|
 
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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 20
| Issue : 1 | Page : 37-43 |
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Eosinophilic esophagitis: An emerging disease
Deepu David
Department of Gastroenterology, Auckland City Hospital, Auckland, New Zealand
| Date of Submission | 28-Sep-2021 |
| Date of Decision | 05-Nov-2021 |
| Date of Acceptance | 16-Nov-2021 |
| Date of Web Publication | 04-Feb-2022 |
Correspondence Address:
Dr. Deepu David
Auckland City Hospital, Auckland
New Zealand
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/cmi.cmi_80_21
Although eosinophilic esophagitis has been a commonly identified condition in Western countries, reports are emerging about an increasing incidence in developing countries. Multiple environmental factors and genetic susceptibility play a role in the development of this condition. Limited treatment modalities are available, and future research hopefully would guide further insights into effective management strategies of this condition.
Keywords: Atopy, eosinophilic esophagitis, six-food elimination diet, topical steroids, two-food elimination diet
How to cite this article:
David D. Eosinophilic esophagitis: An emerging disease. Curr Med Issues 2022;20:37-43 |
| Introduction | |  |
The first characterization of eosinophilic esophagitis (EoE) as a distinct clinical entity was done by Attwood and Straumann in the early 1990s,[1] and the first report in the literature dates from 1978.[2] As an emerging disease, EoE has gradually increased in frequency, and over the last decade, awareness, as well as the incidence and prevalence of this pathology, has increased.[3] In the last 25 years, scientific interest in this domain and the impact of the disease has caused a shift from case series and observational studies to larger, multicenter, randomized controlled trials (RCTs).[4] A recent meta-analysis mentions the incidence rate to be 6.6/100,000 person-years in children and 7.7/100,000 person-years in adults, and the prevalence to be 34 cases per 100,000 children and 42.2 cases per 100,000 adults.[3] It is more common in men, with a male-to-female ratio of 3:1.[5] More than 65% of cases occur during childhood, and there is a peak between 30 and 44 years of age.[6]
EoE has been observed to be of a higher prevalence in Europe and North America as opposed to its lower prevalence in Eastern countries, implying that it could be associated with environmental and immune factors.[6] Studies from Asian countries suggest that the demographic profiles such as age and gender ratios are similar to that seen in Western countries, although with a much lower prevalence. As per literature available, EoE is diagnosed approximately in 1 of 200 endoscopy examinations in Western countries[5],[7] whereas in Asian countries, this is approximately in 1 out of 5000 endoscopy examinations, suggesting a much lower prevalence.[8],[9] The prevalence in Latin American countries, however, is more similar to Asian countries at 1%–1.7%,[10],[11] which is lower than reported studies from the US and Spain (5%–8%).[12],[13] EoE varies according to climate zone and season, with more frequent diagnoses during summer.[14] However, some reports do show that the incidence and prevalence are on a rise in developing countries.[15]
| Pathophysiology | | |
[Figure 1] represents the different stages of EoE from induction/exposure leading to the end result of mucosal inflammation and fibrosis via activation of natural killer cells and T-helper cells aiding eosinophil and mastocyte recruitment.
Environmental and dietary factors
The “hygiene hypothesis” proposed by Okada et al. could explain why individuals from developed countries have a more intense allergic reaction to foods and environmental allergens than they had in the past and why their reaction is stronger than that currently experienced by individuals from developing countries.[16] According to this hypothesis, individuals from developed countries have a lower incidence of general infections, which can be attributed to the eradication of gut bacteria and parasites, mainly by pharmacotherapy. This reduced natural infection rate causes a surge in the incidence of other diseases of allergic and autoimmune origin. This alters the body microbiota and epithelial permeability.[17]
It has been suggested that prenatal factors like maternal fever, natal events like cesarean section, or postnatal events like exposure to antibiotics during infancy and admission to neonatal intensive care units may play a role in pediatric EoE.[18],[19],[20] However, it is not known if these early life factors can be implicated in adult disease.[21] Adult-onset disease has been attributed to more environmental factors such as aeroallergens or antigens from food ingestion. It has been seen that the symptoms of EoE may worsen during spring and fall pollen seasons.[22],[23] Various mechanisms have been suggested to explain this. Small quantities of inhaled or swallowed pollen, in a sensitive person, could trigger this and may cause oedema of the oesophageal mucosa. Antigens in food also may cross-react with allergens in pollen and cause the reaction in a sensitized person.[24]
Population density has also been found to be strongly and inversely associated with esophageal eosinophilia and EoE.[25] Helicobacter pylori which is endemic in many of the developing countries reduces the acid exposure to the esophageal epithelium, which otherwise would increase the permeability of allergens through the epithelium.[26]
Milk, wheat, soy, eggs, peanuts/nuts, and fish/shellfish have been classically described to induce an allergic immune response in the esophagus. This theory is reaffirmed in studies that remove these 6 foods (six-food elimination diet) as one of the therapies.[27] In Western countries, the common food triggers of EoE have been identified as dairy, wheat, and eggs. Whether in Asian countries these foods have the same significance is debatable, as the staple diet more commonly consists of soy and rice. Therefore, when considering dietary interventions, the geographical differences in the types of antigen exposure should be remembered.[28]
Genetic factors
The risk of developing disease in the EoE patients' family is 41% in homozygous twins, 22% in dizygotic twins, and 2.4% in siblings versus 0.055% in the general population.[29] Genetic variants in genes such as CCL26, which encodes eotaxin-3, thymic stromal lymphopoietin, filaggrin, desmoglein-1 (DSG1), STAT6, calpain-14 (CAPN14), and CRLF2 have been identified in patients with EoE.[30] Interleukin (IL-4, IL-5, and IL-13) and complement pathways (Cl-3 and Cl-4) are responsible for the activation of the STAT pathways (STAT5 and STAT6), which are responsible for regulation of molecules such as eotaxin-3, calpain-14, and DSG1, which attract eosinophils to the esophagus. This clumping of eosinophils causes remodeling and deposition of collagen in esophageal tissue leading to disruption of the esophageal epithelial barrier.[31],[32],[33]
| Clinical Presentation | | |
EoE has a wide spectrum of presentation, mainly determined by the age of presentation. Young children usually present with nonspecific symptoms such as feeding difficulties, vomiting, abdominal pain, failure to develop normal eating patterns such as not advancing past liquids/soft solids, and occasionally failure to thrive.[6],[34] Adolescents and adults present with classic symptoms that include dysphagia and food impaction; some patients may also present with symptoms mimicking gastroesophageal reflux such as heartburn, epigastric pain, dyspepsia, and chest pain. Patients often try to develop compensatory mechanisms which help with their symptoms. They try to slow the intake of food with smaller bites and spend more time chewing, or moistening food with sauces. Some drink fluids more frequently between foods, and avoid textured food such as meat and bread.[35] Approximately 60%–80% of children and fewer adults have a history of associated allergic diseases such as asthma, atopic dermatitis, atopic rhinitis, and food allergies.[36],[37]
| Data from India | | |
While gastroesophageal reflux disease (GERD) is a common disease in India, affecting around 7%–15% of the urban and rural population, many of them respond poorly to proton-pump inhibitors (PPIs).[11] A proportion of these could be due to EoE, and on the whole, there is not much information from the Indian subcontinent on the prevalence of EoE. Available data on the clinical manifestations and profile of the disease are extremely limited.[38]
A cross-sectional study from a tertiary hospital in North India, looked at patients with symptoms of GERD for the presence of EoE. Of 190 patients with GERD, esophageal biopsies were available in 185. Of them, 6 had EoE, implying a prevalence of 3.2% among patients with GERD. History of allergy, nonresponse to PPI, and absolute eosinophil counts ≥250/cumm were shown to be significant predictors of EoE. They found no correlation between the presence of EoE and symptom severity. This study concluded that EoE should be considered as a diagnostic possibility, especially in those with the predicting factors.[39] This study again supports the low prevalence of EoE in developing countries such as India.
However, this may not be true in other atopic/Th2 cell-mediated diseases. Asthma has been described in 7% of Indian children between 6 and 14 years of age[40] and allergic rhinitis in 11%–24% of similar-aged children.[41] The prevalence of eczema has been found to be 3.6% among Indian children aged 13–14 years.[42] Compared to these, food allergy has only been reported in 0.14% of children between the ages of 6 and 11 years.[43]
| Diagnosis | | |
The basis of diagnosis in EoE is the presence of clinical symptoms along with positive findings on endoscopy and a supporting histology from esophageal mucosa biopsies.
Endoscopic findings
Findings on endoscopy that are characteristic in patients with EoE include linear depressions on the mucosa, concentric rings [Figure 2], whitish exudates that can mimic candida, Schatzki rings, a reduced diameter of the esophagus, and superficial tears of the mucosa after endoscope introduction.[44],[45] The EoE Endoscopic Reference Score, the classification system for EoE endoscopic findings, has been validated and includes major esophageal features (rings, furrows, exudates, and edema) as well as additional features such as narrow esophageal caliber, feline esophagus, strictures, and crepe-paper esophagus.[46] However, endoscopic findings alone are insufficient for a diagnosis since the endoscopic appearance of the esophagus may be normal in 10%–25% of patients with EoE.[26],[47],[48]
A meta-analysis from 2012[49] of studies with EoE and endoscopic findings reported that the overall sensitivity, specificity, positive predictive value, and negative predictive value of rings on endoscopy were 48%, 91%, 64%, and 84%, respectively; the absence of linear furrows were 40%, 95%, 73%, and 83%, respectively; reduced vasculature were 43%, 90%, 65%, and 79%, respectively; strictures were 15%, 95%, 51%, and 76%, respectively; and white plaques were 27%, 94%, 67%, and 74%, respectively. As opposed to the low sensitivity of each single finding, an overall abnormal endoscopy with at least one of the abnormal features had a higher sensitivity of 87%, specificity of 47%, PPV of 42%, and NPV of 89%.[49]
Histology
As EoE often affects the esophagus in a patchy nature, it is advisable to biopsy multiple areas from both proximal and distal oesophagus. Biopsies from patients with EoE show ≥15 intraepithelial eosinophils per high power field; other findings include basal cell hyperplasia, vascular papillary elongation, eosinophil microabscesses, and lamina propria fibrosis [Figure 3]. | Figure 3: Esophageal mucosa with eosinophil infiltration in eosinophilic esophagitis.
Click here to view |
Blood investigations or/and radiological examinations have limited value in the diagnosis of EoE. Upper GI contrast studies have a low sensitivity in detecting the subtle anatomical changes that happen. However, these have value in ruling out some of the alternate diagnosis, as well as in picking up complications of EoE such as esophageal stricture and small-caliber esophagus.[26],[34]
One of the difficulties in following up diagnosed cases of EoE is that repeated endoscopies are required for assessing response to treatment, especially if embarked on the diet elimination therapy. Other tests are being studied for diagnosis and long-term monitoring of EoE which includes esophageal string test and swallowed Cytosponge test, which can potentially serve as minimally invasive tools to assess disease activity. Ackerman et al.[50] showed eosinophil-associated proteins from EST string samples with an indwelling time of 1 h, to correlate significantly with eosinophil counts from esophageal mucosa. They also reported that both adult patients as well as children and their parents seemed to prefer EST to endoscopy if similar information was obtained.[50] Katzka et al.[51] studied EoE patients who had Cytosponge sampling and then endoscopic biopsy. They found eosinophils to correlate well between the two (r = 0.78, P < 0.0001) in active disease, when they used a cutoff count of ≤15 eos/HPF (sensitivity and specificity, 75% and 86%, respectively). Patients rated their preference for Cytosponge higher than endoscopy (7.27 vs. 6.11, P = 0.002). Unsedated in-office transnasal endoscopy may provide another less invasive method for disease monitoring.[52]
International diagnostic criteria for EoE are as follows: (1) symptoms and signs of esophageal dysfunction; (2) concomitant atopic conditions; (3) endoscopic findings of rings, grooves, exudate, stenosis, luminal narrowing, and fragility of the mucosa or crepe mucosa; (4) ≥15 eosinophils per HPF (60 eosinophils/mm2) in an esophageal biopsy; (5) eosinophilic infiltration should be isolated to the esophagus; and (6) evaluation of disorders other than EoE that potentially contribute to esophageal eosinophilia.[53]
| Differential Diagnosis | | |
The following disorders/diseases are considered to be a differential diagnosis of EoE; GERD; infections such as anisakiasis, schistosomiasis, and toxocariasis; celiac disease; hypereosinophilic syndrome; and other diseases such as eosinophilic granulomatosis with polyangiitis and inflammatory bowel disease.
| Natural History | | |
Studies have shown conflicting conclusions on EoE progression. Many of the long-term studies have shown that only a proportion of patients develop clinical deterioration.[54],[55],[56] Another Swiss study which included 200 adults with EoE found that untreated disease duration was predictive of stricture development. It was found that in patients who had a delay in diagnosis of up to 2 years, the incidence of strictures was 17%, and in those who had a diagnosis between 2 and 5 years, the incidence of strictures rose to 31%. This incidence kept rising significantly to 38% in those with a delay in diagnosis of 8–11 years, 64% with a delay of 14–17 years, and 71% with a delay of more than 20 years. The study concluded that neither the age at onset of symptoms nor the severity of esophageal eosinophilia influenced the presence of stricture formation.[57] Other studies have also shown similar trends, finding a greater duration of delayed diagnosis in patients with more severe esophageal strictures.[58],[59] Whereas few other studies have shown an association between older age and the presence of endoscopic features of fibrostenosis.[60],[61]
| Management | | |
The frequency of symptoms can vary widely, ranging between daily symptoms and a couple of times a month. The severity of symptoms also varies from obstructing food bolus that requires emergency care to dysphagia that may be minor and intermittent. EoE results in slow remodeling of the esophagus, and many patients adapt well by modifying their diet; mincing their food; liquidizing their vegetables; and surviving on soups, smoothies, and liquids.[62]
Diet
Currently, there is no technique available which can reliably identify which food causes symptoms. Skin prick testing identifies allergens associated with IgE-mediated atopies such as eczema and rhinitis but not the EoE. There are two practical modalities to diet appropriation: a 2-4-6 step-up food elimination and a 6 step down food elimination also called six-food group elimination diet (SFGED). There is a poor correlation of symptoms and histological improvement in EoE. Over the past decade, the most common approach has been the elimination of multiple foods – milk, wheat, eggs, soya, nuts, and fish and often legumes. The range of success is 50%–75% for patients after 12 weeks of diet modification, requiring both symptom check and endoscopy with biopsy to ascertain true remission. However, it is difficult to maintain this diet long term.[63]
The 2-4-6 step-up diet was introduced with a perspective that patients may be more likely to comply with diets that are less restrictive in nature as well as the concept of a step-up will encourage patients.[64] It was found that removing milk and wheat from diet resulted in success in 43% of patients, also showing sustainability of this diet in addition to incurring less follow-up costs by requiring only one follow-up visit to scope.[64] As opposed to the SFGED, a step-up diet reduced diagnostic procedure time and requirement by 20%. The remission rates as evidenced by clinical features and histology were 43%, 60%, and 79% for two-food elimination, four-food elimination, and six-food elimination diets, respectively.[64],[65] Whether a patient should be managed with persisting diet change or switch to pharmacotherapy depends on each individual and needs counseling.
Proton-pump inhibitor
The mode of action of PPI in esophageal eosinophilia is still debated. This is especially true since the main differential in EoE is GERD. There could be few scenarios which could cause this.[66],[67] GERD could cause reflux mediated esophageal injury that could either directly cause or allow new antigens/allergens to be exposed to the immune system which in turn contributes to or causes eosinophilia. Another could be that in EoE, the esophageal infiltrate causes dysmotility, thereby predisposing to reflux. It could also be that both GERD and EoE coexist in people and the symptom improvement is because of the improvement in reflux when started on PPI.[66]
It has now also been found in several studies that PPIs, aside from their acid-suppressive action, may be imparting a novel anti-inflammatory effect. PPIs can act as antioxidants, directly inhibit neutrophils and monocytes, decrease expression of pro-inflammatory cytokines, and inhibit or kill multiple bacteria and fungi.[68],[69],[70] Recruitment of eosinophils into the tissues of GI tract as well as other organs such as lungs has been found to be inhibited by PPIs.[71]
Despite the lack of acid reflux in the etiology of EoE, there is a symptom response in 30%–60% of patients in observational and uncontrolled studies, when double-dose PPI (20 mg omeprazole two times per day or equivalent) is used for 6 weeks.[62]
Topical steroids
Recent guidelines from the AGA Institute and the Joint Task Force on Allergy-Immunology support the use of topical steroids in EoE.[4] A review in which eight double-blind placebo-controlled RCTs were included found that 35.1% of patients treated with topical steroids failed to achieve histologic remission compared to 86.7% of patients treated with placebo, leading to an RR of 0.39 (95% CI, 0.26 - 0.58). Adverse events were almost comparable between the two groups. Systemic steroids do not act as well and are associated with higher adverse effects.[4]
Fluticasone spray at 250 μg four puffs twice daily (at night and after breakfast with no mouth washing, food, or fluids for as long as possible) is the recommended dosage.[62] Topical steroids could be used for 3 months in the first instance and thereafter in maintenance therapy or in repeated bolus courses of 3 months.[62] Viscous solution of oral budesonide and an orodispersible budesonide tablet, which can be placed on the tongue and allowed to dissolve in saliva passing gradually into the esophagus, are also available in some countries.[72],[73]
Patients who require a therapeutic dilatation must have continuation of topical steroid as their maintenance therapy.[46] Safety of long term budesonide for GI complaints is well established. The occasional oral thrush easily managed by oral nystatin suspension for 10 days, without cessation of therapeutic topical steroids.[62] Patients with intermittent, mild, or moderate symptoms, could choose between diet modification and PPI.
Emerging and experimental treatment strategies
Multiple new biologic agents are being studied to treat EoE and are in various stages of development.[74],[75] These are RPC4046 (IL-13 monoclonal antibody),[76] dupilumab (against IL-4 receptor alpha component of type 2 receptor monoclonal antibody which blocks IL-4 and IL-13),[77] antolimab/lirentelimab (Siglec-8 monoclonal antibody which promotes eosinophil apoptosis and inhibits mast cell activation),[78],[79] and mepolizumab and reslizumab (IL-5 receptor alpha monoclonal antibody which depletes eosinophils).[80],[81] Benralizumab, another molecule which acts through IL5 receptor alpha subunit, has been recently granted orphan drug designation for the treatment of EoE by the Food and Drug Administration.[75],[82] These therapies are still in experimental phase and once approved hopefully will be beneficial for steroid-refractory EoE.
| Complications | | |
EoE is one of the most common causes for food bolus obstructions worldwide. Bolus extraction could be attained by arranging for an urgent endoscopy with airway protection. Although antispasmodic medications can be tried, this usually is not helpful. Patients should be evaluated clinically and radiologically for surgical emphysema, especially if they are in extreme discomfort, for ruling out the rare event of esophageal perforation, before embarking on endoscopy. Esophageal stricture as a complication can be managed with esophageal dilatation with either a balloon or a Savary-Gilliard dilator.
| Conclusion | | |
EoE has been increasing in prevalence worldwide. Although there are a lot of unknowns about this condition, emerging evidence suggests that modifying the disease with dietary and pharmacological interventions could reduce the long-term complications. There is no formal recommendation yet regarding the need for repeated gastroscopies to assess disease activity periodically or when there is a change in therapy. Future research hopefully would guide further insights into effective management strategies of this condition.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
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