Eosinophilic Oesophagitis in Adults

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					                              Inflammatory Oesophageal Disease

                                        Eosinophilic Oesophagitis in Adults

                                                                                                                                              a report by
                                                                                                 Adam B Kaufman, Matthew S Cohen,
                                                                                            A n t h o n y J D i M a r i n o J r and S i d n e y C o h e n

                                                                       Division of Gastroenterology and Hepatology Thomas Jefferson University Hospital

    Adam B Kaufman is a first-year      Eosinophilic oesophagitis (EO) is an increasingly            paediatric population1. It has been speculated that a
        medical resident at Thomas      recognized disorder of adults as identifying features        large number of patients with oesophageal food
       Jefferson University Hospital.
                                        of this disease are discovered and reported. The             impactions may have previously undiagnosed EO.
Matthew S Cohen is a senior Fellow      clinical spectrum includes four common features:             The prevalence of EO in a community-based adult
in Gastroenterology and Hepatology                                                                   gastroenterology practice among patients who
      at Thomas Jefferson University
                                        • eosinophilic infiltration of the oesophageal               presented with oesophageal food impactions was
                                          squamous epithelium;                                       reviewed. In more than half of these patients,
 Anthony J DiMarino Jr is the Chief                                                                  oesophageal biopsies demonstrated evidence of EO.3
 of the Division of Gastroenterology    • symptoms of         dysphagia      and    food    bolus
and Hepatology of Thomas Jefferson
                 University Hospital.     impactions;                                                EO presumably has an allergic aetiology and it has been
                                                                                                     shown that certain allergic diseases are on the rise in
     Sidney Cohen is the Director of    • characteristic endoscopic findings of a corrugated,        developed countries. Thus, it may be expected that the
          Research in the Divison of
 Gastroenterology and Hepatology of       ringed, or ‘feline’ oesophagus with narrowing,             incidence of allergy-mediated gastrointestinal illnesses
Thomas Jefferson University Hospital.     linear furrowing and a ‘crepe-paper’ fragile               may also be increasing.4 The hygiene hypothesis
                                          mucosa; and                                                suggests that children in developed countries are now
                                                                                                     being raised in more sterile environments and do not
                                        • endoscopic complications of mucosal splitting or           experience early exposure to allergens at an age when
                                          perforation.                                               the immune system can mount an appropriate
                                                                                                     response. Instead, later exposure may cause a
                                        This article will review the epidemiology, clinical          pathologic response to these same allergens and lead to
                                        features, endoscopic findings, complications and             the development of conditions such as asthma and EO.
                                        current treatment options. It will also compare              As paediatric and adult gastroenterologists become
                                        paediatric and adult forms of this illness.                  more familiar with the clinical spectrum, future studies
                                                                                                     on incidence and prevalence should be more accurate.
                                        During the past decade, EO has emerged as a
                                        worldwide disease entity with reports from the US,           Within the last decade, much attention has been
                                        Canada, Europe, Australia, Japan and South                   devoted to the understanding of EO as a disease of
                                        America.1,2 Estimates of incidence and prevalence            possible allergic origin with comparisons often made
                                        have been difficult to determine. Endoscopic                 to respiratory allergic illnesses. Despite overlapping
                                        findings are often subtle, which may lead to an              features, EO is now believed to be unrelated to gastro-
                                        underreporting of cases, particularly in adult               oesophageal reflux disease (GORD). A necessary
                                        populations. Noel reported an incidence of 1/10,000          feature of EO is a dense infiltrate of eosinophils within
                                        per year and a prevalence of 4/10,000 in the                 the oesophageal squamous mucosa, a feature not

                                        1. Noel R J, Putnam P E, Rothenberg M E, “Eosinophilic Esophagitis”, New England Journal of Medicine
                                           (2004);351(9): pp. 940–941.
                                        2. Liacouras C, Spergel J, Ruchelli E, et al., “Eosinophilic esophagitis: a 10-year experience in 381 children”, Clinical
                                            Gastroenterology and Hepatology (2005);3: pp. 1,198–1,206.
                                        3. Desai, T, Stecevic V, Chang C H, t al., “Association of eosinophilic inflammation with esophageal food impactions in
                                            adults”, Gastrointestinal Endoscopy (2005);61(7): pp. 795–801.
                                        4. Fox V, Nurko S, Furuta G, “Eosinophilic esophagitis: it’s not just kid’s stuff”, Gastrointestinal Endoscopy (2002);
                                            56(2): pp. 260–270.
                                        5. Mishra A, Hogan S, Brandt E, Rothenberg M, “An etiological role of aeroallergens and eosinophils in experimental
                                            esophagitis”, Journal of Clinical Investigation (2001);107(1): pp. 83–90.

30                                                                                                         EUROPEAN GASTROENTEROLOGY REVIEW 2006
                                                                              Eosinophilic Oesophagitis in Adults

present in the normal oesophagus. Peripheral                    mediated pathway for the development of EO
eosinophilia may also be present.5 Arora described              involving a T-helper 2 (Th2) lymphocyte-mediated
three theories of the pathogenesis that relate to an            inflammatory picture with increased IL-4 expression
immunoglobin E (IgE) mediated mechanism:                        and activation of eosinophils and mast cells.8

• Initial antigen sensitization occurs within the               Although the pathways that result in EO are yet to
  oesophagus from ingested food, swallowed                      be completely delineated, current research suggests
  aeroallergens/pathogens and secretions from the               that affected patients have an underlying genetic
  upper and lower airway. This theory is                        susceptibility. Antigen sensitization likely occurs
  supported by the response to elimination diets                within the oesophagus and is followed by either an
  seen in some children.                                        IgE-mediated pathway involving IL-5 and eotaxin,
                                                                or a Th2 lymphocyte-mediated inflammatory
• Initial sensitization occurs from inhaled                     response with increased IL-4. Both pathways may
  aeroallergens in the bronchus followed by a cross-            cause eosinophil recruitment to oesophageal tissue,
  reaction to separate allergens in the oesophagus.             with subsequent degranulation resulting in the
  This theory is supported by the cross-sensitivity             pathological changes to the involved layers.
  seen in some people with allergies to combinations
  of aeroallergens and plant-related food allergens             Paediatric Disease
  such as ragwood-banana-melon, birch-apple and
  celery-mugwort-spice.                                         Paediatric EO is a clinical entity with features that
                                                                distinguish it from the adult form of the disease. The
• Sensitization occurs outside of the oesophagus                range of symptoms is broader in children, possibly
  where immune cells of outside origin (bronchus,               related to the inability of children to verbalize their
  skin) communicate with the oesophagus. This                   complaints. Besides dysphagia, food impactions and
  latter theory seems to be less likely as cutaneous            strictures which are more commonly seen in adults,
  lymphocyte-associated antigen (+) T cells are not             children experience more nausea, vomiting/regurgit-
  increased in EO.6                                             ation, chest or epigastric pain, poor feeding, slowed
                                                                growth, water brash and respiratory symptoms of
The cytokines interleukin 5 (IL-5) and eotaxin,                 cough, wheezing and sinusitis.4 Endoscopic evaluation
specifically eotaxin-3, are now believed to play a key          often reveals a subtle granularity of the mucosa with
role in eosinophilic recruitment to the oesophagus.5,           the same corrugations, furrowing, microabscesses and
7 IL-5 has been shown to signal the expansion and               ‘felinization’ that are seen in adults.9 Major compli-
mobilization of eosinophils while eotaxin regulates             cations in children are generally related to mucosal
the homing of eosinophils to a specific area. Mishra            involvement including strictures and tearing on
demonstrated that IL-5 ablated mice do not develop              endoscopy. There are fewer reports of the transmural
eosinophilic infiltration of the oesophagus. This               complications of perforation or rupture than in the
finding suggests a possible future role for anti-IL-5           adult population. Much attention has been directed
therapy.5 In the murine model, eotaxin elimination              towards the treatment of paediatric patients suffering
causes attenuation of eosinophilic infiltration and the         from EO, including the use of food elimination diets,
associated hyperplasia of the oesophageal mucosa.               elemental formulas, topical (swallowed) or systemic
Recently, Blanchard showed that eotaxin-3 levels                corticosteroids, anti-reflux modalities, cromolyn
strongly correlate with disease severity. A single              sodium and leukotriene receptor antagonists. Recently,
nucleotide polymorphism (SNP) in the eotaxin-3                  there have been attempts to target specific chemokines
gene is associated with disease susceptibility.                 including IL-5 and eotaxin.10 Treatment of paediatric
Similarly, genetic deletions of the eotaxin receptor            EO has provided the direction for adult management,
(CCR3) provide a protective effect in genetically               which will be discussed later. Overall, compared with
altered mice.7 Nicholson has also proposed a non-IgE            adults, children with EO have a broader array of

6. Arora A, Yamazaki K, “Eosinophilic esophagitis: Asthma of the esophagus?”, Clinical Gastroenterology and
    Hepatology (2004);2: pp. 523–530.
7. Blanchard C, Stringer K, Mishra A, et al., “Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic
    esophagitis”, The Journal of Clinical Investigation (2006);116(2): pp. 536–547.
8. Nicholson A, Li D, Pastorino U, et al., “Full thickness eosinophilia in oesophageal leiomyomatosis and idiopathic
    eosinophilic oesophagitis. A common allergic inflammatory profile?”, Journal of Pathology (1997);183: pp. 233–236.
9. Orenstein S, Shalaby T, DiLorenzo C, et al., “The spectrum of pediatric eosinophilic esophagitis beyond infancy: A clinical
    series of 30 children”, The American Journal of Gastroenterology (2000);95(6): pp. 1,422–1,430.
10. Liacouras C, “Eosinophilic esophagitis: treatment in 2005”, Current Opinion in Gastroenterology (2006);22: pp.

EUROPEAN GASTROENTEROLOGY REVIEW 2006                                                                                            31
     Inflammatory Oesophageal Disease

         presentations, similar endoscopic evaluations and more             Although there is no consensus, it is generally accepted
         thorough treatment data.                                           that the mean density of eosinophils within the
                                                                            squamous epithelium is >20/high power field (HPF)
         Clinical Features in Adults                                        with EO and <10/HPF with GORD. Newer recom-
                                                                            mendations suggest a criterion of ≥15 epithelial eosino-
         The clinical presentation of EO typically involves                 phils in two or more HPFs or ≥25 eosinophils in a
         younger patients (20 to 40 years old), with a Caucasian            single HPF.15 Other associated findings include lamina
         male predominance.11 There is often a personal or                  propria papillae elongation, basal zone hyperplasia,
         family history of allergic conditions including asthma,            intercellular oedema15, eosinophilic microabscesses3,
         atopic dermatitis, eczema, seasonal allergies and food             hyperplasia of the squamous epithelium with mucosal
         allergies. Patients may complain of solid food                     thickening and morphological alterations that cause
         dysphagia, regurgitation, chronic heartburn refractory             increased lamina propria fibrosis and loss of elasticity.12
         to treatment with acid-reducing medications and food               Changes of EO can be found throughout the length of
         bolus impaction. There is often a long duration of                 the oesophagus. Accordingly, biopsies should be
         symptoms prior to diagnosis. Asymptomatic periods are              obtained both proximally and distally when evaluating
         common. Previous evaluations for GORD and other                    for EO.
         causes of dysphagia, including mechanical obstruction
         and motility disorders, are often unrevealing.                     In the majority of cases of EO, eosinophilic infiltration
                                                                            is limited to the mucosa. However, submucosal,
         Endoscopic Findings                                                muscular and transmural involvement have also been
                                                                            demonstrated. Endoscopic ultrasound (EUS) in
         The endoscopic findings associated with EO may                     children with EO has demonstrated increased total
         range from subtle to striking. The mucosa has been                 wall thickness, expansion of the combined mucosa/
         described as a ‘crepe-paper’ mucosa because of its                 submucosa and increased thickness of muscularis
         fragile, delicate and inelastic appearance.12 Features may         propria when compared with healthy controls. These
         include a small caliber oesophagus with a narrowed and             findings may be related to transmural eosinophilic
         fixed internal diameter, corrugations or multiple con-             infiltration.16 Furthermore, resected segments from
         centric rings similar to the feline oesophagus,13 small            EO patients with perforations have demonstrated
         white papules representing eosinophilic microabscesses,            transmural eosinophilia.8
         longitudinal mucosal furrows and long mucosal tears
         induced by minor trauma during scope passage or                    Complications
         dilation procedures.14 Focal stricturing may be seen
         both proximally and distally. Strictures typically occur           It has been hypothesised that chronic eosinophilic
         in the absence of mucosal ulceration, a feature that may           inflammation causes mucosal fragility and loss of
         distinguish EO from peptic oesophageal injury.4                    elasticity.12 The range of reported complications in EO
                                                                            include mucosal tearing during the performance of
         Histopathology                                                     endoscopy and dilatation procedures, transmural
                                                                            perforation during endoscopy and oesophageal rupture
         Microscopic examination is generally the preferred                 associated with food bolus impaction.17 Accordingly,
         method for confirming a diagnosis of EO. EO is                     several authors advocate cautious endoscopic
         characterized by eosinophils within the oesophageal                management of lumenal narrowings and strictures
         mucosa, a feature not present in the normal                        associated with EO. It has been suggested that
         oesophagus. Because eosinophils have served as a                   oesophageal dilation be considered only in those
         marker of peptic oesophagitis, there has been debate               patients who have failed at least eight weeks of medical
         about the exact number of eosinophils that define EO.              therapy with topical corticosteroids.13

         11. Straumann A, Spichtin H-P, Grize L, et al., “Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult
             patients for up to 11.5 years”, Gastroenterology (2003);125: pp. 1,660–1,669.
         12. Straumann A, Rossi L, Simon HU, et al., “Fragility of the esophageal mucosa: A pathognomonic endoscopic sign of
             primary eosinophilic esophagitis?”, Gastrointestinal Endoscopy (2003);57: pp. 407–412.
         13. Kaplan M, Mutlu E, Jakate S, et al., “Endoscopy in eosinophilic esophagitis: “Feline” esophagus and perforation risk”,
             Clinical Gastroenterology and Hepatology (2003);1: pp. 433–437.
         14. Potter J, Saeian K, Staff D, et al., “Eosinophilic esophagitis: an emerging problem with unique esophageal features”,
             Gastrointestinal Endoscopy (2004);59(3): pp. 355–361.
         15. Parfitt J, Gregor J, Suskin N, et al., “Eosinophilic esophagitis in adults; distinguishing features from gastroesophageal reflux
             disease: a study of 41 patients”, Modern Pathology (2006);19: pp. 90–96.
         16. Fox V, Nurko S, Teitelbaum J, et al., “High-resolution EUS in children with eosinophilic “allergic” esophagitis”,
             Gastrointestinal Endoscopy (2003);57(1): pp. 30–36.

32                                                                                 EUROPEAN GASTROENTEROLOGY REVIEW 2006
                                                                              Eosinophilic Oesophagitis in Adults

We have recently reported a case of spontaneous                 The first-line medical therapy is the use of topical
oesophageal rupture (Boerhaave’s syndrome) in a 56-             corticosteroids, administered as swallowed aerosolized
year-old man with EO. This unusual association                  fluticasone propionate. Second-line options include
widens the clinical spectrum and risk profile of EO.            systemic corticosteroids, cromolyn sodium and
What remains to be determined is whether mucosal                leukotriene receptor antagonists. Future directions may
and transmural fragility correlate with the density and         include the use of monoclonal antibodies like the anti-
depth of eosinophilic infiltration. We have                     IL-5 antibody mepolizumab18. Anti-reflux medications
hypothesized that mucosal infiltration is associated with       have also been utilized with limited success in
strictures and mucosal tears, whereas transmural                achieving symptomatic relief and histologic
involvement is associated with instrumental perforation         improvement. In a series by Liacouras, all 17 paediatric
and spontaneous rupture (Boerhaave’s syndrome).                 patients treated with swallowed aerosolized fluticasone
                                                                had a significant histologic improvement within four
Treatment                                                       weeks. Thirteen of 17 patients experienced partial or
                                                                complete resolution of their symptoms of reflux and
The three main treatment modalities that have been              dysphagia. However, recurrence of eosinophilic
used with varying degrees of success are endoscopic             infiltration to near pre-treatment levels occurred six
intervention, dietary modification and pharmaco-                months after medication withdrawal. Furthermore,
therapy. The majority of treatment data comes from              most patients experienced recurrence of symptoms.2
studies of paediatric populations, with results                 Despite the lack of a significant longitudinal study in
extrapolated to the adult population. Endoscopic                adults, many adult patients have dramatic
therapy mainly consists of dilation procedures aimed at         improvements in both symptoms and histology with
relieving the dysphagia caused by strictures or fixed           the use of swallowed fluticasone. Topical steroids often
rings.10 Both bougienage and balloon dilators have              provide a durable response. However, in some cases,
been used. However, physicians must be aware of the             they may only provide temporary symptomatic
possible complications prior to the performance of              resolution. The need for retreatment is not
these procedures. Furthermore, while patients may               uncommon. Chronic use of topical steroids is not
experience initial symptomatic relief after endoscopic          recommended because of potential side effects,
therapy, dilation does not address the underlying               including thrush. Cromolyn sodium and leukotriene
inflammatory changes.11                                         receptor antagonists interfere with the eosinophilic
                                                                infiltration and degranulation cascade. Prospective
Dietary modifications with food elimination diets and           controlled studies are needed to fully evaluate their
elemental diets with amino acid-based formulas have             efficacy. Nevertheless, montelukast may be a viable
been utilized with some success in paediatric EO                steroid sparing option.19
patients. Allergy testing with skin prick (IgE-mediated)
and patch testing (non-IgE-mediated) has been                   Future Directions
recommended to identify potential food allergens.
Food products believed to be associated with EO                 Despite the recent advances in our understanding of its
include cow’s milk, soy, eggs and wheat. When                   pathophysiology, clinical spectrum and treatment
suspected allergens are identified, withdrawal from the         options, EO remains a disease without a clear aetiology
diet may provide both symptomatic relief and                    and lacking a defined treatment approach. As future
histological improvement.10 If no allergen is identified,       studies further elucidate its pathogenesis, newer
elemental amino acid formulas can be used with                  diagnostic and treatment options may become
gradual reintroduction of foods and frequent evaluation         available. EO carries a significant complication
for symptomatic and histologic recurrence. Liacouras            spectrum that warrants particular attention and sparks
reported improvement in clinical symptoms and                   particular questions. The answers to these questions
oesophageal histology in 98% of children compliant              will hopefully reveal features of EO that will improve
with a restricted diet after allergen identification.2 Most     our recognition and management. ■
adult patients would have great difficulty adhering to
these highly restrictive elimination and elemental diets.       A version of this article containing graphics can be found in
Therefore, dietary modification for EO is seldom used           the Reference Section on the website supporting this briefing
outside the paediatric population.                              (

17. Riou P, Nicholson A, Pastorino U, “Esophageal Rupture in a patient with idiopathic eosinophilic esophagitis”, Annals of
    Thoracic Surgery (1996);62: pp. 1,854–1,856.
18. Remedios M, Campbell C, Jones D, Kerlin P, “Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings,
    and response to treatment with fluticasone propionate”, Gastrointestinal Endoscopy (2006);63(1): pp. 3–12.
19. Attwood S, Bronder C, Morris C, et al., “Eosinophilic oesophagitis: a novel treatment using montelukast”, Gut
    (2003);52(2): pp. 181–185.

EUROPEAN GASTROENTEROLOGY REVIEW 2006                                                                                            33

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