Eosinophilic Esophagitis: Diagnosis, Clinical Implications, and...
Transcript of Eosinophilic Esophagitis: Diagnosis, Clinical Implications, and...
Eosinophilic Esophagitis: Eosinophilic Esophagitis: Diagnosis, Clinical Diagnosis, Clinical Implications, and Implications, and
TreatmentTreatmentSeema S. Aceves, M.D., Ph.D.Seema S. Aceves, M.D., Ph.D.
Assistant Professor, Pediatrics and MedicineAssistant Professor, Pediatrics and MedicineDirector, EGID ClinicDirector, EGID Clinic
University of California, San DiegoUniversity of California, San DiegoRady ChildrenRady Children’’s Hospital, San Diegos Hospital, San Diego
Faculty DisclosureFaculty Disclosure
The University of California, San Diego has a financial interest in Meritage Pharma, the University of California may financially benefit (patent royalties) from this interest if the company is successful in developing and marketing its own product related to oral viscous budesonide. Dr Aceves is a co-inventor of OVB to which UCSD owns the patent. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.Research funding from GlaxoSmithKlineSome slides are from CDHNF, TIGERS and received funding from Takeda
Eosinophilic Esophagitis Eosinophilic Esophagitis (EoE): A Clinicopathological (EoE): A Clinicopathological
DiagnosisDiagnosis
Histologic FeaturesHistologic FeaturesEndoscopic FeaturesEndoscopic Features
Clinical FeaturesClinical FeaturesDistinctions from GERDDistinctions from GERD
Atypical EoE Presenting SymptomsAtypical EoE Presenting Symptoms
CoughCough
HoarsenessHoarseness
PostPost--tussivetussive emesisemesis
““AnaphylaxisAnaphylaxis”” to every food to every food
DemographicsDemographics
0
10
20
30
40
50
60
70
80
90
EE
GI
AI
PA
Caucasian Male
EoE
GIAI
PA EoE
GI
AI
PA
Franciosi et al Clin Gastro Hepatol, 2009
EndoscopicEndoscopic FeaturesFeatures
PallorPallorLichenificationLichenificationLinear FurrowsLinear FurrowsWhite PlaquesWhite PlaquesConcentric RingsConcentric RingsStrictures and NarrowingsStrictures and Narrowings
Furuta et al, Gastroenterology 2007Fox et al, GI Endoscopy 2005
Normal
EoE
Vomiting
Abdominal Pain
Dysphagia
Esophageal Stricture
Age
50%
50%
30% (Pediatric)97% (Adults)
10% (Pediatric)37% (Adult)
Food Impaction
13% (Pediatric)51% (Adult)
Feeding Disorder
13% ??
SymptomsSymptoms
HistologyHistology>15 eosinophils per hpf >15 eosinophils per hpf especially with acid blockadeespecially with acid blockadeTypical Accompanying Typical Accompanying Features:Features:
Basal Zone HyperplasiaBasal Zone HyperplasiaDilated Intercellular SpacesDilated Intercellular SpacesEosinophil Clusters, Eosinophil Clusters, DegranulationDegranulationSubepithelial FibrosisSubepithelial Fibrosis
Furuta et al, Gastroenterology 2007
Making the DiagnosisMaking the Diagnosis
Distinguishing Distinguishing Features from GERDFeatures from GERD
Symptom ComparisonSymptom ComparisonSymptomSymptom Not at allNot at all Mild: No Mild: No
interference with interference with daily activities, daily activities, Meds as neededMeds as needed
Severe: Regularly Severe: Regularly interferes with daily interferes with daily activities or requires activities or requires daily medsdaily meds
Does your child ever have burning in the Does your child ever have burning in the chest?chest?Does your child ever feel food coming back Does your child ever feel food coming back up into his/her throat?up into his/her throat?
Not at all=0, Mild=1, Severe=2Not at all=0, Mild=1, Severe=2
Does your child complain about stomach Does your child complain about stomach pains?pains?Is your child often irritable for no apparent Is your child often irritable for no apparent reason?reason?
How often does your child complain about How often does your child complain about feeling like throwing up?feeling like throwing up?
How often does your child throw up?How often does your child throw up?
How often does your child eat too little or get How often does your child eat too little or get full before finishing his/her meal?full before finishing his/her meal?
How often does your child wake up during How often does your child wake up during the night from belly pain?the night from belly pain?
How often has your child noticed blood in How often has your child noticed blood in his/her stool in the last 3 months?his/her stool in the last 3 months?
Does your child have difficulty swallowing?Does your child have difficulty swallowing?
0
1
2
ANOREXIAEARLY SATIETY DYSPHAGIA
NormalAllergy NonEEGERDEE
***
* **
*
SCO
RE
Aceves et al, Ann of Allergy 2009
Making The DiagnosisMaking The Diagnosis
Other Distinguishing EoE Other Distinguishing EoE FeaturesFeatures
Blanchard, C. et al. J. Clin. Invest. 2006;116:536-547
EotaxinEotaxin--33
53-fold increase in Eotaxin-3 gene expression in EE versus GERD pediatric patients
Thymic Stromal Thymic Stromal LymphopoetinLymphopoetin
Increased TSLP expression in EoEIncreased TSLP expression in EoEGenetic variants in TSLP and EotaxinGenetic variants in TSLP and Eotaxin--3 3 associate with EoEassociate with EoE
Rothenberg et al, Nature Genetics 2010
B Cells and Local IgE ProductionB Cells and Local IgE Production
Increased B cells in :•Epithelium•Vascular Papillae•Lamina Propria
Increased IgE Class Switch
Genes
Vicario et al, Gut 2009Vicario et al, Gut 2009
T CellsT Cells
Increased CD3+Increased CD3+Increased CD8+Increased CD8+Murine EoE Induction Relies on T cellsMurine EoE Induction Relies on T cells
Lucendo et al, 2007Mishra et al, 2007Zhu et al, 2009
ILIL--55EoE patients have Increased ILEoE patients have Increased IL--55ILIL--5 Deficient Mice are Protected from 5 Deficient Mice are Protected from EoEEoEILIL--5 5 miniosmoticminiosmotic pump promotes murine pump promotes murine EoEEoE
Straumann et al, JACI 2001Mishra et al, 2008
ILIL--1313
Mishra & Rothenberg, Gastroenterology 2003Blanchard et al, Clin Exp Allergy 2005
••Instilling ILInstilling IL--13 Causes 13 Causes Murine EEMurine EE••Resolved with antiResolved with anti--ILIL--13 13 AntibodyAntibody
••ILIL--13 treatment promotes 13 treatment promotes EoE transcriptomeEoE transcriptome••ILIL--13 induces the Eotaxin13 induces the Eotaxin--3 3 promoterpromoter
ILIL--1515Increased ILIncreased IL--15 on EoE Gene Chip15 on EoE Gene ChipILIL--15R15Rαα Deficient Mice: Protected from experimental Deficient Mice: Protected from experimental EoEEoEILIL--15 Increased in Human Esophageal biopsies15 Increased in Human Esophageal biopsies
Rayapudi et al, Gastroenterology 2010
Mast CellsMast Cells
•Increased Mast Cells:•Epithelium
•Smooth muscle•Increased degranulated Mast Cells in EE versus GERD
Lucendo, 2007 Aceves, 2009
Kirsch et al, JPGN 2007Konikoff et al, Gastroenterology 2006Lucendo et al, Am J Surg Path 2007
SubepitheliumSubepithelium
Lamina Propria: Lamina Propria: Esophageal RemodelingEsophageal Remodeling
Esophageal Remodeling: FibrosisEsophageal Remodeling: Fibrosis
Human subjects have increased fibrosis
Animal EE Models have increased fibrosis
0
1
2
3
EENormal
Fibr
osis
Sco
re
****
GERD
Fibrosis Score
Aceves et al, JACI 2007Mishra et al, Gastroenterology 2008
Esophageal Remodeling: Esophageal Remodeling: ProPro--Fibrotic FactorsFibrotic Factors
0
100
200
Normal EE
****
TGFβ
Pos
itve
Cells
per h
pf
GERD
0
100
200
EENormal
***
pSM
AD
2/3
posit
ive
cells
per h
pf in
LP
GERD
Aceves et al, J All Clin Immunol 2007
Esophageal Remodeling: Esophageal Remodeling: ProPro--Fibrotic FactorsFibrotic Factors
Eosinophils produce Eosinophils produce TGFTGFββ11
Aceves, J All Clin Immunol 2007Mishra, Gastronenterology
2008
Animals that lack Animals that lack eosinophils are protected eosinophils are protected from fibrosisfrom fibrosis
InflammationInflammation EndoscopyEndoscopy SymptomSymptom
Epithelial:Epithelial:Average Epithelial ScoreAverage Epithelial Score
Prox+Mid+DistalProx+Mid+Distal
Thickened/Furrows r=0.82*Thickened/Furrows r=0.82*White Plaques, r =0.64*White Plaques, r =0.64*
Pallor r=0.62* Pallor r=0.62* Dysphagia + Dysphagia + Anorexia/Early Anorexia/Early
SatietySatietyr=0.32*r=0.32*
Lamina Propria:Lamina Propria:Fibrosis + EosinophilsFibrosis + Eosinophils
Thickened/Furrows r=0.64*Thickened/Furrows r=0.64*DysphagiaDysphagiar= 0.45*r= 0.45*
*p<0.05
Aceves et al, Annals of All Immunol 2009
Inflammation Correlates with Endoscopy and Symptoms
•Severity of Eosinophilic Inflammation in the epithelium and LP can correlate with Endoscopic and Symptom Findings
•Severity of Fibrosis can correlate with Endoscopic and Symptom Findings
Esophageal Remodeling: VascularityEsophageal Remodeling: Vascularity
Normal GERD EE
0
25
50
75
EENormal
***
VW
F po
sitiv
e ve
ssel
spe
r hpf
GERD0
25
50
75
EENormal
***
VCA
M p
ositi
ve v
esse
lspe
r hpf
GERD
vWF Positive Vessels VCAM-1 Positive Vessels
Diagnosing EoE: ?More Than Diagnosing EoE: ?More Than Eosinophil Numbers??Eosinophil Numbers??
Eosinophil peroxidase footprint in absence of intact eosinophils meeting diagnostic criteriaProtheroe et al, CGH, 2009
Clinical ImplicationsClinical Implications
TriggersTriggersChronicityChronicity
ComplicationsComplications
AerollergensAerollergens
and EoE: Causal Linkand EoE: Causal Link
Instillation of:Instillation of:Intranasal AspergillusIntranasal AspergillusIntranasal HDMIntranasal HDMIntranasal Cockroach Intranasal Cockroach Drives Murine EoEDrives Murine EoE
Mishra et al., J Clin Invest 2001 Rayapaudi et al, J Leuko Biol 2010
Aspergillus
AerollergensAerollergens
and EoE: Causal Linkand EoE: Causal Link
EE during pollen seasonEE during pollen seasonSpontaneous disease resolutionSpontaneous disease resolution
Fogg et al,
JACI 2003
Pediatric EoEPediatric EoE
79% Relapsed21% Resolved 33% No Resolution
Assa’ad et al, JACI 2007
Patients with EE diagnosed at Cincinnati Children’s Hospitaln=57
Duration of Follow up: Median 2.58 years (range 0.18-5.61)
Resolved EEn-=38
Persistent EEN=19Duration of follow up:Median 1.3 (range 0.3-5.7)
Resolved EE,No RelapseN=8Duration of follow-up: Median 0.8 years (range 0.2-3.1)
Resolved EE,Subsequent RelapseN=30Duration of follow up: Median 3.2 years (range 0.5-5)
ILIL--13 Effects on Murine EoE 13 Effects on Murine EoE RemodelingRemodeling
IL-13 induces eosinophilia, esophageal thickness, and collagen accumulation Zou et al, J Immuol 2010
ILIL--13, TGFb1, and Periostin13, TGFb1, and Periostin
Increased periostin expression induced by TGFβ
Periostin increases eosinophil trafficking and adhesion
Blanchard et al, Mucosal Immunol 2008
Smooth Muscle DysfunctionSmooth Muscle Dysfunction
Thickened muscular Thickened muscular bundles in EEbundles in EE
Muscular dysfunction Muscular dysfunction with poor relaxationwith poor relaxation
Increased motility Increased motility correlates with correlates with episodes of dysphagiaepisodes of dysphagia Fox et al GI Endoscopy 2003Fox et al GI Endoscopy 2003
KorsapatiKorsapati et al Gastro 2009et al Gastro 2009Nurko et al, Am J Gastro 2009Nurko et al, Am J Gastro 2009
Mast Cells and Smooth Muscle Mast Cells and Smooth Muscle FunctionFunction
Aceves et al, JACI, in press
Food Impaction and Iatrogenic Food Impaction and Iatrogenic ComplicationsComplications
Food Impactions: 35%Food Impactions: 35%Flexible endoscopic bolus Flexible endoscopic bolus removal: 93%removal: 93%Rigid endoscopic bolus Rigid endoscopic bolus removal: 7%removal: 7%Transmural Perforation:Transmural Perforation:
20% Rigid Endoscopy20% Rigid EndoscopySpontaneous rupture in 1 Spontaneous rupture in 1 patientpatient
Straumann et al, Clin Gastroenterol Hepatol 2008
Avoiding Triggers: Avoiding Triggers: FoodsFoods
Elemental FormulaElemental FormulaElimination Diet:Elimination Diet:
TargetedTargetedEmpiricEmpiric
FoodsFoodsElimination diets resolve EEElimination diets resolve EE
Empiric: 50% (adults)Empiric: 50% (adults)--74% (pediatric)74% (pediatric)Targeted: 70%Targeted: 70%
Elemental formula resolves EEElemental formula resolves EE>90%>90%
Addition of foods causes EEAddition of foods causes EEAnimal models using ovalbumin cause EE/EGAnimal models using ovalbumin cause EE/EG
Kagalwalla
et al, Clin Gastro Hepatol
2006 Liacouras et al, Clin Gastro HepatolHogan et al, Nature Immunology 2001
Spergel et al, JACI 2008Song et al, Clin Exp Allergy 2009
Elemental Formula Eliminates EoEElemental Formula Eliminates EoE
70
75
80
85
90
95
100
Kelly 1993
Kelly 1993Kelly 1993
Markowitz2003
Liacouras2005
Spergel 2005
Kagalwalla2006
IgE TestingIgE Testing
Use food extracts as for anaphylaxisUse food extracts as for anaphylaxisMost data is from ChildrenMost data is from Children’’s Hospital of s Hospital of PhiladelphiaPhiladelphia
Food Food ImmunoCAPImmunoCAP Testing: Limited data in Testing: Limited data in EGIDsEGIDs
Overall varying success with RAST based Overall varying success with RAST based elimination dietelimination dietPaucity of dataPaucity of data
Food Patch TestFood Patch Test
Delayed/Cellular HypersensitivityDelayed/Cellular HypersensitivityFresh foods or single item baby foodFresh foods or single item baby foodMilk, egg, soy, wheat used as powders in Milk, egg, soy, wheat used as powders in salinesalineApply in large Finn chamberApply in large Finn chamberRemove at 48 hoursRemove at 48 hoursRead at 72 hoursRead at 72 hours
Dietary Options: Pros and ConsDietary Options: Pros and ConsElemental Elemental FormulaFormula
Directed Directed EliminationElimination
Empiric Empiric EliminationElimination
ComplianceCompliance DifficultDifficult BetterBetter BetterBetterCostCost ExpensiveExpensive ManageableManageable ManageableManageableInvasive?Invasive? Potentially (GT, Potentially (GT,
NGT)NGT)NoNo NoNo
Number of Number of EGDsEGDs
ManyMany Fewer, every 1Fewer, every 1--2 2 foodsfoods
Fewer, every 1Fewer, every 1--2 2 foods (6 in total)foods (6 in total)
TolerabilityTolerability LowLow BetterBetter BetterBetterComplicationsComplications Oral AversionOral Aversion
CostCostTube relatedTube related
Nutritional Nutritional NutritionalNutritional
Response RateResponse Rate >95%>95% 75%75% 75%75%QOLQOL UnknownUnknown UnknownUnknown UnknownUnknown
Oral Viscous BudesonideOral Viscous Budesonide
•
Overall Response Rate to viscous budesonide: 87
•
Overall Response Rate to Placebo + PPI: 0%
Dohil et al, Gastroenterology 2010
0
50
100
150
200
0 2 4 6 8 10 12 14Time (weeks)
Eosi
noph
ils/m
m2
MepolizumabPlacebo
Screening
0
50
100
150
200
0 2 4 6 8 10 12 14Time (weeks)
Eosi
noph
ils/m
m2
MepolizumabPlacebo
Screening
P = 0.387
P = 0.001* - 55.3 %
- 55.3 %
Mean (Mean (±±SD) SD) esophagealesophageal
eosinophils (ECP staining)eosinophils (ECP staining)AntiAnti--ILIL--5 Therapy in EoE5 Therapy in EoE
Straumann et al, Gut 2010
Topical Fluticasone Reverses Topical Fluticasone Reverses Transcriptome ProfileTranscriptome Profile
Blanchard et al, JACI 2007
Treatment Resolves Pathology: Treatment Resolves Pathology: RemodelingRemodeling
LP Eosinophils Fibrosis Score
Aceves et al, Allergy 2010
Treatment Resolves Pathology: Treatment Resolves Pathology: RemodelingRemodeling
Aceves et al, Allergy 2010
TGFβ pSmad2/3
Decreased Vascular ActivationDecreased Vascular Activation
VCAM-1 Positive Vessels Dilated Intercellular Spaces
Aceves et al, Allergy 2010
Aeroallergen Testing: SPT
EoE: >15 eosinophils per hpf despite acid blockade
Food Testing: SPT?APT
Institute Therapy
Elimination Diet
Empiric: 6 Food EliminationDirected: SPT, APT Based
Repeat EGD with Biopsy
Histologic/EGD/Symptom Response
Maintenance
Topical Corticosteroids
>7-10 years old: Fluticasone BID
Budesonide + Sucralose/Maltodexrtin
Food Reintroduction
Histologic/EGD FailureElemental FormulaSystemic corticosteroidsBiologics
ConclusionsConclusions
EoE is a chronic disease of children and adultsEoE is a chronic disease of children and adultsTypical symptoms include dysphagia, abdominal pain, Typical symptoms include dysphagia, abdominal pain, and anorexia/early satietyand anorexia/early satietyPrevalence is increasingPrevalence is increasingSuccessful therapies are diet and topical corticosteroidsSuccessful therapies are diet and topical corticosteroidsComplications: Strictures, RemodelingComplications: Strictures, RemodelingPathogenesis includes EotaxinPathogenesis includes Eotaxin--3, IL3, IL--5, IL5, IL--13, IL13, IL--15, 15, TGFb1 and involves the Epithelium, Innate and TGFb1 and involves the Epithelium, Innate and Adaptive Immunity, Vascularity, and Smooth MuscleAdaptive Immunity, Vascularity, and Smooth MuscleNo surrogate disease markersNo surrogate disease markers