Scandinavian Journal of Gastroenterology
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Incidence and features of eosinophilic esophagitis in dysphagia: a prospective observational study Iain Alexander Murray, Stephne Joyce, Joanne Palmer, Michael Lau & Michael Schultz To cite this article: Iain Alexander Murray, Stephne Joyce, Joanne Palmer, Michael Lau & Michael Schultz (2016) Incidence and features of eosinophilic esophagitis in dysphagia: a prospective observational study, Scandinavian Journal of Gastroenterology, 51:3, 257-262, DOI: 10.3109/00365521.2015.1093166 To link to this article: http://dx.doi.org/10.3109/00365521.2015.1093166
Published online: 08 Oct 2015.
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Date: 22 January 2016, At: 04:20
SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY 2015, VOL. 51, NO. 3, 257–262 http://dx.doi.org/10.3109/00365521.2015.1093166
ORIGINAL ARTICLE
Incidence and features of eosinophilic esophagitis in dysphagia: a prospective observational study Iain Alexander Murray1, Stephne Joyce1, Joanne Palmer2, Michael Lau1 and Michael Schultz1,3
Downloaded by [George Washington University] at 04:20 22 January 2016
1 Gastroenterology Unit, Dunedin Hospital, Southern District Health Board, Dunedin, New Zealand; 2Department of Research and Development, Knowledge Spa, Royal Cornwall Hospital, Truro, Cornwall, UK; 3Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
ABSTRACT
ARTICLE HISTORY
Objective: The incidence and symptoms associated with eosinophilic esophagitis (EoE) varies with geographic location, present in 7–15% dysphagic European or North American adults. We aimed to determine incidence and features of EoE in a dysphagic New Zealand population. Materials and methods: 101 consecutive patients presenting with dysphagia to a New Zealand teaching hospital completed a questionnaire (demographics and history) before upper gastrointestinal endoscopy and esophageal biopsies. Results: The incidence of EoE was 14.1% in those having esophageal biopsies. Patients with EoE were younger (median age 38 years, cohort 58 years: OR 9.2 for age 40; p50.001), more frequently male (19.1% versus 7.4% of females: OR 4.7; p50.05), and had longer symptom duration (median 262 weeks versus 130.6 weeks: p ¼ NS) with non-continuous symptoms (continuous symptoms 8.3% EoE versus 16.2% cohort: p ¼ NS). Progressive symptoms, level of dysphagia and history of allergy/atopy occurred with almost identical frequency in those with and without EoE. Classic endoscopic features of EoE had a sensitivity and specificity of 30.6 and 93.2%, respectively. Conclusions: EoE occurs in an adult dysphagic population in New Zealand with similar frequency to that reported in Europe and North America. Demographics and features of history associated with EoE are described and the need to take esophageal biopsies in this population emphasized by the relatively low sensitivity of endoscopic features for the condition.
Received 23 June 2015 Revised 1 September 2015 Accepted 5 September 2015 Published online 7 October 2015
Introduction Eosinophilic esophagitis (EoE) was first described in 1978 [1] and is increasingly recognized as a cause for dysphagia and food bolus obstruction in Europe and North America. Cases have been reported from all continents except Africa. In adults, EoE usually presents with dysphagia, occasionally food impaction, chest pain, refractory heartburn, or dyspepsia [2]. Its incidence and prevalence appear to be increasing over time [3–6]. Diagnostic criteria have been clarified with expert consensus and depend on histology of esophageal biopsies showing415 eosinophils per high powered field (hpf) in two fields [7]. Eosinophilic esophagitis has previously been reported in New Zealand in a case series of eight patients from Christchurch [8]. Other reports of EoE in the Asian Pacific area include a retrospective review from Australia [9] and nine studies from Asia, predominantly Japan, showing that the prevalence of EoE is considerably less than in CONTACT Dr Iain Alexander Murray, Cornwall, UK. ß 2015 Taylor & Francis
[email protected]
KEYWORDS
Eosinophilic esophagitis/ep, eosinophilic esophagitis/et, epidemiology, Pacific populations, risk factors
Europe and North America, with different presenting features [10]. As EoE is believed to be associated with a reaction to aero-allergens and as New Zealand flora differs substantially from that seen in Asia, Europe and North America, the incidence might vary quite considerably from published values. Evidence for an allergic etiology derives from studies showing it is more common in those with a history of atopy including asthma, hayfever and eczema [3,5]. In asthmatics, those with an allergic phenotype are most likely to have EoE [11]. Aero-allergens have been implicated with a reduced incidence in winter, and lower numbers of eosinophils are seen in those diagnosed in winter months [12–14]. In New Zealand, native bush covers 23% of the land including rimu, unique kauri species (Agathis australi) and kahikatea, so the aero-allergens encountered will differ from those found elsewhere [15]. Other factors known to influence the incidence of EoE in North American and European populations include Department of Gastroenterology, Royal Cornwall Hospital, Truro TR1 3LJ,
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age (mean age in adults at presentation is 33–34 years) [9,16] and gender (most frequent in men) [14,17,18]. Eosinophilic esophagitis can result in abnormalities seen at endoscopy, including esophageal rings, strictures, furrowing or whitish papules (eosinophil microabscesses) but endoscopic appearances can be normal, so endoscopic appearances are not sufficiently sensitive to exclude the diagnosis [13]. The sensitivity of endoscopic changes varies between studies from 15–48%, with a specificity of 90–95% [13]. In Caucasian adults, EoE commonly presents with a history of food bolus impaction [19]. We prospectively evaluated patients attending for upper gastrointestinal endoscopy to investigate dysphagia or food bolus obstruction using a questionnaire to define clinical aspects of their presentation and to determine predictive features of the diagnosis in a New Zealand population. Esophageal biopsies were taken and the sensitivity and specificity of endoscopic appearances, which have been associated with EoE (furrows, ridges, white papules, rings) was also defined.
Methods A total of 101 consecutive patients presenting to Dunedin Hospital, a teaching hospital in South Island, New Zealand for upper gastrointestinal (GI) endoscopy to investigate dysphagia between January 2012 and December 2013 were studied. They were asked to complete a questionnaire before their procedure (Appendix 1). They underwent upper GI endoscopy by one of the six experienced endoscopists (Consultant or Registrar under direct Consultant supervision), all of who agreed to participate in the study, and any abnormalities within the esophagus were noted. Two biopsies were taken from the mid and two from the lower esophagus and were analyzed to determine eosinophil count (in addition to standard histological examination). A diagnosis of EoE required greater than 15 eosinophils per hpf (400) on microscopy. All equivocal cases, especially where an eosinophilic infiltrate was seen but not quantified, were reviewed by a Consultant histopathologist. The incidence of EoE was determined including 95% confidence intervals by the modified Wald method. Continuous variables are presented as medians (IQRs) for non-normally distributed variables and categorical variables as frequencies and percentages. Pearson’s Chi-squared test was used to look at associations between categorical variables and the diagnosis of EoE. Analysis of receiver operator curves was used to determine the most significant differences for age and duration of symptoms. Both were recoded into two
groups. Logistic regression using the Enter technique was then used to explore the association of gender, and age data (40 years,440 years) and diagnosis of EoE. A p-value50.05 was considered significant. Data were analyzed using IBM SPSS v 19 (Armonk, NY). The electronic patient records and endoscopy records of those diagnosed with EoE were reviewed retrospectively to determine if they had received proton pump inhibitors and/or swallowed steroid powder and the effectiveness of these treatments, and whether they had undergone any further upper gastrointestinal endoscopy for ongoing symptoms following diagnosis. The Lower South Regional Ethics Committee approved the study.
Results Of the 101 patients having an upper GI endoscopy for dysphagia, who were studied, 47 (46.5%) were male, median age 58 years (range 15–94 years). 90 completed the pre-endoscopy questionnaire. Of these, 79 described themselves as NZ European (NZE), 4 New Zealanders, and one each of NZE/Maori, Maori, NZ Scot, Dutch, UK European, NZE/gypsy, and NZE/Jewish. A normal endoscopy was the commonest finding (34%) although esophagitis (29%), cancer (4%), and Barrett’s (5%) were all relatively common with all findings shown in Figure 1. Nine patients did not have esophageal biopsies taken, no cause being given by the endoscopist. All patients without esophageal biopsies were greater than 40 years old (range 54–94 years) with the majority having a completely normal esophagus at upper GI endoscopy, two with esophagitis, one candidiasis and one with tertiary contractions. Five of the nine had completed a pre-endoscopy questionnaire. 13 patients had EoE (12.9% on an intention to test basis (95% CI 7.5–20.9%), 14.1% of those who had esophageal 40 35 30 25 20 15 10 5 0
Figure 1. The final diagnosis based on endoscopy appearances and histology for 101 consecutive New Zealand patients presenting with dysphagia.
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Figure 2. Receiver operator curve for age and a final diagnosis of EoE in 101 consecutive New Zealand patients presenting with dysphagia.
biopsies taken (95% CI 8.3–22.8%). Of those with EoE, two had esophageal linear furrows, one feline esophagus, one food bolus, two with a ‘‘corkscrew’’ esophagus, one esophagitis and six had a macroscopically normal esophagus. This gives a sensitivity of 30.6% and a specificity of 93.2% for the ‘‘classical’’ endoscopic findings associated with EoE (food bolus, longitudinal folds, furrows, white papules and feline esophagus) and 46.1 and 93.2%, respectively, if we include corkscrew appearance of the esophagus as an indicator of EoE. Analysis of receiver operator curves showed that the greatest discriminators were for age cut-off 40 years old or 440 years (sensitivity 38% and specificity 19%) and for duration of symptoms 120 weeks or 4120 weeks (sensitivity 45% and specificity 75%) (Figures 2 and 3, respectively). The median age of those with EoE was 38 years, the oldest 63 years old, and 9 of 13 were aged under 40 years (69.2%). This compares to 23 of the 101 whole cohort (22.8%) being aged under 40, median age 58 years and gives an incidence of EoE in the younger group of 39.1% and in the older of 5.1% (p50.001). EoE was more frequent in men (9 of 47: 19.1%) than women (4 of 54: 7.4%: p50.05). Other indicators of EoE were not statistically significant but some appeared numerically large. Patients with EoE had a longer duration of symptoms than those without (average 262 weeks against 130.6 weeks, p ¼ NS). They were less likely to report reflux symptoms than those without (33.3%
against 62.5%, p ¼ NS). Seven out of 12 patients with EoE (58.3%) had at least one atopic/allergic condition (of eczema, hayfever, asthma, or coeliac disease), whereas of those without EoE, 41 of 76 (53.9%) had at least one allergic condition (p ¼ NS). There was a little difference in frequency of pharyngeal level dysphagia (EoE 58.3%, non-EoE 55.8%, p ¼ NS) and many patients experienced dysphagia at more than one level. Those with EoE were less likely to report continuous symptoms (8.3% against 16.2%, p ¼ NS) although this was not statistically significant. They were as likely to report worsening symptoms with time (50% against 57.7%, p ¼ NS). Exploring the potential predictors of EoE based on significant associations with the outcome variable, age, gender, and reflux were put into a logistic regression model using the Enter method, where it was confirmed that reflux was not significant predictor of EoE (p ¼ 0.273). This variable was removed and the model was re-run using age and gender as predictors. The model showed that both age and gender were significant predictors of EoE (Table I). It was found that being under 40 years of age increased the odds of an EoE diagnosis by 9.2 and being male increased the odds by 4.7. The records of those diagnosed with EoE were analyzed 28–42 months after diagnosis (average 38 months). Three had a further upper GI endoscopy, one with a food bolus, two with ongoing dysphagia, one
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Figure 3. Receiver operator curve for symptom duration and a final diagnosis of EoE in 101 consecutive New Zealand patients presenting with dysphagia.
Table I. Predictors of eosinophilic esophagitis. EoE diagnosis Variables
Yes (n ¼ 13) n (%)
No (n ¼ 79) n (%)
Odds ratio (95% CI)
p-Value
Age less than 40 years old Males
8 (61.5) 9 (69.2)
15 (19) 33 (41.8)
9.2 (2.4–36.2) 4.7 (1.1–19.3)
0.001 0.033
with and one without ongoing esophageal eosinophilia. Five had been given a proton pump inhibitor (PPI), five had not and it was unclear in the remainder. Swallowed steroids (budesonide or fluticasone) were prescribed or recommended for all except one (given PPI). The EO patients were not routinely followed up therefore the outcome of therapy was unknown in most.
Discussion We have shown an incidence of EoE in dysphagic New Zealanders of 13–15%, very similar to European/ American populations with uncertainty over the exact incidence because not all patients had esophageal biopsies taken. The reason for failure to take biopsies is unclear but the patients without biopsy were older (average 74 years versus 53.5 years) and did not have endoscopic features to suggest EoE. It seems likely, though disappointing, that the endoscopist chose not to
take biopsies because they thought EoE was an unlikely diagnosis. Because not all patients had PPI and we did not routinely follow-up response to therapy in those who were treated, we are not certain whether some may have had PPI-responsive esophageal eosinophilia rather than true eosinophilic esophagitis (histological findings cannot distinguish). Logistic regression demonstrated younger age and male gender to be highly predictive indicators of a likely diagnosis of EoE, in keeping with previous studies worldwide [5,10,17,18]. Eosinophilic esophagitis is more common in a Caucasian population [20]. Our population was predominantly Caucasian, representative of the demographics of South Island, New Zealand. In Asian populations, the incidence of EoE in those with esophageal symptoms is 2.5–6.6% and food bolus obstruction is unusual, dysphagia is less frequent [10].
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The incidence worldwide is increasing, now equating to 43–55 per 100,000 in Swiss and the US populations. The increase in incidence may partly be due to an increased recognition of the condition with biopsy rates for patients with dysphagia increasing from 36.7 to 68.7% between 1999 and 2009 [18]. Despite this, the frequency of esophageal biopsies taken to investigate dysphagia remains relatively poor; this is important because not all patients with EoE have macroscopically recognizable disease. The failure to take biopsies in nine of the present cohort is most likely due to the endoscopist not considering EoE as a possible diagnosis. Previously, the most common endoscopic findings in EoE in the order of prevalence are: mucosal rings (81%), vertical furrow (74%), strictures (31%), exudates (15%), small caliber (10%), and edema (8%) [19,21]. Since these endoscopic features are also found in other esophageal inflammatory disorders, they are suggestive, not diagnostic, of EoE. A large cohort study of children with EoE revealed a lack in sensitivity of endoscopic findings with a third having normal endoscopic findings [7]. In our cohort, the specificity of endoscopic findings associated with EoE was over 90% but the sensitivity was under 50%, i.e. we were unable to rely on the presence of endoscopic changes to alert us to the need for biopsy, but when present they were highly specific for the diagnosis. There is a strong association between EoE, atopy and allergy. The majority of patients with EoE have a history of allergic diseases, such as food allergy, eczema, and allergic rhinitis [3]. Previously, Spergel et al. [22] have demonstrated the presence of co-existing allergic diseases in EoE in nearly 80% of children and 40–70% of adults. Others have reported that most EoE patients had a family history of allergic diseases [23]. We found that 58% of EoE patients had a self-reported history of at least one of the four allergic conditions questioned (asthma, hayfever, coeliac disease, eczema) but this did not differ significantly from the background incidence of these conditions. The reason for this lack of association with allergic conditions, in our study, could be reliance on self-reporting, a high background incidence of allergic conditions in our population, failure to recognize other allergic conditions, or a true lack of association in our population. We did not take a history of food allergy. The incidence of allergy in our EoE group is similar to that reported by others but the incidence in the non-EoE group is much higher. Our study is limited also by the self-reported nature of symptom duration. The long duration of symptoms both in the EoE and non-EoE groups was surprising. Recently, it has been shown that a significant number of patients with greater than 15 eosinophils per hpf do
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respond to proton pump inhibitor therapy with symptom response in adults of 25–80% and histological response of 33–61% [4]. This had led to a new diagnosis of proton pump inhibitor-responsive esophageal eosinophilia with similar endoscopic and clinical features [24]. We do not have information to determine whether our patients were PPI-responsive although one patient with macroscopic esophagitis had an eosinophil count415 per hpf. Although eosinophil count in reflux is increased, the numbers seen are classically much lower than this. We appreciate that using histology plus endoscopic appearances alone will result in including patients with PPI responsive eosinophilia in our definition of EoE (as per Gretarsdottir, who defined EoE using histological criteria alone [25]). One of our patients, a 47-year old woman had up to 23 eosinophils per hpf, which our pathologists have interpreted as compatible with EoE or florid esophagitis. Endoscopically, she had marked esophagitis so has not been included in our EoE cohort although we appreciate this may be a further limitation of our study. In conclusion, we have demonstrated that EoE is a common cause of dysphagia in a New Zealand population with incidence higher than Asian studies and equal to that seen in North American and European studies. It is more frequent in younger patients, especially those 40 years, although not exclusively so, with a median age at presentation of 38 years and a long duration of symptoms of over 5 years on average, usually not continuous. It is almost three times more common in men. Declaration of interest: The authors report no conflicts of
interest. The authors alone are responsible for the content and writing of this article.
References [1] Landres RT, Kuster GG, Strum WB. Eosinophilic esophagitis in a patient with vigorous achalasia. Gastroenterology 1978;74:1298–301. [2] Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med 2004;351:940–1. [3] Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, et al. First International Gastrointestinal Eosinophil Research Symposium (FIGERS) Subcommittees. Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. Gastroenterology 2007;133:1342–63. [4] Molina-Infante J, Katzka DA, Gisbert JP. Review article; proton pump inhibitor therapy for suspected eosinophilic oesophagitis. Aliment Pharmacol Ther 2013;37:1157–64. [5] Almansa C, Krishna M, Buchner AM, Ghabril MS, Talley N, DeVault KR, et al. Seasonal distribution in newly
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diagnosed cases of eosinophilic esophagitis in adults. Am J Gastroenterol 2009;104:828–33. Wang FY, Gupta SK, Fitzgerald JF. Is there a seasonal variation in the incidence or intensity of allergic eosinophilic esophagitis in newly diagnosed children? J Clin Gastroenterol 2007;41:451–3. Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011;128:3–20. Inns S, Wyeth J, Lamont D, Stace N. Eosinophilic oesophagitis: an emerging important cause for undiagnosed dysphagia. NZ Med J 2006;119:77–83. Soon IS, Butzner JD, Kaplan GG, deBruyn JC. Incidence and prevalence of eosinophilic esophagitis in children. J Pediatr Gastroenterol Nutr 2013;57:72–80. Ishimura N, Shimura S, Jiao D, Mikami H, Okimoto E, Uno G, et al. Clinical features of eosinophilic esophagitis: differences between Asian and Western populations. J Gastroenterol Hepatol 2015;30:71–7. Harer KN, Enders FT, Lim KG, Alexander JA, Katzka DA. An allergic phenotype and the use of steroid inhalers predict eosinophilic oesophagitis in patients with asthma. Aliment Pharmacol Ther 2013;37:107–13. van Rhijn BD, Verheij J, Smout AJPM, Bredenoord AJ. Rapidly increasing incidence of eosinophilic esophagitis in a large cohort. Neurogastroenterol Motil 2013;25: 47–52. Kim HP, Vance RB, Shaheen NJ, Dellon ES. The prevalence and diagnostic utility of endoscopic features of eosinophilic esophagitis: a meta-analysis. Clin Gastroenterol Hepatol 2012;10:988–96. Croese J, Fairley SK, Masson JW, Chong AKH, Whitaker DA, Kanowski DA, et al. Clinical and endoscopic features of eosinophilic esophagitis in adults. Gastrointest Endosc 2003;58:516–22. Department of Conservation, New Zealand. Available from: http://www.doc.govt.nz/documents/gettinginvolved/students-and-teachers/themes/006-nz-forest.pdf (last accessed 23 September 2015).
[16] Prasad GA, Alexander JA, Schleck CD, Zinsmeister AR, Smyrk TC, Elias RM, et al. Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota. Clin Gastroenterol Hepatol 2009;7:1055–61. [17] Franciosi JP, Tam V, Liacouras CA, Spergel JM. A casecontrol study of sociodemographic and geographic characteristics of 335 children with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2009;7:415–19. [18] Moawad FJ, Veerappan GR, Lake JM, Maydonovitch CL, Haymore BR, Kosisky SE, et al. Correlation between eosinophilic oesophagitis and aeroallergens. Aliment Pharmacol Ther 2010;31:509–15. [19] Potter JW, Saeian K, Staff D, Massey BT, Komorowski RA, Shaker R, et al. Eosinophilic esophagitis in adults: an emerging problem with unique esophageal features. Gastrointest Endosc 2004;59:355–61. [20] Dellon ES, Jensen ET, Martin CF, Shaheen NJ, Kappelman MD. Prevalence of eosinophilic esophagitis in the United States. Clin Gastroenterol Hepatol 2014; 12:589–96. [21] Gonsalves N, Kahrilas PJ, Hirano I. Eosinophilic esophagitis (EE) in adults: emerging entity or misdiagnosed malady. Gastrointest Endosc 2005;61:AB132. [22] Spergel JM, Beausoleil JL, Mascarenhas M, Liacouras CA. The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol 2002;109:363–8. [23] Roy-Ghanta S, Larosa DF, Katzka DA. Atopic characteristics of adult patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2008;6:531–5. [24] Moawad FJ, Schoepfer AM, Safroneeva E, Ally MR, Chen YJ, Maydonovitch CL, et al. Eosinophilic oesophagitis and proton pump inhibitor-responsive oesophageal eosinophilia have similar clinical, endoscopic and histological findings. Aliment Pharmacol Ther 2014;39: 603–8. [25] Gretarsdottir HM, Jonasson JG, Bjo¨rnsson ES. Etiology and management of esophageal food impaction: a population based study. Scand J Gastroenterol 2015;5:513–18.
Appendix 1 1. Do you feel food or drink stick within 5 seconds of swallowing? Yes No If not what symptoms do you have? 2. How long have you had these symptoms? 3. Does it happen every time you swallow? Yes No 4. Is it getting worse? Yes No 5. Does it stick a) at the level of your throat b) mid chest c) bottom of your chest/top of stomach 6. Have you lost weight? If so how much 7. Do you often choke when eating? Yes No 8. Do you suffer from a) acid reflux/ heartburn Yes No b) pain on swallowing Yes No 9. Do you take medicine to reduce stomach acidity (eg omeprazole (Losec), lansoprazole (Solox), pantoprazole (Protonix)? Yes No
If so, does it help with your swallowing? Yes No 10. Do you suffer from a)asthma Yes No b)eczema Yes No c)hayfever Yes No d)coeliac disease Yes No 11. What is your ethnic background (please circle)? New Zealand European Mori Pacific peoples Asian New Zealander Other (please state) Thank you for your time and help in completing this questionnaire. If you have any questions or comments please let us know.
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Incidence and features of eosinophilic esophagitis in dysphagia: a prospective observational study Iain Alexander Murray, Stephne Joyce, Joanne Palmer, Michael Lau & Michael Schultz To cite this article: Iain Alexander Murray, Stephne Joyce, Joanne Palmer, Michael Lau & Michael Schultz (2016) Incidence and features of eosinophilic esophagitis in dysphagia: a prospective observational study, Scandinavian Journal of Gastroenterology, 51:3, 257-262, DOI: 10.3109/00365521.2015.1093166 To link to this article: http://dx.doi.org/10.3109/00365521.2015.1093166
Published online: 08 Oct 2015.
Submit your article to this journal
Article views: 139
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [George Washington University]
Date: 22 January 2016, At: 04:20
SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY 2015, VOL. 51, NO. 3, 257–262 http://dx.doi.org/10.3109/00365521.2015.1093166
ORIGINAL ARTICLE
Incidence and features of eosinophilic esophagitis in dysphagia: a prospective observational study Iain Alexander Murray1, Stephne Joyce1, Joanne Palmer2, Michael Lau1 and Michael Schultz1,3
Downloaded by [George Washington University] at 04:20 22 January 2016
1 Gastroenterology Unit, Dunedin Hospital, Southern District Health Board, Dunedin, New Zealand; 2Department of Research and Development, Knowledge Spa, Royal Cornwall Hospital, Truro, Cornwall, UK; 3Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
ABSTRACT
ARTICLE HISTORY
Objective: The incidence and symptoms associated with eosinophilic esophagitis (EoE) varies with geographic location, present in 7–15% dysphagic European or North American adults. We aimed to determine incidence and features of EoE in a dysphagic New Zealand population. Materials and methods: 101 consecutive patients presenting with dysphagia to a New Zealand teaching hospital completed a questionnaire (demographics and history) before upper gastrointestinal endoscopy and esophageal biopsies. Results: The incidence of EoE was 14.1% in those having esophageal biopsies. Patients with EoE were younger (median age 38 years, cohort 58 years: OR 9.2 for age 40; p50.001), more frequently male (19.1% versus 7.4% of females: OR 4.7; p50.05), and had longer symptom duration (median 262 weeks versus 130.6 weeks: p ¼ NS) with non-continuous symptoms (continuous symptoms 8.3% EoE versus 16.2% cohort: p ¼ NS). Progressive symptoms, level of dysphagia and history of allergy/atopy occurred with almost identical frequency in those with and without EoE. Classic endoscopic features of EoE had a sensitivity and specificity of 30.6 and 93.2%, respectively. Conclusions: EoE occurs in an adult dysphagic population in New Zealand with similar frequency to that reported in Europe and North America. Demographics and features of history associated with EoE are described and the need to take esophageal biopsies in this population emphasized by the relatively low sensitivity of endoscopic features for the condition.
Received 23 June 2015 Revised 1 September 2015 Accepted 5 September 2015 Published online 7 October 2015
Introduction Eosinophilic esophagitis (EoE) was first described in 1978 [1] and is increasingly recognized as a cause for dysphagia and food bolus obstruction in Europe and North America. Cases have been reported from all continents except Africa. In adults, EoE usually presents with dysphagia, occasionally food impaction, chest pain, refractory heartburn, or dyspepsia [2]. Its incidence and prevalence appear to be increasing over time [3–6]. Diagnostic criteria have been clarified with expert consensus and depend on histology of esophageal biopsies showing415 eosinophils per high powered field (hpf) in two fields [7]. Eosinophilic esophagitis has previously been reported in New Zealand in a case series of eight patients from Christchurch [8]. Other reports of EoE in the Asian Pacific area include a retrospective review from Australia [9] and nine studies from Asia, predominantly Japan, showing that the prevalence of EoE is considerably less than in CONTACT Dr Iain Alexander Murray, Cornwall, UK. ß 2015 Taylor & Francis
[email protected]
KEYWORDS
Eosinophilic esophagitis/ep, eosinophilic esophagitis/et, epidemiology, Pacific populations, risk factors
Europe and North America, with different presenting features [10]. As EoE is believed to be associated with a reaction to aero-allergens and as New Zealand flora differs substantially from that seen in Asia, Europe and North America, the incidence might vary quite considerably from published values. Evidence for an allergic etiology derives from studies showing it is more common in those with a history of atopy including asthma, hayfever and eczema [3,5]. In asthmatics, those with an allergic phenotype are most likely to have EoE [11]. Aero-allergens have been implicated with a reduced incidence in winter, and lower numbers of eosinophils are seen in those diagnosed in winter months [12–14]. In New Zealand, native bush covers 23% of the land including rimu, unique kauri species (Agathis australi) and kahikatea, so the aero-allergens encountered will differ from those found elsewhere [15]. Other factors known to influence the incidence of EoE in North American and European populations include Department of Gastroenterology, Royal Cornwall Hospital, Truro TR1 3LJ,
Downloaded by [George Washington University] at 04:20 22 January 2016
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age (mean age in adults at presentation is 33–34 years) [9,16] and gender (most frequent in men) [14,17,18]. Eosinophilic esophagitis can result in abnormalities seen at endoscopy, including esophageal rings, strictures, furrowing or whitish papules (eosinophil microabscesses) but endoscopic appearances can be normal, so endoscopic appearances are not sufficiently sensitive to exclude the diagnosis [13]. The sensitivity of endoscopic changes varies between studies from 15–48%, with a specificity of 90–95% [13]. In Caucasian adults, EoE commonly presents with a history of food bolus impaction [19]. We prospectively evaluated patients attending for upper gastrointestinal endoscopy to investigate dysphagia or food bolus obstruction using a questionnaire to define clinical aspects of their presentation and to determine predictive features of the diagnosis in a New Zealand population. Esophageal biopsies were taken and the sensitivity and specificity of endoscopic appearances, which have been associated with EoE (furrows, ridges, white papules, rings) was also defined.
Methods A total of 101 consecutive patients presenting to Dunedin Hospital, a teaching hospital in South Island, New Zealand for upper gastrointestinal (GI) endoscopy to investigate dysphagia between January 2012 and December 2013 were studied. They were asked to complete a questionnaire before their procedure (Appendix 1). They underwent upper GI endoscopy by one of the six experienced endoscopists (Consultant or Registrar under direct Consultant supervision), all of who agreed to participate in the study, and any abnormalities within the esophagus were noted. Two biopsies were taken from the mid and two from the lower esophagus and were analyzed to determine eosinophil count (in addition to standard histological examination). A diagnosis of EoE required greater than 15 eosinophils per hpf (400) on microscopy. All equivocal cases, especially where an eosinophilic infiltrate was seen but not quantified, were reviewed by a Consultant histopathologist. The incidence of EoE was determined including 95% confidence intervals by the modified Wald method. Continuous variables are presented as medians (IQRs) for non-normally distributed variables and categorical variables as frequencies and percentages. Pearson’s Chi-squared test was used to look at associations between categorical variables and the diagnosis of EoE. Analysis of receiver operator curves was used to determine the most significant differences for age and duration of symptoms. Both were recoded into two
groups. Logistic regression using the Enter technique was then used to explore the association of gender, and age data (40 years,440 years) and diagnosis of EoE. A p-value50.05 was considered significant. Data were analyzed using IBM SPSS v 19 (Armonk, NY). The electronic patient records and endoscopy records of those diagnosed with EoE were reviewed retrospectively to determine if they had received proton pump inhibitors and/or swallowed steroid powder and the effectiveness of these treatments, and whether they had undergone any further upper gastrointestinal endoscopy for ongoing symptoms following diagnosis. The Lower South Regional Ethics Committee approved the study.
Results Of the 101 patients having an upper GI endoscopy for dysphagia, who were studied, 47 (46.5%) were male, median age 58 years (range 15–94 years). 90 completed the pre-endoscopy questionnaire. Of these, 79 described themselves as NZ European (NZE), 4 New Zealanders, and one each of NZE/Maori, Maori, NZ Scot, Dutch, UK European, NZE/gypsy, and NZE/Jewish. A normal endoscopy was the commonest finding (34%) although esophagitis (29%), cancer (4%), and Barrett’s (5%) were all relatively common with all findings shown in Figure 1. Nine patients did not have esophageal biopsies taken, no cause being given by the endoscopist. All patients without esophageal biopsies were greater than 40 years old (range 54–94 years) with the majority having a completely normal esophagus at upper GI endoscopy, two with esophagitis, one candidiasis and one with tertiary contractions. Five of the nine had completed a pre-endoscopy questionnaire. 13 patients had EoE (12.9% on an intention to test basis (95% CI 7.5–20.9%), 14.1% of those who had esophageal 40 35 30 25 20 15 10 5 0
Figure 1. The final diagnosis based on endoscopy appearances and histology for 101 consecutive New Zealand patients presenting with dysphagia.
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Figure 2. Receiver operator curve for age and a final diagnosis of EoE in 101 consecutive New Zealand patients presenting with dysphagia.
biopsies taken (95% CI 8.3–22.8%). Of those with EoE, two had esophageal linear furrows, one feline esophagus, one food bolus, two with a ‘‘corkscrew’’ esophagus, one esophagitis and six had a macroscopically normal esophagus. This gives a sensitivity of 30.6% and a specificity of 93.2% for the ‘‘classical’’ endoscopic findings associated with EoE (food bolus, longitudinal folds, furrows, white papules and feline esophagus) and 46.1 and 93.2%, respectively, if we include corkscrew appearance of the esophagus as an indicator of EoE. Analysis of receiver operator curves showed that the greatest discriminators were for age cut-off 40 years old or 440 years (sensitivity 38% and specificity 19%) and for duration of symptoms 120 weeks or 4120 weeks (sensitivity 45% and specificity 75%) (Figures 2 and 3, respectively). The median age of those with EoE was 38 years, the oldest 63 years old, and 9 of 13 were aged under 40 years (69.2%). This compares to 23 of the 101 whole cohort (22.8%) being aged under 40, median age 58 years and gives an incidence of EoE in the younger group of 39.1% and in the older of 5.1% (p50.001). EoE was more frequent in men (9 of 47: 19.1%) than women (4 of 54: 7.4%: p50.05). Other indicators of EoE were not statistically significant but some appeared numerically large. Patients with EoE had a longer duration of symptoms than those without (average 262 weeks against 130.6 weeks, p ¼ NS). They were less likely to report reflux symptoms than those without (33.3%
against 62.5%, p ¼ NS). Seven out of 12 patients with EoE (58.3%) had at least one atopic/allergic condition (of eczema, hayfever, asthma, or coeliac disease), whereas of those without EoE, 41 of 76 (53.9%) had at least one allergic condition (p ¼ NS). There was a little difference in frequency of pharyngeal level dysphagia (EoE 58.3%, non-EoE 55.8%, p ¼ NS) and many patients experienced dysphagia at more than one level. Those with EoE were less likely to report continuous symptoms (8.3% against 16.2%, p ¼ NS) although this was not statistically significant. They were as likely to report worsening symptoms with time (50% against 57.7%, p ¼ NS). Exploring the potential predictors of EoE based on significant associations with the outcome variable, age, gender, and reflux were put into a logistic regression model using the Enter method, where it was confirmed that reflux was not significant predictor of EoE (p ¼ 0.273). This variable was removed and the model was re-run using age and gender as predictors. The model showed that both age and gender were significant predictors of EoE (Table I). It was found that being under 40 years of age increased the odds of an EoE diagnosis by 9.2 and being male increased the odds by 4.7. The records of those diagnosed with EoE were analyzed 28–42 months after diagnosis (average 38 months). Three had a further upper GI endoscopy, one with a food bolus, two with ongoing dysphagia, one
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Figure 3. Receiver operator curve for symptom duration and a final diagnosis of EoE in 101 consecutive New Zealand patients presenting with dysphagia.
Table I. Predictors of eosinophilic esophagitis. EoE diagnosis Variables
Yes (n ¼ 13) n (%)
No (n ¼ 79) n (%)
Odds ratio (95% CI)
p-Value
Age less than 40 years old Males
8 (61.5) 9 (69.2)
15 (19) 33 (41.8)
9.2 (2.4–36.2) 4.7 (1.1–19.3)
0.001 0.033
with and one without ongoing esophageal eosinophilia. Five had been given a proton pump inhibitor (PPI), five had not and it was unclear in the remainder. Swallowed steroids (budesonide or fluticasone) were prescribed or recommended for all except one (given PPI). The EO patients were not routinely followed up therefore the outcome of therapy was unknown in most.
Discussion We have shown an incidence of EoE in dysphagic New Zealanders of 13–15%, very similar to European/ American populations with uncertainty over the exact incidence because not all patients had esophageal biopsies taken. The reason for failure to take biopsies is unclear but the patients without biopsy were older (average 74 years versus 53.5 years) and did not have endoscopic features to suggest EoE. It seems likely, though disappointing, that the endoscopist chose not to
take biopsies because they thought EoE was an unlikely diagnosis. Because not all patients had PPI and we did not routinely follow-up response to therapy in those who were treated, we are not certain whether some may have had PPI-responsive esophageal eosinophilia rather than true eosinophilic esophagitis (histological findings cannot distinguish). Logistic regression demonstrated younger age and male gender to be highly predictive indicators of a likely diagnosis of EoE, in keeping with previous studies worldwide [5,10,17,18]. Eosinophilic esophagitis is more common in a Caucasian population [20]. Our population was predominantly Caucasian, representative of the demographics of South Island, New Zealand. In Asian populations, the incidence of EoE in those with esophageal symptoms is 2.5–6.6% and food bolus obstruction is unusual, dysphagia is less frequent [10].
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The incidence worldwide is increasing, now equating to 43–55 per 100,000 in Swiss and the US populations. The increase in incidence may partly be due to an increased recognition of the condition with biopsy rates for patients with dysphagia increasing from 36.7 to 68.7% between 1999 and 2009 [18]. Despite this, the frequency of esophageal biopsies taken to investigate dysphagia remains relatively poor; this is important because not all patients with EoE have macroscopically recognizable disease. The failure to take biopsies in nine of the present cohort is most likely due to the endoscopist not considering EoE as a possible diagnosis. Previously, the most common endoscopic findings in EoE in the order of prevalence are: mucosal rings (81%), vertical furrow (74%), strictures (31%), exudates (15%), small caliber (10%), and edema (8%) [19,21]. Since these endoscopic features are also found in other esophageal inflammatory disorders, they are suggestive, not diagnostic, of EoE. A large cohort study of children with EoE revealed a lack in sensitivity of endoscopic findings with a third having normal endoscopic findings [7]. In our cohort, the specificity of endoscopic findings associated with EoE was over 90% but the sensitivity was under 50%, i.e. we were unable to rely on the presence of endoscopic changes to alert us to the need for biopsy, but when present they were highly specific for the diagnosis. There is a strong association between EoE, atopy and allergy. The majority of patients with EoE have a history of allergic diseases, such as food allergy, eczema, and allergic rhinitis [3]. Previously, Spergel et al. [22] have demonstrated the presence of co-existing allergic diseases in EoE in nearly 80% of children and 40–70% of adults. Others have reported that most EoE patients had a family history of allergic diseases [23]. We found that 58% of EoE patients had a self-reported history of at least one of the four allergic conditions questioned (asthma, hayfever, coeliac disease, eczema) but this did not differ significantly from the background incidence of these conditions. The reason for this lack of association with allergic conditions, in our study, could be reliance on self-reporting, a high background incidence of allergic conditions in our population, failure to recognize other allergic conditions, or a true lack of association in our population. We did not take a history of food allergy. The incidence of allergy in our EoE group is similar to that reported by others but the incidence in the non-EoE group is much higher. Our study is limited also by the self-reported nature of symptom duration. The long duration of symptoms both in the EoE and non-EoE groups was surprising. Recently, it has been shown that a significant number of patients with greater than 15 eosinophils per hpf do
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respond to proton pump inhibitor therapy with symptom response in adults of 25–80% and histological response of 33–61% [4]. This had led to a new diagnosis of proton pump inhibitor-responsive esophageal eosinophilia with similar endoscopic and clinical features [24]. We do not have information to determine whether our patients were PPI-responsive although one patient with macroscopic esophagitis had an eosinophil count415 per hpf. Although eosinophil count in reflux is increased, the numbers seen are classically much lower than this. We appreciate that using histology plus endoscopic appearances alone will result in including patients with PPI responsive eosinophilia in our definition of EoE (as per Gretarsdottir, who defined EoE using histological criteria alone [25]). One of our patients, a 47-year old woman had up to 23 eosinophils per hpf, which our pathologists have interpreted as compatible with EoE or florid esophagitis. Endoscopically, she had marked esophagitis so has not been included in our EoE cohort although we appreciate this may be a further limitation of our study. In conclusion, we have demonstrated that EoE is a common cause of dysphagia in a New Zealand population with incidence higher than Asian studies and equal to that seen in North American and European studies. It is more frequent in younger patients, especially those 40 years, although not exclusively so, with a median age at presentation of 38 years and a long duration of symptoms of over 5 years on average, usually not continuous. It is almost three times more common in men. Declaration of interest: The authors report no conflicts of
interest. The authors alone are responsible for the content and writing of this article.
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Appendix 1 1. Do you feel food or drink stick within 5 seconds of swallowing? Yes No If not what symptoms do you have? 2. How long have you had these symptoms? 3. Does it happen every time you swallow? Yes No 4. Is it getting worse? Yes No 5. Does it stick a) at the level of your throat b) mid chest c) bottom of your chest/top of stomach 6. Have you lost weight? If so how much 7. Do you often choke when eating? Yes No 8. Do you suffer from a) acid reflux/ heartburn Yes No b) pain on swallowing Yes No 9. Do you take medicine to reduce stomach acidity (eg omeprazole (Losec), lansoprazole (Solox), pantoprazole (Protonix)? Yes No
If so, does it help with your swallowing? Yes No 10. Do you suffer from a)asthma Yes No b)eczema Yes No c)hayfever Yes No d)coeliac disease Yes No 11. What is your ethnic background (please circle)? New Zealand European Mori Pacific peoples Asian New Zealander Other (please state) Thank you for your time and help in completing this questionnaire. If you have any questions or comments please let us know.
