Eosinophilic Esophagitis (EoE)

Allergia e pseudoallergia alimentare
Ripercorrere le linee guida:
presentazione di algoritmi e
protocolli
Roberto Berni Canani, MD, PhD
Chief, Food Allergy Unit
Pediatric Gastroenterology Hepatology and Nutrition Section
Department of Translational Medicine
European Laboratory for the Investigation of Food Induced
Diseases (ELFID)
Ceinge Advanced Biotechnologies
University of Naples ”Federico II”
Typical EoE patient
Atopic male (male to female ratio 3:1), non-ispanic white, who
presents in childhood
Eosinophilic Esophagitis
Epidemiology-Pre 2000
http://www.aic.cuhk.edu.hk/web8/world%20map.j
Eosinophilic Esophagitis
Epidemiology-Worldwide disease!
http://www.aic.cuhk.edu.hk/web8/world%20map.jp
Eosinophilic Esophagitis (EoE)
• Expansion of cases reported worldwide in last 2 decades
• Actual estimated prevalence in pediatric population approximately 4-
10/10,000, incidence rate 0.9-1.3/10,000 new cases per year in US
• 85-90% pts are white and 75-80% male
• Higher disease prevalence in urbanized areas
• Higher rate of atopy (40-75% vs 10-30% normal population)
• Familial occurrence 2-10% of EoE pts. Atopic risk in 50% of cases
• Most common food proteins causing EoE are milk, followed by wheat,
eggs, beef, soy, legumes, chicken.
EoE ESPGHAN Guidelines JPGN 2014
ACG Guidelines AJG 2013
Esophageal rings
Adolescents
and Adults
Chest pain, dysphagia
for solids, food
impaction
Narrow-caliber
esophagus
Linear furrows
esophagus
Nausea, vomiting,
abdominal pain,
sialorrhea, delayed
growth, sleep difficulties
Food aversion, failure
to thrive, regurgitation,
vomiting
White plaque or
exudates
Young children
Boerhaave’s Syndrome
Eosinophilic Esophagitis (EoE)
Chronic, immune/antigen-mediated
esophageal disease characterized
1. Clinically: symptoms of
esophageal dysfunction
2. Histologically: ≥1 esophageal
mucosal biopsy specimens (2-4
biopsy from at least 2 different
sites. 6-9 biopsies=sensitivity
100%) with eosinophilpredominant inflammation ≥15
intraepithelial eosinophils per
hpf; disease isolated to the
esophagus; other causes of
esophageal eosinophilia excluded,
including PPI-REE
ACG Guidelines AJG 2013
Eosinophilic infiltration (>15/hpf)
Eosinophil degranulation
Basal-zone hyperplasia/surface layering**
Eosinophilic microabscess **
ACG Guidelines AJG 2013
Algorithm for EoE diagnosis
ACG Guidelines AJG 2013
Evaluation of Child / Adolescent with Symptoms Suggestive of EoE
(otherwise unexplained feeding difficulty, vomiting, dysphagia, hx. of food impaction)
On PPI treatment ?
No
Yes
EGD with biopsies of proximal and distal parts of esophagus
≥ 15 eos/hpf
Trial of PPI’s for 8 weeks (*).
Monitor for symptoms
EGD with biopsies on PPIs (independent of symptoms)
EoE
≥ 15 eos/hpf &
signs of EoE in EGD
+/- symptoms
>5 but <15 eos /hpf
+/- symptoms
Consider
PPI-REE/
non-EoE allergy
< 5 eos /hpf
+ symptoms
Consider
Functional pain,
achalasia or other
diagnosis
< 5 eos /hpf
no symptoms
Consider
GERD/NERD/
PPI REE.
EoE ESPGHAN Guidelines JPGN 2014
Simon D et al. Allergy 2016
Thymic stromal
lymphopoietin
(TSLP)
Genetic dissection of EoE
Sherrill JD and Rothenberg ME, JACI 2011
Berni Canani R et al. PIP 2012
Epigenetic mechanisms
regulate both Th1 and Th2
differentiation and changes in
promoter methylation are a
prerequisite for FoxP3
expression and Treg
differentiation.
Berni Canani R et al. Nutr Res Rev 2011
MicroRNA signature in patients with EoE
Lu TX et al. JACI 2012
Lu and Rothenberg JACI 2013
Treatment Goals
• Reducing symptoms
• Visual endoscopic changes
• Biopsy-based eos counts and associated
histology
• Protecting and preserving QoL and
nutrition
Greenhawt M et al. JACI 2013
Treatment
endpoints
Treatment endpoints
• 0-1 eos/hpf
• Decrease >90%
• Full basal-zone hyperplasia remission
• Scoring system?
ACG Guidelines AJG 2013
The 3 Ds
• Diet
• Drugs
• Dilation
EoE ESPGHAN Guidelines JPGN 2014
ACG Guidelines AJG 2013
Dietary therapy for EoE
(1) Strict use of an amino acid–based formula
(2) Dietary restriction based on allergy testing
(3) Dietary restriction based on eliminating most
likely food antigens (cow’s milk, egg, wheat, soy, peanuts and
fish/shellfish)
Designed to temporarily avoid certain foods for 4-8 wks (the elimination
phase), followed by a period of systematic reintroduction of these food groups
(reintroduction phase). The purpose of this dietary protocol is to identify
possible food sensitivities and the process may last for up to 9 wks.
EoE ESPGHAN Guidelines JPGN 2014
ACG Guidelines AJG 2013
Exclusion Diets
• “6” food elimination-75%
– Gonsalves N et al, Gastroenterology 2012
– Kagalwalla AF et al, J Pediatr Gastroenterol Nutr 2011
– Kagalwalla AF et al, Clin Gastroenterol Hepatol 2006
• “Tailored” diet-33%-90%
– Molina-Infante et al DDW 2012
– Spergel J et al, Gastrointest Endosc Clin NA 2008
• Elemental diet-95%
– Markowitz JE et al, Am J Gastroenterol 2003
– Kelly K et al, Gastroenterology 1995
Every 7-14 days
ACG Guidelines AJG 2013
Recommended doses of steroids for EoE
Topical swallowed corticosteroids for a minimum of 4 wks and a maximum of
12 wks
Initial doses
• Fluticasone (puffed and swallowed through a metered-dose inhaler)
patients should swallow the metered dose that is delivered into the oral cavity
(and not inhaled), then not eat, drink or rinse their mouth for 30 min
Adults: 440-880 μg twice daily;children: 88-440 μg twice to 4 times daily
(to a maximal adult dose)
•
Budesonide as a viscous suspension mixing a liquid solution of budesonide
0.5 mg / 2 ml (the preparation used in nebulizers) and 5 gram of sucralose (a
synthetic sugar substitute). Children (<10 y): 1-2 mg daily; older children and
adults: 2-6 mg daily
Systemic corticosteroids
For severe cases (eg, small-caliber esophagus, weight loss, and
hospitalization) Prednisone: 1-2 mg/kg
ACG Guidelines AJG 2013
Drugs for EoE
• Cromolyn sodium, leukotriene receptor antagonists, and
immunomodulator agents (azathioprine or 6mercaptopurine) are not recommended.
• Biologic agents (mAbs, such as anti–IL-5, anti–IL-13, antiIgE, and anti-eotaxin) await further clinical studies and
are not recommended
• PPIs might be useful because they might alleviate
symptoms related to secondary GERD (30-75%
responders)
ACG Guidelines AJG 2013
EGID’s Epidemiology
The standardized estimated prevalences of eosinophilic
gastritis, gastroenteritis, and colitis were 6.3/100,000,
8.4/100,000, and 3.3/100,000, respectively. The prevalence of
eosinophilic gastroenteritis was the highest among children age
<5 years, whereas eosinophilic gastritis was more prevalent
among older age groups.
Concomitant allergic disease was most commonly
identified in pediatric patients.
Jensen ET et al. J Pediatr Gastroenterol Nutr. 2016
Clinical point #1
Interpret the mucosal biopsy findings
in the context in which they were
obtained!
Mucosal eosinophilia can be caused
by many different etiologies.
Secondary Eosinophil-Associated Disorders
Non-eosinophilic disorders
• GERD
• IBD
• Infectious diseases
• Connective tissue disorders
• Vasculitides
• Neoplasia
• Iatrogenic causes
Hypereosinophilic syndrome
Treatment of eosinophilic gastritis and
gastroenteritis
• Elimination, oligoantigenic and elemental diets (on the
basis of SPTs, RAST, or APT)
• Systemic steroids if diet restriction is not feasible or has
failed to improve the disease
• TPN or immunosoppressive therapy (azathioprine or 6mercaptopurine) in severe cases, refractory or dependent
on steroids
Treatment of eosinophilic gastritis and
gastroenteritis
Biological agents
• Omalizumab (recombinant humanized
monoclonal IgG against high affinity IgE
receptor)
• Mepolizumab or Reslizumab(humanized
monoclonal IgG against IL-5)
2 wks for 16 wks
750 mg IV every
What’s the destiny of EoE patients?
Bohm M et al. Dis Esophagus. 2016
Types of evolution of EoE
40-50%
20-30%
10-20%
Cytosponge
Cytosponge(Medtronic
(MedtronicGI
GISolutions)
Solutions)
ACG Guidelines AJG 2013
Non-invasive EoE monitoring
transnasal endoscopy-TNE, 2.8-4 mm flexible bronchoscope
Friedlander JA et al. Gastrointest Endosc 2016
EoE recommended treatment algorithm
Greenhwat M et al. JACI 2013
Modified from ACG Guidelines AJG 2013
Roberto Berni Canani, MD, PhD
Chief, Food Allergy Unit
Pediatric Gastroenterology Hepatology
and Nutrition Section
Department of Translational Medicine
European Laboratory for the Investigation
of Food Induced Diseases (ELFID)
University of Naples “Federico II”, Italy
Topical steroids for EoE: clinical
improvement?
Five studies that included 174 patients with EoE were
included in the meta-analysis. Topical fluticasone was
administered in 3 studies involving 114 patients, and
topical budesonide in 2 studies involving 60 patients.
Patients treated had higher complete histological remission (odds ratio[OR] 20.81,
95%confidence interval[CI] 7.03,61.63) and partial histological remission (OR 32.20,
95%CI 6.82,152.04).
There was trend towards improvement in clinical symptoms with topical
steroids as compared to placebo but it did not reach statistical significance
(OR 2.72, 95 %CI 0.90,8.23).
Murali AR et al.
J Gastroenterol Hepatol. 2015
Eosinophil-Gastrointestinal Disorders (EGIDs)
Chronic, immune/antigen
mediated GI disorders with
eosinophil-predominant rich
inflammation
Università degli Studi
di Napoli “Federico II”
Eosinophil Growth and Development
8 days
Eotaxin/b7 integr
IL-5
8-12 hours
Eotaxin
Eotaxin
a4/b7 integrins
and endothelial
MadCAM-1/
ICAM-1
a4/b7
integrins
and
endothelial
MadCAM-1
7 days
2-10 cells/hpf
Università degli Studi
di Napoli “Federico II”
Eosinophil-mast cell axis
Università degli Studi
di Napoli “Federico II”
Eosinophil-Gastrointestinal Disorders (EGIDs)
Atopy 75%
Familial involvement 10-20%
• Atopic
• Non-atopic
• Familial varieties
Università degli Studi
di Napoli “Federico II”
Eosinophil-Gastrointestinal Disorders (EGIDs)
• Mucosal
• Muscular
• Serosal
• Transmural
Università degli Studi
di Napoli “Federico II”
Eosinophil-Gastrointestinal Disorders (EGIDs)
Mucosal
•
•
•
•
•
•
•
•
•
•
decreased appetite, early satiety
nausea, vomiting
abdominal pain
malabsorption
diarrhea
anemia
failure to thrive
occult blood in the stool
protein-losing enteropathy
gastric dysmotility
Università degli Studi
di Napoli “Federico II”
Eosinophil-Gastrointestinal Disorders (EGIDs)
Muscular
• thickening of gut wall
• colicky abdominal pain
• symptoms of gastric
outlet obstruction
• intestinal obstruction
Università degli Studi
di Napoli “Federico II”
Eosinophil-Gastrointestinal Disorders (EGIDs)
Serosal
• abdominal distention
• eosinophilic ascites
Università degli Studi
di Napoli “Federico II”
Eosinophil-Gastrointestinal Disorders (EGIDs)
• Eosinophilic esophagitis (EoE)
• Eosinophilic gastritis
• Eosinophilic gastroenteritis
• Eosinophilic colitis or proctitis
Università degli Studi
di Napoli “Federico II”
Eosinophilic Gastritis
General recurrent GI symptoms: abdominal
pain, vomiting, bleeding, early satiety
Eosinophilic Gastroenteritis
• Stomach (26-81%), small intestine (28100%)
• Abdominal pain, vomiting, diarrhea,
edema, growth retardation
• Anemia, hypoalbuminemia,
steatorrhea
Eosinophilic Gastroenteritis
Eosinophilic Gastroenteritis
eosinophil number, location, activation
Eosinophilic Colitis
• Diarrhea, hematochezia, urgency, tenesmus
• Anemia, CLP
• Normal to granular
to ulcerative
Eosinophilic Colitis
World Health Organization Classification
of Eosinophilic Disorders
• Myeloid and lymphoid neoplasms with eosinophilia
and abnormalities of PDGFRA, PDGFRB, or FGFR1
• Chronic Eosinophilic Leukemia, Not Otherwise
Specified
• Idiopathic Hypereosinophilic Syndrome (HES)
Università degli Studi
di Napoli “Federico II”
Diagnostic criteria of HES
Old definition
Proposed new definition
1. Blood eosinophilia >1500/mm3 or at least 1. Blood eosinophilia >1500/mm3 on at
6 months
least 2 occasions
EGID withor>1500 eos/ul
“overlap
variant oftissue
HES”
evidence
of prominent
eosinophilia associated with symptoms
and marked blood eosinophilia
2. Unknown trigger of eosinophilia
2. Exclusion of secondary causes of
eosinophilia, such as parasitic or viral
infections, allergic diseases, drug-induced
or chemical-induced eosinophilia,
hypoadrenalism, and neoplasms
3. Signs and symptoms of organ
involvement (gastrointestinal
dysfunction, heart failure, CNS
abnormalities, fever, or weight loss)
Simon HU et al. JACI 2010
Diagnostic approach
• Histologic evaluation of multiple biopsies (>6)
• Blood count (peripheral eosinophilia ~50% of pts); ERS/CRP;
iron; albumin; PT; gammaglobulins; total and specific IgE;
steatocrit
• SPT and APT
• H. pylori and parasites
• Serological specific markers: anti-Tgase, pANCA , ASCA
• Serum, urinary, and fecal markers (ECP, EDN, eos.protein X)
• Immunohistological analysis for eosinophil or mast cell
proteins: ECP, EDN, eos. peroxidase, tryptase
• Immunophenotyping of eosinophils and T cells: IL-5 receptor
a-chain and chemokine receptor-3 for eosinophils; CD3 for T
cells
Diagnostic approach
In the presence of peripheral hypereosinophilia
• Bone marrow analysis
• Echocardiogram
• Genetic analysis for FIP1L1-PDGFRA fusion
(evaluation and biopsy of any other potentially
involved tissue)
Università degli Studi
di Napoli “Federico II”
Diagnostic approach
• Eos. quantification (>15-30/hpf in >5hpf)
• Eos. location (intraepithelial, superficial mucosal, crypts)
• Presence of extracellular eosinophilic staining
constituents
• Associated pathologic abnormalities (epithelial
hyperplasia as in the case of EoE)
• Absence of pathologic features suggestive of other
primary disorders (neutrophilia associated with IBD or
vasculitis associated with Churg-Strauss syndrome)
Università degli Studi
di Napoli “Federico II”
Eosinophilic Esophagitis (EoE)
Extensive basal zone hyperplasia with papillary elongation and
fibrosis within the lamina propria; accumulation of eosinophils,
B lymphocytes, CD4+ and CD8+ T lymphocytes,Treg, and mast cells.
Heavy extra cellular deposition of eosinophil granule proteins, such
as eosinophil-derived neurotoxin (identified by specific stains)
.
Università degli Studi
di Napoli “Federico II”
Confirmed diagnosis of EoE
Monitor for symptoms!
Repeat EGD & biopsies in 4 - 12 weeks
Poor adherence ?
Adapt treatment
Drug titration and/or
stepwise food reintroduction
ESPGHAN Position Paper on EoE Management-2014
Most common foods> milk, egg, soy, wheat, chicken
Specificity 74%
98% responded to elimination diet
Diagnostic utility of APT in EE Grade B
Università degli Studi
di Napoli “Federico II”
Microbiome in EoE?
Bacterial populations in
normal esophagus
• Streptococcus is most common
• Different from the mouth
Fillon SA et al PLoS ONE 2012
Grusell EN et al Dis Esoph 2012