Open access peer-reviewed chapter - ONLINE FIRST
Abstract
Eosinophilic esophagitis (EoE) is a chronic immune-mediated clinicopathological condition characterized by symptoms of esophageal dysfunction (dysphagia and food impaction) along with esophageal biopsies showing an eosinophilic infiltrate in the mucosa of 15 or more eosinophils per 0.3 mm3 field, excluding other causes of esophageal eosinophilia. Its prevalence has tripled in the last 10 years. This increase cannot solely be attributed to the rise in gastroscopies performed or greater awareness of the disease among health professionals. It is more common in men, particularly in Western countries, and can be associated with other allergic diseases such as asthma, allergic rhinitis, or atopic dermatitis. Diagnosis is based on the histological examination of esophageal biopsies. Various treatments are available, including proton pump inhibitors, corticosteroids, empiric exclusion diets, or biological drugs. Disease progression can lead to esophageal fibrosis and strictures that may necessitate treatment with endoscopic dilation.
Keywords
- eosinophilic esophagitis
- dysphagia
- eosinophil
- food impaction
- atopy
- food allergy
- elimination diet
1. Introduction
Eosinophilic esophagitis (EoE) was first described in 1993 by Attwood [1] and 1 year later by Straumann [2] as an entity with its own clinical and histological characteristics. Previously, some authors interpreted the presence of eosinophils in the esophageal mucosa as a sign of GERD. In 1995 Kelly et al. described a series of 23 children with GERD refractory to medical and surgical treatment who responded to an elemental diet [3]. The first consensus guideline on EoE was published in 2007 [4]. Since then, interest in EoE has increased from being considered a rare entity to becoming a common diagnosis. It is currently the second cause of esophageal inflammation after gastroesophageal reflux disease (GERD) and the most common cause of dysphagia and food impaction in children and young adults [5, 6, 7].
EoE is associated with the Th2 lymphocyte-mediated inflammatory response, and is considered a form of food allergy, and shares mechanisms of action with atopic diseases such as asthma or atopic dermatitis. In its pathogenesis, the role of eotaxins and interleukins (IL) 13 and 5 stands out.
The most common clinical presentation at diagnosis is dysphagia and food impaction. Diagnosis should be histological, with the most characteristic feature being the presence of an inflammatory infiltrate of eosinophils, which by definition should be greater than 15 eosinophils per field of 0.3 mm3. There are various effective treatments for EoE, ranging from proton pump inhibitors (PPIs), elimination diets, topical corticosteroids, and more recently, biologic drugs. The most frequent complication is esophageal stricture, caused by subepithelial fibrosis secondary to chronic inflammation, and its most effective treatment is endoscopic dilation, with or without topical corticosteroids.
2. Definition
EoE is a defined as a chronic type 2-associated inflammatory disease, immune or antigen driven, characterized by predominant eosinophilic inflammation of the esophagus (greater than or equal to 15 eosinophils per 0.3 mm3 field). Clinically, it is characterized by symptoms related to esophageal dysfunction, with dysphagia and esophageal dysfunction being its predominant symptoms. Years ago, it was necessary to exclude GERD before establishing a diagnosis of EoE. But currently, infiltration by eosinophils in the esophageal epithelium after 2 months of treatment with PPIs is no longer a diagnostic criterion to exclude EoE, but PPIs have become part of the treatment of EoE [8]. This is because it was observed that patients with dysphagia and food impactions who responded to PPIs exhibited the same phenotypic, molecular, and therapeutic characteristics as those who did not respond [9, 10].
There are other entities that present with esophageal eosinophilia and that must be ruled out before establishing a diagnosis of EoE, such as Crohn’s disease, collagen vascular disease, hypereosinophilic syndrome, GERD and esophagitis induced by drugs or infections.
3. Epidemiology
Cases of EoE have been described throughout the world although epidemiological studies have been published in North America, Australia, and Europe. The studies are heterogeneous in terms of the methodology used (case series, randomized clinical trials, case-control studies…) as well as the definitions of EoE used, since this has been modified over the years. Different cut-off points regarding the number of eosinophils are used and the oldest studies exclude EoE that responds to treatment with PPIs as it was considered a different entity.
Incidence rate of EoE appears to be increasing according to the latest published studies. The annual incidence at the Mayo Clinic went from 0.35 cases per 100,000 person-years between 1991 and 1995 to 9.45 cases per 100,000 person-years between 2001 and 2005 [6]. Similarly, other European studies have shown an increase in incidence between 10 and 20 times in less than 20 years [11, 12]. Possible causes would be greater awareness of this entity among gastroenterologists, as well as greater access to endoscopy. But studies suggest that the increase in the incidence rate is due not only to an increase in diagnosis, but also to an actual increase in the disease.
As a result of this increase in incidence, added to the fact that patients are usually diagnosed at an early age and that it does not reduce their life expectancy, the prevalence of EoE has also increased in recent years. Thus, the prevalence has gone from 42.96 cases per 100,000 inhabitants published in 2004 in the United States to current rates between 81 and 100 cases per 100,000 inhabitants published as of 2016 [13, 14, 15]. More recent studies have described prevalence above 100 cases per 100,000 inhabitants in both children and adults [14, 15].
The hygiene theory is one of the reasons that would explain the enormous increase in the prevalence of EoE. Like EoE, other diseases related to more sterile environments, especially during childhood, such as atopic dermatitis, asthma, rhinitis, inflammatory bowel disease or food allergies, have also experienced a notable increase in their prevalence in the last decades. The sterile environment limits the exposure of the immune system to antigenic stimuli, hindering its maturation and promoting hyperreactivity against self or external antigens [16]. It is unknown why foods such as milk, eggs, wheat, or legumes, so common in our diet for thousands of years, are the main triggers for this disease.
Since the definition of EoE changed in 2017–2018 [8, 17], and the response to PPIs transitioned from being a diagnostic criterion to a treatment for the disease, a significant number of patients were included in prevalence and incidence rates. Finally, increased awareness and knowledge among healthcare professionals (not only gastroenterologists) about the disease have allowed for a greater number of diagnoses, both in patients with recent clinical onset and those with long-standing compatible symptoms who had not yet been diagnosed [7].
Different risk factors have been associated with the development of EoE: living in geographical areas with colder temperatures and higher humidity, male sex, Caucasian race, older children and age between 30 and 45 years in adults, atopy, family history of EoE (possible common genetic changes although a shared environmental environment also seems necessary), breastfeeding, and admission to neonatal ICU [7]. The role of aeroallergens and seasonality, extensively studied in EoE, was questioned in a systematic review and meta-analysis published in 2015 with 16,846 patients from 18 studies [18].
4. Etiopathogenesis
Eosinophils are granulocytes produced by the bone marrow related to the immune response to parasitic infections and allergic phenomena. Under normal conditions, the esophageal mucosa does not contain any eosinophils, unlike other organs of the digestive system. Interleukin 5 (IL-5) is considered the main inducer of their expansion and subsequent release into the bloodstream [19] and was one of the first targets in the search for possible treatments for EoE [20]. Once in the blood, eosinophils are recruited by the esophagus through mediators produced by the inflamed tissue, although this mechanism is not well understood yet. Some of the proposed mechanisms studied as potential therapeutic targets include: increased expression of the DD chemokine receptor cCR3 common for eotaxins [21], intercellular adhesion molecule (ICAM)-1 [22], integrin CD11c, prostaglandin D2 receptor CRTH2 [22, 23], and mRNA FLOXP3 [23].
The intestinal epithelium has emerged as a fundamental defense mechanism in maintaining intestinal homeostasis, serving both as a barrier function and mediating between bacteria and the immune system [24, 25]. Esophageal epithelial cells express molecules of the major histocompatibility complex (MHC) class II acting as antigen-presenting cells [21, 23].
In EoE, eosinophils are distributed in an ascending gradient from the superficial layers, in contact with ingested antigens, to the deeper layers [26]. Additionally, they cluster to form microabscesses in the superficial strata [27, 28].
In active EoE, alterations have been demonstrated at different levels in its epithelial barrier: in tight junctions with alteration of some of their components (claudin-1, claudin-4, occludin or proteins of the occludin-1 zonula) [29], in structural proteins responsible for maintaining mucosal integrity (such as E-cadherin, involucrin, or filaggrin) [30, 31], and in the expression of the cytoskeletal protein synaptopodin [32]. All these changes have been related to the depletion of the serine protease inhibitor, kazal type (SPINK) 7, absent in the epithelium of patients with active EoE, contrary to what happens with healthy controls [33]. As a consequence, there is an increase in epithelial permeability, with dilated intercellular spaces allowing the passage of antigens, demonstrated by the overexpression of epithelial antimicrobial peptides and the upregulation of bacterial pattern recognition Toll-like [29, 34].
Thymic stromal lymphopoietin (TSLP), a cytokine closely related to immune-mediated processes such as asthma, atopic dermatitis, inflammatory bowel disease, and EoE, is mainly produced in the esophageal epithelium by epithelial cells, fibroblasts, and other stromal cells. Its induction mechanism is unknown, but it is highly relevant in the activation of antigen-presenting cells, which promote the maturation of T lymphocytes into Th2 cells. Activated Th2 cells secrete cytokines such as IL-13, a key cytokine in EoE. In EoE, IL-13 promotes epithelial dysfunction by dysregulating genes related to the epithelial barrier (CAPN14), reducing proteins like desmoglein-1, inhibiting the expression of filaggrin and involucrin, and altering the expression pattern of TJ-associated proteins [35].
Since its description in 1993, EoE has been associated with atopy. Both patients and their family members suffer more frequently than the general population from diseases such as asthma, allergic rhinitis, atopic dermatitis, drug hypersensitivity, eosinophilia, or elevated levels of IgE in serum [36]. IgE-mediated food allergies are also more common [37]. This significant increase in immune-mediated diseases has been partially justified by the hygiene hypothesis, according to which reduced exposure to allergens during childhood produces changes in the microbiota that condition an altered response of T lymphocytes [38]. In this sense, invariant natural killer T (iNKT) cells, which are stimulated by glycolipid antigens through class I MHC proteins and are related to phenomena of immunotolerance, have been shown to play an essential role in the pathophysiology of EoE. iNKT cells are capable of inducing EoE in animal models [39, 40], are more numerous in the epithelium of patients with EoE compared to healthy controls [41], and furthermore, they normalize after removing allergens from the diet.
Mast cells, mesenchymal cells derived from bone marrow myeloid cells, are increased in patients with active EoE and decrease, like eosinophils, after effective treatment [35]. Mast cell infiltration density has been proposed as a mechanism to differentiate EoE from GERD [42, 43].
In EoE, genetic susceptibility has been demonstrated, which, along with environmental factors and the immune system of each patient, are responsible for the development of the disease. The main gene identified in patients with EoE is eotaxin-3/CCL26, with a 53-fold higher risk than controls. The TSLP receptor and its ligand have been identified in children with EoE [44]. Some single nucleotide polymorphisms (SNPs) have also been identified as risk factors for the disease (genes CCL26, TGFβ and its LRRC32 protein, FLG, TSLP, DSG1, CRLF2, and TLR3) [35]. The predominance of EoE in males has been related to genetic alterations of the sex chromosomes. Thus, mutations in two chains of the IL-13 receptor gene located on the X chromosome, not corrected by the Y chromosome in males, and more recently, an SNP in the gene encoding the TSLP receptor are the most associated with male predominance in EoE [45].
As a result of chronic esophageal inflammation, subepithelial fibrosis occurs, which is common to other processes with eosinophilic inflammatory infiltrates. This fibrosis occurs as a consequence of untreated or inadequately treated inflammation and has been described in children, adults, and animal models, although it does not occur in all cases. Clinically, fibrosis leads to dysmotility, esophageal rigidity, progressive dysphagia, food impaction, and ultimately, stenosis [35]. The main factor associated with progression to fibrosis is transforming growth factor (TGF)-β1, the same factor described for asthma [46].
5. Clinical features
Symptomatology differs between children and adults. Children may present with a wide variety of non-specific symptoms such as abdominal pain, nausea and vomiting, and failure to thrive. Though it is still being characterized, feeding dysfunction is becoming more often acknowledged as an EoE manifestation. It comprises the inability to establish typical eating behaviors (such as not progressing past liquids or soft foods) and the adoption of coping mechanisms (such as eating slowly, chewing food excessively, or refusing to eat solids after having previously eaten them) [47].
In contrast, teenagers and adults are more likely to present with dysphagia, episodes of food impaction and non-swallowing associated chest pain. Dysphagia to solid foods is the most common symptom (70–80%). EoE is discovered in up to 15% of individuals undergoing endoscopic evaluation for dysphagia [6]. As many as 54% of patients have a history of food impaction [48]. Heartburn, especially with the ingestion of alcohol, occurs in 30% of adult patients. Rarely, eosinophilic esophagitis may manifest with spontaneous rupture of the esophagus from forceful retching (Boerhaave’s syndrome) after food impaction [49, 50].
The natural history of the disease in untreated patients progresses from the initial inflammatory pattern, characterized by eosinophilic infiltration as the main histological change, to structural changes with subepithelial fibrosis leading to dysmotility, esophageal rigidity, progressive dysphagia, food impaction, and ultimately, the formation of strictures [7]. The fibrostenotic pattern is uncommon, and although we can find it in both children and adults, the risk of its occurrence doubles with each decade of disease progression without proper diagnosis and treatment [51, 52, 53].
6. Diagnosis
Diagnosis requires the presence of symptoms related to esophageal dysfunction, the presence of an eosinophilic infiltrate in esophageal biopsies and the exclusion of other causes that could lead to both situations [8].
6.1 Endoscopic features
The most frequent endoscopic observations include strictures (21%), esophageal rings (44%), white spots indicating eosinophilic exudates (27%), and linear furrows (48%). The estimated frequency of each endoscopic feature according to a meta-analysis comparing 4678 patients with EoE and 2742 controls is shown in parentheses [54]. There is a validated endoscopic scoring system (EREFS) that evaluates the presence of these signs and may be useful in clinical trials [55].
6.2 Histology
Histological diagnosis of EoE is dependent on eosinophilic infiltration of the squamous epithelium. The vast majority of patients have at least 15 eosinophils per high power field (peak value) in at least one biopsy specimen. This value is thought to approach a sensitivity of 100% and specificity of 96% [8]. Biopsies should be taken from both the distal and proximal esophagus. Different studies have evaluated the number of biopsies necessary for diagnosis. At least six biopsies should be taken from different locations, focusing on areas with endoscopic mucosal abnormalities, mainly white exudates and longitudinal furrows, which are associated with higher peak eosinophil counts [17]. In turn, biopsies of the duodenum and gastric antrum should be taken to rule out eosinophilic gastroenteritis whenever suspected, as its presence may influence treatment.
Other histologic findings suggestive but not specific for EoE include eosinophil microabscesses, eosinophil surface layering, sheets of eosinophils, extracellular eosinophil granules, subepithelial and lamina propria fibrosis and inflammation, basal zone hyperplasia, papillary lengthening and increased numbers of mast cells, B cells, and IgE-bearing cells. There is an EoE-specific histologic scoring system (EoEHSS), validated
6.3 Radiology
Barium studies can help describe anatomic abnormalities and provide information on the length and width of strictures, but they are not sensitive enough to diagnose EoE [57]. Barium tests can also be used to evaluate luminal narrowing that is not visible during endoscopy. According to two recent investigations, esophageal narrowing was not detected during endoscopy in 71% of adults and 55% of children with eosinophilic esophagitis, but it was present during esophagography [58].
6.4 Laboratory tests
In some patients we can observe elevated IgE levels or peripheral eosinophilia, although this is usually mild.
6.5 Other diagnostic tests
Different tests have been evaluated for the diagnosis of EoE such as functional lumen imaging probe, endoscopic ultrasound, impedance planimetry to measure esophageal pressures and distensibility, mucosal impedance contour analysis that evaluates esophageal mucosal integrity, esophageal manometry, and endoscopic confocal laser microscopy. However, they are not routinely used and more studies are needed to standardize their use.
7. Treatment
Treatments for eosinophilic esophagitis vary widely in effectiveness. To date, it has not been demonstrated that combining multiple treatments is more effective than monotherapy. Additionally, combining multiple treatments can lead to errors in result interpretation and poor reproducibility of the trials [59].
We must consider that since symptoms do not correlate with histological alterations, particularly with the density of eosinophilic epithelial infiltration, after each treatment initiation or change, we should perform an endoscopy with biopsy sampling in a recommended period of 8 to 12 weeks. When implementing an empiric food elimination diet, endoscopic evaluations are conducted between 6 and 12 weeks after initiating the diet and after introducing each new food.
Regardless of the treatment that achieves disease remission, the rate of clinical and histological relapse after its withdrawal is very high, so maintenance therapy is recommended [50].
7.1 Dietary management
7.1.1 Elemental diet
The patient receives an amino acid-based formula (elemental), which eliminates all potential food allergens. This is the most effective method, able to induce histological remission in 90.8% (95%CI: 84.7–95.5%) of EoE patients of all ages, but it is difficult to follow, especially for adults, so it is rarely used [60].
7.1.2 Testing-directed elimination diet
It is based on the elimination of foods with positive results to skin prick testing and atopy patch testing. In addition, cow’s milk should be eliminated due to its low negative predictive value in these tests. These diets are in disuse due to their difficulty of implementation and the greater success of elimination diets. This appears to be because the immune mechanism by which EoE develops is not IgE-mediated, an immunoglobulin directly related to food allergies, although its role, as well as that of IgG4, is still not fully understood [35].
7.1.3 Empiric elimination diet
It is the most commonly used dietary therapy. There are two types, the six-food elimination diet (cow’s milk, hen’s egg, soy, wheat, peanuts/tree nuts, fish/shellfish) and the four-food elimination diet (cow’s milk, hen’s egg, soy +/− other legumes, and wheat). The second arose due to the difficulty in carrying out a multi-food elimination diet, resulting in a lack of adherence to the diet. Sequential reintroduction of each of the excluded foods under endoscopic and histological control allows us to identify with certainty the foods responsible for EoE in each patient [61]. In addition, subsequent data showed that fish/seafood and peanuts/nuts were infrequent triggers of EoE, and foods such as cereals, legumes, and meats were more common triggers. Most patients with an identified dietary trigger respond to cow’s milk and wheat elimination (two-food elimination diet). Further data have shown that the efficacy of cow’s milk elimination alone is close to that of four food elimination diet and is easier to follow. A one or two food elimination diet stepping up to a more restrictive four or six food elimination has been proposed as a clinically effective strategy for dietary management of EoE [50].
7.2 Acid suppression
Among the drugs with anti-inflammatory capacity useful in EoE, several clinical trials and prospective studies in adults and children have shown that treatment with PPIs is able to induce histological remission of the disease in 50–57% of patients [62]. An initial treatment is recommended for 8 weeks. The recommended doses of PPIs in adults comprise omeprazole 20–40 mg twice daily or equivalent; in children, 1–2 mg/kg omeprazole or equivalent. A trend toward greater efficacy has been observed when the total dose is divided into two doses per day. After 8 weeks, the clinical, endoscopic and histological response is verified. For those patients who respond to treatment, we must continue the PPI at the lowest dose successful at controlling symptoms [63].
7.3 Topical glucocorticoids
The most studied glucocorticoids in the treatment of EoE are fluticasone and budesonide.
Fluticasone propionate is administered using a metered dose inhaler without a spacer. The medication is sprayed into the patient’s mouth and then swallowed. When the drug is being administered, patients should not inhale, and they should wait 30 minutes afterward to eat or drink. The optimal dose for induction is two sprays (220 mcg each), twice a day [64] and it should last for four to 8 weeks followed by assessment of symptomatic response. The endoscopic and histologic improvement should be assessed 8–12 weeks after initiating the therapy.
Budesonide. Budesonide can be administered as an oral viscous slurry. The dose varies from 1 mg daily children under the age of 10 year and up to 2 mg twice a day in older children and adults. Budesonide suspension should be taken gradually by patients over a period of 5 to 10 minutes. Following this, they should refrain from eating or drinking for 30 minutes. Budesonide in orodispersible tablets (Jorveza®) has recently been approved for its use. The recommended daily dose is 2 mg of budesonide in the form of one 1 mg tablet in the morning and one in the evening. The usual duration of treatment for induction of remission of active EoE is 6 weeks. In patients who do not show an adequate response after 6 weeks, treatment can be extended up to a maximum of 12 weeks. The orodispersible tablet should be taken after the corresponding meal. It should never be chewed or swallowed undissolved. It should be placed on the tip of the tongue and gently pressed against the roof of the mouth, where it will dissolve. This usually takes about 2 minutes. The dissolved material should be swallowed slowly with saliva as the orodispersible tablet disintegrates. The orodispersible tablet should not be taken with liquids or food. At least 30 minutes should elapse before resuming eating, drinking or oral hygiene.
7.4 Biologics
Biologic compounds are in clinical trials targeting both eosinophils, mast cells, and the Th2 inflammatory pathway. Some of them have revealed statistical improvement in eosinophil count for EoE but only dupilumab was found to have improvement in both histology and symptoms to date and has been approved for treatment of eosinophilic esophagitis in the United States and in Europe [65].
Dupilumab, a fully human monoclonal antibody, blocks the receptor for IL-4 and IL-13, essential cytokines in the activation of type 2 inflammation. It is approved for the treatment of other conditions such as atopic dermatitis, asthma, and chronic rhinosinusitis. In EoE, compared to placebo, it achieved statistically significant clinical remission (measured using the Dysphagia Symptom Questionnaire, DSQ) as well as histological remission (defined as ≤6 eosinophils per 0.3 mm3 field) [66]. The recommended dose is 300 mg weekly administered subcutaneously.
7.5 Endoscopic dilatation
Esophageal strictures occur in 10% of patients. Fibrotic rings that cause a reduction in esophageal lumen are even more prevalent [51, 67]. Some strictures or narrowing are not detectable endoscopically [58] and require barium studies or distensibility testing using EndoFLIP [68, 69]. They are more common in the distal esophagus but can occur at any location along the esophagus [70].
Endoscopic dilation is an effective and safe technique for treating esophageal strictures in patients with EoE, regardless of the dilation technique used (balloon dilation or bougie dilators). The success of dilation increases when endoscopic treatment is combined with effective anti-inflammatory therapy such as topical corticosteroids [50].
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