See “Childhood Esophagitis Changes in 30 Years at 1 Center” by Baker et al on page 538.
At the time of diagnosis of eosinophilic esophagitis (EoE), some of the most common questions that are directed to doctors are as follows: what does “many eosinophils” mean?; is EoE secondary to something else or is it a true primary disorder?; can be our child cured? These compelling questions do not find an easy and straightforward answer, because EoE seems to be an evolving disease as a result of both epidemiological and taxonomic standpoints. In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Baker et al (1) present the experience with EoE during the past 30 years at a single center. They report that esophageal eosinophilia fluctuated over time and the most distal biopsies harbored the most density of eosinophils. Taking into account only the highest density of eosinophils or peak eosinophilic count (PEC), the prevalence of biopsies that would fulfill the criteria for EoE in 2011 varied from 11% to 15% compared with 4.3 to 12% in 2000 to 2002, and 5.3 to 9.5% in 1980 to 1988.
Looking retrospectively, the identification of EoE as an independent disease occurred following specific investigations into treatment resistant patients with gastroesophageal reflux disease (GERD). Although overlap cases are well known, the correlation of clinical and pathological findings and the establishment of diagnostic criteria may help differentiating EoE from GERD, proton pump inhibitor (PPI)–responsive EoE and other diseases associated with esophageal eosinophilia to ensure accurate management. Diagnosis is made by the presence of infiltration of the squamous epithelium (≥15 eosinophils per high-power field, HPF) and/or other microscopic features of eosinophilic inflammation; and exclusion of other disorders associated with similar clinical, histological, or endoscopic features, especially PPI-responsive esophagitis in a patient with symptoms suggestive of EoE (otherwise unexplained feeding difficulty, vomiting, dysphagia, and history of food impaction) based on consensus recommendations published first in 2007 and subsequent updates (2–5). Non-EoE diseases associated with esophageal eosinophilia include eosinophilic gastrointestinal diseases, PPI-responsive esophageal eosinophilia, celiac disease, Crohn disease, infection, hypereosinophilic syndrome, achalasia, drug hypersensitivity, vasculitis, pemphigus, connective tissue diseases, and graft-versus-host disease (GvHD) (6–8).
EoE leads to esophageal eosinophilia and future studies may target the intra- and interindividual variability. Endoscopic findings, including rings, strictures, narrowing of the lumen, linear furrows, crepe-paper mucosa, and white plaques along with histological findings, including high PEC, spongiosis (Fig. 1A), eosinophilic microabscesses, superficial layering of eosinophils (Fig. 1B), eosinophilic degranulation, and subepithelial fibrosis, are more commonly seen in subjects affected with EoE than in subjects affected with GERD (9,10). Luna staining is particularly useful in distinguishing intact and degranulated eosinophils (Fig. 1C). Angiogenesis, a feature of chronic inflammation, may be increased facilitating the recruitment of inflammatory cells and reiterating cyclically the inflammatory process (Fig. 1D) (11). From the theoretical standpoint, if a pathologist and the gastroenterologist rely solely on PEC alone, there may be more than a potential bias in overdiagnosing EoE. The introduction of errors in diagnosing new emerging conditions with evolving criteria may also occur with experienced pathologists.
It should be emphasized that EoE is a chronic inflammatory disease. Although cure of this disease may be elusive, studies such as Baker et al (1) and Prasad et al (12) are highly relevant for clinical trials. EoE is a chronic fibrostenosing disease that undoubtedly benefits from prompt recognition and therapy. Current therapy revolves around diet restriction and the use of steroids to reduce the number of intraepithelial eosinophils and improve symptom control (13,14). There is experimental and clinical evidence that eosinophils cause tissue remodeling consisting of fibrosis, angiogenesis, and smooth muscle hypertrophy with clinical consequences of strictures, decreased compliance, dysmotility, and food impactions. Elimination of esophageal eosinophils should prevent complications and histologic remission may require higher doses and additional medications that have associated risks, inconvenience, and expense. To date, there is no evidence of efficacy of therapeutic interventions actually preventing complications and, to the best of our knowledge, we do not know whether esophageal remodeling is reversible in all the patients. Immunomodulators and several antiallergic agents may be assessed as therapeutic alternatives for refractory cases or patients affected with complications.
Studies reviewing chronic diseases with diagnostic criteria changing over decades may be a challenge. Thus, limitations of such studies include their retrospective nature. Relevant clinical factors such as body mass index, history of atopy, passive exposure to cigarette smoking, or other environmental toxins cannot be easily correlated with the histopathology of the esophagus. Furthermore, time-restricted cohorts will never be the same even in the same geographic area, because of migratory flows. The number of biopsies for histological examination has only recently reached standardization suggesting that in the first decades of evaluation a limited number of biopsy specimens may have been underrepresentative of the condition. Finally, health care facilities and endoscopy procedure changes for 3 decades need also to be taken into account suggesting that a prospective evaluation during next 3 decades may be more valid than retrospective studies.
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