Eosinophilic esophagitis (EoE) is a condition in which the esophagus becomes inflamed due to infiltration by eosinophils. It is a clinicopathological disease characterized by clinical symptoms of esophageal dysfunction, detection of >15 eosinophils/HPF, and exclusion of other disorders associated with similar clinical, histological, or endoscopic features, especially GERD [30]. Other histologic features include eosinophil microabscesses, superficial layering of eosinophils to upper third to half of the squamous epithelium, and basal zone hyperplasia with the basal zone occupying more than 20 % of the epithelium [31–33]. Endoscopic features include linear furrowing, white exudates, specks, or nodules, circular rings, linear shearing/crepe paper mucosa with passage of endoscopy, and esophageal stricturing [31, 34–38]. Although none of these are pathognomonic for EoE, the finding of one or more, in the appropriate clinical context, is strongly suggestive of EoE.

The exact incidence and prevalence of EoE is likely underestimated given that the knowledge of, and screening for, EoE is increasing. Noel et al. reported an incidence of ∼1:10,000 children per year in the Midwest United States occurring over a period from 2000 to 2003 [39]. In an analysis of a large administrative database, the period prevalence of EoE from 2009 through 2011 in the United States was estimated to be 56.7/100,000 persons [40]. EoE has a higher prevalence in males than in females; 16 studies identified 754 pediatric patients, 66 % of which were males [30]. It is postulated that 10 % of children with GER, unresponsive to acid suppression therapies , have EoE [41]. Overall, prevalence tends to be higher in individuals with a history of dysphagia and pre-diagnosed/existing cases of GERD, reflux esophagitis, and food impaction [42].

Symptoms experienced by patients differ by age, with adults experiencing dysphagia and food impaction [43–46] and children experiencing feeding refusal or intolerance, GERD-like symptoms, failure to thrive, chest pain, emesis, and abdominal pain [46–49]. The difference in symptoms is attributed to pediatric patients being unable to verbalize what they are experiencing, as well as a longer disease duration leading to fibrosis [50]. This is reflected in endoscopic changes as disease course progresses, with features of EoE shifting away from those that reflect inflammation, such as plaques, toward those that reflect remodeling such as concentric rings, narrowing, and strictures [51].

Etiopathogenesis of the eosinophils remains unknown, but is thought to be related to allergen hypersensitivity, with inflammation resulting from repeated exposure to food and aeroallergens in genetically susceptible individuals [52–54]. Allergic responses have been strongly implicated in the etiology of EoE based on several lines of evidence. The majority of patients with EoE (50–80 %) [54] are atopic based on the coexistence of atopic dermatitis, allergic rhinitis, and/or asthma and the presence of allergic antigen sensitization based on skin prick testing or measurement of plasma antigen-specific IgE. Also, most patients improve on allergen-free diets, providing supportive evidence that antigen is eliciting the disease.

EoE is characterized by Th2-mediated inflammation . The activated Th2 response leads to the recruitment and activation of eosinophils and mast cells, which degranulate, releasing products that instigate tissue damage, remodeling, and fibrosis. IL-5, IL-13, and TGFβ1 are master regulators of EoE [55–58]. They can induce other pro-fibrotic agents in the lamina propria [59]. Mechanisms responsible for esophageal dysmotility associated with EoE are somewhat uncertain, though it is likely that esophageal remodeling is the molecular scaffold responsible. The bulk of remodeling changes occur in the subepithelial compartments [60]. Remodeling includes basal zone hyperplasia, epithelial–mesenchymal transition (EMT), fibrosis, angiogenesis, and smooth muscle hypertrophy/hyperplasia [61]. Tissue fibrosis results in decreased esophageal compliance, increased esophageal stiffness, smaller esophageal diameter, and increased smooth muscle mass with smooth muscle dysfunction. Complications , such as esophageal rigidity, dysphagia, food impactions, and esophageal strictures, seem to be secondary to tissue remodeling. There are limited techniques to evaluate and monitor for tissue remodeling and fibrosis. To date, studies have relied on radiographic and endoscopic surrogates to qualitatively assess degree of fibrosis and compliance of the esophagus [62]. Endoscopic ultrasound or computed tomography scan has confirmed that substantial thickening of the entire esophageal wall occurs in approximately 50 % of cases [63], whereas longitudinal muscle dysfunction with abnormal peristalsis has been identified on both ultrasound and manometry [64].

There are few studies utilizing high-resolution manometry (HRM ) in EoE patients, particularly after treatment. Studies show that HRM is able to identify esophageal motility disorders in only some EoE patients, despite them having symptoms and eosinophils present on esophageal biopsies [65, 66]. The observed motility disorders resolve after successful treatment in almost all of these patients. Pan-esophageal pressurization and weak or failed peristaltic integrity are more often present in adult EoE patients than in healthy controls [66, 67]. This can also be seen in GERD patients . However, it was shown that a longer disease duration increased the prevalence of manometric abnormalities in EoE patients [67]. Similarly, studies in children show that both patients with EoE and GERD have findings of peristaltic dysfunction (i.e., failed peristalsis, aperistalsis, and esophageal spasm features) and lower distal contractile integral adjusted for esophageal body length, with patients with EoE having a higher prevalence of abnormal findings [68]. The same study also evaluated children with MII-pH and found that the great majority of EoE patients have a normal MII-pH profile, while patients with GERD have a markedly higher number of abnormalities picked up. Use of esophageal pressure topography yielded the same results—that abnormal esophageal motility was sometimes picked up in patients with EoE who were similar in frequency and type to patients with GERD and patients with EoE were more likely to have abnormal bolus pressurization patterns thought to be a reflection of reduced esophageal compliance [69].

The current tools of manometry and endoscopy lack the ability to test distensile properties of the esophageal wall, as the pressure–geometry relationship of the esophageal lumen cannot be measured. Kwaitek et al. demonstrated the utility of measuring esophageal body distensibility by high-resolution impedance planimetry (EndoFLIP, endoscopic functional luminal imaging probe) to calculate multiple adjacent cross-sectional areas (CSAs) within a cylindrical bag while simultaneously measuring intraluminal pressure during controlled volumetric distension [62]. Patients in whom EoE was confirmed by biopsy were found to have decreased distensibility of the esophageal body and gastroesophageal junction compared with healthy controls. Neither mucosal eosinophil count, age, gender, nor current PPI treatment predicted this limiting caliber of the esophagus. The same group later investigated the EndoFLIP as a tool to predict the risk of food impaction in EoE [70, 71]. They concluded that EoE patients had a lower maximal reachable CSA, termed the distension plateau, than controls and that this measure predicted the risk of food impaction.

EoE is a chronic and progressive disease . If left untreated, complications, such as food impaction, esophageal stricture, narrow-caliber esophagus, and esophageal perforation, are common. Therefore, once the diagnosis is confirmed, it is important to treat the eosinophilic inflammation not only to control the presenting symptoms but also to preserve the morphological and functional integrity of the esophagus. Besides medications that are geared toward decreasing inflammation, diets avoiding culprit foods is an important therapeutic option [30]. Systemic steroids, while effective, have the downside of systemic symptoms. In a retrospective study of 20 children, oral viscous budesonide mixed with Splenda to create a topical steroid slurry resulted in a 3–4-month resolution or improvement of symptoms in 85 % of patients [72]. This provides a suitable alternative to children who have difficulty with inhalers. Dietary options come in three forms: elemental diet, elimination diet that is determined by identifying trigger foods, or a six-food elimination diet that eliminates the six most common allergens. Esophageal dilation is reserved for symptomatic esophageal strictures.

Among collagen vascular disorders, scleroderma is the most severe and commonly manifests in the gastrointestinal tract. Other collagen vascular disorders with esophageal manifestations are systemic lupus erythematosus (SLE), mixed connective tissue diseases (MCTDs), Sjörgen’s syndrome, and rheumatoid arthritis. Scleroderma is the hardening of tissues resulting from an autoimmune response attacking the body. Systemic scleroderma (SSc) is characterized by remarkable collagen deposition in body tissue, especially the esophagus. SSc affects esophageal tissue and motility in 75–90 % of adult cases [73, 74]; pediatric studies indicate much lower prevalence [75, 76]. In a multicenter study, Foeldvari et al. reported 65 % (88/135) of pediatric SSc patients presented GI tract involvement; only involvement with the skin, joints, and Raynaud’s phenomenon preceded GI tract [77]. Of those 135 cases, under 50 % (n = 63) involved the esophagus [77].

Esophageal smooth muscle becomes atrophied and replaced by fibrous tissue leading to severe motility disturbance of the distal esophagus. A study of SSc revealed that childhood onset is sometimes preceded by trauma in the area of deposition, a unique phenomenon compared to adult cases of scleroderma [76]. It is postulated that trauma releases the neuropeptide ET-1, stimulating collagen synthesis in fibroblasts [76]. In the presence of SSc, esophageal manometry reveals an incompetent LES, low-amplitude peristalsis in the distal esophagus, and a normal proximal esophagus which is made of striated muscle of the esophagus [73]. The retrograde movement of gastric contents, related to LES pressure, exposes the esophagus to acidity, which can compromise peristalsis. Frequent contact between acidic gastric contents and esophageal mucosa degrades tissue quality; esophagitis, bleeding, and strictures are other known complications. However, studies have noted that many who experience reflux secondary to SSc can be asymptomatic [73, 78]. In a study by Weber et al., 15 pediatric patients with scleroderma or mixed connective tissue disease underwent 24-h pH monitoring. While 85 % had an elevated number of reflux events and 50 % had reflux events lasting greater than 5 min, only three patients had clinical symptoms [78]. Aside from manometry, barium esophagram, 24-h ambulatory pH, and endoscopy are also used to diagnose the extent of esophageal disturbance secondary to SSc [73].

Common symptoms o f SSc with esophageal involvement are dysphagia, chest pain, weight loss, food impaction, and early satiety [73, 79]. Weber et al. reported reflux events in over 60 % of pediatric patients with SSc [78]. Overall mortality for SSc with esophageal involvement is very rare; death is usually a consequence of multisystem involvement [76, 77]. Treatment of SSc primarily involves immunosuppressants (prednisone, methotrexate, mycophenolate mofetil, tumor necrosis factor-alpha, cyclophosphamide) [76, 80]. However, the suspected effect of immunosuppressants on fertility must be further evaluated in the pediatric population [81–83]. Gunawardena and McHugh suggest proton pump inhibitors, bulking agents, nutritional supplements, and antibiotics as additional treatment options [79, 84]. More investigation into effective treatment of pediatric collagen vascular disorders with esophageal manifestation is needed.

Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a rare primary disorder that involves the entire gastrointestinal tract (see Chap. 24). Esophageal involvement is very common [85]. Non-idiopathic intestinal pseudo-obstruction is usually secondary to systemic, metabolic, genetic, or mitochondrial etiologies. CIIP is often diagnosed during infancy and childhood, and symptoms are usually both severe and frequent at onset. Patients with esophageal involvement present with clinical symptoms of GER, dysphagia, nausea, vomiting, and weight loss [86, 87]. Dysphagia, however, is usually a chief complaint when CIIP is secondary to another disorder.

Upper GI, endoscopy, manometry, and full thickness biopsies are used to diagnose CIIP. Abnormal manometry is intermittent, and abnormalities include uncoordinated (neuropathic) or low-amplitude (myopathic) contractions with swallowing [86]; these findings are more common than aperistalsis. Decreased LES pressure is also a common clinical finding. Pharmacologic treatment of CIIP is similar to that of other esophageal motility disorders, involving antiemetics, prokinetics, and antispasmodics. Antibiotics are suggested to reduce bacterial growth, which may also benefit abdominal pain, distention, and diarrhea [86].

Lack or poor formation of the enteric nervous system defines Hirschsprung’s disease (HD) (see Chap. 25). Though primarily a disease of the small and large bowel, HD is occasionally associated with abnormal esophageal motility indicated by poor peristaltic wave propagation [88]. Staiano et al. examined esophageal involvement in children with HD, in comparison to those with idiopathic megacolon and healthy controls with no esophageal or colonic diseases. Abnormalities in the amplitude and frequency of distal esophageal body contractions were significantly higher in HD patients than other groups [89]. The severity of HD in this group was unrelated to esophageal involvement. Another study evaluated if upper GI dysmotility in HD patients persists into adulthood [90]. Sixteen adult HD patients and 17 controls evaluated via antroduodenal and esophageal manometry revealed increased contractile activity of the small bowel during fasting and postprandially in HD adults.

Caustic ingestion of harmful substances is a common accident among young children, especially in developing countries. Common signs and symptoms include salivation, oropharyngeal burns, vomiting, bleeding, epigastric and retrosternal pain, and malignant transformation [91, 92]. Esophageal burns, though less common than oropharyngeal, are associated with fibrosis of deep muscle tissue which impairs normal motility. Acids and alkalis produce different types of tissue damage. Esophageal motility studies report low-amplitude and nonperistaltic contractions in patients with dysphagia and stricturing [93–95].

Ineffective motility of the esophagus has evolved from being included in an initial description of nonspecific esophageal motility disorder (NEMD ) to a more precise terminology establishing it as a separate entity. The unifying feature of swallows contributing to the diagnosis of ineffective esophageal motility (IEM) is poor bolus transit in the distal esophagus. In 2001, using conventional manometry, Spechler and Castell defined IEM as having low or normal esophageal sphincter pressure, normal LES relaxation, and greater than 30 % low-amplitude waves characterized by the following: wave amplitude <30 mmHg, peristalsis that does not travel the length of the esophagus, simultaneous contraction <30 mmHg, or aperistalsis [96]. Tutuian and Castell indicated in 2004 that patients with ≥50 % ineffective wet swallows (<30 mmHg) are more likely to have abnormal bolus transit [97]. Blonski et al. showed that this definition was more frequently associated with esophageal symptoms (dysphagia and heartburn) and abnormal bolus transit compared to those who had only 30–49 % ineffective swallows [98]. The Chicago Classification by HRM defines IEM as DCI <450 mmHg s cm with ≥50 % ineffective swallows. No distinction need be made between failed swallows and weak swallows [99]. IEM is the most common abnormality on esophageal manometry, with an estimated prevalence of 20–30 % [100]. With the use of HRM to define IEM, the prevalence of IEM has increased. Boland et al. performed HRM on 350 adult patients referred for esophageal function testing between August 2012 and May 2013 [101]. Thirty-one percent of patients had IEM compared to 21 % 10 years prior, when 350 patients had been evaluated via MII-EM.

Patients with IEM present with various complaints. Analysis of 228 IEM patients in a study showed dysphagia in 25 % of patients, cough in 15 %, chest pain in 13 %, heartburn in 12 %, and regurgitation in 12 % [102]. Among patients with dysphagia, bolus transit was defective in 89 %. The presence of dysphagia with defective bolus transit in patients with severe IEM was also shown in 2008 [103]. IEM thus appears to subdivide into two groups, a more severe form that manifests with dysphagia and is associated with a more defective bolus transit and a milder form of which the clinical significance is not very clear. The association between IEM and GERD is well documented, and IEM is more prevalent in patients with more advanced reflux disease. Multiple studies showed esophageal peristaltic dysfunction was increasingly prevalent with more severe GERD presentation, from non-erosive reflux disease (NERD) to erosive esophagitis (ERD) and Barrett’s esophagus [104–107]. It has not yet been determined whether IEM is a rare primary disorder or merely secondary to increased acid exposure.

Currently there is little data regarding IEM in the pediatric population . In infants with ALTE, prolonged spontaneous respiratory events are associated with ineffective esophageal motility characterized by frequent primary peristalsis and significant propagation failure, thus suggestive of dysfunctional regulation of swallow–respiratory junction interactions [104].

Nonspecific esophageal motility disorders (NEMDs) capture those cases with irregular manometry , but not characteristic of an established disorder [1, 12, 108]. Criteria for NEMDs are ≥30 % of wet swallows with non-transmitted or low-amplitude contractions or at least one of the following contraction abnormalities: triple-peaked contraction, retrograde contraction, prolonged-duration peristaltic waves (>6 s), or isolated incomplete LES relaxation (>8 mmHg) [108]. Low-amplitude contractions are thought to be the most common manometric finding [109]. NEMDs differ from achalasia in that with swallows, there are intermittent normal and abnormal peristaltic waves; complete lack of peristalsis is characteristic of achalasia. Additionally, NEMDs involve low-amplitude waves , whereas DES typically involves high-amplitude pressure waves. Despite these notably distinct symptoms, it is suggested that NEMDs may be an early disease state of achalasia and DES [109]. Naftali et al. reported a minority of patients who progressed from NEMD to achalasia or DES noted during a repeat manometry procedure. In a retrospective study following 43 patients with NEMD over 4 years, 28 patients had repeat manometry for persistent symptoms, and among them, 15 patients had progressed to achalasia. Almost all of them were <46 years old, suggesting that an early age of onset is predictive of disease progression [110].