Mental distress among adult patients with eosinophilic esophagitis

ABSTRACT Rationale Data on the prevalence of mental distress among adult eosinophilic esophagitis (EoE) patients are scarce. Also, a significant gap remains in the understanding of which determinants are related to significant psychological symptoms and whether distressed patients require and receive mental care. Methods Adult EoE patients were invited to complete standardized measures on anxiety/depressive symptoms (HADS) and general psychopathology (SCL‐90‐R). All scores were compared to general population norms. Socio‐demographic and clinical factors were assessed. Results In total, 147 adult EoE patients (61% males, age 43 (IQR 29–52) years were included (response rate 71%). No difference with general population values was found for total anxiety and depressive symptoms (7.8 ± 6.6 vs. 8.4 ± 6.3; p = 0.31). A total of 38/147(26%) patients reported high levels of anxiety and/or depressive symptoms (HADS‐A ≥ 8: 35/147(24%) and HADS‐D ≥ 8: 14/147(10%)), indicative of a possible psychiatric disorder. In a multivariate analysis, age between 18–35 years was independently associated with high levels of anxiety (HADS‐A ≥ 8) (OR 3.0, 95% CI 1.3–6.9; p = 0.01). The SCL‐90‐R Global Severity Index (GSI) was significantly higher compared to the general population (p < 0.001). Significant signs of general mental distress (GSI ≥ 80th percentile) were observed in 51(36%) EoE patients, of which 29(57%) patients denied having any mental problems and only 8(16%) patients received mental care. Conclusion A considerable proportion of adult EoE patients suffers from mental distress, with a 3‐fold risk of significant anxiety in those patients younger than 35 years. Therefore, population‐based studies are required and a proactive approach in the screening for and treatment of these psychological symptoms in EoE practice seems essential.


| INTRODUC TI ON
EoE is a chronic immune-mediated disorder of the esophagus triggered by food allergens, with an Worldwide increasing prevalence with rates almost comparable to inflammatory bowel disease (IBD). 1,2 EoE is characterized by mucosal eosinophilic infiltration and subsequent esophageal dysfunction, which manifests in symptoms of dysphagia for solid foods and food impaction. 3 EoE affects all ages (3:1 male-to-female ratio), with a peak incidence between the ages of 20 and 40 years. 1 At present, the management of EoE involves targeting the esophageal eosinophilic inflammation with drugs or elimination of food allergens. EoE is associated with a substantial disease burden that affects patients' health-related quality-of-life (HRQOL), healthcare systems, and society in general. 4 Multiple aspects such as disturbing symptoms of dysphagia and food impaction and the need for life-long treatment are associated with impaired HRQOL. [5][6][7] A recent medical record review observed a prevalence of psychiatric health comorbidities in almost one-third of EoE patients, in which older age, female gender, and longer symptom duration were found to be associated with the presence of a mental health disorder. 8 Current research has mainly focused on increased risk of developing anxiety and depressive symptoms, measured within the construct of disease specific HRQOL (EoE-QOL-A). 7,9,10 This validated measure consists of 5 domains that evaluates important disease-related topics (e.g., issues related to having a chronic disease or swallowing anxiety) and has been widely used in the EoE-research field. 4,10,11 Still a significant gap remains in our understanding of the impact on mental health and its determinants in this chronic disease and if distressed EoE patients receive mental treatment. Notwithstanding, insufficient treatment of psychiatric comorbidities in patients with a chronic physical illness (e.g., IBD and rheumatoid arthritis) has been associated with more severe symptoms and disease flares, therapeutic non-adherence, and subsequent increased healthcare costs. [12][13][14] However, provision of sufficient mental care in adult EoE patients first requires more insights into the presence of mental distress and its determinants (e.g., clinical and demographic factors). Therefore, we aimed to evaluate in this study: (a) the presence of mental distress among adult EoE patients, (b) the degree to which clinical and socio-demographic factors are related to significant levels of mental distress, and (c) if EoE patients with severe symptoms of general mental distress receive mental care.

| Study design and population
An observational cross-sectional study design was used to assess mental distress among adult EoE patients. Consecutive patients from our EoE cohort (i.e., patients who attended the outpatient clinical of the Amsterdam UMC Motility Center between 2011 and 2020) were invited to participate in this study between July 2019 and February 2020 (i.e., recruitment period). An informed consent letter including self-reported questionnaires was sent to the EoE cohort and distributed at the outpatient clinic during this recruitment period.
Patients with a documented diagnosis of EoE according to the consensus guidelines (i.e., ≥15 eosinophils per high-power-field), aged 18 and over, with a sufficient command of written Dutch to complete a self-reported survey were considered eligible for inclusion. 3 Once consented, all patients completed a paper or digital version of the questionnaires. All data were safely collected and stored by using the Electronic Data Capture Castor. A flowchart of patient inclusion and participation rate is presented in Figure 1.

| Socio-demographics and clinical outcomes
A self-designed (standard fixed choice) questionnaire was used to elicit details concerning socio-demographic and clinical information.
Socio-demographic variables, such as gender and education level (low: primary or secondary school and high: College or University) and specific information on the year of symptom onset and diagnosis of EoE, history of endoscopic interventions and previous dilations, EoE treatment (medical or dietary treatment) and concomitant atopic diseases, were included. In addition, patients were asked if they felt to have current mental health problems and whether they received mental care. Clinical symptoms of dysphagia and food impaction (i.e., clinical disease activity) were evaluated by means of the Straumann Dysphagia Instrument (SDI). 15 Severe clinical disease activity was defined as current symptoms of daily dysphagia and food impaction.

| Anxiety and depression
Anxiety and depressive symptoms were measured with the standardized and validated Hospital Anxiety and Depression Scale (HADS). This 14-item self-assessment scale was developed to screen for depression and anxiety symptoms (recall period of 7-days). The

Key Points
• A significant gap remains in our understanding of the impact on mental health and its determinants in adult EoE patients.
• A considerable proportion of adult EoE patients suffers from mental distress, with a compelling 3-fold risk of significant anxiety during young adulthood (18-35 years).
• A proactive approach in the screening for and treatment of mental health disorders should therefore become an integral part of the medical care of EoE patients.
HADS consists of 7 anxiety and 7 depression items, of which the total scores ranges from 0 (no complaints) to 21 (maximum complaints). A score of ≥8 on either subscales signifies a symptom severity indicative for a possible anxiety and/or depressive disorder. 16 Anxiety and depression symptom scores of all EoE patients were compared to a subgroup of 199 patients, which was derived from 3492 respondents of the general Dutch population. 17

| General mental distress
Symptoms of general mental distress were evaluated by means of the validated Symptom Checklist-90-Revised (SCL-90-R). This questionnaire consists of 90-items to assess for general self-reported psychological symptoms over the past 7 days. The SCL-90-R-items represent 8 domains, including agoraphobia, anxiety, depression, somatization, sensitivity, insufficiency of thinking and acting, hostility and sleep disturbance. 18 Each item is rated on a 5-point scale of distress, ranging from 1 (none) to 5 (extreme). The total SCL-90-R score (Global Severity Index (GSI)) is calculated by substitution of all subdomain scores and ranges from 0 to 450, with higher scores indicative for mental distress. SCL-90-R-scores of our EoE sample were compared to a reference cohort of 2368 respondents (norm group II) of the Dutch general population. 19 In addition, cut-off scores were used to identify patients with severe symptoms of general mental distress, indicated as GSI scores of "above normal" and "high" (corresponding to the 80th percentile of the norm group II), that are clinically relevant and may be indicative of a mental disorder. 19   given an unique study-ID to ensure anonymity.
Atopic constitution was observed in 119 (81%) patients. The median disease duration in our cohort was 3 (IQR 1-6) years, with 49 (33%) patients diagnosed within the prior year. Diagnostic delay, measured as time interval between first reported EoE symptoms and year of diagnosis, was 5 (IQR 2-14) years. In total, 21 (14%) patients had prior esophageal dilation and multiple endoscopic interventions with food bolus extraction were reported in 62 (42%) patients (Table 1).

| Anxiety and depressive symptoms
Evaluation of anxiety and/or depressive symptoms (HADS) showed no difference in the total HADS score in our EoE sample compared to the general population (7.8 ± 6.6 vs. 8.4 ± 6.3; p = 0.31) ( Figure 2).   the only independent factor associated with high levels of anxiety (odds ratio (OR) 3.0, 95% confidence interval (CI) 1.3-6.9; p = 0.01 (Table 2).

| General mental distress
The general psychopathological profile of EoE patients was evalu-   Figure 3B).
Severe symptoms of general mental distress, indicated as GSI scores of "above normal" and "high" (corresponding to the 80 th per-   (Table   S1). Additionally, SCL-90-R-subscales agoraphobia, anxiety, depression, somatization, sensitivity, insufficiency of thinking and acting, hostility and sleep disturbance all showed a significant positive correlation with the total SDI score (all; p < 0.05). (Table S1). (41-60 years), 22 it is certain that young adults diagnosed with EoE are more at risk for the development of significant signs of anxiety.

| DISCUSS ION
Overall, females showed significantly higher levels of mental distress compared to males in our EoE sample. This finding is consistent with previous literature reports on female predominance of common mental disorders in the general population. 23,24 For that reason, it seems notable that the proportion of males and females with significant signs of anxiety on both PRO measures (HADS-A ≥ 8 and SCL-90-anxiety ≥80 th percentile) were equally distributed in our EoE sample. Since men are more prone of stricture development with consecutive risk of increased symptom severity, 25 one could argue that male EoE patients are more exposed to potential anxiety triggers such as impaction with need for upper endoscopy and food bolus dislodgement. This is supported by previous findings on the serious impact of dysphagia and food impaction on patients' fear, and identification of increased symptom severity as predictor of both disease and chocking anxiety. 7,10 Although severe clinical disease activity was not independently associated with high levels of anxiety in our multivariate analysis, SDI scores significantly correlated with scores of the HADS-A and SCL-90-anxiety (Table S1).
Compared to the general population, a greater severity of mental distress in EoE patients was observed, with a substantial proportion of patients (36%) with severe symptom levels (GSI ≥80 th percentile) in our sample. Nevertheless, these results should be interpreted with caution, since the SCL-90-R is not corrected for somatic disorders. 18 In addition, the HADS anxiety and depression scores were not higher compared to the general population, whereas the SCL-90-R-subscales anxiety and depression were significantly higher in  (Table S1). Generally, there is a moderate association between symptoms and biological disease activity (esophageal inflammation) in non-dilated EoE patients. 26,27 We hypothesize that somatization of esophageal symptoms (e.g., dysphagia) in severe distressed EoE patients may help to explain additional variation in symptom severity, once variation in biological disease activity has already been taken into consideration. In IBD-patients, association between somatization and clinically active disease with absence of mucosal inflammation, was suggested to be secondary to somatoform-type behavior or a coexisting functional disease instead of being related to biological disease activity (i.e., mucosal inflammation or extraintestinal manifestations of IBD). 28 The concept of this so-called somatoform-type behavior might also play a role in EoE; the absence of . Each dimension presents the percentage of EoE patients exceeding the norm scores indicated as "above normal" and "high" (≥80th percentile norm group II). 16  Health Organization (WHO) studied the consultation process for mental health reasons, in which the preference for self-management (i.e., managing one's self) has been indicated as main barrier for not seeking mental treatment, even though need for mental care was perceived. [35][36][37] In addition, especially young-and middle-aged patients are more likely to recognize need for treatment but experience more structural barriers to treatment seeking, such as negative attitude toward help seeking, financial problems, and time barriers. 38 Therefore, also a proactive approach toward (unmet) needs for mental care could be suggested for clinical practice.
Several limitations of our study merit attention. First, including patients from a tertiary center is known for limiting the generalizability of outcomes. However, as we included patients from our In conclusion, we observed a substantial presence of mental distress among adult EoE patients, with a compelling 3-fold risk of significant signs of anxiety during young adulthood (18-35 years