Pediatrics

Encephalitis

OVERVIEW: What every practitioner needs to know about eosinophilic gastrointestinal disease

How do you define eosinophilic gastrointestinal disease?

Eosinophilic gastrointestinal diseases (EGIDs) are a broad group of diseases characterized by gastrointestinal complaints and intestinal eosinophilia. A mucosal biopsy is required to make the diagnosis.

EGIDs have been classified in two ways, either according to the organ(s) involved or the layer of the intestinal wall that is affected. When classified by organ system, they can be divided into eosinophilic esophagitis, gastritis, enteritis, and colitis, although more than one organ system may be involved. When classified by stratum of intestinal wall affected by eosinophilic infiltration, EIGDs can be divided into mucosal, muscular, and serosal disease.

What are the symptoms of EGIDs?

The symptoms of eosinophilic esophagitis (EoE) vary according to age of presentation. Children often present with vomiting, abdominal pain, and feeding difficulties, while adults and adolescents more commonly present with dysphagia and food impaction. Eosinophilic gastritis (EG) is associated with abdominal pain and vomiting. Patients with eosinophilic gastroenteritis (EGE) and eosinophilic colitis (EC) usually complain of abdominal pain and diarrhea.

The symptoms of EGIDs also vary by layer of intestinal wall affected. Eosinophilic mucosal disease is associated with diarrhea and bleeding. Muscular disease can cause wall thickening and abnormal motility leading to vomiting, abdominal pain, and obstructive symptoms. Serosal disease can be found in conjunction with mucosal or muscular disease. Symptoms often include abdominal swelling and ascites. Diagnosis may be made by paracentesis, revealing copious eosinophilia

How do EGIDs typically present?

Eosinophilic esophagitis (EoE) can present with symptoms as noted above, as well as feeding problems or abdominal pain in children. Some patients present with symptoms of gastroesophageal reflux disease (GERD) that have been recalcitrant to conventional medical and/or surgical treatment for GERD. EoE is also one of the most common causes of food impaction in children and adults. EG can present with unexplained ulcers.

EGE may present without overt GI symptoms but could have peripheral edema, anemia, or hypoalbuminemia because of mucosal losses. EC can present with symptoms of colitis that are indistinguishable from inflammatory bowel diseases.

What causes EGIDs and how frequently do they occur?

To date, EoE is thought to occur when a genetically primed host encounters a reaction to a food allergy. No predisposing factors have yet been identified, but the epidemiology is following the same trend as the "atopic march" being seen in other allergic diseases such as asthma and eczema, suggesting environmental triggers. Patients with EoE typically have normal physical examinations, and may or may not have peripheral eosinophilia on blood counts. The other EGIDs are idiopathic in nature. No predisposing factors have been identified.

Based on limited data, the current incidence of EoE is estimated at 1 - 4 per 10,000. The disease has a male predominance of 3:1 and affects both children and adults. It has been reported on all continents except Africa. The other EGIDs are very rare diseases, and accurate incidence estimates and epidemiological data are limited. One study suggests an estimated prevalence of EG at 6.3, EGE at 8.4, and EC at 3.3 per 100,000.

Several genes (eotaxin-3, filaggrin, thymic stromal lymphopoietin) have been associated with certain groups of patients with EoE. A recent study showed an increased risk of EoE associated with the 2p33 locus of the genome, correlating with the CAPN14 gene.

How do these pathogens/genes/exposures cause the disease?

Limited basic and translational studies support a role for an aberrant immune response in the pathogenesis of EoE. In mice, overexpression of interleukin-5, interleukin-13, and/or eotaxin-3 leads to eosinophilic inflammation following an exposure to an intraluminal allergen. Some patients with EoE have a distinctive cytokine profile that predisposes them to esophageal eosinophilia following ingestion of allergenic foods. The CAPN14 gene is expressed in the esophagus and is upregulated after response to interleukin-13.

What other diseases share the symptoms of EGIDs?

Gastroesophageal reflux disease is by far the most common disease that shares symptoms, endoscopic findings and histological patterns with EoE. Other diseases that can be confused with EGIDs include inflammatory bowel disease, celiac disease, hypereosinophilic syndrome, and intestinal infections such as Giardia. An emerging body of literature has described a group of patients who have PPI-responsive esophageal eosinophilia. These patients have normal pH study results but have a clinicopathologic response to proton pump inhibition. All other causes of esophageal eosinophilia need to be ruled out before assigning a diagnosis of EoE.

What other clinical manifestations may help with diagnosis and management?

Both children and adults with EoE may present with feeding/swallowing difficulties that may not be easily identified because coping mechanisms have developed. If the patient is simply asked if there are eating or swallowing problems, the answer may be "no." If asked whether food has to be chewed excessively, water is required to facilitate swallowing solid food, or if the patient avoids certain foods such as meats, or breads, the answer may be yes.

Rarely will patients with EGIDs present with anemia, hypoalbuminemia, and intestinal eosinophilia with little to no gastrointestinal symptoms. When treated with corticosteroids, the eosinophilia and other laboratory abnormalities resolve. The pathophysiology of this is unknown.

What should be done if an EGID is suspected?

If symptoms for EoE above are identified, one should treat for GERD with proton pump inhibitors to see if a clinical response is obtained. If not, patients should be referred to a gastroenterologist for further evaluation and potential endoscopy. In adults, symptoms of dysphagia may prompt an evaluation for an alternative diagnosis, such as cancer.

Two guidelines have been published to support this algorithm based on clinical experience, expert opinion, and an increasing amount of supporting literature.

For other EGIDs, if symptoms are not explained by cultures, radiographs, or blood tests, an endoscopy or colonoscopy is indicated to obtain diagnostic information.

What studies can help confirm the diagnosis? How should the results be interpreted?

A mucosal biopsy obtained at the time of endoscopy is required to confirm the diagnosis of EoE. Since EoE is a clinicopathological diagnosis, the biopsy findings must be interpreted in the clinical context in which they were obtained. If the patient was on high-dose proton pump inhibitor treatment at the time, mucosal biopsies of the stomach and small intestine are normal, the esophageal biopsy reveals >15 eosinophils per high power field, and no other diseases are thought to be the cause of the inflammation and symptoms, the diagnosis of EoE can be made.

The diagnosis of the other EGIDs is more complicated as the stomach, small intestine, and large intestine normally have a resident population of mucosal eosinophils. Discussion with the gastroenterologist and pathologist is usually necessary to properly interpret the histological findings in the context of the clinical scenario. Anemia, peripheral eosinophilia, hypoalbuminemia, and electrolyte abnormalities can all be seen but are not required for diagnosis.

Are additional laboratory studies available, even some that are not widely available?

Peripheral eosinophilia may be present but is a non-specific finding for EGIDs as they may be elevated because of other atopic diseases. If eosinophilia is >1500/mm3 for a prolonged period and there is evidence for other target organ damage, hypereosinophilic syndrome should be considered.

Measurements of interleukin-5, eotaxin-3 and interleukin-13 may be helpful to characterize some patients but their clinical relevance is unverified to date.

Are imaging studies be helpful? If so, which ones?

In diagnosing EoE, an upper gastrointestinal series is useful to help exclude other causes of symptoms and assess for possible esophageal stricture - one of the few complications of this disease. Recent evidence suggests that an esophagram is better than endoscopic assessment to determine if a stricture is present or not.

In evaluating patients for eosinophilic gastritis, enteritis and colitis, an upper gastrointestinal series, abdominal computed tomography (CT) scan with oral contrast or magnetic resonance imaging (MRI) may be useful to exclude other causes of symptoms. Since endoscopy cannot assess most of the intestinal mucosa, radiologic tests and capsule imaging may be the only imaging available. These studies may also be helpful in identifying complications that require further attention.

When clinical history raises suspicion for eosinophilic colitis, an abdominal CT with intravenous and oral contrast agents may be helpful. CT examination may reveal right colonic wall thickening with greater involvement of the cecum and ascending colon with less severe to no involvement of the distal colon and terminal ileum.

If you are able to confirm that the patient has eosinophilic esophagitis, what treatment should be initiated?

EoE can be treated by avoidance of potential dietary allergens or with topical steroids. EoE is treated medically with topical steroids using metered dose inhalers commonly used for the treatment of asthma. When used for EoE, the administration technique is completely opposite of that used for asthma. The patient inserts the mouthpiece into the mouth without a spacer, activates the spray without inhaling, and then swallows the aerosolized powder. Topical steroids can also be administered in a viscous solution of budesonide respules mixed with sucralose. Regardless of method of delivery, the patient should not eat or drink for 30 minutes.

Nutritional exclusion of potential dietary allergens is best performed under the expertise of an allergist. If dietary approaches are used, a dietician should be consulted to insure that proper calories, protein, vitamins, and micronutrients are provided. Decisions regarding the therapeutic approach (i.e., medical versus nutritional) are complex and require examination of potential side effects, quality of life and costs.

What are the adverse effects associated with each treatment option?

Topical and systemic corticosteroids have been associated with growth disturbance, cataracts, diminished bone density, behavioral changes, acne and infections. These potential side effects occur rarely with the use of topical steroids. Treatment with dietary therapy can lead to nutritional deficiencies depending on type and extent of food removed.

What are the possible outcomes of eosinophilic esophagitis?

EoE is a chronic disease without an identified cure. In general, patients live a normal life. Treatments are effective in relieving symptoms in 75 - 95% of patients but the overall impact on reducing complications is not yet known. If untreated, patients with EoE may experience esophageal strictures and food impactions. Younger children may experience feeding difficulties. Cancer has not been associated with this disease, and typically surgery is not required.

After a patient experiences clinical and histological remissions, decisions about maintenance treatments will be required to balance out the risks and benefits of either steroids or diet exclusions. Patient will require ongoing treatment that may be daily or intermittent.

Stricture formation is a major complication of EoE. Strictures can be found in over one-third of all patients with an increase in prevalence associated with diagnostic delay. The presence of esophageal strictures correlates with endoscopic fibrotic features, but not with eosinophil counts at time of diagnosis. Additionally, age of EoE symptom onset is also not associated with stricture formation at the time of EoE diagnosis.

How can eosinophilic esophagitis be prevented?

No preventative measures have been identified for EoE or other EGIDs; however, complications of EoE can be prevented with early diagnosis and treatment. As described earlier, delay in diagnosis is the only factor associated with the development of stricture formation. Food impactions can also be lessened with prevention of stricture formation. Reduction in food impactions has been correlated with duration of swallowed topical corticosteroid treatment.

What is the evidence?

In July 2011, the second consensus report with guidelines based on expert clinical experience and review of the literature was published.

The American College of Gastroenterology also released clinical guidelines in June of 2012 providing an evidence-based approach to diagnosing and managing EoE. These reports provide the most up-to-date evidence and guidance for detailed management and treatment of EoE. A similar report has recently been published that examines the evaluation and consequences of esophageal eosinophilia in Europe.

Furuta, GT, Katzka, DA. "Eosinophilic Esophagitis". N Engl J Med. vol. 373. 2015 Oct 22. pp. 1640-8.

(Provides a detailed review of the current state of clinical knowledge of and research into eosinophilic esophagitis.)

Ongoing controversies regarding etiology, diagnosis, treatment

The underlying etiology of EoE is thought to be food allergens but some patients may have environmental or autoimmune etiologies. Diagnostic criteria are based primarily on expert clinical experiences and limited research.

Histological patterns and the number of "diagnostic" eosinophils remains a topic of ongoing definition.

Evaluation for suspected food allergens has not been standardized. Recently, the role of allergy testing in identifying food triggers has undergone more examination. Multiple studies in both adult and pediatric populations have demonstrated that allergy tests have limited predictive value in determining the response to dietary elimination - particularly in predicting response to the most commonly associated food allergens in EoE. Other advantages of directed food elimination diets that are based on allergy testing may include the potential of decreasing the number of foods that must be avoided. What part allergy testing will play in the management of eosinophilic esophagitis in the future is yet to be determined.

Treatments have been limited to steroids and nutritional exclusions; ongoing studies examine the influence of monoclonal antibodies such as anti-interleukin-5 and anti-interleukin-13 for treatment.

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