Allergic and Dietary Immune Disorders

Dietary immune disorders are common in pediatrics and account for a large part of pediatric gastrointestinal (GI) practice. The prevalence and number of different disorders has been increasing. In this guide, we focus on the most common diagnoses.

• Celiac Disease

• Food Protein-Induced Allergic Proctocolitis of Infancy (FPIAP)

• Eosinophilic Esophagitis

Celiac Disease

Celiac disease (CD) results when immune, genetic, and environmental factors interact to cause an intestinal immune reaction to gluten. Gluten, a storage protein found in wheat, barley, rye, and other grains, is the dietary factor that triggers CD in children with a genetic predisposition for the disorder, typically conferred by the DQ2 or DQ8 human leukocyte antigen (HLA) haplotypes. The prevalence of CD ranges between 1 in 300 and 1 in 80.

Pathogenesis

The following figure details the pathway from gluten ingestion to the development of CD. Gluten is digested by luminal and brush-border enzymes into amino acids and peptides. Through modulation of both the innate and adaptive immune systems, gluten-induced inflammation leads to villous atrophy, crypt hyperplasia, and intraepithelial lymphocyte proliferation.

(Source: Celiac Disease. N Engl J Med 2007.)

Symptoms and Signs

Symptoms of CD in pediatric patients are wide-ranging. Some symptoms are gastrointestinal (GI) in nature, some are related to complications associated with prolonged malabsorption, and others are poorly understood. Younger children tend to present with more-typical GI symptoms such as diarrhea and abdominal pain. Older children more commonly present with less-classic GI symptoms and are more likely to have fatigue, weight loss, and/or headaches. Note that some children present counterintuitively with constipation. How the celiac inflammatory process impairs motility is not clear.

Associated conditions: A number of autoimmune and nonautoimmune conditions are associated with an increased prevalence of CD. The reason for these associations, particularly the association with genetic conditions, is not well understood.

Diagnosis

The diagnosis of CD is confirmed by histopathologic analysis of duodenal biopsies obtained during esophagogastroduodenoscopy (EGD).

Testing for CD includes laboratory evaluation followed by upper endoscopy and biopsies in the appropriate clinical context.

• Laboratory testing: Laboratory testing should be considered for patients with particular signs or symptoms and for patients with particular medical conditions associated with an increased burden of CD (see table above). Tissue transglutaminase immunoglobulin A antibody (tTG-IgA) and total IgA levels have long been the first-line laboratory test for identification of patients with suspected CD. Other antibody testing can be considered based on age and associated medical conditions as described in the table below.

  

  (Source: Celiac Disease. N Engl J Med 2012.)

• Gastroenterology referral and upper endoscopy (EGD) with duodenal biopsies: Confirming or excluding a diagnosis of CD with EGD is recommended in the following scenarios:

  • an elevated celiac antibody test

  • a strong clinical suspicion for CD whether or not antibody testing is abnormal

In some contexts, the magnitude of the celiac-antibody-testing elevation is sufficient to make a diagnosis of CD, without EGD. However, given the lifelong dietary modification required to manage CD, the potential negative consequences of a non-biopsy diagnosis should be seriously considered. Gastroenterology consultation is still recommended to ensure no other reasons for endoscopy evaluation are identified and assure proper nutrition and laboratory follow-up.

Multiple biopsies in the duodenum and duodenal bulb are recommended because CD changes may be patchy. Villous atrophy, crypt hyperplasia, and infiltrative changes are classic features seen histopathologically.

If biopsies are inconclusive, human leukocyte antigen (HLA) testing and empiric gluten-free diet (GFD) trial may be helpful. Patients should not undergo a trial of a GFD before the initial endoscopy, due to the possibility for GFD-related mucosal healing and increased likelihood of false-negative testing.

Treatment

In patients in whom a diagnosis of CD is confirmed, strict adherence to a GFD is required for life. Untreated CD is associated with increased morbidity, mortality, risk of adenocarcinoma and intestinal lymphoma, short stature, and osteoporosis. Patients with confirmed CD should meet with both a gastroenterologist and a CD-trained nutritionist to understand the complexity, cost, and implications of the GFD.

Gluten-free diet: Treatment with a GFD is the only scientifically proven treatment for patients with CD. The table below provides a list of starch sources that are compliant and noncompliant with the GFD. Consumption of foods with >20 parts per million of gluten (about one-fiftieth of a slice of toast) consumed daily is sufficient to induce mucosal abnormalities in patients with CD, making strict adherence to the GFD essential. Levels of tTG-IgA can be followed to assess disease activity, and normalization of tTG-IgA levels may correlate with mucosal healing, although repeat endoscopy with duodenal biopsy is the only way to ensure full mucosal healing. Levels that do not improve or rise after normalizing suggest nonadherence or accidental ingestion and the need for consultation with a specialized nutritionist.

This table describes fundamentals of the gluten-free diet, detailing the grains to be avoided, those grains that are safe for consumption, and other sources of gluten-free starch.

(Source: Celiac Disease. N Engl J Med 2007.)

Food Protein-Induced Allergic Proctocolitis of Infancy (FPIAP)

Food protein-induced allergic proctocolitis of infancy (FPIAP) is a common problem in infancy, affecting as many as 17% of young infants. Cow’s milk protein is the leading food that causes FPIAP, followed by soy protein. Symptoms usually begin within the first several weeks of life. The pathogenesis of FPIAP is poorly understood and is related but distinct from immunoglobulin E (IgE)-mediated allergic responses (see Food Allergy in the Pediatric Allergy and Immunology rotation guide). A figure that distinguishes IgE and non-IgE-mediated pathogenesis can be viewed here.

FPIAP is pathologically characterized by varying degrees of colonic inflammation induced by the offending food protein(s). Prognosis is generally good, and most children can tolerate triggering foods without symptoms by 1-2 years of age.

Two related, less common, but more-severe non-IgE-mediated food protein-induced disorders include:

• food protein-induced enteropathy, in which the small bowel is primarily affected

• food protein-induced enterocolitis syndrome (FPIES), in which large portions of the GI tract can be affected and symptoms are severe and life-threatening

  • FPIES ought to be considered when infants present with recurrent vomiting, distention, temperature and hemodynamic instability, and voluminous watery diarrhea within hours of ingesting a potential antigen.

  • Usually presents within the first 2 years of life, similar to FPIAP, but is associated with a more systemic presentation. Typical triggers are milk, soy, rice, and oats.

Symptoms

Symptoms of FPIAP are related to the inflammatory process induced by the food protein in the colon. Symptoms are generally seen in the first few months of life. These include:

• blood in stools, either with or without diarrhea

• mucus-filled stools with or without gross blood

• difficulty passing stool (dyschezia), with or without gross blood

• eczema

Red-flag symptoms and signs of a more serious condition include:

• ill appearance

• weight loss

• significant vomiting or bilious vomiting

• significant abdominal distention

• edema

• dehydrating diarrhea

Testing and Diagnosis

There are no widely accepted guidelines for the testing and diagnosis of FPIAP in pediatric patients in North America. The European Society for Gastroenterology, Hepatology, and Nutrition (ESPGHAN) has established practical guidelines for the diagnosis and management of cow’s-milk protein allergy (CMPA), summarized as follows and in the CMPA evaluation pathway below:

• The first step in evaluating for possible FPIAP is a thorough history and physical exam. A careful review of family history with attention to atopy is also important.

• For patients without anaphylaxis or immediate-type IgE-mediated symptoms, the value of serological tests is limited.

• Stool guaiac testing should be performed to determine if occult blood is present in the stool, although a negative result does not rule out allergy.

• For well-appearing infants with typical FPIAP symptoms, laboratory tests are unnecessary. For infants with prolonged bloody stools, a complete blood count and iron studies are reasonable.

• The gold-standard diagnostic test for non-IgE-mediated CMPA is elimination of all dairy products from the patient’s diet with resolution of symptoms thereafter, followed by a challenge that leads to recurrence of symptoms.

  • Formula-fed infants should be transitioned to formulas containing extensively hydrolyzed proteins.

  • Mothers who wish to continue breastfeeding should be encouraged to continue breastfeeding but must eliminate all dairy-containing products from their diet.

• Mucosal healing may take several weeks, and improvement of clinical symptoms is gradual. Some patients may require transition to a fully elemental/amino acid-based infant formula before a diagnosis of CMPA can be excluded.

For patients with FPIAP, the value of endoscopy with biopsy is limited because findings are nonspecific and generally improve with dietary changes. Endoscopy should be reserved for patients with otherwise significant and persistent symptoms that may be secondary to a diagnosis other than CMPA. The ESPGHAN Stepwise Approach to Diagnosis of CMPA in the Pediatric Population can be found here.

Treatment and Prognosis

Treatment of FPIAP is based on elimination of the offending food antigen from the infant’s diet. Cow’s milk protein, egg, and soy protein are the most common offending foods, in decreasing order of prevalence.

• For breastfeeding infants, mothers should eliminate all dairy products. Improvement usually will occur within 2-4 weeks. Common practice is to start the elimination diet with dairy exclusion. If symptoms do not resolve, egg and soy elimination can be considered. Mothers and other primary caregivers should consult with a dietitian to make sure the mother’s diet and the elimination are optimized.

• For formula-fed infants, switching to an extensively hydrolyzed formula is recommended. Intact soy formulas should be avoided because a good proportion of infants with FPIAP are also sensitive to soy. Rarely, fully elemental (amino acid-based) formula is required for resolution of the symptoms.

No established guidelines exist for standardized reintroduction of offending foods. A common historical practice was to reintroduce foods at 1 year of age. However, a recent trend promotes reintroduction of the withdrawn protein earlier (closer to 6-9 months of age). For infants with significant atopy, it is appropriate to consider reintroduction in collaboration with a pediatric allergist or gastroenterologist.

Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated, eosinophil-predominant inflammatory disorder of the esophagus that results in symptoms of esophageal dysfunction, including dysphagia, midsternal pain with a burning sensation, and food impaction. As with many allergic conditions, EoE prevalence appears to be increasing, with an estimated prevalence of 26 per 100,000 persons in the United States according to a large database study. EoE predominantly affects male patients with a history of atopy. Diagnosis is via endoscopic biopsy of the esophagus.

Treatment

Treatment with elimination diets or ingested topical glucocorticoids are the mainstay of management. Monoclonal antibody therapy with dupilumab has also become a prevalent treatment for EoE. Some patients develop esophageal strictures that require esophageal dilatation. The figure below details the stepwise process from exposure to inflammation to fibrosis that characterizes EoE.

(Source: Eosinophilic Esophagitis. N Engl J Med 2015.)

Symptoms

Children with EoE may exhibit a wide variety of symptoms with variable severity.

• In younger children, presenting symptoms include poor weight gain, picky eating, gastroesophageal reflux disease (GERD), nausea, emesis, and avoidant-restrictive eating.

• In older children and adults, classic symptoms of dysphagia and food impaction are common.

• Detailed history may reveal that a patient with EoE takes small bites, chews food slowly, swallows food after drinking liquids, and avoids foods associated with dysphagia (e.g., meat).

• Significant food- and eating-related anxiety may develop after initial food impaction episodes. As many as half of patients who undergo endoscopy for alleviation of food impaction are diagnosed with EoE.

• Red-flag symptoms that may indicate need for endoscopic treatment of impaction or other causes of esophagitis include the following:

  • persistent sensation of food impaction

  • hematemesis

  • inability to handle secretions

  • fever

Diagnosis

Biomarkers to diagnose EoE and gauge severity of the disease are currently lacking. Peripheral eosinophil count is of limited use because patients with EoE often have other atopic conditions (e.g., asthma and eczema), and as a result, elevated eosinophils may not necessarily represent mucosal inflammation.

Upper endoscopy with esophageal biopsy is the only generally accepted means of diagnosing and monitoring EoE. The role of transnasal endoscopy to monitor treatment response in EoE is expanding as it can avoid the need for general anesthesia.

• On gross examination of the esophagus, characteristic linear furrowing, mucosal friability, white exudates, concentric rings conferring a “trachealized” appearance to the esophagus, and mucosa with a crepe-paper-like texture may be evident (see first figure below).

• Biopsies should be obtained from proximal, mid, and distal regions of the esophagus to gauge severity and extent of the disease.

• Histologically, although several types of intraepithelial inflammatory cells may be observed, at least 15 eosinophils per high-powered field are needed for the diagnosis of EoE. The first image below details commonly encountered mucosal findings in EoE, and the second image details histologic findings in the esophageal biopsy of a patient with EoE.

(Source: Eosinophilic Esophagitis Is an Underlying Cause for Gastrointestinal Concerns in Children. Front Pediatr 2018.)

(Source: Eosinophilic Esophagitis. N Engl J Med 2015.)

Imaging: Although radiologic imaging is not routinely needed for the diagnosis of EoE, patients with advanced EoE may exhibit esophageal narrowing and stricturing on contrast esophagram. Severe stenosis in the distal esophagus may manifest as a Schatzki ring, although these rings are not pathognomonic for EoE. The following image of an esophagram of a patient with EoE shows luminal narrowing secondary to chronic inflammation.

(Source: Eosinophilic Esophagitis Is an Underlying Cause for Gastrointestinal Concerns in Children. Front Pediatr 2018.)

Treatment

Patients with untreated EoE may develop esophageal stricturing, dysphagia, and food impaction. To minimize the likelihood of these complications, patients benefit from coordinated medical care by a gastroenterologist, allergist, and nutritionist.

• Initial management may include measuring serum IgE levels to the most common food allergens, followed by subsequent elimination of those foods with high serum-IgE levels.

• Alternatively, patients may eliminate the six most frequently identified types of allergenic foods (milk, wheat, soy, nuts, eggs, and seafood). Through subsequent reintroduction of these foods and repeat endoscopic evaluation, the elimination diet can be tailored and the patient’s diet may be liberalized.

• Pharmacologic therapy may be undertaken in conjunction with elimination diets.

  • Topical glucocorticoids (administered via ingestion of budesonide or fluticasone from a metered-dose inhaler or mixed into a slurry to be swallowed) may improve fibrosis risk and the likelihood of future need for endoscopic retrieval of an impacted food bolus.

  • Proton pump inhibitors (PPIs) are beneficial in a subset of EoE patients, possibly due to the anti-inflammatory properties.

  • The biologic medication dupilumab inhibits IL-4 and IL-13 to target inflammation in the esophagus. Dupilumab is a subcutaneous injection usually given once every 1 to 2 weeks. It is also used in patients with asthma and eczema and therefore may be beneficial in patients with atopy.

  • Serial esophageal dilations may be beneficial in some patients with esophageal narrowing, stricturing, or recurrent food impactions. Esophageal dilation is a safe procedure with a perforation rate of less than 1%. Although dilation may improve luminal narrowing, it has no role in treating the chronic inflammation that characterizes EoE.

Prognosis

EoE is a chronic, potentially lifelong illness. The long-term effect of elimination diets or ingested glucocorticoid use on patient outcomes is not currently known due to limited research. Nonetheless, the negative effect on quality of life secondary to dysphagia, recurrent food impaction, and dilation procedures, as well as the cumulative effect of chronic inflammation, should guide clinicians and patients to adopt therapies for which short-term benefits have been observed.