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Ruffner Eosinophilic esophagitis EoE is a chronic, progressive immune-mediated disease associated with antigen-driven type 2 inflammation and symp-toms of esophageal dysfunction.. Liacou

Rohit Katial

Preface: Gastrointestinal Eosinophilic Diseases: Updates on Eosinophilic Esophagitis

Glenn T Furuta and Dan Atkins

Kanak V Kennedy, Amanda B Muir, and Melanie A Ruffner

Eosinophilic esophagitis (EoE) is a chronic, progressive immune-mediated disease associated with antigen-driven type 2 inflammation and symp-toms of esophageal dysfunction Research over the last 2 decades has dramatically furthered our understanding of the complex interplay be-tween genetics, environmental exposures, and cellular and molecular in-teractions involved in EoE This review provides an overview of our current understanding of EoE pathogenesis

Pathophysiology and Clinical Impact of Esophageal Remodeling and Fibrosis in

Calies Menard-Katcher and Seema Aceves

Most of the major clinical signs and consequences of eosinophilic esoph-agitis seem to be related to tissue remodeling Important data on remod-eling activity in patients with eosinophilic esophagitis are provided by a range of current and new biologic markers and diagnostics To completely clarify the possible advantages and restrictions of therapeutic ap-proaches, clinical studies should take into consideration the existence and reversibility of esophageal remodeling The degree of mucosal or sub-mucosal disease activity may not be reflected by epithelial eosinophilic in-flammation, which is used to define one criterion of disease activity"

Epidemiologic and Clinical Clues to the Etiology of Eosinophilic Esophagitis 145 Joy W Chang and Elizabeth T Jensen

Despite the rising prevalence and incidence of eosinophilic esophagitis (EoE), the etiology and pathophysiology remain unknown Studies to date suggest that complex interactions between genetic and environmen-tal risk factors result in the development and presentation of disease Ex-amining environmental factors both in the early life and later life exposures offers potential clues for the development of EoE, although challenges ex-ist in making causal inferences due to diagnostic delay and access, ascer-tainment biases, and misclassification of cases The authors review studies supporting early life factors as etiologic factors in the development

of EoE

Clinical Evaluation of the Child with Eosinophilic Esophagitis 157 Maureen Bauer, Nathalie Nguyen, and Chris A Liacouras

The diagnosis of eosinophilic esophagitis (EoE) is based on clinical symp-toms of esophageal dysfunction and eosinophil predominant esophageal inflammation Clinical symptoms in children with EoE vary based on age and may be nonspecific EoE has a male predominance with the majority having comorbid atopic disorders At present, treatment options include medications (proton pump inhibition, swallowed topical steroids), dietary therapy or biologic therapy (dupilumab, approved for those12 years of age) Outside of EoE in the context of oral immunotherapy, EoE is typically chronic requiring lifelong therapy Long-term complications including feeding difficulties, malnutrition, and fibrostenotic disease

Recognition and Management of Feeding Dysfunction in the Pediatric Patient

Angela M Haas, Rebecca J Doidge, and Girish Hiremath

Feeding is a complex skill requiring coordination of multiple body systems Multiple factors are considered in feeding dysfunction in pediatric patients with eosinophilic gastrointestinal disorders, including overall development, nutritional status, mealtime behaviors, and medical comorbidities Symp-toms of feeding dysfunction vary by age, with maladaptive learned feeding behaviors spanning all age ranges Knowledge of the normal acquisition of feeding skills is critical to interpret the impact of the disease and plan ap-propriate intervention Assessment and treatment from a feeding and swallowing disorders specialist can dramatically impact successful out-comes in nutrition, growth, mealtime dynamics and ultimatly quality of life for children and their caregivers in home and social settings

Clinical Evaluation of the Adult with Eosinophilic Esophagitis 185 Luc Biedermann and Alex Straumann

Adult patients with eosinophilic esophagitis (EoE) typically present with a history of dysphagia for solids, sometimes with additional reflux-like pain and a history of prior food impactions In contrast to these alarming symp-toms, the general appearance and physical examination of adult patients with EoE is in line with apparently healthy individuals Therefore, the diag-nosis is based on a history of solid-food dysphagia and eosinophilic tissue infiltration Importantly, the increasing prevalence of EoE variants, that is, typical EoE symptoms in the absence of a relevant eosinophilia, and sev-eral studies with eosinophil-targeting drugs, call the pathogenic role of eo-sinophils into question

Alain M Schoepfer, Ekaterina Safroneeva, and Kathryn Peterson

Edema, rings, exudates, furrows, and strictures (EREFS) represent the ma-jor endoscopic features of eosinophilic esophagitis (EoE) The Endoscopic Reference System (EREFS) grading system is easy to learn and apply dur-ing daily clinical practice in the diagnosis and follow-up of EoE patients When endoscopy is performed by an EoE-experienced physician, the EREFS criteria will identify the majority of EoE patients The EREFS score

from the area of greatest involvement of the esophagus should be

re-ported The EREFS grading system was formally validated as an

endos-copy score and several randomized placebo-controlled trials have

shown responsiveness of the EREFS score to therapeutic interventions

Margaret H Collins, Nicoleta C Arva, Anas Bernieh, Oscar Lopez-Nunez,

Maria Pletneva, and Guang-Yu Yang

Microscopic examination of esophageal biopsies is essential to diagnose

eosinophilic esophagitis (EoE) Eosinophil inflammation is the basis for the

diagnosis, but additional abnormalities may contribute to persistent

symp-toms and epithelial barrier dysfunction Both peak eosinophil count and

assessments of additional features should be included in pre-therapy

and post-therapy pathology reports Pathologic abnormalities identified

in esophageal biopsies of EoE are reversible in contrast to esophageal

strictures

Alfredo Lucendo, Marion Groetch, and Nirmala Gonsalves

Eosinophilic esophagitis (EoE) is a chronic immune-mediated food allergy–

driven disease characterized by eosinophilic inflammation of the

esopha-gus leading to symptoms of esophageal dysfunction Prior studies have

supported the key role of food allergen exposure as the main driver behind

the etiopathogenesis showing that removal of food antigens can result in

disease remission in both children and adults These landmark studies

serve as the basis for the rising interest and evolution of dietary therapy

in EoE This article will focus on the rationale for dietary therapy in EoE

and provide helpful tools for the implementation of dietary therapy in

practice

Gary W Falk and Robbie Pesek

Proton pump inhibitors (PPIs), swallowed topical corticosteroids (STSs),

and dupilumab are highly effective therapies for the treatment of

eosino-philic esophagitis Shared decision-making informs the choice of therapy

and factors such as ease of use, safety, cost, and efficacy should be

ad-dressed PPIs are the most common medication utilized early in the

dis-ease course; however, for nonresponders, STSs are an excellent

alternative Dupilumab is unlikely to replace PPIs or STSs as first-line

ther-apy, except in highly specific circumstances Identification of novel

bio-logic pathways and the development of small molecules may lead to a

wider range of treatment options in the future

Health-Related Quality of Life in Patients with Eosinophilic Esophagitis 265

Maria L van Klink and Albert J Bredenoord

Measuring health-related quality of life (HRQOL) gained relevance in

re-search and clinical practice in patients with eosinophilic esophagitis The

physical discomfort and social and psychological consequences of this

food-related disease substantially affect HRQOL Determinant of an

impaired HRQOL include symptom severity, disease duration, biological disease activity, and psychological factors Patients prioritize symptom re-lief and improved HRQOL as treatment objectives Available treatment op-tions can address these goals; however, there is a suboptimal adherence

to treatment There is a need for enhanced patient guidance and educa-tion The assessment of HRQOL will help to prioritize patient’s needs in management

The Relationship Between Eosinophilic Esophagitis and Immunotherapy 281 Bridget E Wilson, Maria A Sacta, Benjamin L Wright, Jonathan Spergel, and

Nicole Wolfset

Immunotherapy is a treatment approach based on the principle of incre-mental allergen exposure to achieve desensitization Recently, oral immu-notherapy has been introduced as a treatment of IgE-mediated food allergy Some patients receiving oral immunotherapy for food allergy may develop eosinophilic esophagitis Here, we summarize the literature examining this association, its treatment, and outcomes and discuss pos-sible explanations for this clinical phenomenon We further identify poten-tial associations with aeroallergen sensitivity and other forms of immunotherapy including subcutaneous immunotherapy and sublingual immunotherapy Finally, we discuss management of immunotherapy-in-duced eosinophilic esophagitis Epicutaneous immunotherapy is high-lighted as an area of therapeutic investigation

Embracing Diversity, Equity, Inclusion, and Accessibility in Eosinophilic

Amanda B Muir, Dominique D Bailey, and Pooja Mehta

Eosinophilic gastrointestinal diseases (EGIDs) including eosinophilic esophagitis (EoE) are rare diseases in which eosinophils abnormally infil-trate the gastrointestinal tract Because these are rare diseases, there is limited information regarding race and ethnicity in EGIDs and even less

is known about the impact of socioeconomic factors There is some evi-dence that access to care in rural settings may be affecting epidemiologic understanding of EGIDs in the pediatric populations Future work should try to evaluate bias in research and strive for representation in clinical trials and medicine

Pathophysiology of Non-Esophageal Eosinophilic Gastrointestinal Disorders 299 Julia L.M Dunn and Lisa A Spencer

Eosinophilic gastrointestinal disorder (EGID) is an umbrella term encom-passing a group of chronic, immune-mediated disorders characterized by eosinophil-rich inflammation affecting one or more segments of the gastro-intestinal tract A recent consensus in nomenclature and emerging data made possible through multi-center consortia are beginning to unravel the molecular and cellular underpinnings of EGIDs below the esophagus These emerging findings are revealing both overarching commonalities related to a food allergen-driven, chronic, Th2-mediated immune response as well as lo-cation-specific nuances in the pathophysiology of the collective EGIDs Al-together, these advances offer promise for improved diagnoses and more efficacious interventional strategies

Role of Mast Cells in Eosinophilic Gastrointestinal Diseases 311

Paneez Khoury and Joshua B Wechsler

Mast cells play a central role in the pathogenesis of eosinophilic

gastroin-testinal disorders (EGIDs), including eosinophilic esophagitis Their

inter-actions with immune and structural cells, involvement in tissue

remodeling, and contribution to symptoms make them attractive targets

for therapeutic intervention More is being discovered regarding the

intri-cate interplay of mast cells and eosinophils Recent studies demonstrating

that depletion of eosinophils is insufficient to improve symptoms of EGIDs

have raised the question of whether other cells may play a role in

sympto-matology and pathogenesis of EGIDs

Associations of Eosinophilic Gastrointestinal Disorders with Other Gastrointestinal

Salvatore Oliva and Emily Clarke McGowan

Eosinophilic gastrointestinal disorders (EGIDs) are becoming more

com-mon causing significant suffering and reduced quality of life These

condi-tions can affect different parts of the digestive system, either individually or

in combination Recognition of their link to allergic disorders or other

gas-trointestinal (GI) diseases has raised questions about their shared

underly-ing mechanisms, which has had implications for diagnosis and

management The authors critically examine the current understanding

of the connection between EGIDs and allergic conditions (ie, atopic

der-matitis, allergic rhinitis, asthma, and food allergy) and GI diseases (ie,

in-flammatory bowel disease, celiac disease, gastroesophageal reflux

disease, and motility disorders)

Clinical Presentation of Patients with Eosinophilic Gastrointestinal Diseases beyond

Alexandra Papadopoulou and Noam Zevit

The clinical presentation of eosinophilic gastrointestinal diseases beyond

eosinophilic esophagitis (non-EoE EGIDs) varies depending on the

gastro-intestinal segments affected by the eosinophilic inflammation, the extent of

eosinophilic inflammation within the gastrointestinal tract and its depth

through the bowel wall.Non-EoE EGIDs with mucosal involvement tend

to present with diarrhea, malabsorption, and sometimes bleeding, those

with muscular involvement may present with symptoms of obstruction or

pseudo-obstruction, intussusception, and even perforation, whereas

those with serosal involvement may present with eosinophilic ascites

Here we describe the differences in symptoms experienced by children

with non-EoE EGIDs with varying degrees of eosinophilic inflammation

through the bowel wall

Endoscopic Features of Eosinophilic Gastrointestinal Diseases 357

Thomas Greuter and David Katzka

Endoscopic evaluation with biopsies is a mainstay of the diagnosis of

eo-sinophilic esophagitis (EoE) and non-EoE eoeo-sinophilic gastrointestinal

dis-eases (EGIDs) Increasing knowledge has resulted in the development of 2

standardized scoring systems: the Endoscopic REFerence Score (EREFS)

for EoE and the EG-REFS for eosinophilic gastritis, although the latter has not been validated In EGIDs, diagnosis and follow-up focus on eosinophil infiltration in biopsies In this article, we will discuss the most commonly used endoscopic scores in EoE and non-EoE EGIDs, their validity for the diagnosis and follow-up of disease activity, as well as endoscopic inter-ventions and areas of uncertainty

Histopathology of Eosinophilic Gastrointestinal Diseases Beyond Eosinophilic

Nicoleta C Arva, Anas Bernieh, Oscar Lopez-Nunez, Maria Pletneva,

Guang-Yu Yang, and Margaret H Collins

Eosinophilic gastrointestinal diseases (EGID), such as eosinophilic gastritis (EoG), eosinophilic enteritis, and eosinophilic colitis (EoC), are chronic in-flammatory conditions characterized by persistent gastrointestinal symp-toms and elevated levels of activated eosinophils in the gastrointestinal tract EoG and eosinophilic duodenitis (EoD) are strongly associated with food allergen triggers and TH2 inflammation, whereas EoC shows minimal transcriptomic overlap with other EGIDs The level of expression

of certain genes associated with TH2 immune response is associated with certain histopathologic findings of EoG, EoD, and EoC Current im-mune therapy for EoG depletes tissue eosinophilia with persistence of other histopathologic features of disease

Dietary Management of Non-EoE Eosinophilic Gastrointestinal Diseases 383 Mirna Chehade, Bethany Doerfler, and Dan Atkins

Patients with non–eosinophilic esophagitis eosinophilic gastrointestinal dis-eases (non-EoE EGIDs) are prone to nutritional deficiencies due to food-avoidant behaviors, malabsorption, and high nutrition impact symptoms Nutrient deficiencies correspond to the segment, depth, and extent of the gastrointestinal tract involved and can impact organs distant from the gut Patients with non-EoE EGIDs are often atopic, and some appear to respond

to dietary avoidance of specific food allergens Tests to identify food triggers other than response to elimination diets are lacking Dietary restriction ther-apy should be considered in such patients and is best implemented through

a multidisciplinary approach to avoid nutritional complications

Pharmacologic Management of Non–Eosinophilic Esophagitis Eosinophilic

Evan S Dellon and Sandeep K Gupta

Data for pharmacologic treatments for non–eosinophilic esophagitis (EoE) eosinophilic gastrointestinal diseases (EGIDs) are limited Nevertheless, because of the increasing understanding of EGID pathogenesis, a number

of medications are used to treat EGIDs, though all are currently off-label Initial therapy generally starts with corticosteroids, and “topical” delivery

is preferred over systemic due to long-term side effects A number of other small molecules could potentially be used, ranging from allergy medica-tions to immunosuppressants Biologics are also being used and investi-gated for EGIDs and represent promising targeted therapies Multiple therapeutic targets have also been identified, many of which overlap with EoE targets