INTRODUCTION

Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease in children and adults characterized by inflammation of the esophageal mucosa and symptoms of dysphagia, chest pain, heartburn, and food impaction and is one of the most common conditions diagnosed during assessment of feeding problems in children (1). The incidence of EoE has increased dramatically over the previous 3 decades, and EoE is the most common of the eosinophilic gastrointestinal (GI) diseases (2,3). Despite the increase in incidence, the disease remains poorly understood, with much of the research focused on identifying and expanding therapeutic alternatives for disease treatment. Treatments include proton pump inhibitors, swallowed topical steroids, empiric and targeted dietary elimination approaches, and more recently, as of 2022, for children and adults 12 years of age or older, dupilumab (4). In the absence of noninvasive methods of disease monitoring and limited treatment options, patients undergo serial endoscopies to evaluate treatment response and disease progression. While studies have been conducted to evaluate the financial burden of repeat endoscopies, clinic visits, and medications for the treatment of EoE, the psychosocial burden of EoE and other patient-associated and disease-associated factors on the pediatric populations has had limited description (5–13). We sought to increase understanding of this burden by evaluating the psychosocial comorbidities of disordered sleep, anxiety, and somatization in a pediatric population with EoE. We further characterized the psychosocial burden in relation to patient demographic characteristics, disease-associated clinical factors and symptom burden, neurodevelopmental comorbidities, and measures of resilience, hypothesizing that both patient-associated and disease-associated factors would contribute to psychosocial comorbidities.

METHODS Participant selection

Study participants were recruited during routine visits in the pediatric Eosinophilic Gastrointestinal Disorders clinic at Rady Children's Hospital, San Diego/University of California, San Diego between May 2019 and April 2021. The study was approved by the University of California, San Diego Institutional Review Board (Protocol 190374). Of the 105 patients approached, 7 (7%) declined to participate. All study participants provided written informed consent/assent. Our goal was to enroll 100 patients (50 patients aged 8–11 years and 50 patients aged 12–18 years). Patients were approached based on the flow of the clinic and the availability of the study coordinator. We excluded patients being seen for their initial visit and those with significant developmental delays that would have precluded them from completing the surveys. Of the 98 participants enrolled, 1 was excluded because of not having completed any of the surveys, and 10 were further excluded because of concurrent GI diseases such as inflammatory bowel or celiac disease, leaving 87 participants in the study. Participants who completed the study met the criteria of having been diagnosed with EoE per consensus guidelines (≥15 eosinophils per high-power field [eos/hpf] and symptoms consistent with esophageal dysfunction and exclusion of other causes of eosinophilia) (6).

Data collection

Patients (aged 8–18 years) enrolled in the study and completed validated assessments during a routine clinic visit, including EoE symptoms (Pediatric Eosinophilic Esophagitis Symptom Score version 2.0 [PEESSv2.0]), quality of life (Pediatric Quality of LIfe- Eosinophilic Esophagitis [PedsQL-EoE]), anxiety state and trait (State-Trait Anxiety Score for Children), somatization (Child Somatic Symptoms Inventory 24 [CSSI-24]), and sleep disordered breathing (Pediatric Sleep Questionnaire [PSQ]). Resilience measures (Connor Davidson Resilience Scale [CD-RISC]) were added to the protocol following study initiation and with the CD-RISC-10 completed by a subset of participants aged 12 years or older (n = 36). The PEESSSv2.0 assesses symptom burden in EoE. It includes 20 items with a maximum score of 100, with higher scores indicative of higher burden. The PedsQL-EoE was developed specifically for the assessment of quality of life among children diagnosed with EoE (14,15). It includes 33 items, with a total score of 100 for overall quality of life and a score of up to 100 for the domains of Worry, Communication, Treatment, Food Eating, Food Feelings, and Symptoms (I and II). Higher scores on the PedsQL-EoE are indicative of better health-related quality of life. The State-Trait Anxiety Score for Children assesses both State (transitory anxiety states) and Trait (anxiety proneness) anxiety and includes 20 items with a maximum possible score of 60 in each subscale and with higher scores indicative of higher anxiety (16). The CSSI-24 is a 24-item instrument assessing somatic symptoms with a maximum possible score of 96 (17). Higher scores on the CSSI-24 indicate higher somatization. The Sleep-Related Breathing Disorder Scale within the PSQ consists of 22 closed-response questions extracted from the PSQ and a total possible score of 1.0, with scores greater than 0.33 considered suggestive of high risk of a pediatric sleep-related breathing disorder (18). The CD-RISC-10 is a 10-item instrument used in children aged 12 years or older and was introduced at the study midpoint to support secondary analyses of potential protective factors for psychosocial comorbidity (19). The maximum possible score of the CD-RISC-10 is 40, with higher scores indicating higher resilience.

Age, sex, insurance status (private vs public), history of physician-diagnosed neurodevelopmental comorbidities (attention deficit hyperactivity disorder [ADHD] or autism), disease duration since diagnosis, number of encounters in the emergency department for food bolus impactions, number of endoscopies performed, time since most recent endoscopy, and endoscopic and histologic observations including disease activity state at the most recent endoscopy were all abstracted from the electronic health record (EHR). Participant sex was obtained by self-report from a patient-administered questionnaire and documented in the EHR. Participant body mass index from the associated clinic visit was also obtained from the EHR. Subject's disease activity status was determined using the endoscopy closest to the date of their completed surveys and grouped as endoscopies that took place less than 90 days, between 90 and 180 days, and greater than 180 days (approximately 6 months) from participation in the study. Those having <15 eos/hpf were considered to have “inactive” EoE. The EoE Endoscopic Reference Score (EREFS) (20) was calculated from review of endoscopy reporting in the patient electronic health record. Study questionnaire responses and clinical features were entered and managed in the REDcap electronic data capture platform hosted by the Altman Clinical Trial and Research Institute (ACTRI) at the University of California at San Diego (UCSD) (21,22).

Statistical analyses

We first examined the distribution of participant demographic and clinical factors in relation to EoE symptom severity scores and resilience and evaluated differences in symptom severity and resilience in relation to these factors. Next, we assessed demographic, clinical, and disease-associated factors and participant neurodevelopmental comorbidities in relation to quality of life, disordered sleep, state and trait anxiety, and somatization. We compared the total assessment score for disordered sleep, somatization, and quality of life and subscores for state and trait anxiety according to demographic, clinical, and disease-associated factors. Assessment of differences in distribution of scores according to demographic and clinical factors was performed using 1-way tests of analysis of variance. Next, using crude and adjusted linear regression models, adjusted for disease duration since diagnosis, we evaluated whether EoE symptom severity scores, obtained from the PEESSv2.0 assessment, were associated with less favorable scores for quality of life, sleep, somatization, and both state and trait anxiety. In a secondary analysis, using crude and adjusted linear regression models, we examined the association between EoE symptom burden and the individual domains of Worry, Communication, Treatment, Food Eating, Food Feelings, and Symptoms. Furthermore, noting that disease duration may influence assessment results, we examined disease duration as a continuous measure. We also examined the number of treatments in relation to assessment score change, specifically examining treatments according to none, 1, or multiple treatments and examining none or multiple in relation to assessment score. Finally, in an additional secondary analysis, and among the subset of participants completing the CD-RISC assessment, using crude and adjusted linear regression models, we assessed whether higher resilience was associated with more favorable quality of life, sleep, somatization, and anxiety scores. Adjusted models accounted for duration of disease since diagnosis.

RESULTS Primary analyses

Participants were at a mean (SD) age of 12.8 (3.1) years, and 26% (n = 23) were female. Most subjects (n = 71; 82%) had been diagnosed with EoE at least 12 months earlier, and most of them (n = 52; 60%) were being treated with more than 1 treatment approach (including proton pump inhibitors, topical corticosteroids, and/or dietary elimination strategies). One-third (n = 29; 34%) of participants had undergone 7 or more esophagogastroduodenoscopy procedures, and nearly one-third (n = 27; 33%) had experienced a GI-related emergency department visit. Half (n = 44; 50%) had ≥15 eosinophils per high-power field on the biopsy most closely temporally associated with study participation (Table 1). Two-thirds (n = 58) of participants had private insurance and the remaining third (n = 29) had public insurance. Of the 87 participants, 3 had been diagnosed with autism and 10 with ADHD; thus, 14% had been diagnosed with a neurodevelopmental comorbidity (n = 1 participant had been diagnosed with both autism and ADHD).

Table 1. - Demographic and clinical characteristics in relation to EoE symptom severity n (%) PEESSv2.0 (n = 85), mean (SD) P Overall 87 20.8 (15.7) — Sex  Male 64 (74) 20.3 (16.1) 0.57  Female 23 (26) 22.3 (15.6) Age  15–18 27 (31) 21.0 (17.2) 0.80  12–14 26 (30) 19.1 (12.7)  8–11 34 (39) 21.8 (16.7) Insurance  Private 58 (67) 22.0 (15.1) 0.30  Public 29 (33) 18.3 (16.7) BMI  ≤5th percentile 5 (6) 20.8 (24.4) 0.40  Percentile 6–94 72 (84) 21.4 (14.2)  Percentile ≥95 9 (11) 13.4 (22.1) Neurodevelopmental comorbiditya  No 75 (86) 20.5 (15.7) 0.68  Yes 12 (14) 22.5 (16.1) History of anaphylaxis  No 52 (60) 19.2 (15.6) 0.26  Yes 35 (40) 23.1 (15.7) Disease duration  6–12 mo 16 (18) 28.5 (14.6) 0.03  >12 mo 71 (82) 19.1 (15.5) Current treatmentb  None 12 (14) 32.6 (7.9) 0.78  PPI 10 (12) 32.1 (10.6)  TCS 5 (6) 30.4 (8.2)  Dietary elimination 8 (9) 28.0 (4.4)  Multipleb 52 (60) 31.3 (7.9) No. of EGDs  1–3 29 (34) 26.1 (13.7) 0.09  4–6 28 (33) 17.6 (16.2)  7+ 29 (34) 18.8 (16.4) GI-related ED visits  No 60 (69) 20.6 (15.0) 0.90  Yes 27 (31) 21.1 (17.3) Days since previous EGD  <90 69 (79) 21.0 (15.4) 0.33  90–180 10 (12) 14.9 (13.7)  180+ 8 (9) 25.6 (20.0) Active EoE (eos/hpf ≥15)  No 43 (49) 21.0 (14.8) 0.87  Yes 44 (51) 20.5 (16.7) EREFSc  0–1 52 (60) 19.1 (13.7) 0.24  2–8 35 (40) 23.2 (18.2)

ADHD, attention deficit hyperactivity disorder; BMI, body mass index; ED, emergency department; EGD, esophagogastroduodenoscopy; EoE, eosinophilic esophagitis; eos/hpf, eosinophils per high-power field; EREFS, EoE Endoscopic Reference Score; GI, gastrointestinal; IQR, interquartile range; PEESSv2.0, Pediatric Eosinophilic Esophagitis Symptom Score version 2.0; PPI, proton pump inhibitor; TCS, topical corticosteroids.

aIncludes n = 3 autism spectrum disorder and n = 10 ADHD.

bIncludes PPI, TCS, dietary elimination, prednisone.

cEREFS ranged between 0 and 6, with a median (IQR) score of 1 (0–2).

When examining EoE symptom severity in relation to participant demographic and clinical features, no differences in symptom burden were observed across any factors, except for disease duration. Participants with shorter disease duration, defined as 6–12 months since diagnosis, experienced higher symptom burden (P = 0.03) as indexed by their PEESSv2.0 score (Table 1).

Relative to those with private insurance, participants with public insurance had less favorable scores for sleep disordered breathing (P = 0.01). No other participant demographic factors examined were associated with differences in distribution of scores. When examining participant clinical factors in relation to somatization, state and trait anxiety, and quality of life, participants with neurodevelopmental comorbidities had significantly higher scores for somatic symptoms and trait anxiety and lower quality-of-life scores when compared with those without these comorbidities (P < 0.01 for all). They also had higher scores for sleep disordered breathing (P < 0.01). In addition, participants with shorter duration of disease since diagnosis had higher somatic symptoms (P < 0.01) and trait anxiety (P < 0.01) scores compared with those with longer disease duration (>12 months). Higher somatic symptom scores (P < 0.01) and state (P = 0.02) and trait (P = 0.03) anxiety scores were observed for those participants with fewer (1–3) EGDs. The median EREFS in this study sample was 1 (0–2). Participants with EREFS above the median experienced a less favorable EoE-PedsQoL score when compared with those below the median (scores 0–1) (P = 0.01). No other differences in score distribution was observed for any other clinical factors (Table 2).

Table 2. - Distribution of somatization, anxiety, disordered sleep, and quality-of-life scores according to participant demographic and clinical factors n (%) CSSI-24 (n = 85), mean (SD) P STAI-C state (n = 87), mean (SD) P STAI-C trait (n = 87), mean (SD) P PSQ (n = 87), mean (SD) P EoE-PedsQL (n = 86), mean (SD) P Overall 87 11.6 (9.4) — 29.6 (6.0) — 31.2 (8.1) — 0.24 (0.15) — 80.5 (13.8) — Sex  Male 64 (74) 11.2 (8.9) 0.54 29.6 (5.9) 0.99 31.0 (8.0) 0.64 0.24 (0.15) 0.86 76.9 (15.9) 0.15  Female 23 (26) 12.7 (11.0) 29.6 (6.6) 31.9 (8.5) 0.23 (0.14) 81.8 (12.9) Age, yr  15–18 27 (31) 13.8 (12.9) 0.33 30.6 (6.1) 0.12 33.3 (10.1) 0.25 0.22 (0.15) 0.10 80.2 (14.8) 0.31  12–14 26 (30) 10.1 (6.4) 30.8 (5.6) 30.8 (7.4) 0.20 (0.14) 83.7 (9.2)  8–11 34 (39) 11.0 (7.9) 27.9 (6.1) 29.9 (6.6) 0.28 (0.15) 78.1 (15.8) Insurance  Private 58 (67) 12.1 (9.9) 0.44 30.1 (5.7) 0.26 31.9 (8.5) 0.27 0.21 (0.14) 0.01 81.7 (12.6) 0.23  Public 29 (33) 10.5 (8.5) 28.6 (6.6) 29.9 (7.0) 0.30 (0.16) 77.9 (16.0) BMI  ≤5th percentile 5 (6) 12.6 (15.2) 0.12 30.4 (1.1) 0.94 34.4 (3.3) 0.18 0.18 (0.1) 0.56 80.9 (21.3) 0.95  Percentile 6–94 72 (84) 12.0 (9.1) 29.5 (6.2) 31.3 (7.6) 0.24 (0.15) 80.7 (12.6)  Percentile ≥95 9 (11) 5.0 (4.3) 29.3 (6.6) 27.0 (9.9) 0.27 (0.17) 82.2 (16.5) Neurodevelopmental comorbiditya  No 75 (86) 10.5 (8.3) <0.01 29.3 (5.9) 0.29 30.3 (7.4) <0.01 0.22 (0.15) <0.01 82.0 (13.7) <0.01  Yes 12 (14) 18.5 (13.3) 31.3 (6.6) 36.8 (9.9) 0.37 (0.10) 70.8 (10.9) History of anaphylaxis  No 52 (60) 11.7 (9.4) 0.93 30.1 (5.8) 0.39 32.0 (8.9) 0.30 0.23 (0.16) 0.85 80.6 (15.0) 0.93  Yes 35 (40) 11.5 (9.7) 28.9 (6.4) 30.1 (6.6) 0.24 (0.14) 80.3 (12.3) Disease duration  6–12 mo 16 (18) 17.6 (10.2) <0.01 32.0 (7.9) 0.08 36.3 (10.5) <0.01 0.25 (0.15) 0.44 74.2 (14.4) 0.08  >12 mo 71 (82) 10.3 (8.8) 29.1 (5.5) 30.1 (7.0) 0.21 (0.15) 81.7 (13.5) Current treatmentb  None 12 (14) 15.0 (11.6) 0.55 30.2 (6.3) 0.73 32.6 (9.2) 0.78 0.30 (0.16) 0.39 74.6 (21.2) 0.41  PPI 10 (12) 14.0 (9.4) 30.8 (6.0) 32.1 (10.6) 0.21 (0.15) 81.8 (15.9)  TCS 5 (6) 7.8 (8.9) 26.2 (4.0) 30.4 (8.2) 0.16 (0.14) 88.6 (7.7)  Dietary elimination 8 (9) 11.8 (11.9) 29.8 (3.7) 28.0 (4.4) 0.26 (0.12) 80.2 (15.3)  Multipleb 52 (60) 10.8 (11.6) 29.5 (6.5) 31.3 (1.9) 0.24 (0.15) 80.8 (11.4) No. of EGDs  1–3 29 (34) 16.7 (9.7) <0.01 32.0 (7.2) 0.02 34.2 (9.1) 0.03 0.23 (0.13) 0.15 76.4 (14.4) 0.08  4–6 28 (33) 6.1 (5.3) 27.6 (3.7) 28.6 (6.8) 0.20 (0.15) 84.7 (12.6)  7+ 29 (34) 11.8 (9.8) 28.9 (6.0) 30.9 (7.5) 0.28 (0.16) 80.4 (13.9) GI-related ED visits  No 60 (69) 11.6 (8.5) 0.99 30.2 (6.6) 0.21 31.5 (8.0) 0.72 0.24 (0.14) 0.76 80.3 (12.8) 0.87  Yes 27 (31) 11.6 (11.5) 28.4 (4.5) 30.8 (8.3) 0.23 (0.17) 80.8 (16.2) Days since previous EGD  <90 69 (79) 11.8 (9.3) 0.16 29.6 (6.0) 0.26 31.6 (8.5) 0.26 0.25 (0.15) 0.34 80.8 (13.7) 0.14  90–180 10 (12) 6.8 (4.3) 27.7 (3.7) 27.4 (4.5) 0.18 (0.14) 84.9 (8.2)  180+ 8 (9) 15.4 (13.5) 32.4 (8.4)