Posted by: Indonesian Children | May 11, 2010

Eosinophilic esophagitis, Food Allergy And Adverse Food Reaction

Eosinophilic esophagitis, Food Allergy and Adverse Food Reaction

Widodo Judarwanto

Children Allergy Center – Bunda Jakarta Hospital, Indonesia

 

Eosinophilic esophagitis is an allergic inflammatory condition of the esophagus. Symptoms are swallowing difficulty, food impaction, and heartburn. The disease was first described in children but occurs in adults as well. The condition is not well understood, but food allergy may play a significant role.

Eosinophilic disorders are further defined by the area of the body affected. For instance, eosinophilic esophagitis is associated with abnormally high numbers of eosinophils in the esophagus. Eosinophils, a type of white blood cell, are an important part of the immune system, helping us fight off certain types of infections, such as parasites. Many different problems can cause high numbers of eosinophils in the blood including allergies (food and environmental), certain infections (caused by parasites), eosinophil associated gastrointestinal disorders, leukemia, and other problems. When eosinophils occur in higher than normal numbers in the body, without a known cause, an eosinophilic disorder may be present.

Eosinophilic esophagitis (EE) is an allergic inflammatory disease characterized by elevated eosinophils in the esophagus EE is a newly recognized disease that over the past decade has been increasingly diagnosed in children and adults. This increase is thought to reflect an increase in diagnosis as well as a true increase in EE cases. Fortunately, the medical community is responding and new scientific information is emerging to guide management of this disorder, which often persists with ongoing or recurrent symptoms.
Eosinophilic esophagitis is characterized by a large number of eosinophils and inflammation in the esophagus (the tube connecting the mouth to the stomach).  These eosinophils persist despite treatment with acid blocking medicines. People with EE commonly have other allergic diseases such as rhinitis, asthma, and/or eczema.  EE affects people of all ages and ethnic backgrounds. Males are more commonly affected than females. In certain families, there may be an inherited (genetic) tendency.
In individuals with EE, the eosinophils cause injury to the tissue in the esophagus. EE can be driven by food allergy or intolerance: most patients who eliminate food proteins from their diet (by drinking only an amino-acid based formula) improve.

Adverse Food Reaction and Food Allergy

Eosinophilic esophagitis (EE) is an increasingly recognized disorder in the adult population, most often manifested by symptoms of dysphagia and food impaction. Mechanisms involving eotaxin-3, interleukin 5, and signal transducer and activator of transcription 6 have been studied and may represent future therapeutic targets. Patients commonly have a personal and family history of atopy, and both food allergies and aeroallergens have also been investigated as triggers of EE. Traditional allergy-testing methods, including skin prick testing and specific IgE testing, have been used to identify food and environmental allergies. However, new studies suggest that patch testing could add to diagnostic accuracy in EE because the disorder might not be a classic type I allergic response. Although studies of treatment of adults with EE have thus far focused on swallowed fluticasone proprionate, many trials in children have assessed the efficacy of food elimination and elemental diets. These diets, which have been extremely successful in reducing symptoms, have also been shown to induce histological improvement and remission. No similar studies have been conducted in adults; the tolerability of such an intervention may prove more difficult in this population.

Eosinophilic esophagitis (EE) is an increasingly recognized disorder in the adult population, most often manifested by symptoms of dysphagia and food impaction. Mechanisms involving eotaxin-3, interleukin 5, and signal transducer and activator of transcription 6 have been studied and may represent future therapeutic targets. Patients commonly have a personal and family history of atopy, and both food allergies and aeroallergens have also been investigated as triggers of EE. Traditional allergy-testing methods, including skin prick testing and specific IgE testing, have been used to identify food and environmental allergies. However, new studies suggest that patch testing could add to diagnostic accuracy in EE because the disorder might not be a classic type I allergic response.

Although studies of treatment of adults with EE have thus far focused on swallowed fluticasone proprionate, many trials in children have assessed the efficacy of food elimination and elemental diets. These diets, which have been extremely successful in reducing symptoms, have also been shown to induce histological improvement and remission. No similar studies have been conducted in adults; the tolerability of such an intervention may prove more difficult in this population.

The underlying pathophysiology of EE and describes evolving options for more accurately identifying food and environmental allergies. The pediatric trials using food elimination and avoidance diets and suggest that this type of intervention may be an important area of future research in the adult population.

PATHOPHYSIOLOGY

Role of Eosinophils in the Esophagus

The esophageal mucosa is unique in the gut because it is normally devoid of any resident eosinophils. However, eosinophils accumulate in disease states, in lower levels in gastroesophageal reflux disease, and in greater numbers in EE. Further, adult patients with EE usually do not have elevated eosinophils or IgE levels in peripheral blood specimens.10

FIGURE 1. 

FIGURE 1. Basic pathway of eosinophilic activation and degranulation. In a sensitized individual, allergens react with IgE, causing mast cells to migrate to the esophagus. Mast cell degranulation occurs, causing release of eosinophil chemotactic factors, which induce eosinophil migration and degranulation. Eosinophilic granules release a variety of chemokines, cytokines, and cytotoxic proteins, which ultimately cause inflammation and tissue damage. In addition, the toxic granule proteins cause further mast cell degranulation, which perpetuates the cycle. APC = antigen-presenting cell; ECP = eosinophil cationic protein; EDN = eosinophil-derived neurotoxin; EPO = eosinophil peroxidase; IL = interleukin; MBP = major basic protein

 

Basic pathway of eosinophilic activation and degranulation. In a sensitized individual, allergens react with IgE, causing mast cells to migrate to the esophagus. Mast cell degranulation occurs, causing release of eosinophil chemotactic factors, which induce eosinophil migration and degranulation. Eosinophilic granules release a variety of chemokines, cytokines, and cytotoxic proteins, which ultimately cause inflammation and tissue damage. In addition, the toxic granule proteins cause further mast cell degranulation, which perpetuates the cycle. APC = antigen-presenting cell; ECP = eosinophil cationic protein; EDN = eosinophil-derived neurotoxin; EPO = eosinophil peroxidase; IL = interleukin; MBP = major basic protein

In previously sensitized individuals, IgE interacts with a food allergen or aeroallergen, leading to resident mast cell degranulation. Chemokines, histamine, and eosinophilic chemotactic factors are released from the mast cells. These factors induce eosinophil migration and degranulation. Among the products released by eosinophil granules are major basic protein, eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin (Figure 1).

Effect of Eosinophils on the Esophagus

In general, eosinophils have proinflammatory effects, upregulating adhesion systems, mediating cell trafficking, and releasing cytokines, chemokines, and lipid mediators.The cationic proteins that are released cause tissue damage and dysfunction and can ultimately result in fibrosis. The toxic granule proteins also induce further mast cell degranulation, and the cycle of inflammation and tissue damage continues.

When released from eosinophils, major basic protein has been found to induce smooth muscle contraction through actions on muscarinic M2 receptors. This contraction may lead to the sensation of dysphagia in EE, as well as cause episodes of food impaction. These constrictive symptoms from smooth muscle contraction in the esophagus may be mechanistically similar to the bronchoconstriction responsible for symptoms in asthma.

Eosinophil Recruitment to the Esophagus

Given that the normal esophagus is usually devoid of eosinophils, a possible mechanism of their recruitment to the esophagus involving interleukin (IL) 5 has been proposed. A cytokine produced by T helper type 2 (TH2) lymphocytes,16 IL-5 primes eosinophils to react to chemoattractants (eg, eotaxin) and promotes their development, activation, migration, and effector functions. Furthermore, IL-5 increases levels of eotaxin, resulting in a perpetuating cycle of chemoattraction. In patients with EE, esophageal IL-5 is overexpressed, and systemic IL-5 overexpression may promote eosinophil migration to the esophagus. Increases in mast cells and T cells in the esophagus of patients with EE have also been documented.

Eotaxin is a specific eosinophilic chemotactic factor that has a role in promoting eosinophil accumulation and adhesion. It is thought to be involved in the recruitment of eosinophils to the gastrointestinal tract. It promotes adhesion of eosinophils to vascular cell adhesion molecule 1, an adhesion molecule that is expressed on endothelial tissues. Eotaxin, specifically eotaxin-3, has been found to be overexpressed in patients with EE.

The cytokine IL-13 upregulates IgE, is important for eosinophil recruitment and survival, and activates adhesion systems. Studies have shown IL-13 dysregulation in allergic disorders such as asthma, atopic dermatitis, and allergic rhinitis. Further, after direct delivery of IL-13 to the lung, an eosinophilic infiltration, as well as epithelial hyperplasia, developed in the esophagus. Mishra and Rothenberg showed the crucial role that IL-5 and signal transducer and activator of transcription 6 (STAT-6) play in the development of EE. When STAT-6 and IL-5 transgenic knockout mice were then studied, EE did not develop after the intratracheal administration of IL-13 in these strains.

Diagnosis

Diagnosis is obtained during an upper GI endoscopy where biopsies are taken of the esophagus. At the time of endoscopy, ridges or furrows may be seen in the esophagus wall. Presence of white exudates in esophagus is also suggestive of the diagnosis. Sometimes, multiple rings may occur in the esophagus, leading to the term “corrugated esophagus” or “feline esophagus” due to the similarity in the rings of the cat esophagus. A high number of eosinophils are seen on microscopic examination of the biopsy specimens.

Eosinophilic esophagitis may be present even if the esophagus appears, initially, to be normal. This is why the biopsy samples are important to making the diagnosis of EE. A high number of eosinophils(> 15 per high power field) throughout the length of the esophagus suggests the diagnosis of EE.

Skin testing can help identify which foods might contribute to this disease, but often skin testing implicates foods that are not involved. Common allergens of EE patients are cow’s milk, soy, egg, fish and wheat.

History

Eosinophilic esophagitis (often referred to as EE in the United States, or EO in countries which use British spelling) was only discovered in recent years, and little is known about its pathogenesis. EE is a chronic disease associated with an elevated count of eosinophils in the esophagus. Normally, very few or no eosinophils are present in this upper digestive organ. In the past, patients with EE were incorrectly diagnosed as GERD suffererers. These patients were typically prescribed proton pump inhibitors, under the assumption that their problem was caused by excess stomach acid. However, researches have since discovered that EE patients often have a normal pH in their GI tract. The symptoms of GERD and EE are often similar, and this makes the diagnosis more difficult. But when a patient suffering from esophageal discomfort tests normal from an esophageal pH monitoring, GERD is eliminated as a possible cause and EE becomes the main suspect. In fact, GERD patients may also show an elevated count of eosinophils, but this elevation is much lower than in EE patients.

At this time, the only reliable method used to diagnose EE is the upper endoscopy with multiple biopsies. The barium swallow test may show irregularities in the shape of the esophagus caused by EE, but not all patients have such physical characteristics. The endoscopy is performed by a gastroenterologist, a specialist in pathology associated with the GI tract. The upper endoscopy is normally done as an outpatient procedure, with local anaesthetic spray or the administration of mild sedation. Biopsy samples must be taken from multiple sites on the surface of the esophagus, to ensure that the condition is not overlooked.

More recently, researches have begun looking for links between EE and autoimmune diseases. Some EE patients suffer from skin conditions such as psoriasis or seborrheic dermatitis or respiratory conditions such as asthma or allergic rhinitis. At this time, there appears to be no proven link between EE and esophogeal cancer.

FIGURE 2. 

Possible diagnostic and treatment algorithm for dietary intervention alone in adults with eosinophilic esophagitis (EE). EGD = esophagogastroduodenoscopy; Eos = eosinophils; HPF = high-power field. Adapted from Ann Allergy Asthma Immunol,24 with permission.

Treatment

Treatment strategies include dietary modification, medical therapy, and mechanical dilatation of the esophagus. The initial approach to the disorder is often allergy evaluation as described above in an attempt to identify the allergens in the diet or environment. If the offending agent is found, the diet is modified so that these allergens are eliminated. There are cases, especially in children, where there are multiple food allergies involved. Some patients require an elemental diet through the use of a specialty formula. Sticking to this diet and drinking the required amount of formula can be difficult. The use of feeding tubes in these situations is often required. A minority of EE patients appear to be non-atopic (non-allergic), yet still present with this disease. Eosinophilic Esophagitis can cause severe pain in many patients.

Medical therapy begins with acid-inhibition medication. A sizable minority of patients with EE have some reflux component to their condition which warrants such treatment. Proton pump inhibitors are often the first-line medical therapy. EE patients by definition have persistent symptoms even with acid-inhibition therapy. For this reason, alternative medical therapies are often employed. Treatment that targets the inflammation includes swallowed corticosteroids such as fluticasone,a topical viscous budesonide oral suspension, leukotriene modifiers like montelukast, and anti-interleukins such as the anti-IL-5 monoclonal antibody mepolizumab. Other drugs attempt to halt the allergic response; these include antihistamines such as loratadine. Patients with severe symptoms despite these interventions may require oral corticosteroids such as methylprednisolone. Mechanical dilatation may be considered in severe cases of EE that have progressed to esophageal stricture or severe stenosis. Dilatation is accomplished by passing dilators through the mouth and down the esophagus to gently expand its diameter. As the esophagus of patients with EE is rather thin and delicate, care is taken not to perforate the esophagus by overzealous dilatation.

Currently, 2 treatment modalities are available for EE. The first is avoidance of the inciting antigen, best established by an elemental amino acid diet. The second modality is pharmacologic, in which anti-inflammatory medications and biological agents have been used.

Elimination and Elemental Diets—Lessons From Studies in Children

Elimination diets have resulted in impressive clinical and histological improvement . Further, advances in the diagnosis of food allergies, along with an improved understanding of the underlying allergic mechanisms of this disease, could lead to even more success in the future. These diets remove all antigenic stimuli, thereby reducing inflammation.

Kelly et al were the first to report the successful treatment of children with EE using an elemental diet. They used Neocate (Nutrica, Gaithersburg, MD), a 1-crystalline amino acid-based formula that removes all intact complex proteins. Rapid, complete symptomatic resolution occurred in all 10 patients. After follow-up endoscopy, histological improvement was noted in all 10 subjects, with complete resolution documented in 5.

When rechallenged with foods, 9 of 10 patients had recurrent symptoms. In this study, milk, soybeans, wheat, peanuts, and eggs were the most common inciting foods, as determined by open food challenges, which were carried out at home after the initial treatment period. Once the offending food was again eliminated, patients remained asymptomatic for a 6-month follow-up period. Notably, none of the foods that were identified on open challenge to be causative of symptoms were found on skin prick testing. This finding suggests a more complex or mixed allergic mechanism, pointing to the need to evaluate for non-IgE-mediated allergies.

Markowitz et al treated 51 pediatric patients with EE with an elemental diet for 1 month. The diet consisted of free amino acids, corn syrup solids, and medium-chain triglyceride oil; the patients were also allowed water. Of the 51 patients, 48 (94%) required nasogastric tube placement for delivery of this elemental diet. Symptomatic improvement occurred in nearly all patients, and follow-up endoscopy documented a marked decrease in esophageal eosinophilic infiltration. After symptomatic and histological improvement, foods were slowly reintroduced, allowing for evaluation of reactions to each specific food. On the basis on their results, these authors concluded that an elemental diet was the best treatment option for children with EE.

In a study of 24 patients with EE, Spergel et al found that skin prick and patch testing determined the offending food in 75% of patients. Removal of the offending foods led to symptomatic improvement in all patients, with complete resolution of symptoms in 18 of 24. Follow-up biopsy specimens showed histological improvement and, after rechallenge, an increase in eosinophils. Eggs, milk, soybeans, and peanuts were the allergens most commonly identified by skin prick testing, whereas corn, wheat, soybeans, and chicken were the most often identified by skin patch testing.

In a study by Spergel et al of 146 pediatric patients with EE who were evaluated using skin prick and patch testing, 77% showed histological improvement after following an elimination diet for 6 weeks. An additional 13% had symptomatic improvement, but biopsy specimens obtained after the intervention showed a persistent elevation in eosinophils. Esophageal eosinophilia returned after food reintroduction in 39 of 112 patients with EE who had responded to the elimination diet. Ten percent of patients did not respond; these patients tended to be older. Notably, all but 3 of the 15 patients who did not respond to an elimination diet improved when treated with an elemental diet. Overall, these authors reported a greater than 75% treatment success rate for symptomatic and histological improvement through a combination of skin prick and patch testing.

These large reports have led others to treat children with EE using both elemental and elimination diets, with good responses.Liacouras et al found symptomatic improvement in 247 of 381 pediatric patients with EE after dietary manipulation. Of these 247 patients, 75 improved with restriction alone and 172 with an elemental diet, as determined by allergy testing and a combination of skin patch and prick testing. The elemental diet was continued for approximately 6 months, including the reintroduction phase.

In contrast, Teitelbaum et al performed allergy tests on 15 children with EE and identified specific food allergies in 11. These patients were then given restrictive diets (on the basis of skin prick testing and RAST testing results) for 8 weeks, and no symptomatic improvement was noted. Patients without an identified allergy received medical therapy, and 9 of the 11 patients responded to fluticasone propionate. This study suggests that the simple restriction of foods might not be sufficient for treatment and that elemental diets might be necessary. However, these authors did not use skin patch testing and might not have identified accurately all food allergies contributing to the disorder, evaluating only IgE-mediated allergic reactions.

Medical Therapy

Anti-inflammatory therapies, which include fluticasone propionate or budesonide that is swallowed by the patient, have been shown to improve the symptoms caused by EE. The goal is to swallow approximately 80% of the medication, aiming for topical delivery of the medication to the affected areas of the esophagus. Treatment with prednisone or montelukast can improve symptoms but often only temporarily. Symptoms often tend to recur with cessation of treatment, leading to multiple courses of therapy. These therapies, which can be costly, require patients to take medications, possibly on a long-term basis, and may lead to adverse effects. Adverse effects of fluticasone propionate include oral thrush and esophageal candidiasis. However, patients who require systemic corticosteroids are exposed to the multiple, often severe adverse effects associated with the long-term use of these agents.

Recently, an open-label phase 1/2 study evaluated mepolizumab, a monoclonal antibody against IL-5, for patients with severe EE. This medication may reduce the proliferation, maturation, production, activation, and tissue recruitment of eosinophils into the esophagus. Stein et al reported on 4 patients with EE who underwent 16 weeks of treatment with mepolizumab, with follow-up esophageal biopsies at week 20. Results showed improvement in clinical symptoms, enhancement in quality of life, and a decrease in eosinophils on biopsy. Endoscopic findings improved in 3 of 4 patients. The medication was well tolerated overall. Because aeroallergens are a suggested trigger in the development and exacerbation of EE, mepolizumab could be especially effective in patients with an aeroallergen trigger.

Esophageal dilation has been used to address the complications of EE, such as strictures, but provides only a transient improvement. Symptomatic treatment does not address the underlying etiology of the disorder, which, if altered, could ultimately provide a lasting cure. These medications treat the final manifestation of the eosinophilic infiltration without addressing the primary cause. We do not know the long-term prognosis of patients with EE and whether any complications, such as stricture, food impaction, or even esophageal cancer, could be related to a protracted course or to a longer history of active disease. Straumann et al followed up 30 adult patients over a mean of 7.2 years and noted that 97% had persistent dysphagia and 71% an episode of food impaction. This study also suggested that chronic inflammation might lead to permanent structural changes, with a long-term and progressive risk of impairment in function.

Food Elimination Diets

Treatment algorithms for addressing food allergies in patients with EE have been developed. Whereas some recommend patch testing as the method of choice for identifying “culprit foods,” recent studies suggest that a combination of skin prick and patch testing might be the most effective approach. If offending foods are identified, they should be eliminated, and esophagogastroduodenoscopy (EGD), also known as upper endoscopy, with biopsy should be undertaken in 6 to 8 weeks to document a decrease in eosinophils. If 15 or more eosinophils per high-power field are present, the patient should then be given an elemental diet. If no food allergens are identified on patch testing, an elemental diet is recommended at the time of diagnosis, with EGD 4 weeks later to document resolution. If fewer than 15 eosinophils per high-power field are seen, a food allergy would be confirmed as the etiology of the disorder, and a slow reintroduction diet can be undertaken. Foods should be reintroduced every 5 to 7 days, with endoscopy and biopsies performed after a group of 5 foods has been reintroduced. Markowitz and Liacouras have constructed a food chart, which suggests the order in which foods should be reintroduced. The foods most likely to cause a reaction, such as milk, eggs, soybeans, wheat, nuts, and corn, are reintroduced last.

If food allergies are identified to multiple foods (up to 6 or more in some reports), a large number of foods might need to be eliminated. Adherence to such food avoidance diets for the weeks to months necessary for full effect can be difficult in adults who might consider them unpalatable. In many children, successful delivery of the diet requires placement of nasogastric tubes. The most definitive elimination diet is an elemental amino acid diet, which is unpalatable to most adults. However, such a diet could indicate whether a less stringent elimination might be successful. In addition, frequent EGDs with biopsies might not be readily available in some areas, and the cost of the frequent procedures could be prohibitive.

Reference

 

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children’s ALLERGY Center online

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Clinical and Editor in Chief :

dr Widodo Judarwanto

email : judarwanto@gmail.com 

 

Information on this web site is provided for informational purposes only and is not a substitute for professional medical advice. You should not use the information on this web site for diagnosing or treating a medical or health condition. You should carefully read all product packaging. If you have or suspect you have a medical problem, promptly contact your professional healthcare provider. 

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