Eosinophilic esophagitis (EE) is characterized by infiltration of the esophagus with eosinophils without infiltration in other parts of the gastrointestinal tract (1). EE has become increasingly prevalent based on studies in the United States, Switzerland, and Australia (2). We have seen a 35-fold increase from 2 cases in 1994 to 72 cases in 2003 at The Children's Hospital of Philadelphia (3). Gill et al (4) also found an increase in prevalence in their 10-year study of patients in rural West Virginia. Previous studies also have found a male predominance, with a majority of the patients being atopic, ranging from 33% to 70% in different studies (3,5–8). The symptoms of EE have been described as symptoms suggestive of gastroesophageal reflux, which do not respond to gastroesophageal reflux disease (GERD) medications. Other symptoms of EE include dysphagia in older children and failure to thrive in infants (1,7,9–12). The natural history is unknown, but several studies suggest potential progression of untreated disease. Noel et al (7) in a retrospective study of age versus chief complaint found feeding difficulties in the youngest children (median age 2.0 years), vomiting in older children (median age 8.1 years), abdominal pain in the young adolescents (median age 12.0 years), and dysphagia (mean age 13.4 years) and food impaction (median age 16.8 years) in the older adolescents. One possible analysis of this retrospective data is a gradual progression and potential worsening of symptoms from feeding difficulties in infants to strictures and food impaction in teenagers as a natural history of untreated disease. An alternative explanation is that there are different phenotypes. In the adult population, Straumann et al (13) found no remission in disease in their 11-year follow-up of 30 adults. Similarly, Assa'ad et al (14) also described a chronic course in a collection of 87 patients for up to 8 years. They found 19 patients had continuing disease, 30 patients had relapsing disease, and 8 patients resolved after 1 year of follow-up. Interestingly, they found that up to 63% of their patients also had eosinophils in the colon, suggesting involvement or spreading of eosinophilia to other parts of the gastrointestinal tract in their set of patients. We describe our natural history of more than 600 patients. In this cohort, we saw <10% of the patients develop improvement of their EE and no patient had progression of eosinophilia to other parts of the gastrointestinal tract.
PATIENTS AND METHODS
Diagnosis of EE
The diagnosis of EE was made in patients who had at least 1 of the following symptoms: failure to thrive, vomiting, regurgitation, abdominal pain, food impaction, or dysphagia unresponsive to a 2-month therapeutic trial of proton pump inhibitors (PPIs). To confirm the diagnosis, patients underwent esophagogastroduodenoscopy (EGD) with biopsies obtained from the proximal, mid, and distal esophagus, stomach, and duodenum. In some follow-up EGDs of long-established patients, patients had biopsies from only the esophagus. Additionally, patients also underwent colonoscopies if clinically warranted. The biopsies were evaluated under ×40 high-powered microscopic field (HPF) and reviewed by a board-certified pathologist. EE was diagnosed if patients had greater than 20 eosinophils in the most densely involved HPF in the esophagus with normal stomach and duodenal biopsies (1). Repeat biopsies were routinely obtained 6 to 8 weeks after elimination of specific foods and after other therapeutic treatments including the use of swallowed steroids. Year of diagnosis was based on the first positive biopsy showing greater than 20 eosinophils/HPF in the esophagus after treatment with PPI. Initial symptoms were classified into failure to thrive and feeding difficulties, vomiting and GERD symptoms, abdominal pain, dysphagia, and food impaction.
All of the clinical data, including demographics, ethnicity, sex, presenting symptoms, age of diagnosis, and skin and patch test results, were collected in a food allergy database. The data were collected by retrospective and prospective chart review.
Food allergies were identified by a combination of immunoglobulin (Ig)E and non-IgE testing. Skin testing is used to identify IgE-mediated reactions, which account for approximately 40% of the reactions. Patch testing or atopy patch testing examines delayed, non–IgE-mediated reactions. Therefore, food allergens were determined by prick skin testing and patch testing as previously described (15–17). Briefly, skin prick testing was performed by a puncture of purified commercial allergen preparation (Greer Laboratories, Lenoir, NC) on the forearm with a bifurcated needle (Allergy Labs of Ohio, Columbus) by pricking through a drop of the extract, which was then absorbed. Reactions were recorded by measuring the largest diameter of the wheal and flare in millimeters at 15 minutes. Testing was considered positive if the wheal was 3 mm greater than the negative control.
Atopy patch tests were conducted using 1 g of dry foods per 1 mL of isotonic saline solution for soy infant formula, dried egg white, wheat, oat, barley, rye, rice flour, corn meal, and dehydrated potatoes. Three grams of powdered skim milk was mixed with 1 mL of isotonic saline solution for the milk patch testing. The mixtures were placed in Finn chambers on Scanpore (Allerderm Laboratories, Petaluma, CA) and adhered to the patient's back based on the methods of Isolauri (15,17–21). Single ingredient commercially prepared baby food—including fruits, vegetables, and meats—were placed in Finn chambers undiluted. The patches were removed at 48 hours and results were read at 72 hours. Reactions considered positive were classified similarly to the European Task Force for Atopy Patch Testing in Atopic Dermatitis method, with vesicles considered a sign of a positive test (22).
The diagnoses of asthma, allergic rhinitis, and atopic dermatitis were based on physician diagnosis and International Classification of Diseases-9 coding, which identified the initial diagnosis. Findings were confirmed by physician diagnosis of the patient. Our data collection was approved by The Children's Hospital of Philadelphia Institutional Review Board.
We initially identified 620 patients in our database of all of the patients who presented to our Center for Pediatric Eosinophilic Disorders. Of the patients, 562 had confirmed EE after treatment for 2 months with a PPI and treatment of allergic conditions. Additionally, we identified 24 cases of eosinophilic gastroenteritis with eosinophilia located in the esophagus, gastric antrum, and other intestinal locations. The remaining 58 cases of esophageal eosinophilia resolved after treatment with PPI or did not have greater than 20 eosinophils per HPF in the esophagus and therefore did not meet criteria for EE. Additionally, we identified 330 patients with a minimum of follow-up of at least 1 year, with the longest follow-up being more than 14 years, who were further examined for the clinical course of this chronic disorder.
We have found an increase in the annual diagnosis of EE similar to previous studies (3,4,7). It is an extension of our previous results that showed a yearly increase from 1993 to 2004 (3), and now a total of 124 cases in 2006 (Fig. 1). Given that data were collected at a regional and national referral center, a concern is that some of the increase may have stemmed from an increase in referral population. However, the local population in greater Philadelphia has been stable during the last 13 years (23) and our increase in nonlocal patients cannot account for the rise in total patients, because the rise in patients diagnosed with EE also occurred in our local population area (Fig. 1). The patients diagnosed in 2007 were not included because the calendar year is incomplete. Similar to multiple previous studies (1), we found an approximately 3:1 male-to-female ratio, with 421 male and 141 female patients (Table 1).
Most patients in our database were diagnosed in early childhood. Of the patients, 68% were first diagnosed with a positive biopsy at an age younger than 6 years (Fig. 2). Furthermore, 36% of the patients were younger than age 3. The number of cases decreases with age, suggesting a new increase in the disease.
We looked at the initial symptoms that patients reported. We were able to identify initial symptoms that led them to a physician's office in 425 of 562 patients. In the remaining patients, the initial complaints were not listed in their medical record. We grouped our symptoms into 4 general categories: failure to thrive and associated feeding difficulties, GERD symptoms and vomiting, abdominal pain, and dysphagia and food impaction. These patients present with similar symptoms as previously reported (3,4,7,14), primarily being refusal to eat in the toddlers, GERD/vomiting symptoms in the young school-age child, and dysphagia and food impaction in the older children. Because most of our patients are younger than age 6 years, it is not surprising that failures to thrive/feeding issues and GERD-like symptoms are the most common presentations, given that this is the presentation seen in the youngest children (Table 2).
The most common foods identified in our population by the use of prick skin test and atopy patch test were milk, egg, wheat, corn, beef, chicken, barley, oats, rice, and peanuts. Skin prick testing identifies foods that cause an immediate reaction and are IgE mediated. Atopy patch test identifies foods that have a delayed onset of symptoms, which is seen in gastrointestinal reactions. The following foods were confirmed by changes in biopsy after removal or addition of a single food using methods previously reported (15–17): milk, egg, wheat, soy, corn, beef, and chicken (Table 3). These 7 foods accounted for two-thirds of food allergies found in our patients. For the patients who required elemental formula for nutritional supplementation, two-thirds of the patients were taking it orally and one-third required either a nasogastric or gastrointestinal tube.
We also examined the clinical course of our patients with EE with at least 1 year of follow-up. In these 330 patients, the range of follow up was from 1 year to more than 14 years, with an average of 3.2 years. This population has a total of 2526 biopsies or an average of 4.5 EGDs per patient. This population also had 1824 biopsies of the duodenum, 1640 biopsies of the gastric antrum, and 323 biopsies of the colon and ileum (Table 4). All of the patients had upper endoscopies of the esophagus, duodenum, and antrum, and 144 patients had lower endoscopies done at the time of presentation. In all 330 patients, the eosinophilia was isolated to the esophagus. Patients had repeated endoscopies after changes in their medical regimen or dietary therapy. Of the patients, 152 had lower gastrointestinal symptoms of diarrhea, abdominal pain, or bleeding, and 179 colonoscopies were performed. None of these 330 patients had eosinophilic inflammation distal to the esophagus—including the duodenum, antrum, or colon—at any time. In this extensive population, we did not see any patient progress from EE to any other condition, such as eosinophilic gastroenteritis, eosinophilic colitis, or inflammatory bowel disease.
In our population, most patients were treated primarily with dietary therapy in addition to daily PPIs and medical therapy of their allergic rhinitis and asthma. Treatment for the allergic disorders included inhaled corticosteroids (not swallowed), intranasal steroids, antihistamines, leukotriene modifiers, and short- and long-acting β-agonists. Doses of asthma/allergy medications were adjusted for symptoms and seasonal variations. Forty patients were treated with swallowed corticosteroids (Flovent 220 to 880 μg daily or Budesonide 1 mg twice per day) for their EE ranging from 4 months to 4 years in duration, with a mean of 2.5 years. Of these 40 patients, 25 were treated at outside hospitals with swallowed corticosteroids before our evaluation. These 25 patients were switched to dietary management with normalization of their biopsies in all of the cases.
Five patients did not respond to elemental diet and were treated with swallowed corticosteroids (Flovent 440 μg daily) and limited diet with reduction of their esophageal eosinophilia, but not normalization of their esophageal biopsies.
In our entire population of 562 patients, we had only 11 patients with complete resolution of their EE, with reintroduction of all foods and stoppage of all medical therapy for their EE (Table 5). All 11 patients had food causing their EE on onset of disease, with milk and egg being the most common. Grains (rice, oat, wheat, barley, and corn) combined were one-third of the foods found in this tolerant population. Of the patients, 33 developed tolerance to 1 or more of the foods that were causing their EE. In these 44 patients, all were treated with dietary therapy only with no medical therapy for their EE. We did not observe the development of tolerance or resolution in any patients treated with medical therapy. All of the patients treated with swallowed corticosteroids experienced return of their esophageal eosinophilia when the swallowed corticosteroids were stopped.
The length of follow-up in the group that developed complete tolerance was longer than the general EE population (5.2 vs 3.2 years, respectively) (Table 4). There was no significant difference in age of diagnosis. The group that developed complete tolerance had fewer food allergies (2.4 foods) at diagnosis compared with 6.9 food allergies at diagnosis in the entire group. With longer follow-up, additional patients that develop tolerance to all foods may be identified.
Also, for a true natural history of EE, we had 24 patients that returned 6.2 ± 3.6 years after initial evaluation. During this time frame, they had no medical or dietary treatment for their EE. Their families had elected to follow the patients clinically. Twenty of the 24 patients initially presented with the symptoms of GERD and feeding issues, symptoms seen in our youngest age groups. The other 4 patients had abdominal pain as the chief symptom. They reported back to our care with worsening symptoms of dysphagia and food impaction. Their EGDs were unchanged from 35.4 ± 24.8 eosinophils/HPF at the initial evaluation to 39.1 ± 27.9 eosinophils/HPF at the repeat EGD.
We also found a convincing seasonal/pollen variation in 30 patients. These patients had worsening of the EE either clinically or by biopsy during the pollen season, either the spring or fall pollen season. In 29 of the 30 patients, food allergies still are the primary allergen affecting their EE. Their esophageal biopsies only normalized out of pollen season or on allergy medications when on the correct food elimination. It is difficult to tell whether acute asthma symptoms would lead to esophageal eosinophilia because patients do not undergo EGDs when they are acutely wheezing. We also found potential seasonal/pollen influence in another 16 patients, but have not confirmed this with additional biopsies. In these 46 pollen-sensitive patients, all but 1 had food as the major component. It was the same types of food as the non–pollen-sensitive patients. As found in previous studies, the majority (68%) of patients are atopic; 231 patients had asthma, 243 patients had allergic rhinitis, and 78 patients had atopic dermatitis.
We examined our database of 562 patients with confirmed EE. These patients had many similarities to populations described in other studies (3–5,7,13,14). All of the studies, including the present study, reported a 2:1 to 3:1 male-to-female ratio with a similar distribution of symptoms. We have seen a steady increase in the number of new cases of EE on an annual basis. One concern is that our findings may stem from an increase in our referral network because we have become a national center for EE, but our data do not support that the increase is simply because of a change in the referral pattern. In the present database of 562 patients, 468 patients are from the local tristate area of Pennsylvania, New Jersey, and Delaware. We continue to see an increase in the number of newly diagnosed patients with EE in our local population (Fig. 1), despite the local population remaining stable during this period (23). Therefore, the increase in newly diagnosed patients cannot be explained by the increase in referral patient population. Other potential reasons for the increase in the number of newly diagnosed EE patients include increased EGDs with esophageal biopsies owing to the ease of endoscopic evaluation, or increased recognition of the disorder.
A potential genetic component is suggested by the male predominance, and by the increased number of white patients (Table 1). The latter significantly differs from the general population trends of the greater Philadelphia area, based on the 2000 US census (23).
Of our EE population, 68% is younger than age 6 years, also suggesting that this is a new disease and is only now beginning to be identified and treated (Fig. 2); however, additional studies need to be to done to identify whether the disease is just being recognized compared with a true rise in the disease. Although the etiology of the rise of EE remains unclear, it is probably similar to the increase seen in other atopic diseases such as asthma and atopic dermatitis (24–27).
The EE population is highly atopic, with two-thirds of the patients having other allergic diseases. We also have found seasonal variation in a subset of patients. It may be larger, but all of our patients are treated for their symptomatic allergic diseases. (Also, as the younger patients age, they may become more allergic to pollens and increase the number of seasonal patients.) A similar seasonal variation has been noted in several studies (8,28,29). This suggests that allergic disease in another organ system can affect the esophagus, similar to the link with asthma and allergic rhinitis (nose and lung) (30). A potential mechanism would be patients swallowing airborne pollen. These pollens would then interact with the esophageal tissue causing a local allergic reaction and eosinophilia.
Eosinophilic esophagitis appears to be a chronic condition with infrequent relapses and remission from the disease. The only mechanism of outgrowing EE appears to be avoidance of food, not spontaneous remission. In our population, none of the patients with EE have progressed to eosinophilic gastroenteritis and eosinophilic colitis. In contrast to the work of Assa'ad (14), we did not see any abnormal eosinophilia in the colon or stomach in our patients with EE. Our results suggest that EE is a chronic disease similar to asthma and allergic rhinitis. We have only seen development of some tolerance to foods in 44 of 562 patients (8%) in our population. This rate of tolerance is lower than that observed in an IgE-mediated food allergy population, for whom it is 20% in the population allergic to peanuts (31,32) and up to 80% to 90% in the population allergic to milk (33–36). The patients who had outgrown their EE had the longest follow-up, suggesting that as we study the patients over time, a larger group may develop tolerance. This is in contrast to the data by Straumann (13) from 30 adult patients, in which no patients were seen to develop tolerance. Two possibilities for this are that the adult patients already are out of the window to develop tolerance or the strict food avoidance that we recommend increases the chance that tolerance may occur. In Straumann's study, patients were treated with medical therapy or observation. Among our patients who refuse dietary therapy, no patients have outgrown or developed tolerance to foods, suggesting that avoiding the causative agent may help in the development of tolerance.
EE also progresses from feeding difficulties in young childern to dysphagia and food impaction in older children. This progression can be seen in 2 different populations: natural history of untreated disease in the 24 patients or the presenting complaint of children. These findings suggest a potential natural history consistent with previous works (3,7) (Fig. 3). In 1 potential scenario, initial inflammation causes damage to the esophagus and its sphincter causing the reflux symptoms and difficulty eating. As the disease progresses over time, patients develop esophageal thickening (similar to basement membrane thickening in asthma). This thickening of the esophagus leads to a narrow esophagus and difficulty swallowing, and eventually food impaction.
The exception to the lack of progression with EE is those patients with associated eosinophilic gastroenteritis or celiac disease before the diagnosis. Interestingly, in the EE/eosinophilic gastroenteritis patients, EE resolved with diet, and the eosinophilic gastroenteritis did not improve. EE has been recently associated with celiac disease (37). In our patients with EE and celiac disease, EE has been diagnosed after the celiac disease or at the same time.
The group that outgrew EE had fewer food allergies than the general EE population, indicating a possible less allergic phenotype in that tolerant population. Additional natural history studies are needed to identify risk factors for the development of tolerance.
It is possible that multiple phenotypes can exist. The adult phenotype may be different than the pediatric phenotype presenting in infancy or in adolescence. Each phenotype could have symptoms starting at a different age and a different course. Another possibility is that the patients who present in adulthood could have the same phenotype but are more tolerant of symptoms and go later to physicians to be diagnosed.
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