Abstract
Background
Gastric and duodenal mucosa may appear normal in eosinophilic gastroenteritis (EGE). Adult gastroenterologists typically biopsy only in the setting of mucosal abnormalities or symptoms, while pediatric providers biopsy all patients. The biopsy yield of EGE has not been adequately evaluated.
Aims
To evaluate the biopsy yield of EGE in a pediatric cohort and assess predictors of increased biopsy yield.
Methods
We identified patients age 0–18 who underwent upper endoscopy. We recorded endoscopic findings, pathology, demographics, and clinical and laboratory characteristics. We identified EGE cases (>20 eosinophils per high-power field on stomach and/or duodenum biopsy). We compared characteristics between EGE and non-EGE cases, calculated biopsy diagnostic yield, and performed multivariate analysis for predictors of increased biopsy yield.
Results
In 509 patients (55.6% female, mean age 10.3 years, 69.7% white, 58.7% atopic), biopsy diagnostic yield for EGE was 1.2% (6/509) among all subjects, 7.7% (3/39) for those with peripheral eosinophilia (≥500 eos/uL), 9.1% (3/33) for those with hypoalbuminemia (<3.5 g/dL), and 25.0% (3/12) for those with peripheral eosinophilia and hypoalbuminemia. The odds of EGE were 27.8 (95% CI 3.3–231.8) times greater among those with peripheral eosinophilia. The mean total biopsy surface area and number of fragments was similar between patients with and without EGE. The area under the ROC curve for blood eosinophil counts and albumin level for predicting EGE was 0.926.
Conclusions
The biopsy diagnostic yield for EGE is low but increases with peripheral eosinophilia and hypoalbuminemia. Patients with these features should have biopsies obtained, regardless of endoscopic appearance.
Keywords: Eosinophilic gastroenteritis, biopsy yield, endoscopy, hypoalbuminemia, eosinophilia, eosinophilic gastrointestinal diseases
Introduction
Eosinophilic gastroenteritis (EGE) is a chronic disease marked by varying degrees of eosinophil infiltration in the stomach and/or small intestine and accompanying symptoms of gastric and intestinal dysfunction without a secondary cause.[1–3] A relatively rare entity, EGE prevalence is estimated at 8.4/100,000 individuals.[4] The exact etiology of eosinophilic gastrointestinal diseases (EGIDs) remain unknown.[5, 3]
Because EGE presents in a non-specific manner, with commonly reported symptoms including abdominal pain, nausea, and vomiting, diagnosis can be challenging.[6–12] Some clinical features that may increase suspicion include history of atopic disease, peripheral eosinophilia, hypoalbuminemia, and elevated serum IgE level, which have been reported to be associated with EGIDs in several series.[5, 13, 8–10, 12] However, these markers alone are neither specific nor sensitive enough for reliable diagnosis, as they can be found secondary to other disorders and multiple studies have found EGE in the absence of these lab abnormalities.[3, 12]
The endoscopic appearance varies in EGE as well. Endoscopic findings may appear normal or show changes such as mucosal erythema, edema, or erosion.[13, 8, 1, 10, 3] A high degree of suspicion for an EGID is needed, as the diagnosis can be missed if biopsies are not obtained from multiple areas of the GI tract.[8, 1] Currently, it is standard to obtain gastric and duodenal biopsies on pediatric patients for a variety of indications, even in the setting of normal-appearing mucosa.[14] Conversely, adult gastroenterologists typically obtain gastric and duodenal biopsies only if mucosal abnormalities are seen or if specific symptoms suggest a diagnosis (i.e. diarrhea or malabsorption suggestive of celiac disease).[15] Moreover, substantial variation in biopsy practice patterns has been reported.[16]
We sought to evaluate the yield of gastric and duodenal biopsies for the diagnosis of EGE in a pediatric cohort in order to inform further endoscopic practice habits for both adult and pediatric gastroenterologists. We hypothesized that among EGE cases, a significant percentage of endoscopic findings would be normal. Secondary aims of this study included comparing clinical and biopsy characteristics between subjects with and without EGE and assessing clinical predictors of increased biopsy yield.
Methods
Patients and data
We conducted a retrospective cohort study at the University of North Carolina at Chapel Hill (UNC). We performed a search using endoscopic reporting software to identify all patients age 0–18 years who underwent upper endoscopy from May 1, 2018 to May 1, 2019. We obtained the following data: indication for endoscopy, exam date, age, sex, ethnicity, race, and date of birth. We excluded patients with a pre-existing eosinophilic gastrointestinal disorder (including eosinophilic esophagitis [EoE]), known inflammatory bowel disease, gastrointestinal bleeding, liver disease, or esophageal varices. We excluded patients if gastric and/or duodenal biopsies were not obtained. Then, using the electronic medical records of eligible subjects and a standardized data extraction tool, we obtained the following: endoscopic findings, upper endoscopy pathology reports (including histopathologic findings; number and size of biopsy fragments), history of atopic or allergic disorders, use of a proton pump inhibitor (PPI), peripheral eosinophil count, serum albumin, serum c-reactive protein (CRP), serum sedimentation rate, serum total IgE, clinical symptoms, and final diagnosis. For pathology reports, the tissue eosinophil count was set to zero if the number of eosinophils was not specified. For all lab values, the value obtained closest to the endoscopy exam date was recorded. We evaluated each case to determine if it met criteria for EGE, defined as ≥20 eosinophils per high-power field on stomach and/or duodenum biopsy, as per previously reported methods and a paper by Reed et al showing that a mean count of 20 eosinophils/hpf in gastric biopsies identified patients with EGIDs with high specificity.[10, 17] This study was approved by the University of North Carolina Institutional Review Board.
Statistical analysis
We calculated summary statistics for the cohort, both overall and stratified by EGE diagnosis. We used bivariate analysis to compare children with and without EGE, using t-tests for means and chi-square for proportions. We calculated the diagnostic yield of biopsies both overall and stratified by clinical characteristics. We performed multivariate logistic regression to estimate the independent effects of number of biopsy fragments, total biopsy volume, atopic history, peripheral eosinophilia (defined as ≥500 eos/microL), and serum albumin (treated as a continuous variable; g/dL) on EGE diagnosis. All odds ratios were adjusted for all the other covariates listed above. We assessed the diagnostic utility of the identified factors of interest with receiver operator characteristic (ROC) curve analysis and calculated the area under the curve (AUC) and associated sensitivities and specificities. Identified factors of interest were included as continuous variables in the logistic model underlying the ROC curve, and cutoffs that optimized sensitivity and specificity were chosen empirically without regard to what would be considered normal values. All analyses were performed using Stata/MP 16.1 (College Station, TX).
Results
Overall patient characteristics
Our cohort included 509 patients (55.6% female, mean age 10.3 years, 15.3% Black, 65.4 % White, 10.2% Hispanic/Latino ethnicity). The majority of subjects were atopic (58.6%) and 40.6% were on a proton pump inhibitor (PPI) at the time of endoscopy. The average number of biopsy fragments obtained (sum of gastric and duodenal biopsies) was 4.4 (standard deviation (SD) 1.6), and the mean biopsy volume was 49.5 mm3 (SD 43.2). Most gastric and duodenal endoscopy reports noted a normal endoscopic appearance without specific findings (92.3% and 95.9%, respectively). When present, the most common abnormal features were erythema in the stomach (3.9%) and ulceration in the duodenum (0.6%). Peak tissue eosinophil count ranged from 0 to 360 eos/HPF among the entire cohort, and from 0 to 1 eos/HPF among individuals without EGE (Table 1), though in most cases specific counts were not quantified if biopsies were read as normal.
Table 1.
Clinical and biopsy characteristics of pediatric cohort, stratified by eosinophilic gastroenteritis diagnosis
| Characteristic | Subjects with EGE† (n = 6) | Subjects without EGE† (n = 503) | p value |
|---|---|---|---|
| Age (Mean, SD) | 10.7 (7.4) | 10.3 (5.4) | 0.87 |
|
| |||
| Female sex (n, %) | 3 (50.0) | 280 (55.7) | 0.78 |
|
| |||
| Ethnicity (n, %) | 0.90 | ||
| Hispanic/Latino | 1 (16.7) | 51 (10.1) | |
| Not Hispanic/Latino | 5 (83.3) | 425 (84.5) | |
| Unknown/Missing | 0 (0) | 27 (5.4) | |
|
| |||
| Race (n, %) | 0.88 | ||
| American Indian or Alaska Native | 0 (0) | 3 (0.6) | |
| Asian | 0 (0) | 11 (2.2) | |
| Black | 2 (33.3) | 76 (15.1) | |
| Native Hawaiian or Pacific Islander | 0 (0) | 3 (0.6) | |
| White | 3 (50.0) | 330 (65.6) | |
| Other/Unknown | 1 (16.7) | 80 (15.9) | |
|
| |||
| Total biopsy volume (mm3) ‡ (mean, SD) | 49.3 (32.0) | 49.6 (43.4) | 0.99 |
|
| |||
| Total number of biopsy fragments‡ (mean, SD) | 5.4 (1.1) | 4.2 (1.6) | 0.11 |
|
| |||
| Atopy§ (n, %) | 3 (50.0) | 295/502 (58.8) | 0.67 |
|
| |||
| PPI use (at time of endoscopy) | 3 (50.0) | 203/502 (40.4) | 0.64 |
|
| |||
| Serum eosinophils (eos/microL) (mean, SD) | 1.1 (1.0) | 0.2 (0.2) | 0.00 |
|
| |||
| Serum albumin (g/dL) (mean, SD) | 3.7 (1.0) | 4.2 (0.6) | 0.04 |
|
| |||
| Serum CRP (mg/L) (mean, SD) | 1.7 (3.8) | 7.5 (29.6) | 0.66 |
|
| |||
| Serum ESR (mm/h) (mean, SD) | 11.0 (11.9) | 12.3 (16.5) | 0.87 |
|
| |||
| Serum IgE (IU/mL) (mean, SD) ¶ | N/A | 188.8 (441.6) | N/A |
|
| |||
| Gastric endoscopic report findings | |||
| Normal mucosa | 4 (66.7) | 466 (92.6) | 0.02 |
| Erythema | 2 (33.3) | 18 (3.6) | |
| Friability | 0 (0) | 1 (0.2) | |
| Edema | 0 (0) | 3 (0.6) | |
| Erosion | 0 (0) | 5 (1.0) | |
| Ulceration | 0 (0) | 4 (0.8) | |
| Nodularity | 0 (0) | 5 (1.0) | |
| Granularity | 0 (0) | 2 (0.4) | |
| Atrophy | 0 (0) | 1 (0.2) | |
| Pyloric stenosis | 0 (0) | 1 (0.2) | |
| Other †† | 1 (16.7) | 10 (2.0) | |
|
| |||
| Duodenal endoscopic report findings | |||
| Normal mucosa | 6 (100.0) | 482 (95.8) | 0.61 |
| Erythema | 0 (0) | 3 (0.6) | |
| Edema | 0 (0) | 2 (0.4) | |
| Erosion | 0 (0) | 2 (0.4) | |
| Ulceration | 0 (0) | 4 (0.8) | |
| Nodularity | 0 (0) | 2 (0.4) | |
| Atrophy | 0 (0) | 2 (0.4) | |
| Villous blunting | 0 (0) | 2 (0.4) | |
| Other†† |
0 (0) |
10 (2.0) |
|
|
| |||
| Peak tissue eosinophil count‡‡ (eos/HPF) | |||
| mean (SD) | 128.3 (133.6) | 0.0 (0.1) | 0.00 |
| range | 40–360 | 0–1 | |
defined as >20 eos/HPF on gastric and/or duodenal biopsy
sum of gastric and duodenal biopsies
defined as a history of at least one of the following: asthma, environmental allergy, food allergy, eczema, and urticaria
None of the subjected with EGE had serum IgE checked.
Other category for gastric endoscopic report includes: bilious fluid; localized mild inflammation with adherent blood; two umbilicated, submucosal lesions; gelatinous pale yellow material; fundoplication at GE junction; semi-sessile fundic gland polyp; few nodules with superficial apthae in antrum; few small <5mm polyps consistent with fundic gland polyps (reported in the subject with EGE); small amount of retained food; polyps; prolapse gastropathy. Other category for duodenum endoscopic report includes: mucosal flattening; diffuse mildly scalloped mucosa; gelatinous pale material present; nummular lesions; mucosal variance; increased vascular pattern; white specks/mucosal changes; whitish flecks; scalloped mucosa; duodenal fistula; scalloped mucosa and decreased folds.
Defined as either gastric or duodenal tissue eosinophil count, whichever was higher. One subject with EGE was not included in this calculation, as pathology report delineated “increased” for gastric and duodenal eosinophils and noted a diagnosis of EGE but did not report specific number of eosinophils. One of the EGE cases included “increased” eosinophils with a written diagnosis of eosinophilic gastroenteritis in pathology report. This case was excluded from peak tissue eosinophil count calculation.
Abbreviations: EGE = eosinophilic gastroenteritis; SD = standard deviation; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; N/A = not available
EGE patient characteristics
During the study time frame, we identified 6 patients with a new diagnosis of EGE. The majority of these subjects had normal-appearing gastric mucosa (4/6; 66.7%) and duodenal mucosa (6/6; 100%). Half of subjects with EGE were atopic (3/6) and half were on a PPI at the time of endoscopy (3/6). The mean serum eosinophil count was 1.1 eos/microL (SD 1.0) and the mean serum albumin was 3.7 g/dL (SD 1.0). The mean number of biopsy fragments obtained (sum of gastric and duodenal biopsies) was 5.4 (SD 1.1), and the mean biopsy volume was 49.3 mm3 (SD 32.0). Peak tissue eosinophil count ranged from 40 to 360 eos/HPF for EGE cases (Table 1). None of the EGE cases had an IgE level recorded.
Predictors of EGE diagnosis and biopsy yield
The biopsy diagnostic yield for EGE was 1.2% (6/509) among all subjects, 7.7% (3/39) for those with peripheral eosinophilia (≥500 eos/uL), 9.1% (3/33) for those with hypoalbuminemia (<3.5 g/dL), and 25.0% (3/12) for those with peripheral eosinophilia and hypoalbuminemia (Table 2). The odds of EGE was 32.7 (95% CI 2.5 to 426.9) times greater among those with peripheral eosinophilia. There was a numeric trend such that for each point of increasing albumin the odds of diagnosing EGE decreased by a factor of 0.4, although the confidence intervals crossed the null (OR 0.6 [95% CI 0.1 to 3.8]) (Table 3). The mean total biopsy volume and number of fragments was similar between patients with and without EGE (Table 1), and these factors did not significantly affect the odds of EGE. There was a numerical trend such that with each additional biopsy fragment obtained the odds of diagnosis increased by two, although the confidence intervals for this result crossed the null (OR 2 [95% CI 0.8 to 5.9]) (Table 3). The number of biopsy fragments ranged from 1–5 for gastric, 1–5 for duodenum, and 2–9 total for the entire study population. Among subjects with EGE, the number of biopsy fragments ranged from 2–4 for gastric, 2–4 for duodenum, and 4–7 total. The diagnostic yield was higher among subjects with 4 to 7 total biopsy fragments (ranging from 1.1 to 4.4%) than for subjects with 2–3 or 8–9 fragments (each 0%). Notably, there were only 13 subjects total in the 8–9 fragment category (Table 3). The area under the ROC curve for blood eosinophil counts and albumin level for predicting EGE was 0.926 (Figure 1). The cutoffs that optimized sensitivity and specificity were a peripheral eosinophil count of 0.3 eos/microL and an albumin of 3.6 g/dL, yielding a sensitivity of 80% and a specificity of 86%.
Table 2.
Yield of gastric and/or duodenal biopsy for diagnosing eosinophilic gastroenteritis in a pediatric cohort
| Population | Percent of subjects with EGE† (n) |
|---|---|
| All subjects | 1.2% (6/509) |
| Subjects with peripheral eosinophilia‡ | 7.7% (3/39) |
| Subjects with hypoalbuminemia§ | 9.1% (3/33) |
| Subjects with atopy¶ | 1.0% (3/298) |
| Subjects with peripheral eosinophilia and atopy | 7.4% (2/27) |
| Subjects with peripheral eosinophilia and hypoalbuminemia | 25.0% (3/12) |
| Subjects with hypoalbuminemia and atopy | 9.5% (2/21) |
| Subjects with peripheral eosinophilia, hypoalbuminemia, and atopy | 22.2% (2/9) |
| Subjects with 2 total biopsy fragments†† | 0.0% (0/43) |
| Subjects with 3 total biopsy fragments†† | 0.0% (0/87) |
| Subjects with 4 total biopsy fragments†† | 1.1% (1/89) |
| Subjects with 5 total biopsy fragments†† | 3.7% (2/54) |
| Subjects with 6 total biopsy fragments†† | 2.4% (1/41) |
| Subjects with 7 total biopsy fragments†† | 4.4% (1/23) |
| Subjects with 8 total biopsy fragments†† | 0.0% (0/10) |
| Subjects with 9 total biopsy fragments†† | 0/0% (0/3) |
defined as >20 eos/HPF on gastric and/or duodenal biopsy
defined as peripheral eosinophils ≥500 eos/microL
defined as serum albumin <3.5 g/dL
defined as a history of at least one of the following: asthma, environmental allergy, food allergy, eczema, and urticaria
defined as the sum of gastric and duodenal biopsy fragments.
Table 3.
Odds of diagnosing eosinophilic gastroenteritis on mucosal biopsy in a pediatric cohort
| Variable† | OR (95% CI) |
|---|---|
| Total number of biopsy fragments (gastric + duodenal biopsy fragments) | 2.0 (0.8 to 5.9) |
| Total biopsy volume (gastric + duodenal biopsy fragments) | 1.0 (0.9 to 1.0) |
| History of atopy | 0.6 (0.1 to 5.3) |
| Peripheral eosinophilia (≥500 eos/microL) | 32.7 (2.5 to 426.9) |
| Serum albumin (g/dL) | 0.6 (0.1 to 3.8) |
all odds ratios were adjusted for all the other covariates listed.
Figure 1.
Area under the curve for serum albumin and peripheral eosinophil count predicting eosinophilic gastroenteritis in a pediatric cohort
Discussion
Diagnosis of EGE can be challenging, as a high level of suspicion is needed to detect the condition and overall yield of routine biopsies for EGE diagnosis remains unclear. We used a large retrospective cohort to evaluate the diagnostic yield of gastric and duodenal biopsies for EGE and identified clinical predictors that increase biopsy diagnostic yield. We determined that the diagnostic yield of biopsy for EGE is low but substantially increases in the setting of peripheral eosinophilia and hypoalbuminemia. While these features were not common, when present they should prompt strong consideration of EGE. Although the cutoffs for peripheral eosinophilia and hypoalbuminemia in the ROC curve technically fall within the normal range, they are at the edge of normal and provide diagnostic utility without sacrificing sensitivity. In contrast, the number of biopsies, biopsy size, and atopic history were not associated with diagnosing EGE in our cohort.
EGE presents with a variable degree of gastric and small intestinal involvement, a broad range of symptoms, and varying appearance of the intestinal mucosa.[4, 8–10] Since the appearance and clinical characteristics of EGE are non-specific, current adult guidelines for evaluation of dyspepsia or other upper GI symptoms do not support routinely obtaining biopsies without elevated suspicion for EGE; there are not published guidelines for EGE specifically. Importantly, we found that the majority of EGE cases had normal-appearing mucosa on endoscopic report (4/6 gastric and 6/6 duodenum). This finding is in line with the Reed et al. study, which found that 47% of cases of EGE and other eosinophilic disorders (21/45) occurred in the setting of normal-appearing mucosa.[10] One pediatric cohort of eosinophilic gastritis cases found a highly variable mucosal appearance with normal gastric mucosa in three of 30 cases, and determined that gastric eosinophilia may occur in a patchy fashion.[8] Consequently, EGE cases may be missed if biopsies are only obtained when visible mucosal abnormalities are seen.
Certain clinical factors and laboratory values may increase the biopsy diagnostic yield for EGE, thus providing physicians with a prompt to biopsy. Elevations in peripheral eosinophil count, elevated IgE level, and low serum albumin are often seen in EGE cases.[13, 8, 3, 12] Ko et al found that 12/16 (75%) of pediatric patients with eosinophilic gastritis had a peripheral eosinophil count >500/mm3.[8] Among the 44 patients diagnosed with an EGID in the Reed et al. study, 42% of individuals had food allergies and 64% had a family history of atopic disease.[10] Similarly, Talley et al. determined that 50% of 40 EGE patients had a history of allergy, and Pesek et al. found an atopic history in 73% of 123 EGE subjects.[9, 11] Our results suggest that the presence of an elevated eosinophil count and/or low albumin may increase the EGE pretest probability enough to render biopsies worthwhile. We could not determine the role of IgE as a predictor, as none of the EGE cases had recorded IgE levels.
We also explored whether biopsy characteristics alter the likelihood of diagnosing EGE. Significant variability exists in biopsy practice patterns among gastroenterologists.[16] Obtaining biopsies only in the setting of abnormal mucosa may miss cases, particularly as a pediatric study showed that endoscopic appearance correlated with histologic appearance no more than two out of three times.[18] In the present study, biopsy volume and number of biopsy fragments did not significantly alter the diagnostic yield, but the number of biopsies was in a small range (4–7 among EGE cases and 2–9 among non-EGE cases). We did observe a numeric but not statistically-significant trend of increased odds of EGE diagnosis with a higher number of biopsies, and the diagnostic yield was higher among cases with 4–7 total biopsy fragments than for those with 2–3 fragments. We consider these results hypothesis-generating, and larger studies are needed to further investigate this question.
The strengths of the present study include the highly detailed and complete data obtained from endoscopy reporting software and the medical record, which allowed assessment of how laboratory and clinical characteristics modulate the diagnostic yield of biopsy. We also carefully evaluated the relationship between volume and number of biopsy fragments and EGE diagnostic yield. The study cohort was drawn from all pediatric EGE cases obtained over the course of a year, which enabled us to capture endoscopies performed for a wide variety of indications and from a diverse population in which it is standard to routinely obtain biopsies.
An important limitation of our study includes the reliance on chart review only for data collection. With this, the lack of re-review of the original biopsy slides is also a limitation but was not practical with the large numbers in our study population. It does raise the possibility however, that our EGE case rate could be an underestimate. First, the average number of biopsy fragments was a total of 4–5 combined from the stomach and duodenum. In EoE, it has been clearly shown that a larger number of biopsies are needed to optimize diagnostic sensitivity.[19–21] Second, it may be that with a dedicated read to quantify all eosinophil counts, additional patients could be found. Another limitation is that this study also includes only pediatric data, so it cannot be generalized to the adult population. Although current research suggests that EGE possesses similar characteristics in both the adult and pediatric population, it is possible that EGE in adults possesses different clinical predictors and biopsy yield.[13] However, it is not feasible to do this type of study in an adult-only population, as the current adult gastroenterology practice to biopsy only in the setting of abnormal mucosa may miss EGE cases.
In conclusion, in this large retrospective cohort study, we found an overall low rate of EGE diagnosis, as would be expected for a rare disease, despite routine gastric and duodenal biopsies in all pediatric patients undergoing upper endoscopy at our center. However, the presence of low albumin or elevated peripheral eosinophilia greatly increased the diagnostic yield. These data suggest that adult gastroenterologists should consider obtaining gastric and duodenal biopsies if a patient has elevated serum eosinophils and/or low albumin, regardless of symptoms or endoscopic appearance. While the size and number of biopsy fragments obtained did not modulate the diagnostic yield, the overall number of biopsies in our study was still relatively low. Future prospective studies could evaluate the impact of an increased number of gastric and duodenal biopsies in suspected EGE cases.
Highlights.
The biopsy diagnostic yield for eosinophilic gastroenteritis is low overall.
Peripheral eosinophilia and hypoalbuminemia increase biopsy diagnostic yield.
Patients with these features should have ample biopsies obtained during endoscopy.
Acknowledgments
Funding
This work was supported by the National Institutes of Health [T32DK007634].
Declaration of funding interests:
Erica J. Brenner, MD received funding from the National Institutes of Health, grant number T32DK007634.
Evan S. Dellon, MD, MPH reports research funding from Adare, Allakos, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos, Regeneron, Shire/Takeda, consulting fees from Abbott, Adare, Aimmune, Allakos, Amgen, Arena, AstraZeneca, Biorasi, Calypso, Celgene/Receptos, Eli Lilly, EsoCap, GSK, Gossamer Bio, Parexel, Regeneron, Robarts, Salix, Shire/Takeda, and educational grants from Allakos, Banner, Holoclara.
Footnotes
Ethical Approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Conflict of Interests
Authors’ declaration of personal interests:
Erica J. Brenner, MD has no conflicts of interest to report with this study.
Sydney B. Greenberg, MD has no conflicts of interest to report with this study.
Nicole C. Chang has no conflicts of interest to report with this study.
S. Ryanne Corder has no conflicts of interest to report with this study.
Ellen L. Cowherd, MD has no conflicts of interest to report with this study.
Evan S. Dellon, MD, MPH has no conflicts of interest to report with this study.
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Contributor Information
Erica J. Brenner, University of North Carolina Department of Pediatric Gastroenterology, Center for Gastrointestinal Biology and Disease, 333 S. Columbia St. 247 MacNider Hall, CB# 7229, Chapel Hill, NC 27599.
Sydney B. Greenberg, University of North Carolina Department of Medicine, 333 S. Columbia St. 126 MacNider Hall, CB# 7005, Chapel Hill, NC 27599.
Nicole C. Chang, University of North Carolina Center for Esophageal Diseases and Swallowing Bioinformatics Building, 130 Mason Farm Rd, CB# 7555, Chapel Hill, NC 27599
S. Ryanne Corder, University of North Carolina Center for Esophageal Diseases and Swallowing Bioinformatics Building, 130 Mason Farm Rd, CB# 7555, Chapel Hill, NC 27599.
Ellen L. Cowherd, University of North Carolina Department of Pediatrics, 333 S. Columbia St. 260 MacNider Hall, CB# 7220, Chapel Hill, NC 27599.
Evan S. Dellon, University of North Carolina Division of Gastroenterology and Hepatology, Department of Medicine, Center for Esophageal Diseases and Swallowing, Center for Gastrointestinal Biology and Disease, Bioinformatics Building, 130 Mason Farm Rd, CB# 7555, Chapel Hill, NC 27599.
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