Calies Menard-Katcher

Health-Related Quality of Life Over Time in Children With Eosinophilic Esophagitis and Their Families

Objectives: Existing treatments for pediatric eosinophilic esophagitis (EoE) effectively reduce inflammation. The impact of treatment on health-related quality of life (HRQoL) over time for pediatric patients with EoE and their families, however, has not been systematically assessed. We hypothesized that individualized multidisciplinary treatment would improve both child and family HRQoL over time, with improvements associated with decreased symptom severity. Methods: Children with EoE treated in 4 tertiary care centers were enrolled. Baseline assessments occurred at the time of patients’ first evaluation; follow-up assessments occurred at 2 and 6 months after baseline. Presence and severity of 8 EoE symptoms were measured. HRQoL was measured with the Pediatric Quality of Life Inventory parent proxy report, child self-report (CR), and Family Impact Module (FIM). Statistical analyses used mixed-effects modeling to test changes over time for child and family HRQoL. Results: Ninety-seven children were enrolled (ages 2–18 years, mean age 7.7 years ± 4.8, 78% boys, 80% white). Baseline mean symptom number was 3.5 (standard deviation 2.3), and symptom severity was 5.5 (standard deviation, 4.5). HRQoL scores were significantly related to symptom scores (P < 0.001). EoE symptom severity decreased during the study (P = 0.03). Pediatric Quality of Life Inventory parent proxy Total and FIM Total scores improved from baseline to 6 months (respectively, adjusted means 78.4 vs 81.0, P = 0.0006; 68.9 vs 70.1, P = 0.03). Interactions with baseline symptom severity revealed that subjects with lowest symptom severity showed the most improved HRQoL scores (P = 0.0013). Conclusions: HRQoL improved during the course of evaluation and treatment, with positive changes being strongest for patients with less symptom severity at baseline.

Psychosocial dysfunction in children and adolescents with eosinophilic esophagitis.

Objective: Children with eosinophilic esophagitis (EoE) experience daily challenges related to coping with symptoms and the psychosocial effect of this chronic disease. The aim of this study was to identify features of psychosocial dysfunction experienced by children with EoE who were evaluated in a tertiary care program. Methods: We performed a retrospective review of EoE patients and their families’ psychosocial evaluations performed in a tertiary care EoE program. Consecutive evaluations were analyzed to document reports of patients’ disease-related pain/discomfort; feeding/appetite symptoms; sleep, social, and school problems; depression, anxiety; and overall psychological adjustment. Results: Sixty-four patients received psychosocial evaluation during an 18-month period and were analyzed. Sixty-nine percent of children evaluated experienced some form of psychosocial problems, including social difficulties (64%), anxiety (41%), sleep difficulties (33%), depression (28%), and school problems (26%). Adjustment problems were identified in 44% of the sample. Older children experienced more adjustment difficulties than younger children (P = 0.05). Sleep disturbances and feeding problems predominated in the younger children. Anxious behavior and depressive feelings increased with age. Children with gastrostomy tubes (G-tubes) had more social, school, and psychological adjustment problems than those without. Conclusions: The majority of children with EoE who underwent health and behavior evaluation in a tertiary care program experienced psychosocial adjustment and coping problems. Evaluation and management by mental health professionals would likely benefit a majority of patients with this chronic disease.

Contribution of Esophagram to the Evaluation of Complicated Pediatric Eosinophilic Esophagitis.

Objectives: In contrast to peptic strictures, clinically significant strictures in patients with eosinophilic esophagitis (EoE) may be subtle and go unrecognized at the time of endoscopy. We aimed to identify how often stricture was identified by endoscopy as compared with contrast esophagram. Methods: We retrospectively reviewed esophagram and endoscopy examinations of all of the patients with EoE with esophageal stricture seen at a tertiary care pediatric hospital over a 6-year period who had both procedures completed within a 3-month time frame. Medical charts were reviewed for clinicopathologic information including age, duration of symptoms, histology, and treatment. Results: Twenty-two children with EoE-associated stricture completed both esophagram and endoscopic assessments. Esophageal strictures were identified by esophagram, and not endoscopy, in 55% of these children. Patients with stricture identified at esophagram alone had a shorter duration of symptoms (2.1 years duration vs 5.4 years duration, P = 0.03) than the group identified by endoscopy. Preoperative radiographic identification of a stricture was associated with dilation more often being performed. Conclusions: Esophagram is a valuable test to assess esophageal anatomy in children with complicated EoE. Esophagram may be able to detect subtle fibrostenosis earlier in the natural history of the disease than endoscopy.

Ultrastructural features of eosinophilic oesophagitis: impact of treatment on desmosomes

Aims A growing body of evidence suggests a role for altered epithelial barrier function in the pathophysiology of eosinophilic oesophagitis (EoE), but few have described the epithelial structure during inflammation. The purpose of this study was to define ultrastructural features of active, inactive EoE and control subjects oesophageal epithelia. Methods We prospectively enrolled patients undergoing diagnostic upper endoscopy for evaluation of EoE. Mucosal pinch biopsies were obtained from the distal oesophagus and processed for routine histology and electron microscopic assessment. Clinical features of enrolled subjects were analysed and subjects were divided into four groups: normal, gastroesophageal reflux disease (GERD), inactive EoE and active EoE. Representative photomicrographs of the basal and superficial epithelia were reviewed for abnormalities. Desmosomes were quantified on the surface of epithelia three to four prickle-cell layers above the basal layer. Results Twenty-nine paediatric cases (ages 2–18 years) were enrolled in the study. We observed a significant decrease in the number of desmosomes per cell (DPC) of subjects with active EoE compared with inactive EoE, GERD and normal epithelia. With respect to DPC, no significant differences were found between inactive EoE compared with GERD or normal subjects. Additional ultrastructural features observed included epithelial microplicae and evidence of eosinophil transmigration, degranulation, and sombrero formation. Conclusions Consistent with clinical and molecular findings, our ultrastructural data provide support for an altered oesophageal barrier in paediatric cases with active EoE, which may improve following treatment.

Influence of Age and Eosinophilic Esophagitis on Esophageal Distensibility in a Pediatric Cohort

Objectives:Sequelae of eosinophilic esophagitis (EoE) include food impaction and esophageal stricture. Duration of inflammation is a predicted risk factor; however, complications remain unpredictable. Studies using the functional lumen imaging probe (FLIP) have demonstrated decreased distensibility of the esophagus in adult patients with EoE. As the impact of inflammation on the developing esophagus is unknown, we investigated esophageal distensibility in a pediatric cohort to determine the effect of age, ongoing inflammation, and fibrotic features on distensibility.Methods:We conducted a prospective observational study at two tertiary pediatric institutions. Subjects underwent FLIP evaluation during endoscopy to determine distensibility of the esophagus. During stepwise distension, simultaneous intrabag pressure and 16 channels of cross-sectional areas were measured. The minimal diameter at maximal esophageal distention at an intrabag pressure of 40 mm Hg was identified. Distensibility was compared between EoE and non-EoE subjects and between clinical variables within the EoE cohort. Potential confounding variables were identified.Results:Forty-four non-EoE and 88 EoE subjects aged 3–18 years were evaluated. Age positively correlated with esophageal distensibility in the non-EoE cohort, but this trend was not observed in the EoE population. Subjects with EoE had reduced distensibility even after adjusting for age. Active inflammation (eosinophils >15 eos/high-power field), histological lamina propria fibrosis, and various features of a fibrotic phenotype (stricture, food impaction, circumferential rings on endoscopy) were associated with decreased distensibility within the EoE cohort. FLIP was safe, feasible, and well tolerated.Conclusions:These findings suggest that remodeling occurs in the pediatric EoE population, warranting early diagnosis and initiation of therapy prior to the onset of disease complications.

Dilation of Pediatric Eosinophilic Esophagitis - Adverse Events and Short Term Outcomes.

Objectives: Although several studies report on the experience with adult eosinophilic esophagitis (EoE)–related stricture, outcomes for pediatric patients with EoE–associated fibrostenosis and stricture is more limited. To address this, we aim to identify the adverse event (AE) rate and short-term outcomes of the largest reported cohort of children with EoE to undergo esophageal dilation for management of symptomatic esophageal narrowing. Methods: A retrospective assessment of all children, 18 years and younger, who underwent esophageal dilation at an academic childrens hospital during a 5-year period was conducted. Clinical, endoscopic, histologic, and outcomes of dilation were extracted from the medical record. AEs were captured within a standardized endoscopic AE database. Grade 2 AEs (requiring unanticipated medical intervention) were termed significant. Dilation-related events were compared between patients with EoE, without EoE, and those undergoing standard upper endoscopy. Results: Of the 451 total dilations, 68 dilations were performed in 40 EoE patients (mean age 13.8 years, standard deviation 3.3 years [4.6–18.9 years]). Forty-three percent (17/40) had repeat dilation during the study period. Dilation-related grade 2 AE rates in EoE and in non-EoE patients were 2.9% and 3.1%, respectively (P > 0.5). Chest pain (any grade AE) was reported in 14.7% of EoE dilations. No significant associations were found between postprocedural pain and dilation method, final dilator size, medical therapy, or esophageal eosinophilia. No perforations or significant hemorrhage were reported. Conclusions: We conclude that dilation can be performed safely in children with EoE. In the appropriate clinical setting, cautious dilation may be considered in the management of fibrostenotic EoE.

Non- and semi-invasive methods of monitoring eosinophilic esophagitis.

Background/Aims: Monitoring inflammation associated with eosinophilic esophagitis (EoE) relies on the identification of biomarkers that provide an objective measure of disease activity. To date, this metric has been the number of eosinophils in the squamous epithelial tissue. The search for alternative biomarkers as well as alternative methods to capture them has been the topic of much research. Methods: Based on clinical experience and a review of the literature, the aim of this chapter is to identify potential EoE biomarkers and methods to assess them. Results: With respect to the biomarkers, a number of candidates have arisen, including peripheral blood eosinophils, eosinophil granule proteins, Th2-related cytokines and exhaled nitric oxide. Methods to assess these biomarkers have included peripheral blood, luminal lavages and breath collections. Conclusions: Future research will identify the best clinical outcome measure for EoE. While mucosal eosinophilia currently serves as a well-defined metric of inflammation, newer research studies will continue to address whether this number correlates reliably with other patient-reported outcomes, endoscopic findings, molecular analyses or other yet to be defined biomarkers.

Updated international consensus diagnostic criteria for eosinophilic esophagitis: Proceedings of the AGREE conference

BACKGROUND & AIMS Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE to develop updated international consensus criteria for EoE diagnosis. METHODS A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries used online communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences. RESULTS Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents, and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement. CONCLUSIONS EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm2) on esophageal biopsy and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.

Mucosal inflammation, esophageal eosinophilia, and celiac disease: a little "pinch" will have to do you.

When a mucosal surface is injured, inflammatory responses ensue. These responses are characterized by the well-orchestrated accumulation of reparative leukocytes that protect and heal the mucosa during a process that often goes unrecognized. In other circumstances, genetically predisposed hosts encounter exogenous or endogenous triggers that lead to pathological inflammation, tissue damage and organ dysfunction. The gastrointestinal (GI) tract is the target site for this process in a number of diseases including inflammatory bowel diseases, celiac disease and eosinophilic esophagitis (EoE). To date, clinicians are able to directly assess the inflamed mucosal surface only with mucosal pinch biopsies. This is problematic since both clinical and laboratory based studies demonstrate inflammatory responses likely extend deeper into the tissues, outside of the grasp of the 3 mm biopsy forceps. In the case of both celiac disease and EoE, this is certainly the case as evidenced by the systemic manifestations of celiac disease and the submucosal changes observed with imaging studies and in surgical resections of EoE patients. In this light, a broader view of both of these diseases, and in fact, any GI disease characterized by mucosal inflammation is timely and necessary. The recent article by Ahmed and colleagues supports this view as they identify the difficulties in fully interpreting inflammatory patterns associated with esophageal eosinophilia and the associated clinical implications in patients with celiac disease. (1) These authors, and others, note that a high degree of confusion is emerging regarding whether esophageal eosinophilia is a representative pattern associated with celiac disease alone or celiac disease and EoE. Answers to this question are important for both scientific and clinical reasons. The scientific understanding of pathogenetic mechanisms leading to esophageal eosinophilia will lead to definition of novel therapeutic targets. From a clinical standpoint, a number of immediate questions have arisen. Does a patient need both a gluten free diet and topical steroids? Are long-term risks of the esophageal inflammation the same? Do repeat endoscopies need to be performed? Ahmed and colleagues begin to address these issues, by performing a retrospective study that characterizes two subject groups, one with celiac disease and one without, who underwent endoscopy for other clinical reasons. They then go on to determine how many subjects in each group have esophageal biopsies that are characterized by esophageal eosinophilia. When comparing pediatric subjects with well-defined celiac disease to the control group, they found that esophageal eosinophilia occurred similarly in both groups (6.5 % vs. 7.7 % celiac vs. controls). Their results are consistent with an adult study in which 4.2% of adults with celiac disease had esophageal eosinophilia. (2) Ahmed et al conclude that esophageal eosinophilia occurs without regard to the presence of celiac disease. The authors should be commended for including a control group of patients to make their comparison since this supports the conclusion that esophageal eosinophilia is not an uncommon histological finding in the general population undergoing endoscopy or in patients with celiac. It was no doubt tempting to classify their subjects as having EoE, especially in light of their overall EoE-like symptom pattern with dysphagia predominance, but they did not. We applaud them for using the term esophageal eosinophilia and by sticking to recent Consensus Recommendations in their design and analyses. In doing so, we think their results provide a much higher degree of clarity. (3, 4) In comparison, a number of previous studies reporting “EoE” and celiac disease and a recent “mini-analysis”, reported that 0.97–8.2% of patients had “EoE” and celiac disease. (5) While these reports provide similar percentages to Ahmed et al, the use of the term “EoE” is not appropriate, at least to date, since the diagnosis of EoE can only be made after other causes of esophageal eosinophilia are excluded. As they note, a prospective study to fully answer the next set of questions would require a large population of very well defined subjects. Overall, this study sets the stage to define who and why a subset of patients with celiac disease develops esophageal eosinophilia. As the finding of esophageal eosinophilia is uncovered in patients with and without symptoms referable to the esophagus, previous have determined, and upcoming studies will focus on, genetic patterns in well-defined patient populations. For instance, a number of studies provided well-defined risk alleles for celiac disease and an emerging body of evidence is beginning to do this for those with EoE. In this light, Lucendo et al examined the celiac disease HLA risk alleles in adult EoE subjects and found no association. (6) As suggested by the authors, a second tier of studies may begin to examine common inflammatory protein patterns between celiac and EoE in an attempt to link the understanding of the histological finding of esophageal eosinophilia between these diseases. One possible link may be of this could relate to interleukin-15 (IL-15) a ‘hallmark’ of celiac disease. (7) IL-15 is also increased in patients with EoE and in EoE mouse models. (8) Finally, is there commonality in exogenous triggers or epigenetics that relate to esophageal eosinophilia? As the microbiome’s role in intestinal health and disease continues to undergo definition, studies are beginning to identify microbial patterns that may initiate or perpetuate disease activity in celiac patients and IBD. (9, 10) The esophageal microbiome has been reported in “healthy” and GERD subjects but remains to be identified in EoE. (11) Comparison of microbiome diversity and load in the esophagus and duodenum in patients with EoE and celiac will certainly be of interest. So how can we practically use the results of this study and many others that are based on the limited, but realistic, assessments from a small fraction of the esophageal mucosal surface? In our opinion, the clinical evaluation of a patient with esophagitis should be based on a reasonable assessment of symptoms, and treatment should be focused on maximizing growth and development. Both evaluations and treatments should be established on best available evidence and balance risks and benefits of testing and treatments with quality of life. Most importantly, patients with esophagitis, like those defined by Ahmed et al, need to be followed over time to fully establish a diagnosis so that appropriate treatment can be provided. To date, there is limited support for the use of gluten free diet in patients with esophageal eosinophilia and celiac disease. In small case series of patients with esophageal eosinophilia and celiac disease, esophagitis responded to gluten free diet in 0 to 33% of 21 patients (12–16) Because of the limited data and potential co-morbidities and impact on quality of life of additional EoE treatments, we treat patients with celiac disease and esophageal eosinophilia with a proton pump inhibitor and gluten free diet first. Depending on the clinical response and/or the presenting symptomatology, we would then consider either additional dietary elimination or topical corticosteroids. Esophageal eosinophilia is “real” in patients with celiac disease. Ahmed et al provide evidence that this association may be incidental rather than causal. As our understanding of the pathogenesis of esophageal inflammation continues to increase, new diagnostic approaches, biomarkers and therapeutic targets will be defined that can be able to be applied to this unique group and ultimately answer the question of what “real” means, how it occurs and what to do about it.

Eosinophilic Esophagitis - Pathophysiology and its Clinical Implications

Classically, eosinophilic esophagitis is an antigen-mediated chronic disease distinct from gastroesophageal reflux disease. Eosinophilic esophagitis is an emerging clinical problem that is growing in recognition. It is characterized clinically by feeding dysfunction, dysphagia, and reflux-like symptoms. Histologically, eosinophilic esophagitis is identifiable by a dense epithelial eosinophilic infiltrate. Experimental modeling and clinical studies over the last decade have greatly improved mechanistic insights and led to improvements in clinical understanding and the assessment of therapeutic options for patients and their clinicians who manage this disease. Here, we review the clinicopathologic diagnostic criteria and our understanding of eosinophilic esophagitis as an allergic disease with genetic and immunological components. We present studies defining the importance of the epithelial barrier and the concept of barrier dysfunction as an initiating or perpetuating factor for this disease. We discuss the relationship between the symptoms of dysphagia and feeding dysfunction, our current knowledge of the underlying pathophysiologic mechanisms, and advances in clinical assessment of esophageal distensibility and narrowing in eosinophilic esophagitis patients. Finally, therapeutic implications relating to the advances that have led to our current understanding of the pathophysiology of eosinophilic esophagitis are explored.