Background and Aims: Pediatric patients with cystic fibrosis (CF) and pediatric patients with eosinophilic esophagitis (EoE) both can present with feeding problems which can complicate clinical care. This study evaluated the association of eosinophilic esophagitis (EoE) and CF occurring in a single pediatric cystic fibrosis (CF) center.
Methods: Patients with EoE and CF from our center were identified from the electronic medical record and from the Cystic Fibrosis Foundation Patient Registry. Specific endoscopic and biopsy findings of EoE as well as clinical findings and treatment modalities were evaluated in these patients.
Results: Five patients with CF and EoE were identified (1.8% of all patients) over a 13-year time period. The average age at the time of EoE diagnosis was 5.9 years (range 1 to 16 years). Younger patients presented with feeding problems; older patients presented with dysphagia. All patients were treated with proton pump inhibitor therapy, and four patients received oral fluticasone therapy. Two patients received a gastrostomy for elemental formula therapy. Most patients had a documented history of food allergies.
Conclusions: EoE can occur in pediatric patients with CF, and the prevalence potentially may be higher than the general population. Patients with CF and associated feeding problems may need further evaluation for EoE.
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations of the cystic fibrosis transmembrane regulator (CFTR) which subsequently decreases chloride secretion into the luminal surface leading to thickening of secretions and impaired clearance of bacteria (Chong, et al. 2014). Eosinophilic esophagitis (EoE) is an antigen-mediated inflammatory disease associated with esophageal eosinophilic infiltration and is typically defined as histologic findings of ≥ 15 eosinophils per high power field (eos/hpf) in the esophagus ( Papadopoulou, et al. 2014). Although EoE is thought to have an allergic component, such as an association with allergen production to food and pollens, an EoE association also possibly exists with other gastrointestinal (GI) diseases, such as celiac disease (Slae, et al. 2015; Jensen, et al. 2015). Increased eosinophilic infiltration can occur in the GI tract in children with CF, such as can be seen in fibrosing colonopathy (Pawel, et al. 1997). Children with CF also have been noted to have intestinal microbiome changes which can lead to GI inflammation, although the inflammation effect in disease processes such as EoE and the effect of CFTR in relation to an immune response to foods are unclear (Bruzzese, et al. 2014; Wu, et al. 2011). In this study, we evaluated the association of EoE in patients seen at our pediatric CF center in regards to initial clinical symptoms of these patients, their endoscopic diagnosis, and their subsequent treatment of EoE.
Institutional Review Board approval for this study was obtained by both the University of Utah and Primary Children’s Hospital. This study consisted of a retrospective chart review from both the electronic medical record as well as from the Cystic Fibrosis Foundation Patient Registry of patients in our pediatric CF center (http://www.cff.org/LivingWithCF/QualityImprovement/PatientRegistryReport/). Data reviewed for analysis included current age, initial age at EoE presentation, GI symptoms at EoE presentation, presence or absence of exocrine pancreatic insufficiency, initial esophagogastroduodenoscopy (EGD) findings (both endoscopic esophageal visualization and microscopic evaluation of esophageal biopsies to determine eos/HPF), identification of food allergies, use of medical or dietary therapy, and results of last EGD esophageal biopsy results determined as eos/HPF.
The pediatric CF clinic at Primary Children’s Hospital has 280 patients. A total of 5 patients with CF were identified with EoE (1.8% of all patients with CF at our center) over a 13-year time period (2002 – 2015). Table 1 describes the clinical findings of these five patients. The patients’ current average age was 10.6 years (range 3 to 17 years) although the average age at the time of EoE diagnosis was 5.9 years (range 1 to 16 years). All patients were male, and all patients were of Caucasian ethnicity. Clinically, these patients were similar to the rest of the patients in our CF center in that the majority (four of these patients) had homozygous deltaF508 mutations. One patient had exocrine pancreatic sufficiency although the remainder had exocrine pancreatic insufficiency requiring pancreatic enzyme replacement therapy (PERT). Forced expiratory volume in 1 second (FEV1) was available for 3 patients who were old enough to perform pulmonary function testing, and the most recent FEV1 in this group was noted to be 89% of predicted value or higher. Initial GI symptoms included feeding problems (in 2 patients), early-onset satiety (in 1 patient), and dysphagia (in 2 patients). Interestingly, feeding problems were described in the younger children (13 and 16 months old) while dysphagia was described in older children (4 and 16 years old).
Upper endoscopic findings demonstrated esophagitis in 2 patients (1 with an associated esophageal stricture), esophageal furrowing in 2 patients, and a normal-appearing esophagus in 1 patient. Initial esophageal biopsy findings using hematoxylin and eosin staining demonstrated an average increased eosinophilic infiltration of 30 eos/hpf in the proximal esophagus and 35 eos/hpf in the distal esophagus. Initial biopsy results were not available on one patient who was diagnosed with eosinophilic esophagitis at an outside institution although outside clinic notes stated that esophageal biopsies demonstrated esophageal inflammation in the presence of high levels of esophageal eosinophils. The most recent esophageal biopsies in this patient group demonstrated eosinophilic infiltration of 28 eos/hpf in the proximal esophagus and 30 eos/hpf in the distal esophagus.
In terms of EoE therapy, the patients with CF who had exocrine pancreatic insufficiency were already were maintained on proton pump inhibitors (all were on omeprazole prior to endoscopy) in order to potentially improve fat absorption while on PERT (Ng, et al. 2012). The one patient with CF and pancreatic sufficiency also was treated with omeprazole as a treatment modality for EoE after the EoE diagnosis was made. The two youngest patients received omeprazole at a dose of approximately one milligram per kilogram (mg/kg) while the three older patients received omeprazole dosing between ranges of 10mg to 40mg daily. Four patients were treated with oral fluticasone, and the one patient with an esophageal stricture underwent 3 serial esophageal dilations. Two patients underwent gastrostomy placement for failure to thrive and continuing feeding problems, and both patients required elemental (L-amino acid) formula as treatment for their EoE. All patients underwent food allergy testing via allergen-specific IgE serum, skin prick, and atopy patch testing. The most common foods identified by testing included wheat and peanut, in which 3 patients each had an allergy to one of these foods. Two patients had an excellent response to targeted dietary elimination identified via allergy testing. All patients were found to have pollen allergies, and two of these patients required allergy immunotherapy. Interestingly, these same two patients also had seasonal exacerbations of their EoE clinical symptoms which improved once allergy immunotherapy was started.
Table 1: Characteristics of Patients with CF and EoE
This retrospective study demonstrates that EoE was a relatively common presentation in our pediatric CF center. EoE occurring in patients with CF previously has been described in a smaller case series that did not evaluate for prevalence of this disorder in the CF population at its medical center (Goralski, et al. 2013). EoE typically has been described as having an prevalence of 0.05% in the United States while the percentage of patients with EoE in our population with CF was much higher at 1.8%, representing a potential 36-fold increase over the general population. This finding suggests that pediatric patients with CF may be an at-risk group for EoE (Dellon, et al. 2014). Additionally, not every patient with oral aversion, poor growth, and symptoms of gastroesophageal reflux (GERD) has been evaluated for EoE in our CF center; thus, the percentage of patients with EoE could be potentially higher. Clinical symptoms of our patients with both CF and EoE matched what is described as pediatric EoE symptoms in the literature; specifically, feeding difficulties were described in our younger patients while dysphagia were described in older patients (Papadpoulou, et al. 2014).
It is unclear why patients with CF also can have EoE. Children with CF have prolonged acid clearance compared to controls, and GERD can aggravate underlying EoE (Woodsey, et al. 2014; Dellon, et al. 2014). Although intestinal microbiome changes associated with GI inflammation have been described in children with CF, the effect of such microbiome changes are unknown in children with both CF and EoE (Bruzzese, et al. 2014). The potential role of chronic antibiotic use and PERT introduction in relation to the microbiome of infants with CF and EoE also are unknown. Finally, EoE may be more common in regions of higher latitudes in the United States which is where many of our referral patients are located (Li, et al. 2014; Berni, et al. 2015).
Nutrition is a priority in children with CF as good nutritional status is associated with improved pulmonary outcomes (Ally, et al. 2015). Additionally, feeding problems are common in children with CF although the etiology is unclear (Ramirez, et al. 2015; Ward, et al. 2009). Feeding problems, including dysphagia, also are common presenting symptoms in children with EoE and are often an indicator of increased esophaphageal disease activity (Laing, et al. 2010; Martin, et al. 2015). Thus, a child with CF and a feeding problem may have associated EoE and should warrant further clinical evaluation.
This study was retrospective study and only a small number of patients with CF and EoE were identified. Additionally, we recognize that there was the potential of surveillance bias in this patient group as these patients were seen frequently in our pediatric CF center. Regardless, the percentage of EoE patients in our CF pediatric population was considerably higher than the prevalence of EoE in the United States population and may warrant a multi-center study (Dellon, et al. 2014). Thus, two potential future research possibilities exist based on the study findings. First, the Cystic Fibrosis Foundation Patient Registry might be utilized at other pediatric CF centers to determine if EoE is an associated disease risk in patients with CF throughout the United States. Additionally, further attention should be paid to those pediatric CF patients with persistent feeding problems to determine if they, in actuality, have concomitant EoE or other GI diseases, such as celiac disease which also has been described in children with CF (Pohl, et al. 2011; Walkowiak, et al. 2010). Research is needed to determine if certain clinical phenotypes of feeding problems in children with CF exist which can predict EoE.
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Author Disclosure: Catherine McDonald PhD RD has served on the speakers’ bureau for the North American Center for Continuing Medical Education. John F. Pohl MD has received the following funding: INSPPIRE to Study Acute Recurrent and Chronic Pancreatitis is Children, Grant # 10987759, National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases and serves on the speakers’ bureau of Medical Education Resources, Inc. The remaining authors have no other financial relationships to disclose and no conflicts of interest to report. This study was approved as University of Utah IRB Study Approval: IRB_00080560.
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