1-S2.0-S0889856123001066-Main.pdf Hội nghị nhi khoa

E-mail address: CHJOY@med.umich.edu KEYWORDS Eosinophilic esophagitis Epidemiology Early life Environmental factors KEY POINTS The incidence of eosinophilic esophagitis EoE is risin

C l u e s t o t h e E t i o l o g y o f

E o s i n o p h i l i c E s o p h a g i t i s

Joy W Chang,MD, MSa,*, Elizabeth T Jensen,MPH, PhDb

INTRODUCTION

Eosinophilic esophagitis (EoE) is a chronic immune-mediated inflammatory disease characterized by symptoms of esophageal dysfunction and esophageal eosinophilia, affecting both children and adults Since it was first described 30 years ago, EoE has rapidly increased in prevalence and incidence, accounting for substantial health care costs (up to $1.36 billion annually) from emergency room visits, endoscopic proced-ures, outpatient visits, and pharmacologic therapy.1 , 2On an individual level, patients experience chronic symptoms, delayed diagnoses, and challenging treatment regi-mens Despite these system and individual burdens, the etiology and pathophysiology

of EoE are unknown, which hinders attempts at preventing and mitigating disease, and the development of targeted therapies or a cure

Our understanding of potential underlying etiologies and risk factors for develop-ment of EoE stems from epidemiologic clues and observed clinical patterns As a new and relatively rare disease affecting people across the lifespan, many challenges exist in studying the etiology of EoE Diagnostic case definitions have evolved over time, and a variety of factors affect access to care, and diagnosis of EoE requires

a Division of Gastroenterology, Department of Internal Medicine, 3912 Taubman Center, 1500 East Medical Center Drive, SPC 5362, Ann Arbor, MI 48109, USA; b Department of Epidemiology and Prevention, Wake Forest University School of Medicine, 475 Vine Street, Winston-Salem,

NC 27101, USA

* Corresponding author.

E-mail address: CHJOY@med.umich.edu

KEYWORDS

 Eosinophilic esophagitis  Epidemiology  Early life  Environmental factors

KEY POINTS

 The incidence of eosinophilic esophagitis (EoE) is rising and understanding the epidemi-ology of EoE may provide clues into possible etiologic factors.

 EoE is a result of complex interactions between genetic and environmental factors.

 Early life factors that contribute to dysbiosis of the microbiome are associated with other atopic diseases and could be important clues to the etiology and development of EoE.

Immunol Allergy Clin N Am 44 (2024) 145–155

https://doi.org/10.1016/j.iac.2023.12.003 immunology.theclinics.com 0889-8561/24/ ª 2023 The Author(s) Published by Elsevier Inc This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ).

endoscopy with biopsies, current descriptive epidemiologic data likely reflects missed identification of cases or misclassification of non-cases.3–6Another challenge is that given EoE is a relatively uncommon disease, prospective cohort studies to measure true temporal risk factors are generally impractical or unfeasible Despite these chal-lenges and limitations, examining patterns and co-occurring conditions can provide clues to generate hypotheses about the etiology and factors that contribute to the development of EoE

EPIDEMIOLOGIC CLUES

To untangle causes of risk factors for developing EoE, we first look to the disease inci-dence or the proportion or rate of newly developed disease during a time period To date, epidemiologic studies report varying incidence of EoE—from 0.7 cases/ 100,000 up to 10 cases/100,000.7We can hypothesize that these inconsistent esti-mates may be due to bias in ascertainment, varying definitions of cases by diagnostic criteria, differences in source population or time periods examined A review of regional trends shows a higher incidence in North America compared with Europe and Asia, which may be explained by these same factors or could suggest differences

in environmental exposures that contribute to disease pathogenesis.8Although EoE has been reported in Latin America, Middle East, and South Asian countries, the esti-mated prevalence is comparatively lower due to unclear or possibly multifactorial causes Temporal patterns of EoE can also provide insight on the development of EoE Since the disease was described nearly 30 years ago, the incidence has dramat-ically increased, shown in multiple studies to outpace the increase in endoscopies with biopsies, suggesting a true increase in environmental risk factors and/or improved diagnosis.9Recent studies in both Europe and North America show that the incidence may be leveling off, potentially offering new clues for understanding dis-ease pathogenesis.10–12

GENETIC RISK FACTORS

Studies examining the heritability of EoE and intrinsic genetic risk factors point at the development of disease as a multifactorial process In genome wide association and candidate gene studies, EoE has been associated with susceptibility variants related

to type 2 immunity (CCL26, TSLP, POSTN) and epithelial barrier dysfunction (CPN14, FLP, DSG1, SPINK5, SPINK7).13However, genetics alone do not explain the develop-ment of EoE, which does not follow a Mendelian inheritance pattern In comparison to other immune-mediated chronic conditions, heritability estimate for EoE is relatively low In a study of family clustering among twins, heritability among twins was 14.5% with the common environment accounting for 81.0% of the variation.14In addi-tion, concordance for EoE among dizygotic twins (22.0%) was stronger compared with non-twin siblings (2.5%,P < 001), suggesting that not only are environmental

factors implicated but also shared early life factors may be important in understanding disease risk As such, it is posited that genetic factors interact with environmental factors to result in disease development This concept was affirmed in a study demon-strating a protective effect of breastfeeding to the development of EoE in infants with a single-nucleotide polymorphism in CAPN14 (adjusted odds ratio [OR] 0.08, 95% CI 0.01–0.59) compared with those who were not breastfed.15There was no impact on EoE risk regardless of breastfeeding when the single nucleotide polymorphism (SNP) was absent, affirming this concept that among genetically susceptible people, environmental factors not only contribute but may be necessary for the development

of EoE

EARLY LIFE

Of environmental factors, early life factors are perhaps the most studied to date and

provide the most evidence for the development of EoE Early life exposures or those

impacting fetal development and exposures within the first 3 years of life—including

delivery, infant feeding, medication use, and maternal factors—likely influence the

developing gut microbiome, promote dysbiosis, and inform the developing immune

systems are associated risk factors for developing EoE

Prenatal Period

Prenatal factors including maternal complications and medication use have been

associated with an increased risk of EoE In the only study that explored the

associa-tion of maternal fever to the later development of EoE in children, maternal fever

conferred an increased risk (adjusted odds ratio [aOR] 3.18, 95% CI 1.27–7.98), limited

by potential recall bias of the mothers and case patients.16Leveraging a nationwide

population-based database of Danish EoE cases, pregnancy complications (eg,

infec-tions, hypertensive disorders, gestational diabetes, preterm labor) were associated

with EoE (aOR 1.4, 95% CI: 1.0–1.9) and maternal antibiotic use was associated

with developing EoE (aOR 1.5, 95% CI 1.2–1.9) with increased risk with more frequent

use (1 prescription aOR 1.4, 95% CI 1.0–1.8 ; 31 prescriptions aOR 2.1, 95% CI 1.4–

3.2) and timing closer to delivery (third trimester aOR 1.5, 95% CI 1.0–2.1).17Similarly,

in this population, maternal use of acid suppression use was associated with an

increased risk of developing EoE (aOR 1.7, 95% CI 1.0–2.8) in a dose–response

manner (31 prescription aOR 5.1; 95% CI: 1.8–14.8), supporting a relationship

be-tween medications that alter the microbiome as early as the in utero period and the

development of EoE.18

Intrapartum Period

Intrapartum period factors associated with pediatric onset of EoE include preterm

birth and cesarean delivery In a landmark study of this relationship in cases in North

Carolina, Jensen and colleagues reported preterm birth (OR 4.2, 95% CI 0.7–43.4) and

cesarean section delivery (OR 2.2, 95% CI 0.8–6.4) associated with the development

of EoE in childhood.19These findings of preterm labor (Ohio aOR 2.18, 95% CI 1.06–

4.48) and cesarean delivery (Ohio aOR 1.77, 95% CI 1.01–3.09; Massachusetts aOR

3.21, 95% CI 1.20–8.60) are supported in distinct cohorts.16,20Similarly, within the

recent population-based Danish cohort, preterm infants with gestational age between

32 and 34 weeks had the highest rate of EoE (32-week aOR 3.2, 95% 1.5–7.1; 33-week

aOR 3.6, 95% CI 1.8–7.4; 34-week aOR 2.8, 95% CI 1.7–7.6).17However, in this recent

large study, no association was observed between mode of delivery and EoE, once

other confounding factors were accounted for in the analyses

Infancy

During infancy, risk factors including neonatal intensive care unit (NICU) admission,

in-fant medication use and feeding can potentially influence the developing microbiome

and, thus, the risk of EoE The risk of NICU admission on EoE development trended

toward significance (aOR 1.92, 95% CI 0.95–3.89) when controlling for potential

me-diators of medication use.16This is supported by the highest rate of EoE observed in

Danish infants who spent 2 to 3 weeks in the NICU (aOR 2.8, 95% CI 1.2–6.6).17In

addition to maternal antibiotic and acid suppressant use, early antibiotic and acid

sup-pression during infancy have been associated with EoE, further reinforcing dysbiosis

and alterations in the gut microbiome as a potential mechanism in EoE Of these

medication exposures, the most robust evidence to date is in antibiotic use in infancy, first described by Jensen and colleagues (OR 6.0, 95% CI 1.7–20.8) and supported by separate cohorts (Ohio aOR 2.3, 95% CI 1.21–4.38; Massachusetts OR 3.61, 95% CI 1.11–11.74; North Carolina OR 4.64, 95% CI 1.63–13.2; Denmark aOR 1.4, 95% CI: 1.1–1.7), and reflected in insurance claims data (aOR 1.31; 95% CI 1.10–1.56).16,18–22 Although acid suppressants such as proton pump inhibitors (PPIs) are commonly used to treat EoE, their impact during the early life period is not clearly elucidated Observational data show a strong association of acid suppression therapy in infancy (aOR 6.05, 95% 2.55–14.40) and are echoed by a large database study (PPI aOR 2.73, 95% CI 1.93–3.88; histamine type-2 receptor antagonist (H2RA) aOR 1.64, 95% CI 1.27–2.13).16 , 22Another study revealed a strong association between infant acid sup-pression and risk of EoE (aOR 15.9, 95% CI 9.1–27.7) and increased odds of EoE in a dose–response manner (1 prescription aOR 11.4, 95% CI 5.1–25.6; 31 prescriptions aOR 23.5, 95% CI 9.1–60.7).18The role of breastfeeding in EoE is less clear with nonexclusive breastfeeding trending toward increased odds of EoE (OR 3.5, 95%

CI 0.6–19.5) in one study, but nonsignificant association in others.16 , 19 , 20 , 23 Comple-menting these data in pediatric-onset EoE, one study assessed these early life factors

on the development of EoE in adulthood, demonstrating similarly strong associations between preterm delivery (OR 2.92, 95% CI 0.71–12.0), cesarean delivery (OR 3.08, 95% 0.75–12.6), NICU admission (OR 4.0, 95% CI 1.01–15.9), and antibiotic use in in-fancy (OR 4.64, 95% CI 1.63–13.2).21

LATER LIFE AND ENVIRONMENTAL EXPOSURES

Seasonality and Aeroallergens

Moving beyond the early life period, studies of environmental exposures demonstrate associations with and potential relationships with EoE Studies of seasonality on EoE diagnosis and symptoms show trends and differences according to climate, suggest-ing a potential role of aeroallergens or suggest-ingestion of specific seasonally available foods For example, a study of EoE cases from a national database reported an increased risk for EoE among those living in a cold climate zone (aOR 1.4, 95% CI 13.5–1.5) compared with temperate.24 From this same database, seasonal variation was observed in EoE in temperate and cold climates with higher EoE diagnosis in the sum-mer months and differing peak diagnoses by climate zones.25Despite these patterns, conflicting findings from several single-center studies report association between sea-son and EoE, whereas others do not, signaling that aeroallergens do not universally cause or exacerbate EoE Similarly, among studies describing disease recrudes-cence, no significant seasonal differences were observed (27.1% spring diagnosis

vs 21.5% winter,P 5 70).26 , 27Limitations of these studies to date include heteroge-neity in defining seasonal exposure, geographic variations in aeroallergens, and retro-spective designs These findings are also likely biased by a temporal gap between initial symptom onset, report of symptoms, diagnosis, and using the time diagnosis

or clinical presentation as a proxy for disease activity

Environmental Quality

Recent investigation on air and water quality on EoE suggests potential modifiable environmental exposures, although findings from this early work remain inconclusive Emergency room visits for indications of chest pain, dysphagia, and food impaction in the state of Utah were associated with high particulate pollution levels above environ-mental protection agency (EPA) standards.28However, a recent nationwide pathology database study reported increased odds of EoE in regions of the worst Environmental

Quality Index (OR 1.25, 95% CI 1.04–1.50), driven by poor water quality, but

decreased odds of EoE in regions with poor air (OR 0.87, 95% 0.74–1.03) or land

(OR 0.87, 95% CI 0.76–0.99) quality.29Using data collected from private well sampling

in North Carolina, metal contaminants in drinking water (inorganic mercury OR 1.22,

95% CI 1.15–1.28; beryllium OR 1.35, 95% CI 1.30–1.39; thallium OR 1.25, 95% CI

1.21–1.29) has been associated with EoE.30

Other posited exposure risk factors associated with EoE include proximity to swine

farming operations (aOR 2.56, 95% CI 1.33–4.95) and housing components (brick

exterior aOR 1.83, 95% CI 1.11–3.02; gas heating 14% EoE vs 8% controls,

in vivo mouse studies demonstrating impaired esophageal epithelial barrier

dysfunc-tion and esophageal eosinophilia with detergent exposure may also explain evolving

trends in EoE.33The absolute impact of these exposures on the development or

exac-erbation of EoE is unknown and calls for further investigation

Prior Infections

With the rise in allergic disease coinciding with the decrease inHelicobacter pylori in

the last few decades, specifically in Westernized countries, an inverse association

be-tweenH pylori and atopic conditions is observed in studies to date.34The role of

in-fectious agents in the development or protection against EoE has been theorized,

but with conflicting findings In a systematic review and meta-analysis of 11 adult

and pediatric observational studies, H pylori exposure was inversely associated

with EoE (OR 0.63, 95% CI 0.51–0.78) and esophageal eosinophilia (OR 0.62, 95%

CI 0.52–76), suggesting a protective effect ofH pylori infection.35Conversely, a large

multicenter case-control study of European adults and children reported the

preva-lence ofH pylori was not different between EoE (OR 0.97, 95% CI 0.73–1.30) and

con-trol cases.36In a recent nationwide case-control study of Swedish histopathology,

antecedent infections conferred with an increased risk of EoE (OR 2.01, 95% CI

1.78–2.27), with further increased odds of sepsis with a diagnosis of EoE.37

CLINICAL CLUES

Comorbidity with Other Atopic Disorders

Clues about the etiology of EoE can also be found by examining its co-occurrence with

other diseases EoE is frequently comorbid with atopic diseases such as allergic

rhinitis (OR 5.09, 95% CI 2.91–8.90), asthma (OR 3.01, 95% CI 1.96–4.62), eczema

(OR 2.85, 95% CI 1.87–4.34), and food allergies (aOR 1.3, 95% CI 1.23–1.32), which

share several clinical and epidemiologic similarities.38–42 Much like EoE, the

preva-lence and incidence of atopic diseases has risen in recent decades, in part due to

factors that may be explained by the hygiene hypothesis and alterations in the

micro-biome Early life exposures shaping the gut microbiome and immune homeostasis are

also posited in the development of atopic conditions, and similarly, observational

studies of atopic conditions report a relationship between disease development and

early life use of medications (acid suppressants, antibiotics) and environmental risk

factors (eg, aeroallergens).43

Eosinophilic Esophagitis and Gastroesophageal Reflux Disease

Although EoE was initially thought to be a variant of gastroesophageal reflux disease

(GERD), it is now recognized as a clinically distinct disease As symptoms can be

shared between the two disease states—EoE can precipitate symptoms of heartburn

and regurgitation and GERD can cause dysphagia—differentiating the two disease

states and determining the role of PPI in the treatment of both has been challenging and evolved over the last 2 decades Despite the understanding of GERD as a sepa-rate entity from EoE, it has been hypothesized that one could contribute to the devel-opment of the other.44Acid damage and GERD are hypothesized to increase mucosal permeability of the esophagus, increasing antigenic exposure of food groups Conversely, the infiltration of eosinophils and associated immune products can cause acid reflux through impaired esophageal motility (decreased acid clearance) and the anti-reflux barrier (relaxation of the lower esophageal sphincter) However, there is a lack of evidence to support these pathways as the sole etiology or predominant risk factor for developing EoE In reality, EoE and GERD likely coexist in certain patients but the interaction of the two disease processes is not well characterized

Eosinophilic Esophagitis and Inflammatory Bowel Disease

In searching for etiologic clues in EoE, parallels to inflammatory bowel disease (IBD) (Crohn’s disease, in particular) are often drawn as both conditions are immune-mediated inflammatory states which can progress to fibrostenotic complications Not only are there clinical analogies between the diseases but also several studies demonstrate disease co-occurrence The initial single-center cohort study using diag-nostic codes reported the prevalence of esophageal eosinophilia in IBD cases (0.25%) and prevalence of confirmed EoE in IBD (0.10%) but without significant differences be-tween EoE patients with or without IBD.45Despite these low prevalence rates, concur-rent EoE is two times higher in IBD than in the general population (0.05%) In a population-based analysis of insurance claims in the United States, the risk of EoE was higher among patients with Crohn’s disease or ulcerative colitis, and the risk of IBD was higher among those with EoE compared with people without either disease.46

The risk of EoE was higher among those with IBD and vice versa In contrast, an in-verse relationship between EoE and Crohn’s disease (aOR 0.64, 95% CI 0.51–0.78), but not ulcerative colitis (aOR 0.97, 95% CI 0.75–1.24) using a national repository of histologic records from largely adult patients.47Focused cohort studies of pediatric EoE report heterogeneous prevalence from 0.35% in Italian children to 2.2% in Amer-ican children from two tertiary centers.48–50

The reason for the observed overlap between EoE and IBD remains elusive, and when observed in the same patient, it is unclear whether these represent two distinct diseases Eosinophilic infiltration of the gastrointestinal mucosa has been observed in Crohn’s disease and ulcerative colitis Still, EoE and IBD are currently thought of as distinct diseases with potentially shared mucosal immune dysregulation Currently, clinical guidelines recommend excluding IBD as a secondary cause when making a diagnosis of EoE.4Despite being unique chronic inflammatory diseases of the GI tract, several similarities include epidemiologic trends (eg, rising incidence, disease enrich-ment in Westernized countries, early life risk factors), diagnostic challenges (eg, endo-scopic assessment, poor reliance on symptoms), and management goals (eg, induction and maintenance therapies, long-term disease remission, chronic disease control) exist between EoE and IBD Similar to EoE, the etiology of IBD remains un-known, and interactions between genetic, environmental, microbial, and lifestyle fac-tors are thought to be necessary for disease development

Eosinophilic Esophagitis and Celiac Disease

As another chronic immune-mediated gastrointestinal disorder, celiac disease (CD) has been hypothesized to be etiologically similar to EoE Both likely arise from environ-mental, genetic, and immunologic factors, and are more prevalent in Westernized countries, induced by consuming food triggers, and treated by dietary avoidance

strategies Although some case reports and observational single-center studies,

pre-dominantly in children, demonstrate potential co-occurrence with prevalence of EoE in

CD up to 4%, others report conflicting findings that patients with CD are not more

likely to have esophageal eosinophilia on endoscopy and a diagnosis of CD is not

associated with an increased risk of EoE.51–61In a cohort of adult EoE patients,

John-son and colleagues reported an increased rate of potential CD (13.6%), higher than the

expected prevalence in the general population, and whose EoE resolved with gluten

avoidance.62 Using a national pathology database, Jensen and colleagues

demon-strated that although the odds of EoE were 26% higher among those with CD

compared with those without (aOR 1.26, 95% CI 0.98–1.60), there was only a weakly

positive association when a more stringent case definition was applied.63

The potential association between EoE and CD remains uncertain due to or current

understanding of EoE as a Th2-mediated disease versus CD as a Th2-mediated

pro-cess, and conflicting findings, potentially due to heterogeneity in biopsy sampling,

defining a diagnosis of EoE instead of esophageal eosinophilia in CD, and limited small

studies to date

SUMMARY/FUTURE DIRECTIONS

Over the last 2 decades, the incidence and prevalence of EoE has dramatically

increased, with recent evidence of potential tapering Along with these epidemiologic

trends, studying early life and later life environmental factors provides clues about the

etiology of EoE Of these, the most consistent and compelling support is for early life

factors such as antibiotic use Although epidemiologic studies have been and will

continue to be critical for hypothesis generation and evaluation of potential etiologic

factors in the development of EoE, caution must be taken in interpretation and clinical

application Identifying and distinguishing pattern from “noise” that can contribute to

bias and incorrect inferences remains a significant challenge As such, applying casual

inference methods to better discern associative versus causal effects, recognizing

mediators in associations, and disentangling confounder factors are crucial In

addi-tion, future studies probing additional mechanisms for how environmental factors

contribute (eg, dysbiosis, epigenetic modifications) are needed

CLINICS CARE POINTS

 Importance of obtaining a detailed history of atopy or environmental exposures in the care

of individuals with eosinophilic esophagitis (EoE) Although prevention of EoE may not be

possible in established cases, establishing comorbid exposures/allergic disease may play a role

in the management of EoE.

 The development of EoE is multifactorial, a result of complex interactions between

environmental exposures in genetically susceptible individuals.

 The most compelling and strong evidence for risk factors to developing EoE is in early life

factors However, studying environmental risk factors is encumbered by numerous threats

to validity Future studies with comprehensive exposure assessment are needed.

DISCLOSURE

Study concept and design: J.W Chang and E.T Jensen Drafting of the article: J.W

Chang and E.T Jensen Critical revision of the article: J.W Chang and E.T Jensen

This work was supported by funding in part by NIH, United States awards

K23DK129784 (J.W Chang), R01AI139126 (E.T Jensen), and R01ES031940 (E.T Jensen)

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