Differentiation of PPI -Responsive Esophageal Eosinophilia and...

Student: Marijn Warners S1721771 Klinische begeleiders AMC: Drs. B.D. van Rhijn, arts onderzoeker Dr. A.J. Bredenoord, gastro-enteroloog en staflid afdeling Maag Darm en Lever-ziekten AMC Klinisch begeleider UMCG: Dhr. Van Dullemen, gastro-enteroloog en staflid afdeling Maag Darm en Lever-ziekten UMCG

Differentiation of PPI-Responsive Esophageal Eosinophilia and Eosinophilic Esophagitis by

Endoscopic signs

Differentiation of PPI-Responsive Esophageal Eosinophilia and Eosinophilic Esophagitis by Endoscopic signs

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Index

Abstract ............................................................................................................................................................................ 3

1. Introduction .................................................................................................................................................................. 4 1.1 Definition ........................................................................................................................................................ 4

1.2 Epidemiology ............................................................................................................................................... 4

1.3 Clinical manifestations .................................................................................................................................. 5

1.4 Pathogenesis ................................................................................................................................................ 5

1.5 Diagnosis ....................................................................................................................................................... 6

1.5.1 Histology ....................................................................................................................................... 6

1.5.2 Endoscopic Signs ........................................................................................................................... 7

1.5.3 Radiologic findings ........................................................................................................................ 8

1.5.4 Follow-up ...................................................................................................................................... 8

1.6 Treatment ..................................................................................................................................................... 9

1.6.1 Treatment outcome ...................................................................................................................... 9

1.6.2 Pharmacologic therapy ............................................................................................................... 10

1.6.3 Dietary therapy ........................................................................................................................... 10

1.6.4 Proton pump inhibition .............................................................................................................. 11

1.6.5 Dilatation .................................................................................................................................... 11

1.7 Research question ...................................................................................................................................... 12

2. Material and methods ................................................................................................................................................ 13

2.1 Study design and patients population ......................................................................................................... 13

2.2 Statistical analysis ........................................................................................................................................ 15

3. Results ......................................................................................................................................................................... 16 3.1 Baseline characteristics ................................................................................................................................ 17

3.2 Evaluation endoscopic signs ......................................................................................................................... 17

3.3 Quality of life and clinical characteristics .................................................................................................... 18

3.4 Correlations .................................................................................................................................................. 19

4. Discussion and conclusion .......................................................................................................................................... 20 4.1 Aim ............................................................................................................................................................... 20

4.2 Results .......................................................................................................................................................... 20

4.3 Results compared to previous research ....................................................................................................... 21

4.4 Limitations .................................................................................................................................................... 21

4.5 Conclusion .................................................................................................................................................... 22

5. Bibliography ................................................................................................................................................................ 23


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Abstract/Samenvatting Introduction: Eosinophilic esophagitis (EoE) is a chronic antigen mediated disease histological characterized by eosinophil-predominant inflammation. Proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is a new terminology for EoE patients who respond to PPI treatment, this group accounts for one-third of patients with esophageal eosinophilia. If we could predict the response to PPI treatment based on endoscopic signs presented at baseline endoscopy (rings, white exudates, furrows, edema, crepe paper esophagus and strictures), patients would be spared from unnecessary additional endoscopies to assess response to treatment. We aimed to determine which endoscopic signs could distinguish PPI-REE from EoE. Methods: High-quality endoscopic images of 30 adult EoE and 30 adult PPI-REE patients were included in this study. Baseline characteristics were collected and compared between groups. If patients showed complete clinical remission after a PPI trial for ≥ 8 weeks they were classified as PPI-REE. Per patient, ≥3 depersonalised images were incorporated in a slideshow and scored by 2 experienced endoscopists, a validated classification system was used. EoE and PPI-REE were statistically compared by a Chi-square and Mann-Whitney U test. Results: Baseline characteristics were highly comparable between EoE and PPI-REE patients (age 35.2 ± 11.9 vs. 39.9 ± 14.3 years, 33% vs. 13% female, Caucasian race 96% vs 82%, atopia 89% each, eos/hpf 35 (20 – 75) vs 30 (20-90)). Endoscopic signs at diagnostic endoscopy did not differ significantly between groups (rings p=0.893, white exudates p=0.209, furrows p=0.696, edema p=0.828, crepepaper esophagus p=1.000 and stricture p=0.071). Conclusion: Based on endoscopic signs at baseline endoscopy EoE and PPI-REE cannot be distinguished before a PPI trial. Demographic and clinical characteristics did not differ between groups. Patients should undergo an additional endoscopy to evaluate histological response to PPI treatment. Introductie: Eosinofiele oesofagitis is een chronische antigeen-gemedieerde ziekte die histologisch wordt gekenmerkt door een ontsteking met een evidente eosinofilie. Protonpomp inhibitie responsieve oesofagiale eosinofilie (PPI-REE) is een nieuwe term voor patiënten met EoE die reageren op een behandeling met PPI, ongeveer een derde van alle patiënten met oesofagiale eosinofilie valt onder deze nieuwe subgroep. Wanneer wij tijdens de diagnostische endoscopie zouden kunnen voorspellen of patiënten reageren op een behandeling met PPI aan de hand van endoscopische tekenen die kenmerkend zijn voor EoE (ringen, witte exsudaten, groeven, oedeem, crepepapier oesofagus en strictuur) zouden deze patiënten niet nog een endoscopie hoeven ondergaan ter evaluatie van deze behandeling. Methode: Endoscopische beelden van 30 EoE en van 30 PPI-REE patiënten werden geïncludeerd. Patiënt karakteristieken en demographische gegevens werden verzameld en vergeleken tussen beide groepen. Patiënten werden geclassificeerd als PPI-REE wanneer zij na acht weken PPI gebruik compleet klachten vrij waren. Per patiënten werden ten minste drie endoscopische beelden aan de hand van een slide show beoordeeld door 2 ervaren endoscopisten. De beelden werden gescoord aan de hand van een gevalideerd classificatie systeem. De chi-square en de Mann-Whitney U test werden gebruikt voor de statistische analyse. Resultaten: Patiënt karakteristieken en demografische gegevens waren vergelijkbaar tussen EoE en PPI-REE patiënten (leeftijd 35.2 ± 11.9 vs. 39.9 ± 14.3 jaren, vrouwen 33% vs. 13%, Kaukasisch ras 96% vs. 82%, atopie 89% in beide groepen, eos/hpf 35 (20 – 75) vs. 30 (20-90)). Endoscopische tekenen gescoord aan de hand van beelden van de diagnostische endoscopie verschilden niet significant tussen beide groepen (ringen p=0.893, witte excudaten p=0.209, groeven p=0.696, oedeem p=0.828, crêpepapier oesophagus p=1.000 en strictuur p=0.071). Conclusie: Endoscopische tekenen kunnen voorafgaand aan de behandeling met PPI geen onderscheid maken tussen PPI-REE en EoE patiënten. Demografische en klinische karakteristieken verschilde niet tussen beide groepen. Tijdens een tweede endoscopisch moet worden geëvalueerd of patiënten histologisch reageren op PPI behandeling.


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Introduction 1.1 Definition In 2007, the first guideline for the definition and management of eosinophilic esophagitis (EoE) was formulated, which was updated in 2011. In these latest guidelines EoE is defined as “A chronic antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by an abnormal accumulation of eosiophils in the esophageal mucosa”.(1)(2) EoE has been increasingly diagnosed over the past decade.(3) The first cases of EoE were described in 1978.(4) At that time, eosinophilic esophageal infiltration had been already described in gastro esophageal reflux disease (GERD). However, careful review of these reports has raised questions about the diagnoses since the eosinophilic infiltration was more evident and not only confined to the distal esophagus. In addition, no objective evidence of reflux was seen on a 24-hour pH monitoring study and many of these patients did not respond to proton pump inhibitors (PPI) therapy. Despite this early analysis no guidelines determining diagnostic criteria and making recommendations for evaluation and treatment have been published until 2007. Esophageal eosinophilia is not exclusively found in EoE and it has a broad differential diagnosis, including GERD, celiac disease, drug-associated esophagitis, eosinophilic gastrointestinal diseases, hypereosinophilic syndrome, Crohn’s disease, achalasia and collagen vascular disease.(5) Therefore, to diagnose EoE secondary causes of esophageal eosinophilia must be ruled out. The differentiation between GERD and EoE is often based on a lower eosinophil count and positive pH monitoring studies in GERD patients. Furthermore patients characteristics differ, EoE patients are predominantly men with an atopic constitution. Nowadays tools to diagnose EoE, used in daily practice are; histopathological 2 or more biopsy specimen with eosinophil infiltration based on a threshold number of ≥15 eosinophils per high power field (hpf) in combination with esophageal dysfunction whereby these findings are not responsive to PPI treatment. This definition is debatable since several studies have identified a subgroup of patients with esophageal eosinophilia and dysfunction who have no objective evidence of reflux on a 24-hour pH study but who are evidently responding symptomatically and histologically to PPI treatment.(6) This confusing finding have led to a new terminology; PPI responsive esophageal eosinophilia (PPI-REE).(7) 1.2 Epidemiology Estimates of the prevalence of EoE vary widely in the literature. The incidence and prevalence of eosinophilic esophagitis appears to be increasing. Currently, EoE represents the main cause of dysphagia and bolus impaction in adult patients. A large retrospective cohort study assessed this incidence of EoE in Western Europe in the last 15 years; and found a rise from 0.01 in 1996 to 1.31 per 100 000 persons in 2010.(3) The incidences of EoE in the USA and other Western European countries are even higher, and the steady increase results in a constantly increasing prevalence.(8) Currently, the described prevalence of EoE in westernised areas range between 40 and 55 individuals per 100,000 inhabitants; this prevalence is comparable with that of Crohn’s disease.(9) This rapid increase over the past 20 years is thought to be multifactorial, and may be a result of increased recognition as well as a ‘true’ increase in allergic diseases.(10) The latter could be due to an environmentally driven cause, also known as the hygiene hypothesis, whereas western lifestyle and a lack of early childhood exposure to infectious agents due to high level of hygiene are potential factors contributing to the increases susceptibility to allergic diseases including EoE.(11) Although epidemiological information on this relatively new disease is limited, there seems to be a male predominance with men being three to four times more often affected. Furthermore, patients are more likely to be Caucasian.(12)(10) The disease can be diagnosed at all ages, however symptoms most often start in the second or third decade of life.


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1.3 Clinical manifestations EoE is characterized by symptoms of esophageal dysfunction including solid-food dysphagia, food impaction, heartburn, regurgitation, upper abdominal pain and vomiting.(13) The clinical presentation may differ between children and adults; children are mostly presented with heartburn, regurgitation, emesis, abdominal pain, feeding difficulties, and less often with failure to thrive and diarrhea whereas in adults symptoms are typically solid-food dysphagia and food impaction.(14)(15)(16) It remains unclear if symptoms also vary by race and sex. Some reveal that clinical manifestations differ since white patients predominantly suffer from dysphagia and are less likely to present with failure to thrive. Male patients present themselves more often with dysphagia, whereas female patients present with abdominal pain and nausea.(17) On the other hand recently published data showed that while dysphagia differed by gender and race among EoE patients, the majority of symptoms and clinical findings did not differ between groups.(18) Most patients have symptoms many years before presentation. They develop compensatory behaviour to avoid symptoms, including avoiding certain foods and prolonged chewing. This compensatory behaviour and a lack of knowledge among general practitioners might cause a diagnostic delay. Straumann et al. measured a diagnostic delay time with a median of 5 years, calculated as the period from appearance of first symptoms to diagnosis. (16) 1.4 Pathogenesis In the last decade substantial advances in the understanding of the immunopathogenesis have been made. Nevertheless, many uncertainties still exist and further research is warranted. The pathogenesis can be partly explained by an allergic immune reaction, in which IgE and T cell mediated hypersensitivity to ingested food or inhaled aero allergens play an important role.(17) This theory is supported by the high rates of atopic diseases seen in EoE patients, the presence of allergic rhinitis and dermatitis, asthma or food allergies vary from 24 to 93%. (1)(19) The assumption that aero allergens play an important role may be supported by seasonal variation in the onset of symptoms. A higher incidence is seen during spring and fall, seasons with an increased outdoor allergen exposure.(20) Furthermore several publications have documented sensitization rates through skin prick tests to outdoor and indoor aeroallergens (19)(21) Sensitization to pollens that cross-react with plant-derived food allergens may cause high rates of food allergies in patients with EoE.(22) In the allergic immune reaction, antigens are exposed to B-cells, which induce activation of type 2 helper T-cells (Th-2). After re-exposure to the antigen, antigen specific IgE-coated mast cells are activated, leading to a release of numerous cytokines, among them IL-5, IL-13 and eotaxin-3. Eotaxin-3, which is released by epithelial cells, mast cells and Th-2 cells, attracts eosinophils. (23). The eotaxin-3 gene (CCL26) is the most overexpressed gene in the esophagus from EoE patients compared to healthy controls.(24) As pointed out earlier not only eotaxin-3 expression is increased but also Il-5 and Il-13. The latter cytokine which causes overexpression of eotaxin-3, fibroblast collagen synthesis and IL-13 stimulates production of transforming growth factor Beta (TGF-B) by macrophages.(17) IL-5 plays an important role in the production of eosinophils in the bone marrow, and IL-5 supports the survival, activation, and recruitment of eosinophils to the esophagus(25) The global allergic pathway is represented in figure 1. Eosinophils physiologically produce cationic proteins, enzymes and neurotoxins as a defence mechanism against helminth infections. In EoE patients the excess of eosinophils, caused by the previous explained immune reaction to a recurring exposure to allergens, contributes to extensive tissue remodelling. These structural changes of the esophageal mucosa including superficial layering, basal zone and smooth muscle hyperplasia, papillaryelongation, lamina propria fibrosis and angiogenesis. These findings are frequently seen in EoE biopsies.(26)(27) Furthermore, smooth muscle contraction can be induced by the interaction of eosinophil products with muscarinic M2 receptors in the esophagus. This may explain reports of esophageal dysmotility in some patients with EoE.(28)


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Besides the known allergic reaction to allergens, acid reflux may be an exacerbating factor in the pathogenesis of EoE. Since acid can increase esophageal epithelial permeability it could also facilitate the passage of antigens through the epithelial surface. In this surface antigens can bind to antigen presenting cells which can cause and increase expression of proteins that serve as chemo attractants to eosinophils.(29) Further studies need to define the exact pathogenesis of EoE and the role that acid reflux may play.

Figure 1. A proposed model to explain cellular mechanisms involved in eosinophilic esophagitis (EoE) pathogenesis. *Copyrights © Medscape.org. J. Richter. Department of medicine. Temple university school of medicine. Philadelphia, PA.

Finally a genetic predisposition to EoE may exist. Previous research concluded that 6.8 % of the patients had a family history of EoE.(30) In pediatric patients EoE has been associated with variants at the Thymic stromal lymphopoietin gene incorporated at the chromosome 5q22. This gen expresses a cytokine that controls Th2-cell responses.(31) 1.5 Diagnosis 1.5.1 Histology Current standards for diagnosis are at least two esophageal biopsies revealing eosinophilic infiltration the squamous epithelium with a peak count of 15 eosinophils per hpf. These mucosal biopsy specimens are fixed in formalin, embedded in paraffin and stained with hematoxylin and eosin for pathologic examination by light microscopy.(6). A high power field represents the area visible under the maximum magnification power of the objective being used, typically a 400x magnification with an area of 0.24 mm². Besides the eosinophilic infiltration, histopathological analysis may reveal other inflammatory signs including microabscess formation, superficial layering of eosinophils, extracellular eosinophil granules, basal cell hyperplasia, subepithelial lamina propria fibrosis and increased other cell types, such as lymphocytes.(32) These findings are not specific for EoE but add additional information about the severity of inflammation. There is a noticeable variability in the degree of eosinophilic infiltration among biopsies. Since obtaining too little biopsies may bias the outcome, 2 – 4 biopsies should be obtained from at least two different esophageal levels.(33) Histopathological evaluation may be helpful in determining the cause of esophageal


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eosinophilia. Especially the differentiation between GERD and EoE plays an important role in histopathological analysis. A significant eosionphil infiltration in the proximal esophagus was seen in EoE in comparison with lower numbers in patients with GERD.(34) Furthermore microabscesses, mast cell infiltration and surface layering of eosinophils are more often associated with EoE than with GERD.(1) Promising data showed that the presence of cationic proteins produced by eosinophils may distinguish EoE from GERD.(35) Eosinophil degranulation may also be a marker of EoE while this feature is an indicator of eosinophil activation which is predominantly seen in EoE patients(Figure 2.).(36)

Figure 2. Histology of the esophagus: A. Normal esophagus, B. EoE with eosinophil infiltration, C. EoE with superficial layering of surface eosinophils (arrow), D. EoE with microabscess (arrow).* *Copyrights © 2011 American Academy of Allergy, Asthma & Immunology

1.5.2 Endoscopic signs The endoscopic presentation of EoE is quite variable. Due to inflammation mucosal changes may occur and become visible during endoscopy. The underlying mechanisms, explaining these endoscopic signs, are active inflammation and eosinophilic infiltration in superficial layers. These mechanisms believed to occur at all stages of the disease. The fibrotic processes are initiated by remodelling of the deeper layers of the mucosa, this occurs over time with chronic inflammation.(37) Characteristic endoscopic signs associated with the diagnosis of EoE include fixed esophageal rings, white exudates or plaques (representing eosinophilic microabscesses), longitudinal furrows, edema (also described as mucosal pallor or decreased vascularity), diffuse esophageal narrowing and esophageal lacerations induced by passage of the endoscope (also called crepe paper esophagus). This laceration is an indicator for mucosal fragility (Figure 3.).(38) Strictures seen in EoE patients can be quite similar to a Schatzki ring; a thin, symmetrical, mucosal structure located at the esophagogastric junction.(39) Müller et al. showed that 21% of patients with a Schatzki ring were also diagnosed with EoE. Since these endoscopic signs have been reported in other esophageal disorders and since 17% of patients with EoE have a normal appearance of the esophagus, isolated endoscopic signs do not prove EoE. In the updated guidelines no recommendations regarding the role of endoscopic findings have been pointed out.(40) On the other hand, since the same systematic review reported sensitivity rates up till 93%, these endoscopic signs could provide useful additional information.(41) In daily practice, endoscopic signs are often used as supportive evidence to


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diagnose EoE and to rule out other causes of esophageal abnormalities including GERD (in which esophageal erosions are more evident), achalasia and infectious esophagitis. Furthermore endoscopic evaluation can be useful to determine outcome of treatment. Several studies have reported a significant improvement of esophageal signs after topical steroid treatment.(42) Hirano et al. proposed a classification and grading system which demonstrated reasonable interobserver agreement of endoscopic signs. The utilization of this system may improve diagnostic utility and it could simplify comparison of severity among clinicians.(43)

Figure 3. Characteristic endoscopic signs of EoE. A. rings, B. furrows, C. white exudates, D. crepepaper esophagus.

1.5.3 Radiologic findings Although barium contrast radiography can generally be useful for identifying anatomic esophageal malformations or mucosal abnormalities, the sensitivity and specificity of radiography as a diagnostic test for EoE is little. Strictures, fixed rings, diffuse corrugation and small calibre esophagus can be seen but since these signs are not specific, radiographic imaging is not a recommended routine diagnostic test for EoE.(1) In fibrostenotic complications, where dilatation is recommended, radiography can be performed prior to this treatment to measure the length and exact diameter of esophageal strictures.

1.5.4 Follow up Although it has been more than 25 years since publication of the first reports of EoE no consensus follow up data are available. The natural course of 30 EoE patients showed that the chronic disease led to persistent dysphagia but did not affect nutrition state.(16) The hypotheses that EoE may lead to an increased risk of local malignancy development due to the chronic inflammatory character of the disease has not been proven. The debate on the presence or absence of a positive correlation between clinical symptoms and esophageal eosinophilic infiltration or inflammation is still open. Some studies demonstrated a correlation between symptoms and inflammation, (44) whereas others report no correlation.(45) Due to this discrepancy, histopathologic features of esophageal biopsies must be interpreted in conjunction with the clinical findings to diagnose EoE appropriately.

http://nl.bab.la/woordenboek/engels-nederlands/appropriately


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1.6 Treatment There has been a remarkable progress in the knowledge and recognition of EoE, but in every new disease new knowledge is followed by controversy which adds new questions. There is variety in symptom presentation, histological and endoscopic findings but above all there is discrepancy about the best therapeutic management of EoE. Therapeutic options are pharmacologic therapy, elimination diets and in some cases endoscopic dilatation, which will be further explained in following chapters.

1.6.1 Treatment outcome The ideal endpoints of therapy for EoE would be complete remission of symptoms and esophageal eosinophil infiltration. But clinical experience reveals that complete remission is rare. Clinical and histological improvement is a more realistic goal.(40) To compare different sorts of therapy, improvement is a vague variable. For example, in literature histologic endpoints have varied from a remission defined by 0 eos/hpf 42 to a decreases eosinophils count with 90%.(46) To define clinical outcomes different scoring systems have been used, these scoring systems may sometimes be combined with eosinophil count, making it even harder to compare treatment outcomes. Furthermore symptoms alone are not a reliable determinant of disease activity and response to therapy because symptoms do not always correlate with eosinophil count and endoscopic signs.(7) On the other hand in some cases symptoms remain whereas no eosinophil infiltration can be seen. 1.6.2 Pharmacologic therapy Topical steroids Topical steroids are an effective therapy for EoE. They improve symptoms as well as endoscopic and histological abnormalities and it may reverse inflammatory changes by preventing tissue remodelling and the formation of fibrosis.(47) However, recurrence of symptoms almost always appear when medication is discontinued.(15) Topical steroid therapy is generally safe, however long-term use of steroid can cause sight effects due to significant toxicity, therefore it is not recommended for chronic use. A well-known short-term side effect is esophageal candidiasis which has been reported in 5-30% of cases.(1) Despite the fact that it has been over 5 years since publication of the first case report of topical steroids, long-term side effects have not been evaluated.(48) Finally, chronic steroids use may induce initial remission but it could eventually lead to steroid resistance. Budesonide and Fluticasone are the best known topical steroids, they are mostly used as a multi-dose inhaler or as an aqueous nebulizer solutions and must be swallowed to coat the esophagus. Oral viscous Budesonide, which consist of aqueous Budesonide mixed with a sugar substitute, can be used as well to provide optimal topical medication delivery. Since there has been a lack of uniformity in medication dosage and duration of therapy, practical guidelines were formulated by Dellon et al. (35) Systemic steroids In the only randomized trial comparing topical with systemic steroids, systemic therapy successfully achieved initial histologic and clinical improvement. Although Prednisone may resulted in a greater degree of histologic improvement compared to topical steroids, the severity and the amount of adverse effects such as hyperphagia, weight gain and Cushingoid features were more evident which makes systemic steroid therapy not a favourable first therapeutic choice.(49) In paediatric patients chronic use of systemic steroid can cause growth suppression and it reduces bone density.(50) Since there was no evidence for an associated short- or long-term clinical advantage, systemic prednisone is reserved for patients who do not respond to topical therapy or who need a rapid improvement in symptoms.


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Biologicals Biological therapies, mast cell stabilizers, immunomodulators or leukotriene inhibitor are potential future treatments, although so far no significant clinical or histological improvement has been seen.(51)(52) Studies are limited and their efficacy is not yet established. Further studies utilizing these medications are needed to define their aid in EoE treatment.(1) 1.6.3 Dietary therapy Patients with EoE frequently have a history of coexisting atopic diseases such as asthma, food allergies, allergic dermatitis or rhinitis. Furthermore they may have sensitization to several environmental and food allergens, demonstrated by positive skin prick test. Using this test, Gonsalves et al. showed that EoE is mostly triggered by one of the following six food antigens: soy, egg, milk, wheat, nuts and seafood.(53) Several studies reported clinical, histological and endoscopic improvement after food-elimination diets. Although frequent recurrence of inflammation after food reintroduction has been seen. These diets can be divided in those based on allergy tests, those with empiric food elimination and those with total elimination of all possible allergens (elemental diet using an amino-acid formula). The latter has shown to be the most effective but it is also the most expensive and time consuming treatment.(54) The goal of this diet is not only temporary improvement but it focuses on maintaining this remission by eliminating patient specific food antigens. Since this dietary solution could be an alternative to a lifelong pharmacologic therapy elemental formula treatment is mainly tested in paediatric patients.(22)(55)(54) However, especially in paediatric patients nutrition must be adequate to preserve normal growth and development, hence consultation with a dietician is necessary to monitor satisfactory caloric intake. Preliminary observations suggest that the use of dietary therapy in adults is useful, although this dietary approach should fit into the individual lifestyle and adherence to therapy. Gonsalves et al. found a histologic improvement in 78% of the patients after the six-food elimination diet and Peterson published a substantial histologic improvement in 94% of the cases after elemental diet. Contrarily, in the latter study no symptomatic improvement was reported. This lack of correlation between histologic remission and clinical improvement has been seen in some therapeutic en dietary adult studies.(56)(48) Due to this disassociation, observation of clinical symptoms and a subsequent endoscopy after reintroduction of specific food groups are necessary to identify which food triggers inflammation in EoE patients. This time-consuming and costly process is used to identify the specific food group that must be eliminated from a patient’s diet completely for the rest of their life’s due to the chronic character of EoE. 1.6.4 Proton pump inhibition In updated guidelines EoE is histologically characterized by a peak esophageal eosinophilic infiltration over 15 eos/hpf, combined with clinical symptoms related to esophageal dysfunction for which GERD is not the underlying cause. The latter diagnostic parameter can be proven by a negative pH-monitoring test and by a lack of clinicopathologic response to proton pump inhibition. Eosinophilic infiltration is seen in GERD as well but less prominently (<7eo/hpf) and more confined to the distal esophagus.(57)(40) These previous guidelines are dated since multiple studies have demonstrated a clinical and histological response to PPI therapy.(58)(6)(59) Additionally no differences in therapeutic response have been observed when comparing PPI to topical steroids.(60) About one third of all EoE patients respond to PPI treatment, this high response rate in combination with the low incidence of sight-effects and the ease of administration, PPI is an attractive option for initial treatment. Nevertheless further research must be done to define specific recommendations on dosage and duration of therapy and to evaluate long-term follow-up of these patients.(61)(59) Nowadays patients with esophageal dysfunction are undergoing upper endoscopy. After confirmed eosinophila patients start with an 8 week PPI trial. If no clinical or histological response is seen on repeated endoscopy EoE can be diagnosed (Figure 4.).


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Figure 4. Diagnostics Algorithm for possible approach to esophageal eosinophilic infiltration.

1.6.5 Dilatation Endoscopic signs may reflect the natural history of EoE, since in the earlier stages of the disease inflammatory processes such as white plaques and decreased vasculature are more evident. Whereas as the disease progresses fibrotic signs, including rings and strictures, are observed more frequently.(41) Eventually advanced fibrosis, which does not respond to short-term dietary therapy, can become the main problem. Endoscopically this process appears as a diffuse narrow esophagus or as a stricture. Since these narrowing signs are commonly seen in EoE patients, and since pharmacological or dietary therapies are less effective in fibrostenotic complications, numerous reports described esophageal dilatation as an effective treatment for this complication.(40) It has been one of the principal therapy strategies for adult patients. Dilatation showed to be effective in decreasing dysphagia, with a mean duration of response for more than a year.(62) Nevertheless in general practice, dilatation is reserved for patients with strictures that persist in spite of medical or dietary therapy. This reluctance to dilate among gastroenterologist is probably due to the fact that dilation does not decrease inflammation and has long been thought to induce high perforation rates.(63) However, this lack of enthusiasm may not be justified since considerable systematic reviews reported excellent results concerning symptom improvement and low incidences of complications.(62)(64)

First Endoscoy:

eosinophilia ≥ 15 eos/hpf

PPI trail > 8 weeks

Second endoscopy

No clinical or histological

response

EoE

Clinical and histological

response

PPI-REE


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1.7 Research question Eosinophilic esophagitis (EoE) is a chronic antigen mediated disease which has been increasingly diagnosed over the past decade.(65)(3) EoE is histological characterized by eosinophil-predominant inflammation and infiltration, and clinically by symptoms related to esophageal dysfunction.(2) Characteristic endoscopic signs associated with EoE include fixed rings, strictures, edema, longitudinal furrows and white exudates. These findings are not pathognomonic but are supportive evidence of the diagnosis EoE.(38) Differentiation between the most commonly encountered etiologies of esophageal eosinophilia (EoE and GERD) can be difficult; nowadays EoE is distinguished from GERD by its higher eosinophil count more confined to the proximal esophagus, normal esophageal acid exposure, immune/antigen-mediated character of the disease and by a lack of clinicopathologic response to proton pump inhibition (PPI).(1) This latter criterion is debatable since multiple studies have demonstrated that a significant group of EoE patients responded clinical and histological to PPI therapy. (59)(60)(61) The confusing finding that anti-GERD therapy has been useful for EoE patients led to a new terminology; PPI responsive esophageal eosinophilia (PPI-REE).(40) PPI-REE accounts for almost one third of adults with esophageal eosinophilia.(66)(67)(68) The underlying pathogenic mechanism of PPI-REE is poorly understood and several studies have called into question how to make a proper distinction between EoE and PPI-REE.(7)(61) It remains unclear if PPI-REE is a subgroup of GERD, of EoE or that it is a whole new entity. To prove esophageal eosinophilic infiltration, endoscopic examination is unavoidable in the diagnostic pathway for these three entities. Endoscopic signs may help to differentiate between groups. Recent guidelines require the exclusion of PPI-REE in patients with esophageal eosinophilia by an 8 week PPI trial (20-40mg twice daily).(40) If repeated endoscopy shows no histopathological remission after PPI, EoE can be diagnosed. If we could predict the response to PPI treatment based on endoscopic signs, patients would be spared from unnecessary additional endoscopic interventions and diagnostic delay would be prevented. Thereby would it be cost effective to reduce the amount of endoscopies. Furthermore if endoscopic signs could distinguish the two groups it could provide additional information regarding the pathogenesis of both groups. The aim of this study was to determine which baseline endoscopic signs could distinguish PPI-REE from EoE. Furthermore, we assessed clinical, demographical and eos/hpf in PPI-REE and EoE patients.


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2.Material and methods

2.1 Study design and patient population This retrospective study was conducted in the Academic Medical Centre (AMC), Amsterdam. All included patients had been referred to the AMC and before dividing patients into two different groups (PPI-REE and EoE) clinical and histological characteristics were reviewed. Baseline endoscopic images and reports (concentric rings, longitudinal furrows, white plaques, crepepaper esophagus, edema, strictures, Schatzki rings, erosive esophagitis and hernia diaphragmatica), demographic data, history of coexisting atopic diseases and pharmacological history from 101 consecutive adult patients (18 – 67 years of age) known with EoE were collected. EoE was diagnosed based on an eosinophil count greater than 15 eos/hpf combined with typical symptoms of esophageal dysfunction (e.g., dysphagia, food impaction, heartburn, or feeding intolerance). Other causes of esophageal eosinophilia such as GERD were ruled out. Pathology reports were reviewed and the degree of eosinophilia (eos/hpf). In some reports the exact number of eosinophils was not described, the pathologist either described the infiltration as more that 15 eos/hpf or mentioned the severity of infiltration without eosinophil count. Inclusion criteria were: age >18 years, clinicopathological diagnosis of EoE and treated with PPI solitarily (20-40 mg twice daily of any of the available PPI) for at least eight weeks. Since the minority of the patients underwent an upper endoscopy after PPI trial, the primary outcome of this study was clinical response. Patients were classified as PPI-REE if they did no longer have any symptoms of esophageal dysfunction including dysphasia, food impaction, heartburn or feeding intolerance after treatment. Symptomatic patients after PPI were classified as EoE. Patients enrolled for this study completed several questionnaires. To assess quality of life, a validated Dutch version of the SF-36 quality of life questionnaire, has been used, which is a questionnaire that has been developed to assess a wide range of healthcare settings and patients. It measures health-related quality of life divided in eight domains: physical functioning (PF), role limitations due to physical problems (RP), bodily pain (BP), general health (GH), vitality (VT), role limitations due to emotional problems (RE), social functioning (SF), and mental health (MH).(69) Furthermore, patients completed a symptom questionnaire based on previous validated applications for upper gastro diseases including achalasia and GERD, due to the lack of a uniform validated questionnaire for EoE. The charts and images from these patients date from 2007 to 2013. Most of the diagnostic baseline endoscopies were performed in the AMC by experienced gastroenterologists. If not all data were present in the AMC database, the baseline images and medical charts were collected from referring hospitals (TerGooi Hospital Hilversum, Diaconessenhuis Leiden, Diakonessenhuis Utrecht, University Medical Centre Leiden and Utrecht, Antonius Hospital Nieuwegein, Amphia Hospital Breda, ZorgSaam Hospital Terneuzen, Flevo Hospital Almere, Slotervaart Hospital Amsterdam, Rivas Hospital Gorichem and Onze Lieve Vrouwen Gasthuis Amsterdam). Since a general transparent electronic health record does not exists in the Netherlands, approval to collect these medical charts was obtained from all patients before approaching referring hospitals. Due to the retrospective character of this study we used endoscopic images which were already generated during diagnostic endoscopy; therefore no additional interventions were required and no special informed consent was needed for the usage of these images. The study was approved by the medical ethical committee of our institution. After reviewing the charts two equally sized groups, PPI-REE vs. EoE were composed. From this group 22 patients were excluded due to an unfulfilled PPI trial, inconsistent use of medicine or due to an obfuscation combination with other EoE related medicines. Subsequently to this first step of the inclusion process, the best images based on the highest quality regarding sharpness and motionless were selected to a minimum of four images per patient. From the previous selected 79 patients


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another 19 patients were excluded due to low quality images, leaving a total of 30 subjects per group. An inclusion diagram is provided in Figure 4.

Figure 5. Inclusion diagram depicting the number of patients meeting inclusion criteria, the number of patients excluded at different steps of inclusion process and the number of patients included in final analysis.

All images were made equal in size and incorporated into a slideshow (Microsoft PowerPoint 2003: Microsoft Inc, Redmond, Wash). These images were not post-processed and only modified to erase the patient’s name, day of birth, date and chart number. Every slide, consisting of a minimum of three images from the same endoscopy, was blinded and scored by two gastroenterologists working in an academic medical setting. Both reviewers were experienced endoscopists. Since the images were reviewed by two observers an interobserver variability was seen. In case of disagreement between the reviewers, a researcher familiar with EoE, made a decision. This composed score was used for statistical analyses. The slides were scored in accordance with the classification recently introduced by Hirano et al. (Table I).(43) Previously formulated by Schoepfer et al, endoscopic features of EoE were also classified into the following categories: inflammatory signs including whitish exudates, edema, and linear furrows and fibrostenotic signs including rings, stricture, crepepaper esophagus and diffuse narrow esophagus.(37) The fibrostenotic, inflammatory and total scores of endoscopic features per patients were summarised afterwards. Before scoring the slides a pictorial atlas with representative images and written descriptions of the grading scheme were handed to the reviewers. All images used for this training purpose were not included in the PowerPoint presentation.

101 Patients diagnosed with EoE in AMC Database

79 patients after 8 weeks PPI trial

PPI-REE

N = 30

EoE

N= 30

19 not enrolled due to unsuitable endoscopic images

22 not enrolled due to inconsistent medicine use


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Table I. Classification and grading system for the endoscopic assessment of the esophageal features of eosinophilic esophagitis

Major Features Grade Description

Concentric rings 0 None 1 Mild, subtle circumferential ridges 2 Moderate, distinct rings that do not impair passage of a

standard endoscope. 3 Severe, distinct rings that do not permit passage of a

diagnostic endoscope

Exudates 0 None 1 Mild, lesions involving < 10% of esophageal surface area 2 Severe, lesions involving > 10% of the esophageal surface

area

Furrows 0 Absent

1 Present

Edema 0 Absent

1 Present

Stricture 0 Absent

1 Present

Crepe-paper esophagus 0 Absent

1 Present

Narrow esophagus 0 Absent

1 Present

2.2 Statistical analysis Statistical analysis was performed using SPSS 20. Descriptive statistics were used to characterize the study population. Associations between categorical variables were tested with the Chi-square test for linear trend; Fisher’s correction was used when necessary. Continuous variables were assessed using the 2 sample t test of a Mann-Whitney U for parametric and nonparametric data. Spearman’s rho was used to describe correlations between continuous variables. Data were described as median ± inter quartile range (IQR) or mean ± standard deviation for continuous variables and as frequencies for categorical variables. Differences between study groups were considered statistically significant when p < 0.05.


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3.Results

3.1 Baseline characteristics During the study period, 101 charts were screened and eventually 60 patients met the inclusion criteria, from which two equal groups, EoE vs. PPI-REE were composed. An inclusion diagram is provided in Figure 4. There was no significant difference in age between EoE and PPI-REE (35.2 ± 11.9 vs. 39.9 ± 14.34 years, p < 0.173). The total study cohort contained fewer females (23%), this minority of females was seen in both groups with no significant difference (33% vs. 13%, < 0.067). Most patients in this study were Caucasian although the PPI-REE group consisted of a greater proportion of patient from Arabic origin (4% vs. 18% p = 0.092). Life style determinants such as smoking, BMI and the use of alcohol were comparable between groups. Atopic constitution and hypersensitivity to ingested or inhaled food allergens was equally seen in both groups. The diagnostic delay between PPI-REE and EoE was 9.61 ± 8.91 vs. 9.59 ± 11.86 years. This delay was defined as the time between the age at onset of symptoms PPI-REE vs EoE (30.18 ± 16.64 vs. 23.63 ± 12.317 years) and the age at diagnosis (39.79 ± 13.95 vs. 33.56 ± 12.48 years). These clinical characteristics of EoE versus PPI-REE patients are denoted in Table II.

Table II. EoE vs. PPI-REE descriptives

EoE (n=27)

PPI-REE (n=28)

p-value

Ethnicity, n (%) Caucasian 26 (96%) 23 (82%) 0.092

Alcohol, n (%) Yes 19 (70%) 25 (86%) 0.168

Smoking, n (%) Yes 7 (26%) 11 (39%) 0.291

Isac sensitized any, n (%) Yes 19 (70%) 20 (74%) 0.761

Isac sensitized food, n (%) Yes 12 (44%) 17 (63%) 0.172

Atopia, n (%) yes 24 (89%) 25 (89%) 0.962

Positive FA Allergy, n (%) Yes 17 (63%) 17 (61%) 0.864

Eos/hpf Median (IQR) 35 (20 – 75) 30 (20 – 90) 0.767

Diagnostic delay Median (IQR) 4 (1 – 20) 9 (2.25 – 13.75) 0.577

Age at diagnosis Median (IQR) 30 (24 – 44) 40.50 (30.25 – 47.75) 0.095

Time since diagnosis Median (IQR) 1 (0 – 2) 1 (0.25 – 3) 0.351

BMI Median (IQR) 24.65 (21.26 – 27.16) 25.58 (23.49 – 27.44) 0.167

The prescribed types of PPI did not differ significantly between groups (Table III.); nevertheless Esomeprazol was prescribed more often in the EoE group (20% vs. 7%) and Pantoprazol in the PPI-REE group (30% vs. 10%). The PPI doses were comparable (p = 0,350), whereas predominantly a dose of 40mg daily was prescribed for 50% of the PPI-REE and for 40% of the EoE patients.

Table III. EoE vs. PPI-REE PPI use

EoE (n=30)

PPI-REE (n=30)

PPI type Rabeprazolnatrium 4 (13%) 2 (7%)

Esomeprazol 6 (20%) 2 (7%)

Omeprazol 17 (57%) 17 (57%)

Pantoprazol 3 (10%) 9 (30%)

Daily PPI dose 20 mg 6 (20%) 2 (7%)

40 mg 12 (40%) 15 (50%)

80 mg 12 (40%) 13(43%)


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3.2 Evaluation endoscopic signs The endoscopic sighs were compared using Hirano’s grading system. Endoscopic signs of PPI-REE and EoE patients did not show any significant differences. (Table IV) (Figure 5-8). The numbers of fibrotic and inflammatory features, and the total number of endoscopic features did not significantly differ between both groups. Table IV shows that PPI-REE patients are less likely to develop fibrotic or inflammatory signs, and in their total score is lower. Due to the small differences no conclusions can be drawn. Table IV. EoE vs. PPI-REE endoscopic signs

EoE (n=30)

PPI-REE (n=30)

p-value

Rings, n (%) None 10 (33%) 8 (27%) 0.893 Mild 10 (33%) 13 (43%) Moderate 6 (20%) 7 (23%) Severe 4 (13%) 2 (7%)

White exudates, n (%) None 8 (27%) 10 (33%) 0.209 Mild 13 (43%) 16 (53%) Severe 9 (30%) 4 (13%)

Furrows, n (%) Yes 21 (70%) 24(80%) 0.371

Edema, n (%) Yes 29 (97%) 28 (93%) 0.554

Stricture, n (%) Yes 18 (60%) 11 (37%) 0.071

Crepe-paper , n (%) Yes 3 (10%) 3 (10%) 1.000

Inflammatory signs Median (IQR) 4 (2.75 – 4) 3 (2.75 – 4) 0.582

Fibrotic signs Median (IQR) 2 (1 – 4) 2 (1 – 3) 0.589

Total score Median (IQR) 6 (3.75 – 7.25) 5 (3 – 7) 0.395


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I. Rings II. White exudates

III. Furrows IV. Edema

V. Crepepaper esophagus VI. Stricture Figure 5. A graphic representation of the scored endoscopic signs in EoE vs. PPI-REE patients. Graph III to VI show the percentages of presence endoscopic sings

3.3 Quality of life and clinical characteristics Eosinophilic esophagitis patients register more often pain while eating (p = 0.007), especially raw vegetables and solid fruit give significantly higher discomfort scores (p = 0.009). Furthermore they report more frequently dysphagia for liquids (p = 0.033). Nevertheless they do not experience more episodes of food impaction and EoE patients do not receive more often treatment with topical steroid or dilatation(Table V.). On the other hand evaluation of the SF-36 quality of life questionnaire showed that EoE patients scored lower on social functioning ( 80.09 ± 24.08 vs. 92.41 ± 13.32, p = 0.041), mental health (73.51 ± 19.03 vs. 84.42 ± 11.48, p = 0.035) and vitality (56.91 ± 24.65 vs. 71.42 ± 16.71, p = 0.026). Furthermore, EoE patients perceived lower general health than PPI-REE patients (58.70± 27.02 vs. 75.60 ± 20.49 p = 0.019). In addition, the overall standard mental component scale of quality of life was also significantly decreased is eosinophilic esophagitis patients (46.78 ± 10.74 vs.


19

53 ± 5.23, p = 0.0031). Other categories of the SF-36 questionnaire did not show remarkable differences (Table V.).

Table V. EoE vs. PPI-REE quality of life questionnaire and clinical characteristics

EoE (n=27) PPI-REE (n=28) p-value Restrictions in life, n (%) yes 13 (48%) 10 (36%) 0.350

Impaired in eating, n (%) Never 8 (30%) 15 (54%) 0.030

Sometimes 14 (52%) 12 (43%)

Often 5 (18%) 1 (3%)

Problem swallowing solids, n (%) Never 5 (19%) 19 (68%) 0.008

Sometimes 20 (74%) 6 (21%)

Always 2 (7%) 3 (11%)

Problem swallowing rice, n (%) Never 14 (52%) 20 (71%) 0.188

Sometimes 10 (37%) 6 (22%)

Always 3 (11%) 2 (7%)

Problem swallowing liquids, n (%) None 19 (70%) 26 (93%) 0.033

Mild/Severe 8 (30%) 2 (4%)

Pain during meal, n (%) None/Mild 14 (44%) 21 (75%) 0.007

Sometimes 10 (37%) 7 (25%)

Always 5 (19%) 0 (0%)

Food impaction this year, n (%) Yes 8 (30%) 11 (39%) 0.452

Reflux, n (%) None 11 (41%) 61 (57%) 0.908

Mild 9 (33%) 1 (4%)

Moderate 6 (22%) 10 (36%)

Severe 1 (4%) 1 (4%)

Dilatation ever, n (%) Yes 3 (11%) 3 (11%) 0.962

Steroid use ever, n (%) Yes 19 (70%) 15 (54%) 0.200

Role Physical Median (IQR) 100 (50 – 100) 100 (100 – 100) 0.523

Bodily pain Median (IQR) 84 (51 – 100) 92 (61.25 – 100) 0.527

Social Functioning Median (IQR) 87.5 (62.50 – 100) 100 (87.5 – 100) 0.041

Mental Health Median (IQR) 80 (60 – 88) 88 (80 – 92) 0.035

Role emotional Median (IQR) 100 (66.66 – 100) 100 (100 – 100) 0.04

Vitality Median (IQR) 60 (40 – 75) 72.52 (60 – 85) 0.026

Physical functioning Median (IQR) 100 (85 – 100) 97.50 (90 – 100) 0.611

3.4 Correlations The correlation between maximum eosinophil densities and the inflammatory, fibrotic and total scores of endoscopic signs was not significant (p=0.529, p=0.924, p=0.717). As stated in literature, Schoepfer et al. found a trend between diagnostic delay and esophageal stricture forming.(70) Nevertheless in our cohort no correlation was found between diagnostic delay and the severity of inflammatory, fibrotic and total score of endoscopic signs (p=0.355, p=0.057, p=0.0.06)


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4. Discussion and conclusion 4.1 Aim EoE is a chronic disease thought to be best treated with lifelong use of topical corticosteroids or a lifetime of diet restrictions. Recently, several studies showed that a large cohort of EoE patients respond to PPI, this relatively safe and ease of administrated medicine may be considered a primary therapy.(59)(60) Recent guidelines require the exclusion of PPI-REE in patients with esophageal eosinophilia by an 8 week PPI trial (20-40mg twice daily).(40) If repeated endoscopy does not show histopathological, EoE can be diagnosed and further treatment options must be discussed. If we could predict the response to PPI treatment based on endoscopic signs, patients would be spared from unnecessary additional endoscopic interventions. Thereby would it be cost effective to prevent a second endoscopic procedure. The aim of this study was to determine which baseline endoscopic signs could distinguish PPI-REE from EoE. Furthermore, we assessed clinical, demographical and eos/hpf in PPI-REE and EoE patients. Furthermore we wanted to assess whether clinical, demographical and eos/hpf could distinguish PPI-REE from EoE patients. 4.2 Results This is the first study in which endoscopic images of EoE and PPI-REE patients have been prospectively classified and compared. We found that endoscopic signs identified and classified on baseline endoscopic images can not distinguish EoE from PPI-REE. Furthermore the demographic and clinical characteristics did not differ between groups. Additionally we found that the patient-reported quality of life is impaired in EoE patients compared to PPI-REE patients. Since eosinophilic esophagitis is a chronic disease and response to treatment vary, it is likely that quality of life is impaired in patients with persisting complains under PPI treatment. Due to the fact that the quality of life questionnaires were not collected before the PPI trial these findings can not be used as a differentiating diagnostic tool. This study may imply that PPI-REE is more likely to be a sub-phenotype of EoE instead of a new entity with a different pathogenesis. On the other hand patients with esophageal eosinophilia who response to PPI must not immediately be adjudged to GERD due to the typical symptoms of esophageal dysfunction, the higher eosinophil count and the predominantly atopic constitution of these patients. Hirano et al. divided the PPI-REE group into three subtypes: PPI-REE attributable to GERD, PPI-REE attributable to EoE and PPI-REE that is distinct form either GERD or EoE.(29) This division was made, considering that there might be an overlap between GERD patients presented with a high eosinophil count and EoE patients presented with clinical symptoms, endoscopy findings, or pH testing consistent with GERD.(29) This theory could explain a small subset of patients with esophageal eosinophila who respond to PPI and may be fortified by the results of Sayej et al. They found that patients who had ≥ 15eos/hpf at three biopsies levels were less likely to respond to PPI treatment compared to patients who had ≥15 eos/hpf at 2 or 1 biopsy levels, considering that for the latter group the diagnose EoE was debatable.(59) Hence nowadays GERD is associated with lower eos/hpf compared to EoE, nevertheless recent studies pointed out that some patients with GERD can have dense eosiophilia with numbers ≥15/eos.(71) Interaction between GERD and EoE and the overlap described by Hirano et al. may partly explain response rates to PPI treatment. Although it is debatable if this theory can explain the high prevalence of PPI responsive patients found in literature. Almost one third of all paediatric EoE patients respond to PPI.(61) This prevalence is largely comparable to the prevalence seen in adult studies, with response rates varying from 39 to 71 %. (59)(61) Another theory which might explain these considerable response rates to PPI is the emerging evidence that acid exposure could be a cofactor contributing to the pathogenesis of EoE. Some


21

studies assume that the esophageal eosinophil infiltration may be due to GERD. Since it has been proven that acid exposure may contribute to an increased esophageal permeability due to mucosal damage that damages the epithelial tightjunctions. This increased permeability could function as an entrance for ingested dietary allergens that trigger an immune reaction and eosinophil infiltration.(72)(73) In addition the response to PPI in patients with esophageal eosinophilia may be linked to the capability of PPI to heal damaged esophageal epithelia. (74) Or PPI response could be explained by decreasing the acid reflux, this previous mentioned probable cofactor in the pathogenesis of EoE. Thereby other studies are reporting in vitro anti-inflammatory effect of PPI, independent of acid suppression. Cheng et al. described that in vitro esophageal cells stimulated by IL-5 and IL-3 cytokines showed markedly lower eotaxin-3 levels when exposed to esomeprazol. Probably because esomeprazol stimulates a release of IL-4 in esophageal cell lines, this cytokine blocks the secretion of eotaxin-3.(75) Eotaxin-3 is a cytokine that attracts eosinophils. The exact pathogeneses of EoE remains unclear and a distinction in pathogenesis between EoE and PPI-REE can not be made. Further basal research is warranted to clarify these matters. 4.3 Results compared to previous research Regardless to the unknown differences in pathogenesis, clinical research which is comparable to our study concerning this distinction has been done. Results of these previous works are consistent with our study. Schroeder et al. identified no clinical or histological findings that distinguished EoE from GERD and PPI-REE. So far the only component differentiating PPI-REE from EoE is the response to PPI. In two retrospective studies no demographic, symptomatic, pH study analyses, endoscopic or histological differences were found between PPI-REE and EoE.(61)(59) Dranove et al. retrospectively assessed endoscopic signs by using patient charts and Sayej et al. results were based on one gastroenterologist who evaluated the endoscopic findings, this could lead to subjective results. Dellon et al. recorded endoscopic findings using a standardized case report form, whereas the gastroenterologist could not classify the degree of severity. Contrary to these studies, our study focussed principally on the differences in endoscopic signs, whereby the endoscopic images were prospectively scored to the degree of severity by three experienced observers. Contrary to our results Dellon et al. found significantly more esophageal rings, narrowing, linear furrows and edema in EoE patients. We did see a slightly higher total score of all endoscopic signs in EoE patients (5.63 ± 2.34 Vs 5.17 ± 1.82) although this difference was not significant. Furthermore they reported a higher prevalence of Schtazki’s rings in PPI-REE patients (21 vs. 4% p=0.001) while in our study strictures were more seen in EoE patients (60 vs. 37% p=0.07). The discrepancy between these studies could be due to a considerable inter-observer variability for analysing endoscopic signs of EoE. Peery et al. found that the sensitivity, specificity, and predictive values of endoscopic findings alone are insufficient to diagnose EoE.(76). On the other hand recent updated guidelines state that the diagnostic utility is improved due to the new scoring system created by Hirano et al. (38) So minimising the inter-observer variability and in order to create an objective outcome the endoscopic features in this study were assessed by three gastroenterologists and classified in accordance with this validated classification. 4.4 Limitations Drawing conclusions the limitations of this study must be pointed out. Due to the retrospective design patients were not treated by the same PPI treatment protocol. Different dosage and sorts of PPI were used although both aspects did not differ between two groups. The diagnosis of EoE rests on the identification of clinicopathological features and the elimination of other causes of esophageal eosinophilia. Especially the differentiation between GERD and EoE can be difficult, GERD is mostly ruled out by a negative pH study. The clinicopathological profile of our cohort did fit the diagnostic criteria for EoE although pH was only monitored in the minority of


22

patients. Esophageal biopsies were reviewed by different independent pathologists in multiple hospitals; in this study previously recorded histological reports were used whereby not all charts contained the exact eosinophil count. Due to this lack of information correlation between eosinophil density and the severity of endoscopic signs could not be estimated properly. Quality of life has been measured using a general SF-36 quality of life questionnaire because no validated form exclusively for EoE has been published yet. These questionnaires were not completed in the same period and moreover not exactly before the PPI trial, therefore quality of life is a descriptive feature which can not be used as a distinguishing tool between PPI-REE and EoE. The primary outcome, entire clinical response to PPI treatment, was not assessed by a standard questionnaire. To obtain response rates, patients charts were evaluated and if responsiveness to PPI was not documented properly, patients were called or seen on the out patients clinic. Due to the retrospective character of this study, histological response was unfortunately not available from all patients. Dissociation between clinical and histological response has been described in literature. Moline et al. showed that clinical remission was seen in patients despite persistence of eosinophilia. These data suggest that clinical response might not be representative for histological response. Despite the fact that clinical response is an important outcome for patients quality of life, histological response is warranted because an ongoing infection can cause further tissue remodelling, fibrosis and stricture forming. Since a transient PPI response has been described in previous work another limitation of this study is the lack of follow-up. Dohil et al. suggested that patients with PPI response should have continued monitoring during and after the PPI trial.(58) Nevertheless this transient response has only been described in paediatric patients and whether this transient response represents a new sub-phenotype further research is essential, therefore this aspect was not implemented in our study. Furthermore a disadvantage of this study is the use of still images rather than video clips. These images have been collected from different hospitals and differ in quality. Since baseline endoscopies were taken before the initiation of this study, gastroenterologists did not pay special attention to collect high quality pictures. Nevertheless patients with low quality images were excluded, due to this strict selection quality was guaranteed. A disadvantageous effect of this selection procedure is the decline of the sample size. The small size of the cohort is a shortcoming, which limits the statistical interpretation of the results. Nonetheless, most studies concerning EoE include comparable sample sizes as we could aspect to the relative low general prevalence of EoE and PPI-REE. 4.5 Conclusion Endoscopic signs cannot differentiate between PPI-REE and EoE The current approach to EoE with endoscopy, PPI-trial and re-endoscopy should not be changed based on this study. Currently the only feature differentiating PPI-REE from EoE is the response to PPI treatment. Despite the fact that the mechanism for the PPI response is not completely understood, PPI could be used as a diagnostic tool for EoE.


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