High-resolution EUS in children with eosinophilic “allergic” esophagitis

doi:10.1067/mge.2003.33

Gastrointestinal Endoscopy

Volume 57, Issue 1, January 2003, Pages 30-36

Presented in part at the American Society for Gastrointestinal Endoscopy Symposium for Pediatric Endoscopy, Digestive Disease Week, May 21-24, 2000, San Diego, California, and at the World Congress for Pediatric Gastroenterology, Hepatology, and Nutrition, August 5-9, 2000, Boston, Massachusetts (Gastrointest Endosc 2000;51:AB133, J Pediatr Gastroenterol Nutr 2000;31:AB1118).

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Abstract

Background: The pathophysiology of dysphagia associated with eosinophilic esophagitis is unknown. This study investigated possible anatomic alterations in children with eosinophilic esophagitis in comparison with healthy children by using high-resolution EUS to precisely measure individual tissue layers of the esophagus. Methods: Children with eosinophilic esophagitis (n = 11) and control children (n = 8) without esophagitis were prospectively evaluated by high-resolution EUS with a 20-MHz catheter US probe during an endoscopic examination. Real-time measurements of the distal esophagus were obtained including the thickness of the total wall, combined mucosa and submucosa, muscularis propria, and circular muscle. Results: Statistically significant differences were found between patients with eosinophilic esophagitis and control patients for mean values for thickness of the total wall (respectively, 2.8 vs. 2.1 mm; p = 0.004), combined mucosa and submucosa (respectively, 1.6 vs. 1.1 mm; p = 0.001), and muscularis propria (respectively, 1.2 vs. 1.0 mm; p = 0.043). Mean values for circular muscle did not differ between patient groups. Conclusion: High-resolution EUS reveals significant expansion of the esophageal wall and individual tissue layers including the combined mucosa and submucosa, and muscularis propria in children with eosinophilic esophagitis compared with healthy control patients. (Gastrointest Endosc 2003;57:30-6.)

Section snippets

Patients

Children with EE and control children without esophagitis were prospectively enrolled for study after obtaining informed consent under a human studies protocol approved by the institutional review board of our hospital. Control patients were selected from children undergoing diagnostic endoscopy for clinical indications with no gross or histologic evidence of esophagitis. Patients were assigned the diagnosis of EE if they met all of the following criteria: (1) Grossly abnormal endoscopic

Results

A total of 19 children were enrolled (Tables 1 and 2): 11 with EE (9 boys, 2 girls; mean age 9.5 years, range 3.4-18.2 years) and 8 control children (6 boys, 2 girls; mean age 9.3 years, range 2.0-15.3 years)(mean age, p = 0.869).

. Patients with eosinophilic esophagitis

Patient No.	Age (y)	Gender	Clinical symptom	Total wall	Mucosa + submucosa	Muscularis propria	Circular muscle
Empty Cell	Empty Cell	Empty Cell	Empty Cell	Mean sonographic layer thickness (mm)
1	11.8	M	Impaction	4.2	2.2	2.0	ND
2	18.2	M	Impaction	3.6	2.0	1.4	0.7
3	4.1	F	Dysphagia/vomiting	2.6	1.4	1.2	0.5
4	8.9	M

Discussion

EE is increasingly recognized as an uncommon but not rare disease of childhood that was previously mistaken for gastroesophageal reflux disease. It is a distinct clinicopathologic disorder.1, 9 Although most frequently described in children, EE has also been reported in adults.10, 11 Studies in pediatric patients1, 12, 13, 14 show a striking male predominance, as noted in the present study. There is evidence of atopy in 60% to 80% of patients, which manifests as asthma, eczema, food

Acknowledgements

The authors are indebted to Lisa Heard, RN, Clinical Coordinator and Kate Donovan, Special Projects Assistant in the Children's Hospital Endoscopy Unit for their invaluable assistance with this study, Dr. Athos Bousvaros and Dr. Leslie Higuchi for contributing patients, Dr. Jacques Van Dam for initial instruction in the technique of GI endosonography, and Dr. John Saltzman for helpful comments and suggestions.

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The gastrointestinal system is a hollow organ affected by fibrostenotic diseases that cause volumetric compromise of the lumen via smooth muscle hypertrophy and fibrosis. Many of the driving mechanisms remain unclear. Yes-associated protein-1 (YAP) is a critical mechanosensory transcriptional regulator that mediates cell hypertrophy in response to elevated extracellular rigidity. In the type 2 inflammatory disorder, eosinophilic esophagitis (EoE), phospholamban (PLN) can induce smooth muscle cell hypertrophy. We used EoE as a disease model for understanding a mechanistic pathway in which PLN and YAP interact in response to rigid extracellular substrate to induce smooth muscle cell hypertrophy. PLN-induced YAP nuclear sequestration in a feed-forward loop caused increased cell size in response to a rigid substrate. This mechanism of rigidity sensing may have previously unappreciated clinical implications for PLN-expressing hollow systems such as the esophagus and heart.
Endoscopic Ultrasound Can Measure Esophageal Remodeling in Eosinophilic Esophagitis
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Although esophageal widening is a normal consequence of growth in pediatric individuals, esophageal remodeling plays a major role in the morbidity of pediatric and adult eosinophilic esophagitis (EoE). However, the disease is defined by esophageal dysfunction and mucosal eosinophilia. One potential explanation is the difficulty in quantitating remodeling.
This prospective, IRB-approved longitudinal study evaluated endoscopic ultrasound (EUS) in 78 children, adolescents, and young adults referred to a single academic medical center for esophageal indications. Patients with proven EoE had serial EUS exams that measured total wall thickness (TWT) and esophageal wall sublayers during routine endoscopies to manage their disease. Student t tests and mixed linear models were employed to compare groups.
TWTs from the distal (2.3 ± 0.5 vs 1.7 ± 0.3, P < .01) and mid esophagus (2.1 ± 0.5 vs 1.6 ± 0.3, P < .05) were increased in active EoE patients > 10 years of age compared with similarly aged controls. After achieving clinical and histologic remission, their TWTs were significantly decreased (distal: 1.9 ± 0.4 vs 2.3 ± 0.5, P < .05; mid: 1.7 ± 0.4 vs 2.1 ± 0.5, P < .05). Mixed linear models further demonstrated that during active EoE, TWTs, esophageal muscle layers, and the mucosa and submucosa were thickened in older adolescents at both sites (P < .05 for each). In remission, TWTs returned to control values.
This pilot study demonstrates that EUS, a unique application of point-of-care ultrasound, can identify the esophageal remodeling that occurs in older adolescents with active EoE. Furthermore, EUS has defined this remodeling as a transmural phenomenon that occurs in the mid and distal esophagus and can completely reverse with adequate treatment.
Endoscopy in Pediatric Eosinophilic Esophagitis
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Very early onset eosinophilic esophagitis is common, responds to standard therapy, and demonstrates enrichment for CAPN14 genetic variants
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Eosinophilic esophagitis (EoE) is a chronic, food antigen–mediated disease characterized by esophageal dysfunction and intraepithelial eosinophil accumulation.
We hypothesized that very early onset EoE (V-EoE) would be enriched for early-life and genetic factors and have worse presentation and prognosis than later-onset pediatric EoE (L-EoE).
We conducted a single-site, retrospective review comparing patients diagnosed at age 12 months or less (V-EoE, n = 57) and age 14 to 18 years (L-EoE, n = 70). These patients underwent medical record, EoE Histology Scoring System, Endoscopic Reference Score, and EoE Diagnostic Panel assessment when sample availability permitted. Genetic association used 2 EoE genotype repositories. Data were analyzed using chi-square tests, t tests, Wilcoxon rank-sum tests, Spearman correlations, cluster analysis, and logistic regression.
Among pediatric patients with EoE, diagnosis most commonly occurred within early life (0-24 months, 17%). V-EoE was more likely to attain histologic remission via dietary restriction (P < .0001). Basal zone hyperplasia and eosinophil inflammation were greater in V-EoE (P < .05). Esophageal strictures more commonly occurred in L-EoE (P = .03). V-EoE had lower endoscopic scores (P < .05). Molecular expression was very similar between groups. Cesarean delivery was more common in patients with V-EoE (P = .03). Patients with V-EoE demonstrated enrichment of CAPN14 common genetic variants.
Early-life diagnosis of EoE is a common occurrence. V-EoE responds to standard therapy without early evidence for complications, suggesting a less severe prognosis than hypothesized. Molecular pathogenesis is preserved between V-EoE and L-EoE. Cesarean delivery and CAPN14 genetic variation likely promote earlier disease development.

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^☆: Reprint requests: Victor L. Fox, MD, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.

^☆☆: 0016-5107/2003/$30.00 + 0

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Original ArticlesHigh-resolution EUS in children with eosinophilic “allergic” esophagitis☆,☆☆

Abstract

Section snippets

Patients

Results

Discussion

Acknowledgements

Gastroenterology

Gastrointest Endosc

Gastroenterology

Gastroenterology

Gastrointest Endosc

Gastrointest Endosc Clin N Am

Gastroenterology

Am J Gastroenterol

J Clin Immunol

Gastrointest Endosc

Gastrointest Endosc

Gastrointest Endosc

Gastroenterology

Gastrointest Endosc

Original Articles
High-resolution EUS in children with eosinophilic “allergic” esophagitis☆,☆☆