Clinical Presentation

Esophageal phase dysphagia is a common presentation of EoE. This is typically seen in school-age children and teenagers who present to the emergency department with esophageal food impaction. Many of these children will describe prior episodes of food feeling “stuck” in their esophagus and engaging in maneuvers to dislodge the bolus, such as drinking water. Vomiting is another common symptom, particularly in infants and young children. Other symptoms include abdominal pain and feeding refusal [31]. There are no characteristic physical or laboratory findings of EoE. Diagnosis rests on endoscopic and histological findings.

Diagnosis

Endoscopic findings suggestive of EoE include edema, linear furrowing (Fig. 37.1), white plaques (Fig. 37.2), trachealization, and paper esophagus [32]. Esophageal stenosis can be found in advanced cases. However, the esophagus can appear normal in some patients (Fig. 37.3), especially in infants and young children. Mucosal biopsies will show eosinophilic infiltration, eosinophilic microabscesses, basal cell hyperplasia, and varying degrees of fibrosis involving the lamina propria. Eosinophilic infiltration of the esophagus is the cardinal feature, and most authorities consider greater than 15 eosinophils per high-power field consistent with EoE [32–34]. The predictive power of this finding is greatest when present in biopsies proximal to the distal esophagus. For this reason, obtaining proximal and distal esophageal biopsies is recommended when evaluating children for EoE (Fig. 37.4). The differential diagnosis includes gastroesophageal reflux disease, inflammatory bowel disease, and eosinophilic gastroenteritis. The latter two should be suspected when the eosinophilic infiltration extends beyond the esophagus.

Treatment

The treatment of confirmed EoE usually involves collaborative care from gastroenterology, allergy, otolaryngology, and nutrition. The treatment goals include providing relief from current symptoms and preventing progression to esophageal stricture. The treatment strategy can be divided into two broad categories. The first is elimination of the offending antigen if possible. This strategy is not possible if the antigen cannot be identified. It may also not be possible if it is part and parcel of the patient’s environment or if the patient has numerous inciting antigens. The expertise of an allergist is key to this strategy. Food antigens are most amenable to this strategy, and empiric elimination of the common foods associated with EoE is often carried out (Fig. 37.4). This can be done one at a time. A more common practice is to remove four or six of the most likely foods all at once and then reintroduce them one at a time after histological follow-up. Sometimes an elemental diet may be required. Empiric food elimination is challenging and requires the involvement of an expert dietitian. Drug therapy is the second approach. Topical steroid therapy in the form of a slurry or swallowed from a metered dose inhaler is the most widely used drug treatment. Drug therapy is useful when an antigen cannot be found or removed or where compliance with an elimination diet is inadequate [35].

Prognosis

The main long-term complication of uncontrolled EoE is esophageal stricture formation. Compliance with an effective diet or drug regimen should prevent this complication. Unfortunately, compliance can be problematic in part due to the difficulty of adhering to an elimination diet or cumbersome treatments. This can be compounded by the lack of symptoms to motivate the patient despite ongoing destructive esophageal inflammation. At present, histological follow-up is the only practical way to assure treatment efficacy, but parents may be reluctant to subject their children to the endoscopy required to obtain the biopsies for histology.

Clinical Manifestations

The presenting complaint for EoE in the otolaryngology setting is similar to gastroenterology with one or more symptoms of dysphagia. In young children, this includes laryngopharyngeal reflux, regurgitation, vomiting, food avoidance, liquid dysphagia, failure to thrive, and nonspecific gastrointestinal complaints. Atopic dermatitis (atopy) in a child with uncontrolled laryngopharyngeal reflux may be evidence of EoE related to cow’s milk protein allergy [36]. The adolescent will present with difficulty swallowing and discomfort with solid food. However, dysphagia with solid food and food impaction is usually a late finding of EoE and a direct consequence of uncontrolled eosinophilic inflammation leading to esophageal fibrostenosis, a result of chronic secretion of cytotoxic agents that damage the esophageal epithelium and the release of remodeling factors such as transforming growth factor beta [12–14].

Nasal symptoms and rhinosinusitis are reported in approximately one-quarter of children with EoE [37, 38]. Symptoms include nasal congestion, obstruction, rhinorrhea, postnasal drip, facial pressure and pain, cough, pharyngitis, fever, and headache. There are several common symptoms shared between EoE and rhinosinusitis including chronic cough, hoarseness, and dysphagia [39]. Eosinophilic inflammation is a major hallmark of both rhinosinusitis and EoE. Tissue response to eosinophil degranulation is likely the pathophysiologic connection between the two diseases [39]. A possible mechanism for the relationship between EoE and rhinosinusitis is chronic allergen exposure through the nose and mouth. Chronic exposure in the nose results in rhinosinusitis. When the allergens are swallowed and enter the esophagus, eosinophil activation results in mucosal damage and EoE. In patients with recalcitrant gastrointestinal manifestations of rhinosinusitis (vomiting, regurgitation, nocturnal cough), EoE is a likely culprit.

Children with EoE may present with laryngeal symptoms of cough, hoarseness, globus sensation, and sleep-disordered breathing. Patients with EoE-associated laryngeal disease share similar characteristics to those with gastrointestinal symptoms, including a history of atopy and allergic rhinitis [39]. The initial indication may suggest laryngopharyngeal reflux as the cause of these symptoms. However, several reports describe patients with laryngeal disease refractory to acid reflux therapy who were eventually diagnosed with EoE [40–42].

EoE has also been implicated in the etiology of laryngeal diseases such as recurrent croup and subglottic stenosis. Recurrent croup is characterized by the abrupt onset of inspiratory stridor (most commonly at night) accompanied by a barky cough, hoarseness, and dyspnea [39]. Many of the triggers of recurrent croup are associated in the etiology of EoE, such as aeroallergens and asthma [37, 39, 41, 42]. Additionally, some patients with EoE and recurrent croup have been found to have concurrent subglottic stenosis (SGS). SGS is caused by chronic inflammatory changes in the subglottic region that lead to airway fibrostenosis. Patients with SGS present with symptoms of stridor, cough, croup, and airway obstruction. Severe stenosis requires surgical correction. Several groups have reported on the association between EoE and SGS [40, 41, 43]. An increased failure rate after airway reconstruction surgery has been observed in patients with EoE [44, 45]. Thus, in many institutions, an evaluation for EoE and treatment, if necessary, has become the standard of care for airway surgeons before attempting laryngotracheal reconstruction [39]. This includes esophagoscopy with proximal and distal esophageal biopsies when conducting preoperative airway surveillance (microlaryngoscopy and bronchoscopy).

The pathophysiology of laryngeal symptoms and diseases in EoE patients is poorly understood. The larynx is located in close proximity to the oronasal cavity and esophagus, especially in young children. Airway inflammation may be mediated by esophageal eosinophilic degranulation and Th2 cytokine response leading to laryngeal inflammation and edema [39]. Diffuse laryngeal edema can lead to hoarseness and the other previously described laryngeal symptoms. Additionally, it is plausible that eosinophilic proteins such as eosinophilic cationic protein and major basic protein can exert a cytotoxic effect on airway mucosa leading to the obstructive airway symptoms seen in patients with EoE and laryngeal disease.

Management

Similar to gastroenterology, early and accurate diagnosis is key to the management of EoE. This is often in the setting of an aerodigestive work-up for dysphagia and airway stenosis. Awake flexible fiberoptic laryngoscopy is used to examine possible disease manifestation in the upper airway in the early evaluation of patients with suspected EoE.

Close collaboration with gastroenterology, allergy/immunology, nutrition, and speech is paramount to effective treatment and is often culminated in a dedicated EoE multidisciplinary clinic. Feeding modifications, dietary restrictions, proton pump inhibitor, and topical steroid therapy (inhaled or slurry) are employed. Treatment strategies are tested for effectiveness with esophageal biopsies and histologic evidence of improvement. Laryngotracheal reconstruction will be delayed until EoE is safely controlled. Solid food dysphagia and esophageal fibrostenosis will be addressed with endoscopic dilation (often repeated), but treatment of the underlying disease is still required.

Role of Allergies in EoE

EoE is considered an atopic disease similar to asthma and allergic rhinitis as all are driven by a T helper (Th) 2 cell response leading to production of cytokines including IL-4, IL-5, and IL-13 [9, 46]. These cytokines activate and recruit eosinophils, as well as mast cells and basophils, to the esophagus leading to inflammation of tissues. As a result, patients develop clinical symptoms of gastrointestinal dysfunction and are at long-term risk for developing esophageal fibrosis [14, 47]. For many, this allergic inflammation is driven by exposure to antigenic food proteins which can be lessened by removal from the diet [2, 48]. There is some evidence that aeroallergens may activate EoE in a similar manner. As a result, identification of these triggers is an important aspect of EoE management.

Role of Allergy Testing in EoE

There are three different types of testing that can be performed to confirm a clinical suspicion of allergy: skin prick testing, serum-specific IgE testing, and atopy patch testing. Skin prick testing (SPT) involves the placement of an allergen extract onto the skin which is then “pricked” with a device to introduce the allergen into the epidermis or upper dermis where it can interact with mast cells in the skin. If a patient has IgE antibodies to the allergen, a reaction will be elicited, and a wheal with surrounding erythema will develop at the test site. Serum-specific IgE testing is an ELISA-based test utilizing the Phadia ImmunoCAP system (Thermo-Fisher/Phadia, Kalamazoo, MI) to detect the presence of IgE antibodies in the serum. In IgE-mediated food allergy, skin prick testing and/or serum-specific IgE testing are useful tests to confirm a clinical history of food allergy. Positive and negative predictive values are generally high, and clinical decisions can be made based upon the findings. Another form of testing called atopy patch testing (APT) can be utilized to identify non-IgE-mediated triggers in allergic conditions such as eczema and allergic contact dermatitis. In this form of testing, fresh foods or chemicals are placed into an aluminum Finn chamber which is then applied directly to the patient’s back. The test is left on for 48 h after which it is removed and the area examined and again at 72 h. If the patient has the presence of erythema and/or vesicles at the site of the test, the reaction is considered positive.

Although it is well established that foods are a common trigger for EoE, the role of allergy testing to identify the specific food trigger is less clear. There have been multiple studies evaluating the effectiveness of different forms of allergy testing for guiding the management of EoE. Overall, the results have been somewhat disappointing. In a study by Rodriguez-Sanchez et al., 73.1% of adults with EoE could obtain disease remission by utilizing an elimination diet based upon serum-specific IgE results compared to only 53% in those who empirically eliminated the top six most common triggers [49]. Unfortunately, other studies have not found allergy testing to be as reliable. In a study by Gonsalves et al., 50 adults underwent food elimination diets for treatment of their EoE. Skin testing was able to predict triggering foods in only 13% of subjects [50]. Spergel et al., in their study of pediatric EoE, found the negative predictive value for skin prick testing and atopy patch testing to be 92% (milk, the most common trigger, was only 44%); however, the positive predictive value was only 44%. If these tests were utilized to guide dietary management, patients had histologic remission only 53% of the time [51]. In a study utilizing APT to direct treatment of EoE in adults, nearly 50% had positive testing results, but only 16% had histologic remission based upon elimination of the food(s) that caused the positive test result. The authors estimated that the sensitivity of APT for EoE was only 5.9% with a specificity of 92% [52]. In a meta-analysis of dietary interventions for EoE, allergy testing directed elimination diets led to remission in only 45.5% of subjects, which was less efficacious than empiric elimination or elemental diets [53]. Given these results, the ability of currently available forms of allergy testing is limited to accurately predict EoE food triggers.

Role of Dietary Modification in Treatment of EOE

Although allergy testing remains limited in its ability to identify specific food triggers, there is little doubt that food elimination diets are an effective form of treatment for EoE. Elimination of the suspected culprit food(s) frequently reduces esophageal eosinophilia and improves clinical symptoms. One of the seminal studies demonstrating the effectiveness of food elimination diets was performed by Kelly et al. who demonstrated that use of an elemental formula for 6 weeks could lead to significant reduction in clinical symptoms as well as number of esophageal eosinophils [48]. Subsequent studies have shown that elemental formula diets can induce remission in more than 95% of EoE patients [54, 55]. Two other approaches have also been utilized: allergen-directed elimination and empiric elimination. Allergen-directed elimination diets involve the removal of food(s) based upon clinical symptoms seen following ingestion and/or positive results determined through allergy testing. As described above, remission utilizing this form of therapy can be achieved in 24–65% of patients [49–53]. Certain foods appear to be more common triggers including cow’s milk, wheat, hen’s egg, and soy, which have led to the use of empiric elimination diets (Fig. 37.4). Rather than removing foods based upon history of clinical reaction or allergy testing results, food triggers are removed individually or in groups. These diets are generally more effective than allergen-directed elimination and are better tolerated by patients than elemental diets. Single food elimination of cow’s milk can be effective in up to 65% of cases, and elimination of the six most common food triggers (6-FED) (cow’s milk, hen’s egg, wheat, soy, peanut/tree nuts, and fish/shellfish) can be effective in up to 81% of patients [56, 57]. Other combinations such as two food (milk and wheat) and four food (cow’s milk, hen’s egg, wheat, and soy) elimination have also been utilized [58, 59]. In general, if single or limited group elimination diets are ineffective, patients are asked to remove additional foods until remission is obtained. Once remission is achieved, suspected trigger(s) may be kept out of the diet long-term or reintroduced one at a time with periodic endoscopic and histological evaluation. If patients experience worsening of their clinical symptoms and/or worsening endoscopic and histologic findings on subsequent endoscopy, the food is then re-removed.

Aeroallergens in EoE

Although food is the most common trigger for EoE, aeroallergens have also been implicated. The literature remains sparse, but several case reports and studies from single centers have shown that aeroallergens can trigger worsening clinical symptoms and eosinophilic inflammation of the esophagus [60, 61]. This is unsurprising given that many EoE patients have other atopic diseases, many of which can be triggered by aeroallergens. In sensitized subjects, the mechanism is believed to be due to the inhalation of pollen into the upper airway which is then swallowed, activating Th2 cytokines. There may also be cross-reactivity between food and aeroallergens that share similar protein structures leading to increased recognition of aeroallergens by tissue eosinophils and mast cells [62]. In such patients, symptoms usually worsen during the peak pollen season and improve when pollen counts subside [63–65]. Some authors have suggested that EoE is diagnosed more frequently during certain times of the year, although a meta-analysis by Lucendo et al. found no significant variations in seasonal diagnosis [66]. These findings may indicate that EoE patients living in certain regions may be more affected than others. It is also uncertain whether aeroallergens actually trigger disease development or serve as an exacerbating factor only. Management of those patients affected by aeroallergens is also uncertain. Typical seasonal allergy treatments such as antihistamines do not seem to reduce clinical symptoms or eosinophilic inflammation. Swallowed corticosteroids do abate both clinical symptoms and inflammation and have been utilized as treatment during pollen seasons. Allergen immunotherapy, which is an effective long-term treatment for seasonal allergic rhinitis, has an unclear role in EoE. There has been limited work to evaluate its utility in treating EoE, although at least one case report has suggested efficacy [67].

Summary

The allergist plays an important role in the multidisciplinary approach to managing EoE. Given the association with other atopic disorders, the allergist is uniquely positioned to accurately assess food and environmental triggers as well as other confounders such as allergic rhinitis that may impact a patient’s disease. Although the role of current allergy testing is limited, there is important information that can be gleaned that could guide management. For those patients that elect to start a food elimination diet, the allergist, in combination with a dietitian, can ensure successful implementation. Close collaboration with other specialists, including otolaryngology, gastroenterology, and speech-language pathology, should be consistent to optimize the changes for obtaining disease remission.

History

Children with reported feeding issues should initially undergo a thorough clinical feeding evaluation under the supervision of an experienced SLP with knowledge of pediatric feeding and swallowing dysfunction. This referral may come from the child’s primary care physician or after the child has had an initial visit with a specialist such as an otolaryngologist, gastroenterologist, or allergist.

Children referred for a feeding evaluation may present with any of the following conditions: failure to thrive, vomiting, reflux symptoms, choking with liquids, lengthy feeding times, and/or gagging or choking with early solids [25, 27]. Toddlers and older children referred for a feeding evaluation are often described by caregivers as “picky eaters,” who will not accept solids that are not pureed. These children also typically prefer liquids to solids [68].

During the feeding evaluation, the SLP obtains detailed information from the caregiver about the child’s past and present feeding history, including any other concomitant medical issues that could be negatively impacting the child’s feeding progression. These would include upper airway anomalies, reflux, and possible food allergies. Information about the feeding environment at home and the child’s behaviors during mealtimes is also pertinent. During the feeding evaluation, the child should be observed by the SLP with a typical feeding.

Oral Sensory and Oral Motor Assessment

The child’s oral motor and oral sensory systems are assessed during the clinical evaluation. Bottle feeders are evaluated for safety and efficiency during feeding. If the child is having frequent emesis and/or is not gaining adequate weight, referral to a gastroenterologist may be warranted if the infant’s bottle-feeding skills are judged to be adequate and there are no overt signs/symptoms of aspiration.

For older infants and toddlers, parents may report that a child gags with initial offerings of more textured solids. While this type of concern is common for this age group, more thorough oral sensory and oral motor assessment is warranted. A child may have delayed or impaired oral motor skills and is not able to safely manage a solid, thus requiring more manipulation prior to swallowing and prompting a gag response. Oral motor deficits, such as ankyloglossia, may contribute to the child’s issues with oral preparation of the bolus. Reflux-related changes or upper airway obstruction may contribute to the child’s sensory gag response. The SLP should observe the child’s sensory responses to varying tastes, temperatures, and textures of solids presented. Though an unknown diagnosis of EoE can be present at this time, oral motor and oral sensory system delays or deficits independent of EoE should be carefully examined as contributing factors to the child’s feeding difficulties [69].

Treatment

In cases of children with feeding disorders who have a mild reflux history or resolved upper airway obstruction, caregivers may be able to use learned therapeutic feeding techniques at home to help with a child’s feeding progression. However, children with diagnosed eosinophilic gastrointestinal disorders will require more intensive interventions. Though reflux may occur concurrently with EoE, a child’s symptoms may not significantly improve with acid-suppression therapy alone [32]. Using an amino acid-based formula or a six-food elimination, diet has been shown to be particularly effective in resolving symptoms in patients with suspected food allergies [48, 57].

Direct feeding therapy, in conjunction with medical therapy, is fundamental in helping children with both oral motor and oral sensory dysfunction and aiding in the acceptance of food reintroduction in cases of pediatric EoE [68]. A child has likely developed negative responses to foods which do not simply disappear with reduction or absence of eosinophils. In addition, children may be fearful or anxious about mealtime, and mealtime dynamics can become complicated and stressful for both the child and the family members, affecting quality of life for the entire family [27].

Feeding therapy sessions may focus first on the child’s oral hypersensitivity and slowly progress with acceptable tastes and textures of foods. Oral motor skills may then be addressed once a child’s hypersensitivity improves. Focus on the overall mealtime environment is also discussed with the caregiver(s), as consistency and routine can play key roles in the success of the child’s feeding progress.