Eosinophilic esophagitis (EoE) is a chronic, immune-mediated esophageal disease characterized by esophageal dysfunction and eosinophil-rich inflammation. Symptoms include dysphagia (difficulty swallowing), food impaction, chest pain, and heartburn. Diagnosis requires endoscopic biopsy, with current guidelines recommending four to six tissue samples from the esophageal mucosa. Treatment aims to reduce inflammation and reverse esophageal fibrosis. Dietary therapy, particularly the elemental diet, has emerged as a key approach in managing EoE.
Understanding Eosinophilic Esophagitis (EoE)
EoE is a chronic allergic disease that is defined by marked eosinophilic inflammation and symptoms of esophageal dysfunction. It is the most characterized eosinophilic gastrointestinal disorder (EGID). EoE is a heterogeneous disease that severely impacts the quality of life of affected patients. The choice of therapy (medication or diet) might depend on the different disease phenotypes (allergic vs. non-allergic, inflammatory vs. fibro-stenotic), patient's age (adult vs. childhood-onset), food habits, patient/family preference, and familiar financial resource.
The prevalence of EoE is estimated to be about 0.5-1/1,000 patients in the USA, varying widely across different countries and mostly prevailing in Caucasian patients and male sex. However, in the last 20 years, several epidemiological studies showed a significant increase in the epidemiology of EGIDs, partially related to improved medical awareness and knowledge through modern diagnostic instruments. It was also postulated that changes in environmental factors may have contributed to the significant increase in EoE epidemiology. A recent study found that the pooled prevalence of EoE is 34.4 cases/100,000 inhabitants and is higher for adults than for children (42.2/100,000 vs. 34/100,000).
Genome-wide association studies have identified multiple susceptibility genes associated with EoE risk and a complex model of disease inheritance. EoE is a multifactorial disease typically characterized by a type 2 (T2) inflammation. The impaired epithelial barrier function plays a pivotal role in the pathophysiology of EoE, inducing the release of alarmins (thymic stromal lymphopoietin, IL-15, IL-33), which then activates the type 2 innate lymphoid cells (ILC2) and basophils. The subsequent release of IL-4, IL-5, and IL-13 recruits and expands the eosinophilic inflammation. The consequences of this sustained inflammation include tissue remodeling and esophageal dysfunction. Esophageal fibrosis begins in the early phases of the disease course, initially involving the lamina propria. Fibrosis has been found in 57-88% of young patients and children and 89% of adult patients with EoE.
Although the pathogenesis is not entirely understood and is likely non-IgE-mediated, food allergens are known to trigger EoE, stimulating the already dysregulated immune cells through the impaired esophageal epithelial barrier. Most patients with EoE are allergic to 1-3 foods that trigger esophageal inflammation. Esophageal inflammation is resolved once the food(s) is removed from the diet, and reproducibility reactivates it when the culprit allergen(s) is reintroduced.
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Dietary Management of EoE
EoE can be managed using pharmaceutical [(topical) corticosteroids)] and/or dietary therapy. Topical steroids are moderately effective in paediatric and adult EoE patients. However, side effects preclude long‐term use, and since the underlying cause is not affected, the inflammation recurs once the (topical) steroid is withdrawn. Studies have shown that, without treatment, progressive narrowing of the oesophagus occurs. Dietary elimination of disease‐triggering allergens could provide a long‐term, drug‐free and sustainable solution, which is desirable since EoE is a chronic disease and most patients are children or young adults. The three main approaches in dietary management are:
- Allergy test‐directed elimination, based on positive allergy test results.
- Empiric elimination, based on most common allergic triggers (i.e. milk, wheat, egg, soy, peanuts/tree nuts, and fish/shellfish).
- Elimination of all table foods and substitution by an exclusively elemental (amino acid‐based) diet.
A recent systematic review showed that empiric elimination diets yield moderate response rates (71%), whereas the effect of test-directed elimination diets is questionable (45%). On the other hand, elemental diets are highly effective in children, showing rapid resolution of symptoms and histological remission in more than 95% of the patients. The effect of an elemental diet has only been investigated once in adult patients with EoE. In that study, the elemental diet induced complete histological disease remission in 72% of the patients. However, symptoms did not improve and drop‐out rates were rather high (38%). Patient adherence to an elemental diet is challenging, not only in adults but also in children, due to unpalatability and monotony of the formula. Nevertheless, over the past decade the quality and variability in the formulas has improved.
Three main dietary approaches, such as the elemental, empiric, and allergy test-directed elimination diets, have been proposed with variable efficacy rates and specific advantages and disadvantages. According to international guidelines, the diet approach is considered the first-line treatment of EoE and is as effective as medication therapy. It is widely demonstrated that foods are the primary triggers of EoE; indeed, food elimination diets (FEDs) have demonstrated complete remission of EoE, with higher rates (>90%) in patients treated with elemental diet than empirical FEDs and test directed diets. However, FEDs are challenging and are not risk-free. Patients on diet therapy may potentially develop nutritional deficiencies, eating disorders and experience a low QoL and high psychological impacts.
Before prescribing a FED, allergists and gastroenterologists should consider several clinical aspects, such as (1) disease-severity and patient's nutritional status, (2) presence of maladaptive feeding behaviors or/and food allergies, (3) family and patient preferences, and (4) financial resources. Then, clinicians should widely explain to patients and their families the advantages and disadvantages of diets to choose judiciously. Children and adults, candidates for diet therapy, should also be informed of the need to undergo several endoscopic and clinical evaluations to confirm or assess disease remission. Patients and parents of children with EoE should know that more restrictive diet therapies (elemental and empirical FED) may be expensive and alternative foods may be often found only in specialty stores. On the other hand, clinicians should guarantee a strict follow-up with upper GI endoscopy to evaluate the remission 6-12 weeks after diet beginning and each food reintroduction.
The Elemental Diet: A Detailed Look
The elemental diet consists of removing all foods. Thus, patients are exclusively fed with an amino acid-based formula for at least 6 weeks. The elemental diet is the most effective treatment, and several studies reported high complete remission rates in children and adults with active EoE. EoE patients treated with the elemental diet experienced a significant reduction in their symptoms and achieved complete histologic remission in 90 and 94% of pediatric and adult cases, respectively. The elemental diet is a fundamental therapeutic option, especially in severe EoE cases. However, the elemental diet is not the first-line approach for its limitations in most cases. Elemental diet is often proposed as rescue therapy or temporary solution in adults and adolescents with refractory EoE when all other treatments alone or in combination have failed. In toddlers or young children with active EoE complicated by failure to thrive, the elemental diet is generally considered a valid and useful therapeutic option with the highest patient compliance.
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In severe disease or when large volumes of the amino acid-based formula are required to meet the caloric needs and restore the good nutritional status, nasal-gastric (NG) or gastric (G) tube feeding is a temporary solution. These interventions should be discouraged in the long-term treatment, especially in children with feeding disorders, because they are often fraught with difficult solid food oral reintroduction and progressive feeding skills regression. Although the elemental diet can induce a rapid disease-remission in only 2 weeks, several disadvantages limit its adherence. The poor palatability, highly restrictive nature, costs, and psychosocial isolation are the main reasons for treatment discontinuation and low compliance. To remedy these issues, the elemental diet is often modified, introducing one or two less allergenic foods (generally vegetables or fruits) in addition to the amino acid-based formula. Moreover, elemental formulas are also available in flavored and unflavored formulations to address patient taste and preferences. Pediatric elemental formulas are nutritionally complete but do not contain dietary fiber.
What to Do Before Starting the Elemental Diet
Ideally, you should consult with a qualified healthcare provider regarding your symptoms and what you might hope to gain from the diet. Based on your condition, your healthcare provider might recommend the diet for three to five days to manage acute symptoms, or for several weeks to give your digestive system a restorative rest and reboot. They'll also let you know how much of the formula to take to meet your body’s caloric needs. Healthcare providers often lean toward higher-calorie recommendations to make sure you won’t feel too hungry or depleted during the diet.
Guidelines During the Elemental Diet
On the full elemental diet, you don’t eat any other foods. The point of the diet is to replace food and minimize digestive activity. Following the diet exactly allows your gut the rest it needs to heal. You may be allowed to drink tea without anything added. Sometimes healthcare providers recommend a “half-elemental diet” for people who need a secondary source of nutrition or who are transitioning into or out of the full diet. In this case, the elemental formulas provide half of your calories, and the other half come from food. There are some formulas specifically marketed for a half-elemental diet, which may not be completely elemental - for example, they may contain MCT oil or whey. These are not completely broken-down sources of protein or fat, but they are generally easy to digest and make the half-diet easier to follow.
Tips for Surviving the Elemental Diet
This diet is very restrictive, and it can be challenging. To stick to the diet successfully, healthcare providers recommend that you:
- Keep it cold: Blending the formula with ice, smoothie-style, makes it more palatable.
- Sip it slowly: Sip it slowly to prevent nausea and drink plenty of water between “meals."
- Make it portable: Have a temperature-controlled thermos to keep your formula in so you don’t get hungry when you’re out and about.
- Stay busy: Distract yourself with fun, non-food-related activities and good company.
Possible Side Effects of the Elemental Diet
During the diet, you may experience symptoms that make you wonder if it’s actually helping your condition or making it worse. Medical guidance can help you sort through this. Symptoms may include:
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- Abdominal cramping: The first few days on a liquid diet may loosen poop that has been stuck in your colon, causing gas and discomfort as the residual poop is pushed out. This is a symptom that feels bad temporarily but indicates that something good is happening.
- Detox symptoms: During bowel rest, your liver may take the opportunity to offload extra toxins. This can lead to temporary detox symptoms, including headaches, lightheadedness, nausea and fatigue. Detox feels bad for a few days, but most people feel much better afterward.
- Bacteria die-off symptoms: If you have small intestinal bacterial overgrowth or small intestinal fungal overgrowth, the elemental diet can effectively starve them of food in your lower digestive tract, causing them to die off in great numbers. This can give you detox symptoms. These symptoms usually begin several days into the diet and recede after several days more.
- Reduced motility: It’s common to have less frequent bowel movements on the elemental diet. This may lead some people to believe they’re constipated, especially if they have residual poop in their colon that hasn’t come out yet. The diet doesn’t cause constipation, but it can slow down your bowel function. This is natural and generally no cause for concern.
What to Do After the Elemental Diet
It’s important to reintroduce foods gradually as your digestive system is ramping back up again. Healthcare providers typically recommend following a half-elemental diet or a low-FODMAP diet during the transition. They may also recommend probiotics to re-populate your gut with beneficial flora, and prokinetic agents to stimulate your bowels to begin moving more regularly again. As you return to your more regular diet, pay attention to the way different foods affect your digestive system.
Study on Elemental Diet for EoE
In a prospective study, 21 patients with active EoE, confirmed by biopsies showing ≥15 eosinophils per microscopic high power field (HPF) and symptoms of oesophageal dysfunction were included. Patients underwent endoscopy before and 4 weeks after diet. Histological disease activity (peak eosinophil count/HPF), and endoscopic signs were scored by physicians. Symptoms and adherence to the diet were evaluated by questionnaires. In total, 17 (81%) of the patients completed the diet, of whom 12 (71%) showed complete histological response (≤15 eosinophils/HPF) and 4 (24%) showed partial histological response (≥50% reduction of baseline eosinophil count). Peak eosinophil counts decreased significantly after the diet from 40 to 9 per HPF (P ≤ 0.001). A marked improvement in endoscopic signs was observed. Symptoms decreased significantly in all subjects, and 15 patients (88%) became completely asymptomatic (P ≤ 0.001).
Patients were included between December 2014 and September 2015. Subjects were recruited from the out‐patient clinic of the Academic Medical Centre in Amsterdam, a referral hospital for EoE in the Netherlands. Adults were eligible for enrolment if EoE was diagnosed according to current guidelines, defined as typical symptoms of EoE (dysphagia and/or food impaction), and presence of more than 15 eosinophils per high power field (HPF) during acid‐suppressant treatment. Patients were excluded if they had a severe comorbidity scored as ASA class III or higher, a history of other gastrointestinal diseases, had undergone surgery of the digestive tract (except from appendectomy), or were unable to stop anticoagulants or topical or systemic steroids in the two months preceding the study and during the study.
After signed informed consent, patients visited a dietician with expertise in EoE. Patients' eating habits, dietary eliminations and metabolic needs were analysed, using a complete 3‐day food diary. Although the amino acid‐based formula provides complete nutrition, considerable weight loss has been described as associated to its use. To guarantee sufficient intake, the minimal daily formula consumption was calculated based on a patients' body mass index and weekly physical activity. To diminish drop‐out rates, a 24‐h elemental diet test day was incorporated in the study protocol, to enable patients to take a weighted decision concerning study participation. During the diet, patients were carefully monitored by means of a weekly consult with their dietician or physician who evaluated body weight, side effects and patients' adherence to the diet. Adherence was monitored by means of weekly questionnaires in which patients reported protocol violations and daily formula consumption. Subsequently after the trial, patients specified their level of formula acceptance on a completely acceptable‐unacceptable Likert scale, in which 0 represented completely acceptable and 6 represented completely unacceptable.
All participants underwent a baseline endoscopy and a follow‐up endoscopy after 4 weeks of elemental diet (Neocate Nutricia, Utrecht, the Netherlands). The primary endpoint of this study was the proportion of patients in histological disease remission, defined as a peak eosinophil counts of less than 15 eosinophils/HPF (complete remission). Partial responders were patients with ≥15 eosinophils/HPF after diet, but with a decline of more than 50% of pre‐diet peak eosinophil count. Symptoms of dysphagia were measured per questionnaire recording the frequency and severity of dysphagia on a 5‐point Likert‐type scale analogous to the Straumann Dysphagia Instrument (SDI). The total scores were composed of a sum of the frequency of symptoms, where 0 represents no symptoms in the past week and 5 represents daily symptoms, and the severity of symptoms where 0 represents no complains and 5 represents severe complains. Total scores ranged from 0 to 10. The Straumann Dysphagia Instrument is a questionnaire that has been used previously in placebo‐controlled clinical EoE trials.
In this trial, a newly developed amino acid‐based formula was used (Neocate Nutricia, Utrecht, the Netherlands). This product is suitable and nutritionally adequate for adults when used as a short‐term sole source of nutrition. The formula was available in pineapple/orange or grape flavour and each package contained 237 kcal. Patients were only permitted to drink water or black/green tea without sugar during the diet.
Once remission was established after 4 weeks of elemental diet, patients were offered a stepwise food reintroduction schedule outside this study protocol, with the objective of identifying the disease‐triggering foods and establishing a normal diet. The four most common allergic triggers for EoE (i.e. milk, soy, wheat and egg) completed with patient‐specific allergenic foods, as determined by diet history, were sequentially reintroduced, starting with the food least likely to trigger EoE. First, soy was reintroduced, followed by egg, wheat and finally milk. Each food group was introduced during 1-2 weeks, as Peterson et al. showed that eosinophils increased within a week after introduction of the allergic food. After reintroduction of every food group, symptoms were evaluated using the modified Straumann Dysphagia Instrument.
Thirty‐four EoE patients, who presented with clinically active disease and were otherwise also eligible for participation, were invited for a visit at the out‐patient clinic. After the test day, nine patients dropped out because they judged the elemental diet formulation to be unpalatable (n = 7), because of personal circumstances (n = 1) or because their use of an anticoagulant could not be interrupted (n = 1). Eventually, 25 patients were enrolled and underwent the first endoscopy, after which another four patients were excluded due to spontaneous disease remission at baseline (≤15 eosinophils/HPF). During the first two weeks of the diet, two patients dropped out because of unpalatability and the life style modifications that came along with the diet. One patient tolerated the diet but became very anxious about the second endoscopy and cancelled the procedure. In summary, of the 21 patients who started the diet, 18 patients underwent the second endoscopy. Finally, 17 patients were included for final analyses, since one patient was excluded due to poor adherence.
Seventeen (81%) of the 21 patients who started the diet completed the trial, of whom 12 (71%) showed complete histological response (≤15 eosinophils per HPF) and another four (24%) patients showed partial histological response (≥50% reduction of pre‐diet eosinophil counts). In addition, all complete responders also had a reduction of more than 50% of pre‐diet eosinophil count. One patient was classified as nonresponder since there was still a remarkable oesophageal eosinophilia after diet, despite a reduction in peak eosinophil count of 33%. On a group level, peak eosinophil counts decreased significantly from 40 (29-80) to 9 (1.5-17.50) per HPF after diet, (P < 0.001). There is a significant decline in peak eosinophil count after treatment (P < 0.001).
Six-Food Elimination Diet (SFED)
The six-food elimination diet (SFED) is the most frequently employed dietary therapy in patients with EoE. An upper endoscopy and biopsy is performed after six weeks of the SFED diet. Responders then have a new food group reintroduced every two to four weeks. Results obtained from two studies conducted in Chicago and Spain show that about 70 percent of patients showed symptomatic and histologic response after eliminating specific allergens from their diets. Multiple studies have found milk (60 percent) and wheat (30 percent) to be the most common food triggers.
The first proposed FED was founded on avoiding the six most common food-triggers of EoE in the Western diet, such as milk, wheat, egg, soy/legumes, peanut/tree nuts, and seafood/fish. Patients should be advised that all these foods should be avoided both in fresh and backed forms. The 6-FED effectively induces histologic remission in about 74% of children and 70% of adults with EoE. Studies assessing the efficacy of 6-FED have been fundamental to find that the most common food triggers are cow's milk (up to 85% of the pediatric cases), followed by wheat/gluten (up to 60%), egg, and soy/legumes with geographic variations, primarily due to the different food cultures. Consequently, nuts and fish/seafood rarely trigger EoE.
Although 6-FED is less restrictive than the elemental diet, it still can be challenging to avoid all the six groups of foods. Several drawbacks limit the adherence to 6-FED due to the high level of dietary restriction and the need of frequent upper GI endoscopies to identify the culprit food(s). For these reasons, 6-FED is generally not considered the ideal therapeutic approach in most EoE patients. Therefore, subsequent studies proposed and assessed the utility of less restrictive FEDs that consisted of avoiding the most common food triggers.
Alternative Diagnostic Procedures
Studies conducted at Mayo Clinic have tested a procedure that facilitates sampling of the esophagus without the need for endoscopy. This test uses a swallowed, dissolvable gelatin capsule that covers an esophageal sponge attached to a string. The string and sponge can be pulled out of the mouth after five minutes. Studies using this alternative to endoscopy have yielded promising results, and the test is much-preferred by patients.
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