Abstract
Background:
Children with aerodigestive dysfunction often undergo triple endoscopy (flexible bronchoscopy, rigid direct laryngoscopy and bronchoscopy, and esophagogastroduodenoscopy) for diagnostic evaluation as well as screening prior to airway reconstruction. Prevalence and risk factors for eosinophilic esophagitis (EoE) in this population are poorly understood.
Methods:
A retrospective chart review was performed for pediatric patients, aged 0–21 years, who received a triple endoscopy with biopsy from January 1, 2015, to December 31, 2019, at the Children’s Hospital at Montefiore (CHAM). Bivariate and multivariable analyses were used to compare the baseline characteristics between patients with and without EoE to assess for potential predictors of EoE.
Results:
Of the 119 cases included in the analysis, 16.0% (19) received a histopathologic diagnosis of EoE following triple endoscopy. Patients with EoE were more likely to have a family history of eczema (p = 0.02) and a dairy-free diet (p = 0.02). Age, sex, history of environmental allergies, and recency of initiating oral diet were not significantly associated with increased odds of an EoE diagnosis.
Conclusions:
A family history of eczema and a diet lacking allergenic foods, such as milk, may be associated with an increased risk of a future diagnosis of EoE in patients with aerodigestive dysfunction. Larger, multi-institutional studies are needed to identify early predictors of EoE.
Keywords: esophagitis, eosinophilic, disease early detection, atopic hypersensitivity, food allergy, hypersensitivities, food, endoscopy
Introduction:
Eosinophilic esophagitis (EoE) is diagnosed in 2.3 to 90.7 per 100,000 children, predominantly among white males.1,2,3 Presenting symptoms include chronic cough (up to 50%), dysphagia, abdominal pain, or feeding disorders.2,3 Among children with EoE, 10 to 18% initially present to an otolaryngologist, rather than a gastroenterologist. These patients are typically younger than those who first present to gastroenterologists (3 versus 10 years old, respectively).4–6 Previous studies have reported that between 3 to 6% of children with aerodigestive symptoms refractory to medical management who undergo a triple endoscopy are found to have EoE.3,7,8 A prior study has also shown that older children, aged 6 to 12 years, and African American children with EoE undergo less frequent endoscopy compared with both younger and White patients, respectively.9
Previously reported data has outlined conditions associated with EoE, including allergic rhinitis, rhinosinusitis, asthma, eczema, reflux, food or environmental allergies, and history of esophageal food impaction.2,6,10,11
In pediatric aerodigestive centers of excellence, the indications for triple endoscopy include chronic cough, recurrent croup, and screening prior to laryngotracheal reconstruction (LTR). Untreated or uncontrolled EoE has been associated with airway reconstruction complications such as graft failure or restenosis.12 Furthermore, there is evidence that a preoperative multidisciplinary workup is associated with increased rates of tracheostomy decannulation and resolution of symptoms in pediatric patients who underwent LTR. This suggests that there is a positive impact of such evaluations on perioperative outcomes.13 Universal preoperative screening with triple endoscopy for all patients undergoing LTR has therefore become commonplace at many aerodigestive centers.10 Nevertheless, triple endoscopy is resource-intensive, and factors associated with a higher likelihood of an EoE diagnosis in children undergoing these procedures are understudied.
In our institution, we observed that several children who underwent screening with triple endoscopy prior to LTR had histopathologic evidence of EoE in the absence of typical EoE symptoms. Some of these medically complex children were also slowly advancing their diet to include items such as wheat and dairy products. They were often simultaneously undergoing ventilator weaning as preparation for airway reconstruction. These observations suggested that the prevalence and risk factors for histopathologic findings of EoE among pediatric aerodigestive patients warranted further study. Therefore, we sought to characterize preoperative risk factors associated with the histopathologic diagnosis of EoE among children undergoing triple endoscopy at our institution’s pediatric aerodigestive center. We hypothesized that, in our aerodigestive population at Montefiore Medical Center, the histopathologic diagnosis of eosinophilic esophagitis (EoE) would be associated with factors such as age, sex, feeding method, recent dietary changes, a personal and family history of atopy, and the indication for endoscopy.
Methods:
This study was approved by the Albert Einstein College of Medicine Institutional Review Board (IRB# 2019-10994). A retrospective chart review was performed for all pediatric patients, aged 0–21 years, who received a triple endoscopy (flexible bronchoscopy, rigid direct laryngoscopy and bronchoscopy, and esophagoscopy with biopsy) from January 1, 2015, to December 31, 2019, at the Children’s Hospital at Montefiore (CHAM).
Data were extracted from the electronic medical record using the current procedural terminology (CPT) billing codes for flexible esophagoscopy with biopsy (43202), bronchoscopy (31622, 31624), tracheobronchoscopy (31615), direct laryngoscopy (31515, 31520, 31525, 31526), laryngotracheal reconstruction (31580, 31551, 31552, 31553, 31554, 31584, 31587), as well as the ICD-10 code for the diagnosis of EoE (K20.0). This was also cross-referenced with our institution’s pediatric gastroenterology procedure database (maintained in the Provation version 5.0.470.22 (Minneapolis, MN) system). Inclusion criteria included elective endoscopy. Exclusion criteria included emergency endoscopy for foreign body removal and hemoptysis.
132 charts were identified. Of those, 13 charts were excluded from analysis: 9 were excluded due to alternate indications for triple endoscopy (such as for a foreign body), and 4 were excluded due to the triple endoscopy being performed at an outside hospital. In total, 119 charts were included for analysis.
Histopathologic diagnosis of eosinophilic esophagitis (EoE) was the outcome of interest, defined as the presence of ≥ 15 intraepithelial eosinophils per high-power field (eos/hpf) in either the mid or distal esophagus. Patient variables included: age, sex, race, allergic history, history and severity of asthma, family history of eczema, family history of atopy, initiation of oral diet within 6 months of the procedure, diet including gluten, diet including dairy, presence of tracheostomy, and history of tracheostomy. A diet including dairy was inclusive of hydrolyzed and unhydrolyzed cow’s milk formula.
Statistical analysis was conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Bivariate analysis was used to compare the baseline characteristics between patients with and without EoE (the outcome of interest). Age and variables with an alpha ≤ 0.1 on bivariate analysis were selected for potential inclusion in the multivariable logistic regression model with an alpha ≤ 0.05 to account for the sample size of this study.
Results:
Among the 119 patients who underwent triple endoscopy at our institution’s pediatric aerodigestive center from 2015–2019, 19 (16.0%) were found to have histopathologic evidence of EoE (Table 1). Of all participants, 76 (63.9%) were male, 7 (5.9%) were white, 56 (47.1%) were Hispanic, 32 (26.9%) were non-Hispanic black, and 24 (20.2%) were of unknown race. The median age was 3.7 years at the time of triple endoscopy (Table 1).
Table 1.
Demographic and clinical characteristics (N = 119)
| EoE(N=19) | No EoE (N=100) | p-value | |
|---|---|---|---|
|
| |||
| Age, median (IQR) | 4.3 (2.6–7.9) | 3.6 (2.0–6.4) | 0.50 |
|
| |||
| Male, n (%) | 14 (73.7) | 62 (62.0) | 0.33 |
|
| |||
| Race, n (%) | |||
| Non-Hispanic White | 0 (0) | 7 (7.0) | |
| Non-Hispanic Black | 6 (31.6) | 26 (26.0) | 0.47 |
| Hispanic | 11 (57.9) | 45 (45.0) | |
| Other | 2 (10.5) | 22 (22.0) | |
|
| |||
| History of environmental allergies, n (%) | |||
| Yes | 12 (63.2) | 39 (39.8) | 0.06 |
|
| |||
| History of asthma, n (%) | |||
| Yes | 13 (68.4) | 67 (67.7) | 0.95 |
|
| |||
| Rating of asthma, n (%) | |||
| Mild | 9 (69.2) | 31 (55.4) | 0.71 |
| Moderate | 4 (30.8) | 20 (35.7) | |
| Severe | 0 (0) | 5 (8.9) | |
|
| |||
| Family history of eczema, n (%) | |||
| Yes | 11 (57.9) | 26 (26.0) | 0.006 |
|
| |||
| Family history of atopy, n (%) | |||
| Yes | 10 (52.6) | 48 (48.0) | 0.71 |
|
| |||
| Started PO within last 6 months, n (%) | |||
| Yes | 5 (26.3) | 13 (13.1) | 0.17 |
|
| |||
| Diet includes gluten, n (%) | |||
| Yes | 14 (73.7) | 74 (75.5) | 1 |
|
| |||
| Diet includes diary, n (%) | |||
| Yes | 11 (57.9) | 76 (77.5) | 0.09 |
|
| |||
| Tracheostomy at time of endoscopy, n (%) | |||
| Yes | 7 (38.9) | 21 (21.4) | 0.14 |
IQR = Interquartile Range. EoE: eosinophilic esophagitis.
The most common indications for triple endoscopy included upper airway obstruction, dysphagia, and recurrent croup (Table 2). Most cases of dysphagia identified were of an unspecified nature. Tracheal and glottic stenosis were the most common sites of airway obstruction (41.4% and 37.9%, respectively, Table 2).
Table 2.
Indications for Triple Endoscopy in Pediatric Aerodigestive Population
| Indication, n (%) | Whole sample (N=119) | EoE (N=19) |
|---|---|---|
|
| ||
| Uncontrolled/persistent asthma | 9 (7.6) | 1 (5.3) |
| Chronic cough | 12 (10.1) | 3 (15.8) |
| Recurrent pneumonia | 13 (10.9) | 0 |
| Recurrent croup | 18 (15.1) | 2 (10.5) |
| Dysphagia | 28 (23.5) | 4 (21.1) |
| TEF | 4 (14.8) | 1 (25.0) |
| Vascular Ring | 1 (3.7) | 0 |
| Hematemesis | 3 (11.1) | 0 |
| Unspecified | 19 (70.4) | 3 (75.0) |
| GERD | 5 (4.2) | 0 |
| Airway Stenosis | 29 (24.4) | 9 (47.4) |
| Glottic stenosis | 12 (41.4) | 2 (22.2) |
| Subglottic stenosis | 1 (3.5) | 3 (33.3) |
| Tracheal stenosis | 11 (37.9) | 4 (44.4) |
| Multi-level stenosis | 5 (17.2) | 0 |
| Hemoptysis | 3 (2.5) | |
| Failure to thrive | 1 (0.8) | 0 |
| ALTE/ BRUE | 1 (0.8) | 0 |
| 0 | ||
EoE: eosinophilic esophagitis. TEF: tracheoesophageal fistula. GERD: gastroesophageal reflux disease. ALTE: acute life-threatening event. BRUE: brief resolved unexplained event.
On bivariate analysis of patients with EoE versus those without EoE (Table 1), family history of eczema was most strongly associated with a diagnosis of EoE (p=0.01). History of environmental allergies (p=0.06) and diet inclusive of dairy (p=0.09) were also associated with a diagnosis of EoE. Age, gender, race, history and severity of asthma, family history of atopy, start of a PO diet within the last 6 months, diet inclusive of gluten, and tracheostomy at the time of triple endoscopy were not associated with EoE diagnosis.
Age, history of environmental allergies, family history of eczema, and diet inclusion of dairy were included in the multivariable logistic regression model (Table 3). In the multivariable analysis, a family history of eczema (OR 4.02, p = 0.006) was positively associated with an EoE diagnosis, while diet containing dairy (OR 0.26, p = 0.02) was inversely associated with an EoE diagnosis. Age (OR 1.02, p = 0.73) and history of environmental allergies (OR 2.20, p = 0.17) were not significantly associated with an EoE diagnosis.
Table 3.
Multivariable Analysis: Odds of Histopathologic Diagnosis of Eosinophilic Esophagitis Among Children Undergoing Triple Endoscopy
| Variable | Odds Ratio (95% CI) | p-value |
|---|---|---|
| Age at time of procedure (years) | 1.02 (0.91–1.15) | 0.73 |
| History of environmental allergies | 2.20 (0.72–6.72) | 0.17 |
| Family history of eczema | 4.02 (1.3–12.49) | 0.02 |
| Diet includes dairy | 0.26 (0.08–0.81) | 0.02 |
Discussion:
This study aimed to identify preoperative risk factors associated with EoE diagnosis in children presenting to an urban pediatric aerodigestive center. This study found that a family history of eczema and a diet excluding dairy are preoperative risk factors for EoE while further demonstrating the benefits of triple endoscopy screening in aerodigestive centers. Other risk factors, such as a personal history of environmental allergies and age at the time of triple endoscopy, were not significantly associated with a diagnosis of EoE on multivariable analysis. Understanding early risk factors of EoE can prompt physicians to recommend triple endoscopy screenings in such patients.
Atopy-associated conditions such as eczema and food allergies have been shown in previous studies to be correlated with EoE.4,14,15 The finding that a diet containing dairy was inversely associated with a diagnosis of EoE may seem counterintuitive to the well-established association between food allergy and EoE. One explanation for this finding may be that patients were placed on a dairy-free diet prior to triple endoscopy. These patients may have had worsening of symptoms, especially gastrointestinal symptoms of dysphagia, after consuming dairy; observant parents and/or healthcare providers may have initiated a dairy-free diet prior to triple endoscopy.
The most common indications for triple endoscopy in this study were upper airway obstruction, nonspecific dysphagia, and recurrent croup. The majority of patients reviewed had a combination of airway and gastrointestinal (GI) symptoms similar to previous studies also showing an aerodigestive presentation of EoE.3,16 The patient population in our study has a higher prevalence of EoE at 16.0%, compared to other studies with less than 6% in similar patient populations that have refractory airway and/or GI symptoms.3,16 Our patient population in the Bronx, NY has a high prevalence of asthma, especially among Hispanic and non-Hispanic black children of low-income families, associated with inner-city pollution and inadequate access to healthcare.17 Given these significant social risk factors, asthma and EoE may be grossly underdiagnosed in children in the Bronx. Due to the variety of symptoms in EoE presentation, the time to diagnosis is often delayed by years due to lack of clinical suspicion for EoE. 6
This study is limited due to its retrospective nature. Pathologists reviewing biopsy samples were not blinded to the patient’s clinical history. Slides were also re-reviewed following diagnosis, which may have minorly altered the incidence rate of EoE in our patients. Future directions include prospective and multi-institutional studies to determine predictors of EoE in pediatric aerodigestive populations, and to help guide clinical care, advancement of oral diet, and shared decision-making with patients and families prior to triple endoscopy in this complex population.
Conclusion:
This study sought to identify predictive factors of EoE in pediatric patients undergoing triple endoscopy procedures within an urban pediatric aerodigestive program via a retrospective study. A family history of eczema and a diet excluding dairy were found to be statistically significant preoperative risk factors for EoE diagnosis. Further studies are required to determine predictors of EoE in pediatric aerodigestive populations and guide selection for endoscopy procedures.
Acknowledgments:
We would like to acknowledge Christina Shin, BA, Nick Yu, BS, and Sharan J. Shah, MD for their contribution to data collection and Jianyou Liu, MS; Juan Lin, PhD for statistical collaboration.
Footnotes
Presented at the Society for Ear, Nose, and Throat Advances in Children (SENTAC), December 1-3, 2022, Philadelphia, PA.
Disclosures: Dr. Loizides is the Medical Director of Clinical Development at Albireo Pharma. This company’s work is in rare liver disease and is not associated with eosinophilic esophagitis (EoE) or any of the symptoms/signs or conditions described in this manuscript.
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