Pediatric Patients with Eosinophilic Esophagitis and Their Parents Identify Symptoms as the Most Important Treatment Outcome

Eosinophilic esophagitis (EoE) is a chronic antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by an eosinophil-predominant inflammation [1‒3]. In the pediatric population, the symptomatology varies with age, ranging from gastroesophageal reflux disease-like symptoms in infants to dysphagia and food impaction in adolescents [3]. Diagnosis is made based on a combination of clinical and histological findings and the exclusion of other conditions that might be associated with esophageal eosinophilia. Treatment options range from pharmacological and dietary therapies to esophageal dilation. The main goals are improvement of symptoms, EoE-related quality of life, and remission of histopathological features [4‒6]. Selection of therapy for EoE is highly individualized and takes into account their efficacy, safety, disease activity, patient preferences, and availability of resources, e.g., for elimination diet [5, 7]. Untreated EoE leads to esophageal remodeling by fibrous tissue deposition with formation of esophageal strictures with the inherent risk of food bolus impactions and associated esophageal perforations [8, 9]. Given the chronic nature of EoE and its tendency to relapse within a few weeks to months following discontinuation of therapy, long-term therapy is usually needed [10]. However, targeted treatment of symptoms may not be sufficient since their correlation with endoscopic and histologic activity is limited [11, 12]. Management and follow-up of chronic diseases are complex and the importance of a physician-parent-child partnership is essential to maintain a bond of trust and promote compliance with a proposed attitude. In pediatric studies, patient-centered communication style has been associated with increased medication adherence and perceptions of control and competence in managing a chronic disease [13, 14]. Increased child participation in medical consultations may improve the exchange of relevant clinical information since they can share information that parents do not have, thereby reducing some complications and improving young people's decision-making and satisfaction with healthcare [13, 15, 16]. Up to now, there exist no data regarding the opinion of pediatric EoE patients and their parents regarding relevant therapeutic goals.

Therefore, we aimed to systematically assess which short- and long-term therapy goals pediatric EoE patients and their parents consider important. Additionally, we evaluated demographic and clinical characteristics associated with pediatric patients’ and parents’ choice of therapy goals.

Between April 2018 and October 2020, pediatric EoE patients (4–16 years of age) and parents, who provided written informed consent, were prospectively recruited to the study from six tertiary centers (C. Braegger, Zurich, H. Köhler, Aarau; G. Marx and P. Müller, St. Gallen; V. McLin and L-M Petit, Geneva; A. Nydegger and A. Giroud Rivier, Lausanne; S. Schibli and C. Sokollik, Bern) and three private practices (J. Ezri, Lausanne; M. Tempia-Caliera, Geneva; L. Garzoni, Geneva) in Switzerland (ethics committee approval CER-VD 2017-01587). EoE diagnosis followed the European EoE guidelines from 2017 and was based on the presence of symptoms of esophageal dysfunction, a peak esophageal eosinophil count of ≥15 cells per high power field, and lack of other disorders associated with esophageal eosinophilia [3].

The study was carried out in three parts according to guidelines from ISPOR, the Professional Society for Health Economics and Outcomes Research [17, 18]. The study phases are depicted in online supplementary Figure 1 (for all online suppl. material, see https://doi.org/10.1159/000535242).

First, we developed a brochure including a questionnaire for pediatric EoE patients and their parents. This brochure contained general information about EoE epidemiology, pathogenesis, clinical presentation, the diagnostic approach, natural history, and activity assessment of the disease (brochure provided at the discretion of the reviewers). Information regarding the limited correlation between symptoms and histological/endoscopic findings was explained in depth. The brochure included definitions of medical terms as well as illustrations. The questionnaire contained the demographics of pediatric patients and their parents, characteristics of EoE, presence of atopic diseases, current and past EoE-specific therapies, and short- and long-term therapeutic goals of patients and parents. For parents, the level of education was assessed using the International Standard Classification of Education (ISCED): upper secondary education (level 3); second stage of tertiary education leading to an advanced qualification (level 6) or higher [19]. The brochure and questionnaires were written in French language given the fact that the study was launched in the French-speaking part of Switzerland.

Second, we conducted focus interviews with pediatric patients and their parents using a semistructured interview guide, in which questions and probing strategies were outlined to assess appropriateness of the recall period as well as patients’ and parents’ understanding of instructions, stem, response options, item format, and brochure [17, 18]. They were held in French language with an experienced clinical investigator and recorded. Input from patients and parents was used to continuously improve the brochure and the questionnaire. Following each focus interview, a cognitive summary report and item-tracking matrix were created, in which all changes proposed by patients and parents were documented. During the sixth pediatric interview and the 9th parental interview, patients and parents deemed the brochure and the questionnaire to be easy to understand, and the brochure content to be sufficiently informative to allow answering all questions. At this moment, a saturation of patient and caregiver feedback was achieved. In the final questionnaire, pediatric patients and their parents were asked to rank the short (defined as “in the next 3 months”) and long-term (defined as “in 1 year or longer”) importance (on five levels, from very important to not at all important) of the therapy effect on symptoms, quality of life (QoL), endoscopic inflammation, stricture formation, histological inflammation, and fibrosis. Symptoms and quality of life specific to EoE were also assessed using simplified validated instruments [20, 21]. The validated brochure and questionnaire were then translated into German. After interviews with 3 German-speaking adolescents and 3 parents the brochure and questionnaire were considered to be validated [17, 18].

Thirdly, the standardized brochure and questionnaire were sent to five tertiary centers and three private practices of pediatric gastroenterologists. Patients aged ≥11 years completed the questionnaire in absence of their parents. Parents of pediatric patients ≥11 years completed the questionnaire in absence of their child. Parents of children aged <11 years completed the questionnaire in presence of their child. The age cutoff was based on findings that children at around 10 years of age are able to participate meaningfully in personal healthcare decision-making [22]. Patients were identified by database research. The educational brochure on EoE and the questionnaires were sent to patients and parents in paper form (with colored images) by mail, including an instruction how to complete the documents and a stamped envelope for the return of the completed questionnaires.

Data were entered into an Excel database and analyzed using Stata (version 13.1, TX, USA). QQ-plots were used to analyze data distribution. Numerical data are presented as median, interquartile range (IQR), and range. We used a non-parametric test of trend for the ranks across ordered groups (extension of the Wilcoxon rank-sum test) to explore differences between two groups. The treatment effects identified as “very important” and “quite important” were put together as key effects. The agreement between patient and caregiver goals was analyzed using Cohen’s kappa and percent agreement. Cohen suggested the kappa result be interpreted as follows: values ≤0 as indicating no agreement and 0.01–0.20 as none to slight, 0.21–0.40 as fair, 0.41–0.60 as moderate, 0.61–0.80 as substantial, and 0.81–1.00 as almost perfect agreement. Multivariable logistic regression was performed to identify the factors potentially associated with the importance rankings of all individual therapy effects. We used the following independent variables: anti-inflammatory therapy at time of study inclusion (defined as use of swallowed topical steroids, systemic steroids, proton-pump inhibitors, and food elimination diets; ordered as no vs. yes), gender (female vs. male), and at least one atopic comorbidity other than EoE ever in life (no vs. yes). A p value <0.05 was considered statistically significant.

Survey response rate was 45/112 (40.2%). A total of 67 patients/parents were unwilling to participate. The clinical characteristics of the survey’s respondents are shown in Table 1. Half of the pediatric EoE patients had asthma, allergic rhinitis, or food allergies (47%, 53%, and 57%, respectively). At inclusion, 63% of patients ≥11 years of age and 80% of patients <11 years of age were managed with swallowed topical corticosteroids (STC), proton-pump inhibitors (PPI), or elimination diets, respectively. Eleven patients (37%) ≥11 years of age and 3 patients (20%) <11 years of age had no anti-inflammatory therapy at inclusion.

The ranking of the importance of short- (in the next 3 months) and long-term (in 1 year or longer) therapy goals is shown in Figure 1 and online supplementary Tables 1–3. Pediatric patients identified improvement in the following domains as most important in short- and long-term, respectively: symptoms (73% vs. 77%), quality of life (53% vs. 57%), histologic inflammation (47% vs. 50%), histologic fibrosis (40% vs. 33%), endoscopic inflammation (47% vs. 40%), and widening of strictures (33% vs. 40%).

Parents of children ≥11 years old classified improvement in the following domains as most important in short- and long-term, respectively: symptoms (70% vs. 83%), quality of life (63% vs. 80%), histologic inflammation (67% vs. 77%), histologic fibrosis (47% vs. 63%), endoscopic inflammation (77% vs. 80%), and widening of strictures (40% vs. 53%).

Parents of children <11 years old classified improvement in the following domains as most important in the short- and long-term, respectively: symptoms (87% at both timepoints), quality of life (87% vs. 80%), histologic inflammation (73% vs. 80%), histologic fibrosis (47% at both timepoints), endoscopic inflammation (67% vs. 87%), and widening of strictures (53% vs. 60%).

The agreement between child and caregiver regarding therapy goals was assessed in Table 2. Parents and children disagreed about most outcomes except for symptoms improvement. When stratified whether patients were with or without therapy, parents and children without therapy disagreed about the long-term outlook on symptoms improvement. When children were on therapy, there was moderate agreement on long-term outlook on symptoms improvement. Regarding improvement in QoL, parents and children disagreed on the short-term and there was none to slight agreement on the long-term.

When using multivariable ordered logistic regression analysis, anti-inflammatory therapy at inclusion in pediatric patients was positively associated with putting greater emphasis on improvement of histologic fibrosis (OR: 8.70, 95% CI: 1.78–42.62, p = 0.008) and endoscopic inflammation (OR: 7.93, 95% CI: 1.55–40.58, p = 0.013) in the short-term (Table 3). In the long-term, being on anti-inflammatory therapy was also positively associated with putting greater emphasis on reduction in both histologic and endoscopic inflammation (OR: 6.15, 95% CI: 1.25–30.24, p = 0.025; OR: 12.56, 95% CI: 2.28–69.23, p = 0.004, respectively) and histologic fibrosis (OR: 5.56, 95% CI: 1.24–25.00, p = 0.025). Pediatric EoE patients with at least one atopic comorbidity ever in life were less likely to be concerned about controlling endoscopic inflammation and strictures (short-term OR: 0.11, 95% CI: 0.01–0.88, p = 0.038; OR: 0.07, 95% CI: 0.01–0.54, p = 0.011, respectively; long-term OR: 0.10, 95% CI: 0.01–0.93, p = 0.043; OR: 0.03, 95% CI: 0.002–0.42, p = 0.009, respectively).

We present the results of the first study to systematically evaluate pediatric patients’ and parents’ perspective on therapeutic goals after having been educated on different aspects of EoE by means of a specifically created brochure for patients and parents. Our study contains several messages of clinical relevance. First, pediatric EoE patients and parents consider the effect of therapy on symptom improvement as the most important goal both in the short- and long-term. Second, parents find short- and long-term improvement in QoL to be more important than children themselves. Third, maintaining treatment to control inflammation even in the absence of symptoms is considered to be important by 83% of children and parents. Fourth, there is poor agreement regarding treatment goals between patients and parents, with the exception of symptom improvement. Fifth, pediatric patients on anti-inflammatory therapy are more likely to be concerned about reduction in endoscopic inflammation and histologic fibrosis compared to patients off anti-inflammatory therapies. And sixth, patients with at least one atopic condition other than EoE are less likely to be concerned about various aspects of biological disease activity.

As EoE is a chronic disease, it is important to develop long-term therapeutic strategies, taking into account disease activity based on the level of symptoms, quality of life, histologic, and endoscopic activity [8, 23, 24]. Without any doubt, the management of chronic diseases is complex, particularly in pediatrics, as an appropriate understanding of the medical condition by patients and parents is necessary to ensure a good physician-patient partnership. Such an empowerment through education is essential to best guide families in the choice of therapy and thus to attempt to optimize long-term therapeutic adherence.

Therapeutic goals in EoE are evolving. While in the early years of EoE care, symptom control was considered to represent the most relevant treatment outcome, later data showed a poor correlation between symptoms and histologic/endoscopic disease activity [25]. Untreated histologic and/or endoscopic disease activity leads to esophageal stricture formation with the inherent risk for food bolus impactions [26]. As such, the focus moved away from pure symptom control to a combined assessment of patient-reported outcomes (PRO) and biologic activity [27]. It is self-evident that patients and parents put most emphasis on symptom control and QoL as a therapeutic outcome in the short- and long-term. Nevertheless, histologic and endoscopic disease activity are taken into account as therapeutic goals as well by patients and parents after having been provided with a structured education on different aspects of EoE. Our results in a pediatric cohort of EoE patients are comparable to those in a Swiss study in adults that were systematically questioned about short-term and long-term therapeutic goals after a structured education on different aspects of EoE was provided using a patient brochure [28]. In this study with the adult population, symptoms were as well identified as most important treatment goal in the short- and long-term run [28]. Furthermore, the results of our study are in line with the recently published guidelines on monitoring and treating EoE [29]. In our current study, short- and long-term improvement in QoL was more important for parents than children themselves. In analogy to other chronic diseases and from our clinical experience, compliance tends to decrease as the disease goes into clinical remission. Our study revealed that pediatric patients with other chronic conditions, such as atopic conditions, were less concerned about the biological activity of the disease. Pediatric patients receiving targeted therapy were more concerned about histological and endoscopic remission.

Our study has several strengths as well as some limitations. We present the first study in a pediatric cohort of EoE patients that systematically evaluates treatment goals of patients and their parents. Patients and parents were educated on different aspects of EoE by a brochure that was co-developed with them and finally validated with respect to content, following the ISPOR guidelines. The brochure assures that education level regarding different aspects of EoE was comparable among patients and parents. Furthermore, the questionnaires were co-developed in close collaboration with patients and parents and validated by them as well which assures the validity of our results. As a limitation, we have to mention the limited sample size of the pediatric EoE population and their parents.

In conclusion, we found that the most important therapeutic goals for pediatric EoE patients and parents were short-and long-term improvement in symptoms. Furthermore, there was poor agreement between pediatric patients and parents regarding therapeutic goals except for symptom improvement. Such knowledge about treatment goals of pediatric EoE patients and their parents has the potential not only to improve the therapeutic alliance between patients/parents and pediatricians but also to improve long-term outcomes.

The authors thank patients and their parents for their collaboration.

The study protocol including all related questionnaires was approved by the Local Ethics Committees (lead commission CER-VD, approval number 2017-01587). Patients and parents provided their written informed consent to participate in this study.

Thea von Graffenried has no relevant financial, professional, or personal relationships to disclose. Ekaterina Safroneeva reports (1) consulting fees from Avir Pharma, Inc., Aptalis Pharma, Inc., Celgene Corp., Novartis AG, and Regeneron Pharmaceuticals Inc.; (2) being an employee of Tillotts Pharma AG. Christian Braegger has no relevant financial, professional, or personal relationships to disclose. Jessica Ezri has no relevant financial, professional, or personal relationships to disclose. Luca Garzoni has no relevant financial, professional, or personal relationships to disclose. Alexa Giroud Rivier has no relevant financial, professional, or personal relationships to disclose. Thomas Greuter reports consulting contracts with Falk Pharma GmbH and Sanofi-Aventis and a research grant from Novartis. Henrik Köhler has no relevant financial, professional, or personal relationships to disclose. Valerie A McLin has no relevant financial, professional, or personal relationships to disclose. George Marx has no relevant financial, professional, or personal relationships to disclose. Pascal Müller has no relevant financial, professional, or personal relationships to disclose. Laetitia Marie Petit has no relevant financial, professional, or personal relationships to disclose. Susanne Schibli has no relevant financial, professional, or personal relationships to disclose. Christiane Sokollik has no relevant financial, professional, or personal relationships to disclose. Michela Tempia-Caliera has no relevant financial, professional, or personal relationships to disclose. Marcel Zwahlen has no relevant financial, professional, or personal relationships to disclose. Alain Schoepfer received consulting fees and/or speaker fees and/or research grants from Avir Pharma, Inc., Adare/Ellodi Pharmaceuticals, Inc., AstraZeneca, AG, Switzerland, Celgene Corp., Dr. Falk Pharma, GmbH, Germany, Glaxo Smith Kline, AG, Nestlé S. A., Switzerland, Novartis AG, Switzerland, Receptos, Inc., and Regeneron Pharmaceuticals, Inc. Andreas Nydegger has no relevant financial, professional, or personal relationships to disclose.

Work was supported by a grant from the Swiss National Science Foundation (32003B_204751/1 to Alain Schoepfer) and the Swiss EoE Foundation (to Alain Schoepfer).

Study concept and design – 1, acquisition of data – 2; analysis and interpretation of data – 3; drafting of the manuscript – 4; critical revision of the manuscript for important intellectual content – 5; statistical analysis – 6; obtained funding – 7; administrative, technical, or material support – 8; study supervision – 9. Thea von Graffenried: 1, 2, 3, 4, and 5; Ekaterina Safroneeva: 1, 2, 3, 4, 5, 6, 7, and 8; Christian Braegger, Jessica Ezri, Luca Garzoni, Alexa Giroud Rivier, Thomas Greuter, Henrik Köhler, Valerie McLin, George Marx, Pascal Müller, Laetitia Marie Petit, Susanne Schibli, Christiane Sokollik, and Michela Tempia-Caliera: 2, 3, and 5; Marcel Zwahlen: 1, 3, 5, 6, and 7; Alain Schoepfer: 1, 2, 3, 4, 5, 6, 7, 8, and 9; Andreas Nydegger: 1, 2, 3, 4, 5, 6, 8, and 9.

Thea von Graffenried, Ekaterina Safroneeva, Alain M. Schoepfer, and Andreas Nydegger contributed equally to this work.Edited by: H.-U. Simon, Bern.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.