum eosinophils correlated with the severity
of Eosinophilic esophagitis
Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, et al. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology. 2007;133(4):1342-63.
Allergy Evaluation
• Peripheral blood eosinophil count
• Food allergen and Aeroallergen sensitization -- Skin-prick tests
- Allergen-specific IgE in serum
- Delayed skin patch testing
: Food protein sensitization
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
26 Pts with EoEIdentify by BX
SPT+ Milk&EggPatch+Wheat
SPT & Patch test
Avoid food
Resolution18 Pts
Partial improve
6 Pts
Loss F/U2 Pts
Overall, after intervention, esophageal eosinophil
counts improved from 55.8 to 8.4 eosinophils/HPF
Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA. The use of skin prick tests and patch tests to identify causative foods in eosinophilicesophagitis. The Journal of allergy and clinical immunology. 2002;109(2):363-8.
Treatment
• A trial of specific food allergen and aeroallergen avoidance
• Systemic or topical glucocorticoids
• Anti–IL-5 monoclonal antibody
• Anti– human IL-13 antibody
• Siglec-F
• PPI
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Specific food allergen and aeroallergen avoidance
• Indicated for patients with atopic EoE
• If results are unsatisfactory or avoidance is difficult for practical reasons
- A diet consisting of an elemental (amino acid–based) formula
- Avoidance of the most common allergic foods (cow’s milk, soy, wheat, egg, peanut/tree nuts, seafood/shellfish)
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Kagalwalla AF, Sentongo TA, Ritz S, Hess T, Nelson SP, Emerick KM, et al. Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clinical gastroenterology and hepatology : the official clinical practice
journal of the American Gastroenterological Association. 2006;4(9):1097-102.
60 Pts with EoE
ELED25 Pts
SFED35 Pts
6 weeks later Esophageal Bx Specimen was
obtained
SFED gr. Improve Esophageal inflammation
26 Pts(74%)
ELED gr improveEsophageal inflammation
22 Pts (88%)Kagalwalla AF, Sentongo TA, Ritz S, Hess T, Nelson SP, Emerick KM, et al. Effect of six-food elimination diet on clinical and
histologic outcomes in eosinophilic esophagitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2006;4(9):1097-102.
Kagalwalla AF, Sentongo TA, Ritz S, Hess T, Nelson SP, Emerick KM, et al. Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clinical gastroenterology and hepatology : the official clinical practice
journal of the American Gastroenterological Association. 2006;4(9):1097-102.
Systemic or topical glucocorticoids
• Systemic glucocorticoids are used for acute exacerbations
• Topical glucocorticoids are used to provide long-term control
Rothenberg ME. Middleton's Allergy ; 8th edition. 2014. p. 1095-1106
Systemic or topical glucocorticoids
Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. The Journal of allergy and clinical immunology.
2011;128(1):3-20.e6; quiz 1-2.
Konikoff MR, Noel RJ, Blanchard C, Kirby C, Jameson SC, Buckmeier BK, et al. A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology.
2006;131(5):1381-91.
Konikoff MR, Noel RJ, Blanchard C, Kirby C, Jameson SC, Buckmeier BK, et al. A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology.
2006;131(5):1381-91.
36 Pts with EoE
880 g of FP21 Pts
Placebo15 Pts
3 mnths later Esophageal Bx Specimen was
obtained
50% of FP PtsImprove
9% of Placebo PtsImprove
Konikoff MR, Noel RJ, Blanchard C, Kirby C, Jameson SC, Buckmeier BK, et al. A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology.
2006;131(5):1381-91.
Result
• FP decreased esophageal eosinophil levels,
with a more pronounced effect in nonallergic individuals
Konikoff MR, Noel RJ, Blanchard C, Kirby C, Jameson SC, Buckmeier BK, et al. A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology.
2006;131(5):1381-91.
Eo/HPFIn Proximal Esophagus
Eo/HPFIn DistalEsophagus
P (Value)
FP 65.9 +/- 25.3 84.6+/-19.7 .03
Placebo 1.4+/-1.1 19.6+/- 12.9 .04
Anti–IL-5 monoclonal antibody
Spergel JM, Rothenberg ME, Collins MH, Furuta GT, Markowitz JE, Fuchs G, 3rd, et al. Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. The Journal of
allergy and clinical immunology. 2012;129(2):456-63, 63.e1-3.
Spergel JM, Rothenberg ME, Collins MH, Furuta GT, Markowitz JE, Fuchs G, 3rd, et al. Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. The Journal of
allergy and clinical immunology. 2012;129(2):456-63, 63.e1-3.
Spergel JM, Rothenberg ME, Collins MH, Furuta GT, Markowitz JE, Fuchs G, 3rd, et al. Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. The Journal of
allergy and clinical immunology. 2012;129(2):456-63, 63.e1-3.
Spergel JM, Rothenberg ME, Collins MH, Furuta GT, Markowitz JE, Fuchs G, 3rd, et al. Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. The Journal of
allergy and clinical immunology. 2012;129(2):456-63, 63.e1-3.
227 Pts with EoE
Reslizumab 1 mg/kg56 Pts
Reslizumab 3 mg/kg57 Pts
Reslizumab 2 mg/kg57 Pts
Placebo
% Reduction Eo59 %
% Reduction Eo67 %
% Reduction Eo64 %
% Reduction Eo24 %
Siglec-F
Rubinstein E, Cho JY, Rosenthal P, Chao J, Miller M, Pham A, et al. Siglec-F inhibition reduces esophageal eosinophilia and angiogenesis in a mouse model of eosinophilic esophagitis. Journal of pediatric gastroenterology and nutrition.
2011;53(4):409-16.
• New approach is to target the sialic acid–binding
immunoglobulin-like lectin F (Siglec-F)
• An inhibitory receptor expressed on eosinophils
• Siglec-F inhibition was useful in a mouse model of
EoE.
Proton Pump Inhihitor
• PPI are useful
1. Eliminate GERD as a cause of esophageal
eosinophilia.
2. GERD is a comorbid disease
3. PPI-responsive esophageal eosinophilia
• Mechanism of PPI
1. Primarily involve acid blockade
2. Other mechanisms
Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. The Journal of allergy and clinical immunology.
2011;128(1):3-20.e6; quiz 1-2.
Proton Pump Inhihitor
• Recommended PPI dose that should be used to
eliminate PPI-responsive esophageal eosinophilia
- Adults
20-40 mg, once or twice daily for 8 to 12 weeks
- Children
1 mg/kg per dose, twice daily for 8 to 12 weeks
Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. The Journal of allergy and clinical immunology.
2011;128(1):3-20.e6; quiz 1-2.
Prognosis
• EoE requires prolonged treatment, similar to allergic asthma.
• Natural history of EoE has not been fully delineated.
• Results of a 15-year follow up study of esophageal eosinophilia indicate that
Vast majority of patients have ongoing symptoms from childhood into adulthood.
DeBrosse CW, Franciosi JP, King EC, Butz BK, Greenberg AB, Collins MH, et al. Long-term outcomes in pediatric-onset esophageal eosinophilia. The Journal of allergy and clinical immunology. 2011;128(1):132-8.
Prognosis
• If left untreated, chronic EoE will likely develop into progressive esophageal scarring & dysfunction -> consideration of esophageal dilation
• The risk for developing Barrett esophagitis, especially in pts with coexisting EoE and GERD
• Pts with EoE are at increased risk for developing other forms of EGID -> routine surveillance of the entire GI tract by endoscopy
Rothenberg ME. Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis. Gastroenterology. 2015.
Rothenberg ME. Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis. Gastroenterology. 2015.