Eosinophilic esophagitis after congenital diaphragmatic hernia

To the best of our knowledge, this is the first literature report of EoE as a follow-up complication of CDH.

The outcome of newborns with CDH has improved rapidly with recent advances in perinatal intensive care, resulting in an increasing survival [8]; however, in follow-up studies of infants born with CDH, many complications including gastrointestinal problems have been described [8]. In particular, GERD is reported in up to 62 % of CDH survivors [9]. Many factors may contribute to the pathogenesis of GERD after CDH repair. The combination of increased abdominal-intrathoracic pressure gradient, resulting from positioning the hernial contents into the abdominal cavity during the repairing procedures, and the underdevelopment of the diaphragmatic crus may increase the strain on the crus facilitating the passage of gastric contents to the esophagus [10]. Moreover, abnormality of the esophageal dimensions might also contribute to development of gastroesophageal reflux [10]. Finally, there is evidence of abnormal enteric innervation in CDH and it is likely that esophago-gastric peristalsis is abnormal [10]. The clinical presentation of CDH-associated GERD may vary, including recurrent vomiting and regurgitation, recurrent episodes of bradycardia and respiratory arrest, failure to thrive and recurrent pneumonia [11]. In adult CDH survivors, incidence of esophagitis complicating GERD is 54 %, which is significantly higher than the expected 2 % of endoscopic assessed esophagitis in the general adult population [12]. Considering these data, a long-term follow-up for GERD, including endoscopic evaluation, is mandatory in CDH survivors.

The association between GERD and EoE has been long investigated. The exact interplay between these diseases remains unclear. However, possible explanations for the interaction between EoE and GERD include three major mechanisms. The first hypothesis speculates that both diseases coexist but unrelated: GERD has a high incidence in general population, affecting approximately 20 % of adult in western countries, so unrelated coexistence is very likely. Regarding the second pathogenetic mechanism, it has been demonstrated that EoE induces esophageal remodeling with tissue fibrosis that might affect lower esophageal sphincter, favoring GERD. Moreover, eosinophils produce several substances that alter esophageal motility, causing delayed esophageal clearance of refluxed material and increasing contact time with refluxed gastric juice, thus promoting the development of GERD. Finally, as third hypothesis, it is possible that GERD contributes to or causes EoE by inducing epithelial changes that predispose to EoE. It has been demonstrated that the normally impermeable esophageal mucosa, when exposed to acid, becomes permeable for peptides up to 20 kDa. Therefore, the deeper esophageal layers may become exposed to allergens that might cause EoE. In addition, GERD may contribute to esophageal eosinophilia by inducing the expression of eosinophil chemoattractants [13].

The diagnosis of EoE is defined by multiple criteria: symptoms related to esophageal dysfunction; histologic evidence of eosinophilia limited to the esophagus (and not in other parts of the gastrointestinal tract), where finding 15 esophageal intraepithelial eosinophils per HPF is accepted as the minimum threshold for diagnosis; the disease should remit with treatments of dietary exclusion, topical corticosteroids, or both; the esophageal eosinophilia should not be responsive to proton pump inhibitor (PPI) therapy alone [2].

Because the presenting symptoms are similar, many patients are initially thought to have GERD. The main histologic characteristic of EoE is the presence of eosinophils in the esophageal mucosa and submucosa, whereas eosinophils virtually are absent in the normal esophagus. Eosinophils may also be present in other conditions, especially reflux esophagitis. Although the esophageal eosinophil count in patients with GERD seldom surpasses 7 eosinophils/HPF, in EoE they reach far higher concentrations; in the proper clinical context, a peak count of more than 15 intraepithelial eosinophils/HPF is required for the diagnosis of EoE. For a definite differentiation from reflux esophagitis, it is suggested that symptoms and histology do not improve on adequate antireflux treatment, preferably with PPIs [2].

In our report, a 2-year-old boy developed EoE as a follow-up complication of CDH repair. The case meets the definition for EoE because the number of intraepithelial eosinophils was considerably higher than 15 and because antireflux treatment was unsuccessful. As previously theorized for other congenital gastrointestinal malformations, i.e. esophageal atresia and tracheoesophageal fistula, we speculate that, in CDH patients, GERD, a well-recognized consequence of CDH, could predispose to EoE by altering the esophageal mucosal permeability to allergens and by inducing the expression of eosinophil chemoattractants. Furthermore, after CDH repair, esophageal motility disturbances may prolong the exposure to potential allergens for the already-damaged mucosa, increasing the risk of local sensitization to potential antigens.

These observations suggest the possibility of considering EoE in CDH survivors with GERD-like symptoms and dysphagia refractory to antireflux medications.

The differential diagnosis between GERD and EoE is fundamental in order to set up a targeted therapy. In particular, EoE will not respond to antireflux therapy but only to dietary exclusion, topical corticosteroids, or both; finally anedoctal cases have reported the efficacy of omalizumab in the treatment of EoE [14].