Abstract
Despite dramatic advances in our understanding of the pathogenesis and course of disease in the relatively short timeframe since the discovery and first description of eosinophilic esophagitis (EoE) less than three decades ago, many open questions remain to be elucidated. For instance, we will need to better characterize atypical clinical presentations of EoE and other forms of esophageal inflammatory conditions with often similar clinical presentations, nut fulfilling current diagnostic criteria for EoE and to determine their significance and interrelationship with genuine EoE. In addition, the interrelationship of EoE with other immune-mediated diseases remains to be clarified. Hopefully, a closer look at the role of environmental factors and their interaction with genetic susceptibility often in context of atopic predisposition may enable identifying the candidate substances/agents/allergens and potentially earlier (childhood) events to trigger the condition. It appears plausible to assume that in the end—comparable to current concepts in other immune-mediated chronic diseases, such as for instance inflammatory bowel disease or asthma bronchiale—we will not be rewarded with the identification of a “one-and-only” underlying pathogenetic trigger factor, with causal responsibility for the disease in each and every EoE patient. Rather, the relative contribution and importance of intrinsic susceptibility, i.e., patient-driven factors (genetics, aberrant immune response) and external trigger factors, such as food (or aero-) allergens as well as early childhood events (e.g., infection and exposure to antibiotics and other drugs) may substantially differ among given individuals with EoE. Accordingly, selection and treatment duration of medical therapy, success rates and extent of required restriction in dietary treatment, and the need for mechanical treatment to address strictures and stenosis require an individualized approach, tailored to each patient. With the advances of emerging treatment options, the importance of such an individualized and patient-centered assessment will increase even further.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Pathogenesis of eosinophilic esophagitis: “epidemiology and insights from environmental factors”
The epidemiology of eosinophilic esophagitis—an accelerated emergence in the face of a rapidly changing environment
Eosinophilic esophagitis (EoE) refers to a chronic, inflammatory, TH-2-type immune-mediated disease exclusively affecting the esophagus with rapid emergence [1,2,3] subsequent to its first description almost three decades ago [4, 5]. Until recently, EoE was a representative of orphan diseases. However, both epidemiological studies and everyday clinical practice not only indicate that the disease is relatively common (at least in the western world) [1,2,3]. EoE has also been recognized as THE leading causes of esophageal dysphagia and food impaction in adults [6], as well as an important underlying etiology of failure to thrive and refusal of adequate food intake in children [7].
Currently, the prevalence of EoE in the western world is around 1 in 2500 individuals (1–9/100,000) [1, 3]. As it is the case with any dramatic increase in incidence of a given rather novel disease, the following question arises: Is there just an increase in physicians’ awareness and therefore a lower threshold to detect the condition that might have always been (and still is) present in a relatively stable epidemiological distribution?
The clear answer is no. Although there has been a moderate increase in the overall rate of esophageal biopsies obtained during upper endoscopy in recent years, there is an incomparably larger increase of the fraction of biopsies from the proximal and distal part of the esophagus with high eosinophilic counts (above the diagnostic threshold of > 15 eosinophils per high-power field) [8, 9]. These dynamics can only be explained by an genuine increase in EoE—in excellent congruency with numerous epidemiological investigations [1, 2, 10, 11].
The association of EoE with atopic disease has been repetitively confirmed, with at least 60% of EoE patients currently or previously suffering from concomitant atopic diseases [2, 12,13,14]. The crucial importance of environmental factors to impact on the integrity of epithelial barrier function has been recognized and a matter of extensive research in other immune-mediated diseases with predominant TH-2 response, including asthma, allergic rhinitis, atopic dermatitis, or food allergies [15]. Environmental factor most likely are important in developed and developing countries alike [16]; indeed, the pace of changes in environmental factors is likely to be even higher in the latter. Perhaps the most extremely rapid and fundamental change in environmental exposure occurs in immigrants, where an assimilation of the hosting country’s risk for several immune-mediated diseases, e.g., IBD [17] has been observed in immigrants and their offspring, typically within very few decades.
A multitude of factors are assumed to play a role in EoE’s etiopathogenesis, including genetics, altered immune response, and alterations in the dietary composition in specific and environmental factors in general. While the reasons for the steep increase in epidemiology still remain rather elusive, the accelerated emergence of EoE within a relatively short interval of less than three decades in itself is a strong advocate for a crucial role of environmental factors [18] in chronic immune-mediated diseases (including IBD [17, 19], psoriasis [20], or asthma [21]) in general, so as specifically in EoE [22].
Environment in EoE: established and presumptive factors
It is nowadays widely accepted that EoE in the vast majority of patients represents a distinctive form of food allergy [23, 24]. Therefore, it may be hypothesized that a considerable fraction of all environmental factors a given individual is exposed to in conjunction with the global geographic distribution of these factors might represent a proxy of variance in food intake (i.e., type and composition of dietary components). Currently, there is an important limitation regarding the available literature on environmental factors’ potential role in EoE. Most of the research was conducted in relatively circumscribed geographic regions, such as the USA (entire country or only cohorts from circumscribed regions, e.g., North Carolina) or Spain, representing only a small fraction of those regions of the world, where EoE is common and evidently are not at all representative for regions with (at least for the time being) low prevalence. To put this limitation in a nutshell: While as an example brick exterior housing [25] may provide insights for the situation in North Carolina and other western countries alike, we are evidently in need for future research on potential causative environmental factors in regions of the world, where brick exterior in housing are entirely inexistent.
While the aggregation of cases of EoE appears to be high within families, studies in twins and families rather support the predominant role of concomitant environmental exposure as compared to genetic heritability [18].
Environmental factors may even play a role as early as prior to birth. Maternal fever during pregnancy (adjusted odds ratio, aOR 3.18) as well as preterm labor and c-section (aOR 2.18 and 1.77, respectively) were found to be associated with developing EoE in the future [26, 27]. Furthermore, antibiotics in infancy might increase the risk of EoE in adulthood (OR 4.46) [27].
Eosinophilic esophagitis may be more common in rural regions with a lower population density [28], which appears somewhat counter-intuitive, as IBD [29] and atopic diseases appear to be more frequent in urban living conditions with presumed protective effects of frequent childhood contact with farm animals [30]. Rather in line with the hygiene hypothesis [31] on the other hand and in contrast to the former observation—gastric Helicobacter pylori infection has consistently been shown to be negatively associated with EoE in a multitude of different investigations [32,33,34]. In addition, having had a (furry) pet in infancy was found with a considerably reduced associated risk of EoE (aOR 0.58) [26]. Interestingly, EoE may be considered as a rather late landmark in the atopic march’s stretch of way [35].
Aside from typical hygiene aspects, housing conditions might be of additional importance, as EoE was independently associated with living in a house with brick exterior (aOR 1.83) [25].
There are discrepant results regarding seasonal differences in EoE. While a large US case–control study identified a small but consistent seasonal increase in EoE incidence in summer (pointing to the potential role of pollen/aeroallergens) [36], a recent large meta-analysis from Spain did neither observe variations in incidence nor clinical recurrence [37]. A study from the US indicated, that individuals living in a cold climate zone had a roughly twofold increased risk of dysphagia, esophageal eosinophilia. and eosinophilic microabscesses [38].
EoE is increasingly recognized in developing countries or—when it comes to chronic immune-mediated disease typically associated with westernized living conditions—rather untypical regions of the world, including for instance Saudi Arabia [16].
While smoking is the best-studied environmental factor in inflammatory bowel disease, surprisingly little is known on the potential role of smoking on the occurrence of course of disease in EoE. In a case–control study, smoking independently decreased the risk of suffering from EoE in multivariate analysis (OR 0.47) [39]. Contrary, to what one might expect according to the robust evidence in Crohn’s disease, no increased risk of fibrostenotic disease was observed among smoking EoE patients [39]. Furthermore, no significant impact of alcohol intake (even with daily reported intake) on the risk of EoE was observed [39].
Current intake of NSAIDs was found to be associated with a decreased risk in EoE [39], whereas prior intake of antibiotics and PPI use in infancy revealed a risk increase of EoE in childhood (aOR 2.3 and 6.05, respectively) [26, 27, 40].
Looking at environment in EoE and learn about its pathogenesis?
Although the importance of environmental factors in the pathogenesis of EoE has increasingly received recognition in recent years, discrepantly little knowledge and research is currently available in comparison to for instance genetics [22, 41]. This indicates, that a re-evaluation of the scientific community’s research priorities might be worthwhile and a more intensive exploration of environmental factors might harbor the potential to advance our understanding of EoE in general and its recent dramatic epidemiological rise in specific. Evidently, the underlying reason—it might be indeed more appropriate to assume that there are several potentially synergistic reasons, with distinctive and variable importance according to individual patients—for the steep rise in EoE’s incidence still remain speculative [42]. However, the rapidly changing environment and complexity of EoE patients’ exposures to environmental influences throughout lifetime render it likely that an increased investigations of the environment might be fruitful to advance our understanding of the pathogenesis of EoE.
To conclude, in a disease as multifactorial as EoE, it certainly is plausible to increase our attention, dedication, and scientific focus on a key component of its pathogenesis [43], which is the environment.
Typical clinical presentation, diagnosis, and treatment of eosinophilic esophagitis
Definition and characterization of eosinophilic esophagitis
Since the first description of eosinophilic esophagitis (EoE) in the early nineties of the twentieth century, this syndrome is defined as a clinico-pathological entity [4, 5]. Because the esophagus is a hidden organ and because this particular inflammatory condition seldom provokes relevant systemic effects, the clinical part of its dichotomous definition consists almost exclusively of symptoms. Clinical findings are mainly unremarkable and as such physical examination and laboratory analyses do not in general exhibit significant abnormalities [44]. The pathological part of EoE’s definition relies on the histological examination of esophageal biopsy specimens, showing a predominant infiltration with eosinophils [44]. Of note, as a transient eosinophilic tissue infiltration may occur under many circumstances, chronicity is a further element required for diagnosing EoE [45].
Clinical manifestation of EoE in adults and children
According to the guidelines, “symptoms of esophageal dysfunction” is the umbrella-term of EoE’s clinical manifestation [46]. In adults and adolescents, dysphagia for solids up to food impaction is the leading symptom occurring in almost 95% of patients [44]. However, non-swallowing-related chest pain—occurring either spontaneously or induced by particular maneuvers such as physical exercise or drinking of alcoholic and/or sour beverages—is reported in more than half of adult and adolescent patients [47]. In contrast, children present a much broader spectrum of symptoms, whereas food refusal, chest pain, abdominal pain, diarrhea, regurgitation, vomiting, and failure to thrive are the leading ones [47]. This non-specific presentation requires a proper differential diagnosis including gastroesophageal reflux, celiac disease, intestinal malformations, Crohn’s disease, food allergies, and functional disorders. For pediatricians, diagnosing EoE is therefore a much bigger challenge as for adult gastroenterologists.
Endoscopic manifestations of EoE
Although there is no pathognomonic endoscopic sign associated with EoE, upper endoscopy is the first step in the evaluation of a patient with solid food dysphagia [48]. A considerable number of different endoscopic features are associated with EoE, the leading ones being longitudinal furrowing, white exudates, edema, long- and short-segment stricture Schatzki ring, corrugated rings, and crêpe paper mucosa [49] (Fig. 1). These signs usually appear in random combination in any given patient. White exudates, edema, and longitudinal furrowing reflect acute inflammation, whereas rings and strictures are a consequence of fibrosis due to a long-standing eosinophilic inflammation. In order to standardize the assessment of the endoscopic manifestations, endoscopists use the so-called EREFS classification, which includes the five major signs [50]. Important, all these signs are suggestive of the diagnosis of EoE, but the endoscopic suspicion requires histologic confirmation. There are even some reports of normal appearing mucosa in EoE. A history of solid food dysphagia requires therefore always a structured biopsy sampling even in the absence of obvious endoscopic abnormalities.
Typical endoscopic features of EoE. Edema may often only be a subtle and patchy finding as illustrated in a, where submucosal vessels are readily visible in the right (no edema) but not in the left part (edema present) of the picture. More pronounced edema, rings, and furrows are depicted in b, whereas in c furrows are more severe with few exudates, which frequently tend to be located within or adjacent to furrows. Extensive white exudates covering nearly the entire surface of the esophagus are shown in d
Histo-pathological manifestation of EoE
A relevant infiltration of the esophageal epithelium with eosinophils is the histological hallmark of EoE [44]. The eosinophils are typically accumulated beneath the surface of the epithelium, often agglomerated to so-called microabscesses and sometimes already degranulated [51]. However, EoE is not a single-cell disease and numbers of different sub-sets of lymphocytes and mast cells are increased as well in the inflamed mucosa of the esophagus. The further characterization of the inflammatory cells and of the mediators has shown that EoE exerts mainly a Th2 inflammatory pattern [52]. In addition to the cellular infiltration, several non-cellular, structural abnormalities occur in EoE. Dilated intercellular spaces, surface layering, basal zone hyperplasia, and papillary elongation are alterations associated with acute inflammation and with an increased cellular turnover. The eosinophils are late-phase inflammatory cells with powerful repair properties [53]. A chronic inflammation leads therefore to fibrosis of the involved organ [54]. In EoE—in contrast to reflux disease—in the lamina propria usually a substantial fibrosis can be seen [55]. The eight leading EoE-associated alterations are summarized and graded in a histological scoring system, called EoE-HSS [51]. It is recommended using this instrument when evaluating esophageal biopsies for the purpose of randomized clinical trials. However, in observational studies or regular clinical practice, performing EoE-HSS on a routine basis may be too cumbersome.
Diagnostic criteria of EoE
Based on the above-mentioned considerations, a firm diagnosis of eosinophilic esophagitis requires the following three items:
-
A prolonged existence of symptoms attributed to esophageal dysfunction
-
An eosinophil predominant infiltration of the esophageal epithelium with peak values of more or equal than 15 eosinophils per high-power field (HPF)
-
An exclusion of other reasons for esophageal tissue eosinophilia, mainly reflux disease, eosinophilic gastroenteritis, Crohn’s disease, and connective tissue disorders [44]
Of note, since the recognition that PPI-responsive eosinophilia is nothing else than typical EoE with the only exception that it responds in addition to the established treatments to PPI as well [56], the diagnostic PPI-trial is obsolete and therefore not anymore requested for establishing the diagnosis [57].
Natural history and complications of EoE
When confronted with a new disease, the understanding of the natural history is crucial for making any decisions regarding monitoring and treatment. Despite the fact that our understanding of the natural history of EoE is still limited, it has become clear that it is a chronic disease with either chronic-persistent or chronic-relapsing course [45]. Currently, EoE seems to not harbor an increased risk for malignancies, but long-term follow-up is required to confirm this observation. The main concern is that a long-standing, untreated eosinophilic inflammation leads to fibrosis with wall thickening, abnormal fragility and strictures, finally evoking a structural and functional damage of the esophagus [55, 58]. This so-called remodeling [59] predisposes to several complications: Acute food bolus impaction is the leading complication of untreated EoE. During the course of their disease, more than one-third of adult patients will experience long-lasting food impactions with the necessity for endoscopic removal [60]. This frightening and risky complication is a sword of Damocles hanging permanently over almost all EoE patients. Long-lasting impactions harbor the risk for retching-induced esophageal rupture (Boerhaave’s syndrome), procedure-related perforation and aspiration pneumonia [60]. In addition, remodeling can impair the function of the lower esophageal sphincter (LES) leading to a secondary reflux. In a case series, 10 of 26 (38%) adult EoE patients had pH monitoring confirmed coexisting reflux disease [49]. Finally, we have to admit that our knowledge of the natural history of EoE is still fragmentary.
Goals of and indications for treatment
As a consequence of EoE’s dichotomous definition, the primary therapeutic goal is a dichotomous as well: resolution of symptoms and control of the inflammation [47]. From the patients perspective resolution of symptoms is the main treatment target[61]. However, as an ongoing eosinophilic inflammation results in a long-term organ damage, control of eosinophilic inflammation has to be regarded as an at least as important therapeutic goal. A cut-off of less than 15 eosinophils per high-power field has shown to be an appropriate endpoint in several therapeutic trials [57]. In conclusion, the ideal therapeutic intervention in EoE has to improve symptoms as well as to control the inflammation.
Therapeutic options: drugs, diet, and dilation (DDD)
EoE is in the vast majority of patients an allergic response induced by food proteins, but shares in addition similarities with gastroesophageal reflux disease. Drugs used to treat allergies and reflux disease have therefore intensively been tested as medical treatments for EoE. However, if the causative food can be identified an elimination diet is an attractive, non-medical treatment option. Finally, in refractory EoE, dilation can be needed. The therapeutic options can therefore be summarized as the 3 D’s: drugs, diet, and dilation [47].
Medical treatment of eosinophilic esophagitis
Corticosteroids
In the first study demonstrating that systemic corticosteroids are able to bring active EoE into remission, a series of pediatric patients with esophageal eosinophilia and chronic reflux-like symptoms unresponsive to aggressive anti-reflux therapy were treated with methylprednisolone [62]. After corticosteroid therapy, all but one patient had dramatic clinical and histological improvement. Shortly afterwards, it was demonstrated that EoE patients responded even to treatment with swallowed, topically acting corticosteroids (STC) [63]. Ten years later, a prospective controlled trial comparing prednisone with swallowed fluticasone showed that STCs were as effective as systemic corticosteroids but had fewer side effects [64]. This study provided the first strong evidence that EoE can be controlled without the use of systemic corticosteroids. Meanwhile, a substantial number of controlled clinical trials have confirmed that STCs such as budesonide, fluticasone, ciclesonide, or mometasone deposited on the esophageal surface are highly efficient in adult and pediatric EoE patients in bringing active EoE clinically and histologically in remission [47]. Overall, the response rates with STCs were between 50 and 93%. The main drawback of corticosteroid treatment is that almost all patients rapidly relapse after cessation of therapy [65, 66]. Therefore, corticosteroids are able to control, but not to cure EoE. The main side effect of STCs is colonization with Candida albicans, occurring in 10 to 15% of the patients. This infection is often asymptomatic and requires only a therapy in case of symptoms. Respecting the well-documented efficacy and the favorable safety profile, the European Medicines Agency EMA has approved the first budesonide preparation—an oral-dispersible budesonide tablet specifically designed for the esophageal administration (Procedure No. EMEA/H/C/004655/0000)—for the treatment of EoE. Since EoE is a chronic disease and relapses occur rapidly after cessation of an induction treatment, a maintenance therapy is required. Subsequently, two controlled long-term studies using budesonide have demonstrated that this compound is able to maintain a clinico-histological remission in up to 75% of the patients, whereas less than 5% of the participants under placebo were still in remission after one year of treatment [67]. Of note, as four of the total 136 patients (≈3 % ) exposed to budesonide had decreased morning cortisol levels, further studies evaluating the safety of the long-term use of STCs are needed. Today, it is still prudent to exercise caution, when treating children and adults with high doses of swallowed topical corticosteroids for longer time periods.
Proton pump inhibitors
Proton pump inhibitors (PPI) are recommended in EoE patients with coexisting gastroesophageal reflux disease (GERD) [44]. Given the high prevalence of GERD in a general population, it is likely that both diseases can coexist. However, the interplay between EoE and GERD is more complex [68] and it is also possible that an impairment of the lower esophageal sphincter may lead to secondary reflux and that a hypersensitivity of the eosinophil-inflamed esophageal mucosa could provoke reflux-like symptoms even in absence of obvious reflux. Moreover, it is meanwhile established that a subgroup of EoE patients, initially called PPI-responsive esophageal eosinophilia, responds to PPI even in the absence of reflux. Although real-world data suggest STC the most effective treatment option, PPI are much more frequently prescribed as first line therapy than STC (76.4% vs. 10.5%) according to a European registry, predominantly with patients from Spain [69]. Furthermore, it remains to be determined where PPIs must be positioned in the treatment algorithm of EoE, because so far no robust studies directly comparing the efficacy and long-term safety of PPI with STC drugs are available.
Immunosuppressants (thiopurines)
As already mentioned, in on average 70% of patients, remission can be achieved with STCs. In other words, roughly 30% of EoE patients do not achieve the therapeutic goals despite properly performed treatment with STCs. In analogy to steroid-refractory inflammatory bowel disease, immunosuppressants have been evaluated in these patients. Indeed, in a small series of adult patients with refractory EoE. purine analogues have shown promising results [70]. Surprisingly, this treatment modality has not been further evaluated.
Biologics
Interleukin 5 (IL-5) plays a critical role in maturation, differentiation, activation, and tissue recruitment of eosinophils. Mepolizumab and reslizumab—both humanized anti-IL-5 antibodies—are highly specific anti-eosinophil drugs. Three controlled trials with these anti-IL-5 blockers have demonstrated a significant reduction of eosinophils in the esophageal tissue and in the peripheral blood [71,72,73]. Unfortunately, both substances exerted only minimal clinical benefits in all three studies. However, it currently remains unclear, whether use of non-validated outcome instruments in these trials are at least in part associated with the observed lack of clinical improvement. Because IL-4 and IL-13 play a key role in the pathogenesis of EoE as well, treatment with monoclonal antibodies blocking these two cytokines were evaluated too. RPC4046, a pure IL-13 blocking compound, and dupilumab, a combined blocker of the IL-13 receptor and the alpha-unit of the IL-4 receptor, have shown in phase 2 trials promising results [74, 75]. Both drugs are currently further evaluated in phase 3 trials. In conclusion, among the already evaluated biologics, IL-13 and IL-4 blockers appear to represent the most promising approach in patients with refractory EoE.
Dietary treatment of eosinophilic esophagitis
Eosinophilic esophagitis is mainly induced by food proteins. Avoidance of a contact between the esophageal surface and food proteins has demonstrated to reliably resolve symptoms and inflammation, opening a door toward a causative non-medical treatment [76]. Currently, the challenge is to identify both the culprit food categories and those patients who are suited for a dietary intervention. As IgE’s do not play a key role in inducing the inflammatory response [77], IgE-based tests such as skin prick tests or determination of food-specific serum IgE’s are not reliable in the search for causative nutrition. In general, the following principal dietary approaches can be differentiated:
Elemental diet
Twenty-five years ago, a pediatric case series has shown that a protein-free diet using an acid-based formula is able to bring more than 90% of EoE patients in remission [76]. This so-called elemental diet is therefore currently the most efficient dietary regimen. Nevertheless, taste and costs of the formulations are markedly affecting the quality of life of the patients. Currently, there are two potential indications, namely, in patients refractory to medical and less restrictive dietary treatments as well as a radical initial modality to enforce a remission in severely diseased patients.
Targeted elimination diet
The identification of the culprit food group(s) and consecutive individualized elimination would represent the most stringent and elegant treatment for EoE. Unfortunately, the validity of different methods of allergy testing—for instance, skin prick tests, atopy patch tests, serum IgE, microarrays—to identify culprit food categories is disappointingly low because the majority of these tests is IgE-based and IgE’s play in EoE only a subsidiary role [77]. The targeted elimination diet is therefore, as long as no meaningful diagnostic tools are available, of limited value.
Empiric elimination diet
Empiric elimination diet turns the perspective from the patient to the risk of particular food categorizes provoking allergic responses. Starting with the elimination of the six most critical food categories (6-FED)—milk, gluten, egg, soy, peanut/tree nuts, fish, and seafood—followed by stepwise and controlled re-introduction (step-down strategy) is currently the best evaluated dietary treatment modality in EoE. According to a meta-analysis, remission in about three quarters of patients can be expected [78]. Because the controlled re-introduction requires serial endoscopies, this form of dietary treatment is cost- and time-intensive. The most frequently identified culprit foods are milk, gluten, and eggs. In addition, frequently only one or two of the six foods were identified as triggers [79, 80]. This suggests that less comprehensive forms of dietary restriction might be comparably effective. Indeed, a shift of paradigm starting with a 1- or 2-FED followed by a step-up strategy is increasingly advocated and has shown first promising results [81]. This approach is easier to follow and might increase the acceptance of dietary treatment approaches in both patients and physicians.
Treatment of eosinophilic esophagitis with dilation
A chronic, untreated eosinophilic inflammation induces fibrosis leading to wall thickening, loss of elasticity and stricture formation [54, 55]. Beside the acute inflammation, this so-called remodeling can create symptoms and in addition is a risk for food bolus impactions. Because the response of this fibrosis to anti-inflammatory treatment is slow, however, dilation is the treatment of choice when symptoms persist despite successful treatment of the inflammation. Important, the underlying inflammation is not influenced by this procedure [82]. Summarized, dilation is an efficient measure to control symptoms but should be used as second-line treatment and only in combination with a medical or dietary anti-inflammatory treatment.
Atypical presentation of eosinophilic esophagitis
EoE beyond esophageal eosinophilia
Esophageal eosinophilia is the hallmark of EoE; an eosinophilic infiltration of at least 15 eosinophils per high-power field is required to correctly and unambiguously establish the diagnosis [14]. However, the pivotal role of eosinophils has been questioned lately. The only modest correlation between symptoms and esophageal eosinophilia suggests the presence of other pathogenic mechanisms beyond pure eosinophilic infiltration [83]. Indeed, the newly developed EoE histology scoring system that takes into account various histologic changes (such as basal zone hyperplasia, spongiosis, and lamina propria fibrosis) appears to outperform peak eosinophil counts for both EoE diagnosis and monitoring [51]. In addition, eosinophil-targeted treatment with the monoclonal antibodies mepolizumab and reslizumab—despite achieving dramatic reduction in eosinophil counts—did not induce clinical response [71,72,73]. Therefore, adhering to an arbitrary chosen cut-off value (15 eos/hpf) to dichotomize patients into having EoE vs. having no disease is probably too simple. As it is known for other diseases, subtypes or variants might exist unraveling EoE as a spectrum disorder. The classical EoE with a significant eosinophilic infiltration might only be the tip of the iceberg representing the most extreme and most appealing phenotype of this disease spectrum.
EoE-like disease
In Switzerland, a new EoE-like phenomenon termed as EoE-like disease has been described in 2016 [84]. Five patients (four females, one male) from four families with known EoE were evaluated for typical EoE symptoms (dysphagia for solids, food impactions, and chest pain), but without esophageal eosinophilia upon histological examination. These symptoms persisted despite high-dose PPI treatment, but responded rapidly to swallowed topical steroids (clinical remission in 4/5). While endoscopic changes were only subtle (slight mucosal irregularities such as fine nodules and rings), these patients showed T cell infiltration (CRTH2 negative, not fulfilling criteria for lymphocytic esophagitis) and moderate mast cell infiltration, and gene expression abnormalities similar to classical EoE (such as MUC4 and CDH26 genes), suggesting a uniform underlying pathogenesis [84]. Motility abnormalities and GERD, two potential differential diagnoses, were excluded by high-resolution manometry and 24-h impedance pH monitoring in 3/5 patients. Of note, expert pathology review of histologic slides (hematoxylin and eosin staining) showed minor lymphocytic infiltration and signs of chronic inflammation captured by the EoE histology scoring system such as basal zone hyperplasia and papillary elongation. The latter suggests that even with simple histology patients with EoE-like disease might be identified and distinguished from patients without esophageal pathologies.
A multicenter observational study revealed indeed a high proportion of EoE-like disease patients with presence of EoE histology scoring system features, CRTH2-negative T cell infiltration and disturbed epithelial integrity [85]. The latter might indicate—as it is known for EoE—an epithelial barrier defect enabling allergen translocation and promotion of inflammation. Intriguingly, in 8 patients, progression from EoE-like disease to classical EoE was observed after a median of 14.0 months (IQR 3.6–37.6) supporting the hypothesis of a broader spectrum disease (such as inflammatory dysphagia syndrome IDS or inflammatory disease of the esophagus IDE), where EoE presents the most extreme variant (Fig. 2).
Lymphocytic esophagitis
The term lymphocytic esophagitis has first been coined by Rubio et al. in 2006 [86]. The authors reported on 20 patients with chronic esophagitis showing “high numbers of intraepithelial lymphocytes gathered mainly around peripapillary fields and by none to occasional intraepithelial granulocyte.” Fifteen years later, the entity of lymphocytic esophagitis remains poorly defined [87]. In contrast to EoE, patients tend to be older and more often females; particularly females in their sixth decade appear to be affected [88,89,90]. However, the clinical presentation with solid food dysphagia being the most common symptom is indistinguishable from that of EoE. Other lymphocytic esophagitis symptoms such as chest pain, heartburn, nausea, and abdominal pain are also known from patients with EoE [88,89,90,91]. As it is seen for EoE-like disease, endoscopic findings are commonly subtle or absent (in up to one-third endoscopy has been reported as completely normal). Still, EoE typical inflammatory and/or fibrotic signs (furrows, rings) can be observed [88, 90, 91]. Histologically, the diagnosis is based on the original description by Rubio and colleagues [86], defined as typical pattern with high numbers of intraepithelial lymphocytes (usually more than 20–30 per hpf), gathered mainly in peripapillary fields, peripapillary spongiosis (dilated intercellular spaces), and absence of intraepithelial granulocytes [92].
As large long-term follow-up studies and molecular characterization are missing, it remains unknown if there is an overlap between lymphocytic esophagitis and EoE or if they represent two completely distinct and mutually exclusive disorders. At least, preliminary results from the aforementioned multicenter study on EoE-like disease suggest some possible overlaps with regards to mRNA profiles and also some transition/progression between lymphocytic esophagitis, EoE-like disease, and EoE [85].
Clinical implications of EoE variants and future perspectives
EoE-like disease and lymphocytic esophagitis share the same clinical presentation as EoE, while the EoE typical esophageal eosinophilia is absent. Still, histologic changes can be detected based on the EoE histology scoring system and intraepithelial lymphocytes. Molecular analyses and first follow-up studies suggest some potential pathogenic overlap (Fig. 1). Long-term follow-up studies with inclusion of patients at various expert centers, together with in-depth big data analyses will pave the role toward a more detailed characterization of these entities. Of particular interest will be the question whether EoE-like disease and lymphocytic esophagitis are—like EoE—food allergen mediated. Epithelial barrier dysfunction at least implicates a potential role of such allergens entering the esophageal mucosa.
Knowledge of EoE variants is crucial as otherwise patients not fulfilling the diagnostic cut-off criteria for EoE may end up as being considered as having functional disease. Histological evaluations (plus immunohistochemistry and mRNA profiles) however clearly show that this is not the case. Whether these conditions represent distinct entities, subtypes, or variants of EoE, or early stage or burned out EoE remains to be determined. Investigation of these conditions will not only likely answer such uncertainties but also help to gain pathogenic insights into an EoE pathophysiology beyond eosinophilic infiltration and thereby pave the road to novel non-eosinophil-targeted medications.
Differential diagnosis of esophageal eosinophilia
Although EoE represents the epitome of eosinophilic infiltration in the esophageal tissue, esophageal eosinophilia (EE) has been described in many other diseases. In fact, to diagnose EoE accurately, in addition to symptoms related to esophageal dysfunction and an eosinophilic count ≥ 15 eos/hpf, differential diagnosis must be excluded [14, 57, 93, 94]. However, since these differential diagnoses are themselves often associated with EoE, another reason of EE never excludes a concomitant EoE.
Unlike in other part of the gastrointestinal (GI) tract [95, 96], eosinophils are not normal inhabitants of the esophageal mucosa. Hence, an EE should result in a diagnostic workup. In this review, we summarize the latest data about EE other than EoE.
Gastroesophageal reflux disease
One of the most common causes of EE is GERD. When faced with the question of whether a GERD or an EoE is present, several things must be considered. First of all, it should be emphasized that GERD and EoE can coexist and are not mutually exclusive. In a patient with an erosive esophagitis and a pathological 24-h pH-metry, a diagnosis of GERD may be established [97], but this never excludes a coexisting EoE. Secondly, there exist no criterion to distinguish GERD from EoE. Clinically, they share similar symptoms [98], endoscopic features are not specific for EoE [99], and a high number of eosinophilic count (eos/hpf) may be also present in GERD [100]. However, an eosinophil count (eos/hpf) lower than 5 is highly suggestive of GERD [101], but does not exclude EoE reliably [102]. Thirdly, patients responding to PPI therapy are indistinguishable from EoE [14, 57, 103]. Hence, PPIs are currently considered as treatment option in EoE and not as a diagnostic criterion [104, 105]. Having discussed all the hurdles above, how can we make a distinction between GERD and EoE in daily life? Since there exists no test to rule out GERD, the clinical presentation of the patient is key and a precise history of symptoms is of crucial importance. An interesting approach is suggested by Cotton et al., who proposed a diagnostic model for diagnosing EoE demonstrating dysphagia as the most reliable predictor [106].
Celiac disease (CeD)
Former studies suggested an association between celiac disease and EoE/EE with an up to 10% prevalence of EE in CeD patients and, inversely, a prevalence of CeD in EoE patients [107,108,109,110,111,112]. However, newer data are more conflicting [113] and refute these former findings [112, 114, 115]. The higher incidence of EE in CeD patients may be explained due to referral and selection bias. A recently published study demonstrated a prevalence of around 1% of EE in CeD patients [116]. Furthermore, HLA DQ2 and DQ8 haplotypes are not increased in adult EoE patients compared to the general population [117]. Hence, there is hardly any evidence supporting EE being a CeD-associated finding [118] and not more common than in the general population. The recommendation to obtain duodenal biopsies to rule out CeD in patients with EE is therefore questionable.
Inflammatory bowel disease
Most guidelines suggest excluding IBD as a cause of EE [14, 94]. However, EE in Crohn’s disease and ulcerative colitis is rare [119,120,121,122] and is accompanied nearly always with an inflammation in stomach and duodenum. Moreover, the inflammation in the esophagus is unspecific [123, 124] and rather has a lymphocytic than an eosinophilic pattern [125, 126]. Although a recent publication showed a fivefold increased risk of EE in IBD [127], it is possible that most of these patients had rather an EoE than an isolated EE. Large epidemiologic data support a positive association between IBD and EoE with a up to fivefold increased risk of EoE in IBD patients and inversely an up to sixfold increased risk of IBD among EoE patients [128]. Interestingly, but not in line with the former data [128], a study investigating a large database could not show a relationship between UC and EoE, but even found a significant inverse relationship between EoE and CD [129]. Nevertheless, since isolated EE in IBD is rare, a precise medical history about swallowing difficulties is key to not miss a concomitant EoE.
Motility disorders
Many case series indicate that achalasia can lead to EE, mostly with only small numbers of eosinophils in the mucosa, but higher eosinophilia in the muscularis propria [100, 130, 131]. Inversely, it is well-known that EoE may lead to motility dysfunction [132,133,134] making it difficult to distinguish whether the eosinophilic infiltration is caused by achalasia or vice versa.
Autoimmune connective tissue disease
Although most connective tissue diseases, such as eosinophilic granulomatosis with polyangiitis, lupus erythematodes, rheumatoid arthritis, systemic sclerosis, Sjögren syndrome, or scleromyositis may cause tissue eosinophilia in the GI tract, it occurs mostly in the small bowel, stomach, or colon [135, 136]. An esophageal involvement is a rarity [136, 137] and as opposed to EoE, most patients are female, have no atopy, and present with peripheral eosinophilia [136].
Autoimmune skin diseases
In case of an oral or esophageal involvement, pemphigus vulgaris (PV) [138, 139] and bullous pemphigoid (BP) [140, 141] may present with similar symptoms to EoE, namely, dysphagia and EE. However, the typical histology with linear deposits of IgG and/or C3 along the basement membrane in BP and in the epidermis in PV as well as the involvement of the skin, facilitates a distinction between an EoE and an esophageal involvement of PV or BP.
Infections
A hallmark of eosinophils is their role in helminthic infection resulting in a migration to areas of parasitic infection [96]. Although the majority of cases results in an eosinophilic infiltration of the ileum or appendix, case reports found EE in patients with pinworm infection (Enterobius vermicularis) [142] and with anisakiasis [143].
Non-esophageal eosinophilic gastrointestinal disorders, hypereosinophilic syndrome
In case of an involvement of eosinophilic infiltration in other parts of the gastrointestinal tract and absence of known causes of eosinophilia, the disease is classified as eosinophilic gastritis, gastroenteritis, or colitis, irrespective of EE [144]. These non-esophageal eosinophilic disorders (nEGIDs) present with a variety of symptoms based on the affected site (organ) and extent (layer) with or without esophageal involvement [145]. It is noteworthy that an eosinophilic infiltration in the GI tract distal to the esophagus is found physiologically and therefore no defined threshold for the number of eos/hpf in nEGIDs exists [146]. Furthermore, mucosal biopsies may be normal in a muscular or subserosal involvement.
Hypereosinophilic syndrome (HES) is defined as a an eosinophil count more than 1500 cells/ml without secondary causes for at least 1 month and evidence of end organ manifestation attributable to the eosinophilia [147]. It is characterized by multiorgan system infiltration by eosinophils, but may involve esophageal tissue resulting in EE with dysphagia [148, 149].
Rare causes
Other rare causes of EE are summarized in Tables 1 and 2.
In summary, the most common disease associated with EE besides EoE is GERD. Therefore, before ruling out very rare diseases, a precise medical history is key and leads mostly to the correct diagnosis.
References
Arias A, Perez-Martinez I, Tenias JM et al (2016) Systematic review with meta-analysis: the incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies. Aliment Pharmacol Ther 43:3–15. https://doi.org/10.1111/apt.13441
Prasad GA, Alexander JA, Schleck CD, Zinsmeister AR, Smyrk TC, Elias RM, Locke GR III, Talley NJ (2009) Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota. Clin Gastroenterol Hepatol 7:1055–1061
Dellon ES, Hirano I (2018) Epidemiology and natural history of eosinophilic esophagitis. Gastroenterology 154:319–332.e3. https://doi.org/10.1053/j.gastro.2017.06.067
Straumann A, Spichtin HP, Bernoulli R, Loosli J, Vögtlin J (1994) Idiopathic eosinophilic esophagitis: a frequently overlooked disease with typical clinical aspects and discrete endoscopic findings (Idiopathische, eosinophile Osophagitis: eine haufig verkannte Krankheit mit typischer Klinik und diskretem endoskopischem Bild). Schweiz Med Wochenschr 124:1419–1429
Attwood SE, Smyrk TC, Demeester TR et al (1993) Esophageal eosinophilia with dysphagia. A distinct clinicopathologic syndrome. Dig Dis Sci 38:109–116
Sengupta N, Tapper EB, Corban C, Sommers T, Leffler DA, Lembo AJ (2015) The clinical predictors of aetiology and complications among 173 patients presenting to the Emergency Department with oesophageal food bolus impaction from 2004-2014. Aliment Pharmacol Ther 42:91–98. https://doi.org/10.1111/apt.13237
Gonsalves N (2014) Distinct features in the clinical presentations of eosinophilic esophagitis in children and adults: is this the same disease? Dig Dis 32:89–92. https://doi.org/10.1159/000357078
Dellon ES, Erichsen R, Baron JA, Shaheen NJ, Vyberg M, Sorensen HT, Pedersen L (2015) The increasing incidence and prevalence of eosinophilic oesophagitis outpaces changes in endoscopic and biopsy practice: national population-based estimates from Denmark. Aliment Pharmacol Ther 41:662–670. https://doi.org/10.1111/apt.13129
Warners MJ, van Rhijn BD, Curvers WL, Smout AJPM, Bredenoord AJ (2015) PPI-responsive esophageal eosinophilia cannot be distinguished from eosinophilic esophagitis by endoscopic signs. Eur J Gastroenterol Hepatol 27:506–511. https://doi.org/10.1097/MEG.0000000000000331
Giriens B, Yan P, Safroneeva E, Zwahlen M, Reinhard A, Nydegger A, Vavricka S, Sempoux C, Straumann A, Schoepfer AM (2015) Escalating incidence of eosinophilic esophagitis in Canton of Vaud, Switzerland, 1993-2013: a population-based study. Allergy 70:1633–1639. https://doi.org/10.1111/all.12733
Hruz P, Straumann A, Bussmann C et al (2011) Escalating incidence of eosinophilic esophagitis: a 20-year prospective, population-based study in Olten County, Switzerland. J Allergy Clin Immunol 128:1349–1350.e5. https://doi.org/10.1016/j.jaci.2011.09.013
González-Cervera J, Arias Á, Redondo-González O et al (2017) Association between atopic manifestations and eosinophilic esophagitis: a systematic review and meta-analysis. Ann Allergy Asthma Immunol 118:582–590.e2. https://doi.org/10.1016/j.anai.2017.02.006
Simon D, Marti H, Heer P et al (2005) Eosinophilic esophagitis is frequently associated with IgE-mediated allergic airway diseases. J Allergy Clin Immunol 115:1090–1092. https://doi.org/10.1016/j.jaci.2005.01.017
Lucendo AJ, Molina-Infante J, Arias Á, Arnim U, Bredenoord AJ, Bussmann C, Amil Dias J, Bove M, González-Cervera J, Larsson H, Miehlke S, Papadopoulou A, Rodríguez-Sánchez J, Ravelli A, Ronkainen J, Santander C, Schoepfer AM, Storr MA, Terreehorst I, Straumann A, Attwood SE (2017) Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management in children and adults. United European Gastroenterol J 124:205064061668952–205064061668358. https://doi.org/10.1177/2050640616689525
Celebi Sözener Z, Cevhertas L, Nadeau K, Akdis M, Akdis CA (2020) Environmental factors in epithelial barrier dysfunction. J Allergy Clin Immunol 145:1517–1528. https://doi.org/10.1016/j.jaci.2020.04.024
Al-Hussaini A, Semaan T, El Hag I (2013) Eosinophilic esophagitis in a developing country: is it different from developed countries? Gastroenterol Res Pract 2013:526037. https://doi.org/10.1155/2013/526037
Agrawal M, Corn G, Shrestha S et al. (2020) Inflammatory bowel diseases among first-generation and second-generation immigrants in Denmark: a population-based cohort study. Gut. https://doi.org/10.1136/gutjnl-2020-321798
Alexander ES, Martin LJ, Collins MH et al (2014) Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis. J Allergy Clin Immunol 134:1084–1092.e1. https://doi.org/10.1016/j.jaci.2014.07.021
Ananthakrishnan AN (2013) Environmental triggers for inflammatory bowel disease. Curr Gastroenterol Rep 15:302. https://doi.org/10.1007/s11894-012-0302-4
Enamandram M, Kimball AB (2013) Psoriasis epidemiology: the interplay of genes and the environment. J Invest Dermatol 133:287–289. https://doi.org/10.1038/jid.2012.434
Subbarao P, Mandhane PJ, Sears MR (2009) Asthma: epidemiology, etiology and risk factors. Can Med Assoc J 181:E181–E190. https://doi.org/10.1503/cmaj.080612
Lyles J, Rothenberg M (2019) Role of genetics, environment, and their interactions in the pathogenesis of eosinophilic esophagitis. Curr Opin Immunol 60:46–53. https://doi.org/10.1016/j.coi.2019.04.004
Davis BP, Rothenberg ME (2016) Mechanisms of disease of eosinophilic esophagitis. Annu Rev Pathol 11:365–393. https://doi.org/10.1146/annurev-pathol-012615-044241
Capucilli P, Cianferoni A, Grundmeier RW, Spergel JM (2018) Comparison of comorbid diagnoses in children with and without eosinophilic esophagitis in a large population. Ann Allergy Asthma Immunol 121:711–716. https://doi.org/10.1016/j.anai.2018.08.022
Corder SR, Tappata M, Shaheen O et al. (2020) Relationship between housing components and development of eosinophilic esophagitis. Dig Dis Sci. https://doi.org/10.1007/s10620-020-06063-2
Jensen ET, Kuhl JT, Martin LJ et al. (2017) Prenatal, intrapartum, and postnatal factors are associated with pediatric eosinophilic esophagitis. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2017.05.018
Dellon ES, Shaheen O, Koutlas NT, Chang AO, Martin LJ, Rothenberg ME, Jensen ET (2020) Early life factors are associated with risk for eosinophilic esophagitis diagnosed in adulthood. Dis Esophagus 34. https://doi.org/10.1093/dote/doaa074
Jensen ET, Hoffman K, Shaheen NJ, Genta RM, Dellon ES (2014) Esophageal eosinophilia is increased in rural areas with low population density: results from a national pathology database. Am J Gastroenterol 109:668–675. https://doi.org/10.1038/ajg.2014.47
Gent AE, Hellier MD, Grace RH, Swarbrick ET, Coggon D (1994) Inflammatory bowel disease and domestic hygiene in infancy. Lancet 343:766–767
Radon K, Windstetter D, Poluda AL, Mueller B, Mutius E, Koletzko S, Chronische Autoimmunerkrankungen und Kontakt zu Tieren (Chronic Autoimmune Disease and Animal Contact) Study Group (2007) Contact with farm animals in early life and juvenile inflammatory bowel disease: a case-control study. Pediatrics 120:354–361. https://doi.org/10.1542/peds.2006-3624
Bach J-F (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347:911–920. https://doi.org/10.1056/NEJMra020100
von Arnim U, Wex T, Link A, Messerschmidt M, Venerito M, Miehlke S, Malfertheiner P (2016) Helicobacter pylori infection is associated with a reduced risk of developing eosinophilic oesophagitis. Aliment Pharmacol Ther 43:825–830. https://doi.org/10.1111/apt.13560
Shah SC, Tepler A, Peek RM et al (2019) Association between Helicobacter pylori exposure and decreased odds of eosinophilic esophagitis-a systematic review and meta-analysis. Clin Gastroenterol Hepatol 17:2185–2198.e3. https://doi.org/10.1016/j.cgh.2019.01.013
Dellon ES, Peery AF, Shaheen NJ, Morgan DR, Hurrell JM, Lash RH, Genta RM (2011) Inverse association of esophageal eosinophilia with Helicobacter pylori based on analysis of a US pathology database. Gastroenterology 141:1586–1592. https://doi.org/10.1053/j.gastro.2011.06.081
Hill DA, Grundmeier RW, Ramos M et al (2018) Eosinophilic esophagitis is a late manifestation of the allergic march. J Allergy Clin Immunol Pract 6:1528–1533. https://doi.org/10.1016/j.jaip.2018.05.010
Jensen ET, Shah ND, Hoffman K, Sonnenberg A, Genta RM, Dellon ES (2015) Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis. Aliment Pharmacol Ther 42:461–469. https://doi.org/10.1111/apt.13273
Lucendo AJ, Arias Á, Redondo-González O, González-Cervera J (2015) Seasonal distribution of initial diagnosis and clinical recrudescence of eosinophilic esophagitis: a systematic review and meta-analysis. Allergy 70:1640–1650. https://doi.org/10.1111/all.12767
Hurrell JM, Genta RM, Dellon ES (2012) Prevalence of esophageal eosinophilia varies by climate zone in the United States. Am J Gastroenterol 107:698–706. https://doi.org/10.1038/ajg.2012.6
Koutlas NT, Eluri S, Rusin S et al (2018) Impact of smoking, alcohol consumption, and NSAID use on risk for and phenotypes of eosinophilic esophagitis. Dis Esophagus 31:1–7. https://doi.org/10.1093/dote/dox111
Kuhn BR, Young AJ, Justice AE, Chittoor G, Walton NA (2020) Infant acid suppression use is associated with the development of eosinophilic esophagitis. Dis Esophagus 33:33. https://doi.org/10.1093/dote/doaa073
Jensen ET, Kuhl JT, Martin LJ et al (2018) Early-life environmental exposures interact with genetic susceptibility variants in pediatric patients with eosinophilic esophagitis. J Allergy Clin Immunol 141:632–637.e5. https://doi.org/10.1016/j.jaci.2017.07.010
Spechler SJ (2018) Speculation as to why the frequency of eosinophilic esophagitis is increasing. Curr Gastroenterol Rep 20:26. https://doi.org/10.1007/s11894-018-0633-x
Dowling PJ, Neuhaus H, Polk BI (2019) The role of the environment in eosinophilic esophagitis. Clin Rev Allergy Immunol 57:330–339. https://doi.org/10.1007/s12016-018-8697-9
Liacouras CA, Furuta GT, Hirano I et al (2011) Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 128:3–20.e6; quiz 21-2. https://doi.org/10.1016/j.jaci.2011.02.040
Straumann A, Spichtin H-P, Grize L, Bucher KA, Beglinger C, Simon HU (2003) Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. Gastroenterology 125:1660–1669
Furuta GT, Liacouras CA, Collins MH et al. (2007) Eosinophilic esophagitis in children and adults: a systematic review and consensus recommendations for diagnosis and treatment. 2011 DDW Abstract Supplement 133: 1342–1363. https://doi.org/10.1053/j.gastro.2007.08.017
Straumann A, Katzka DA (2018) Diagnosis and treatment of eosinophilic esophagitis. Gastroenterology 154:346–359. https://doi.org/10.1053/j.gastro.2017.05.066
Varadarajulu S, Eloubeidi MA, Patel RS, Mulcahy HE, Barkun A, Jowell P, Libby E, Schutz S, Nickl NJ, Cotton PB (2005) The yield and the predictors of esophageal pathology when upper endoscopy is used for the initial evaluation of dysphagia. Gastrointest Endosc 61:804–808. https://doi.org/10.1016/s0016-5107(05)00297-x
Remedios M, Campbell C, Jones DM, Kerlin P (2006) Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointest Endosc 63:3–12. https://doi.org/10.1016/j.gie.2005.07.049
Hirano I, Moy N, Heckman MG, Thomas CS, Gonsalves N, Achem SR (2013) Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system. Gut 62:489–495. https://doi.org/10.1136/gutjnl-2011-301817
Collins MH, Martin LJ, Alexander ES, Boyd JT, Sheridan R, He H, Pentiuk S, Putnam PE, Abonia JP, Mukkada VA, Franciosi JP, Rothenberg ME (2017) Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring. Dis Esophagus 30:1–8. https://doi.org/10.1111/dote.12470
Straumann A, Bauer M, Fischer B, Blaser K, Simon HU (2001) Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response. J Allergy Clin Immunol 108:954–961. https://doi.org/10.1067/mai.2001.119917
Rothenberg ME, Mishra A, Brandt EB et al (2001) Gastrointestinal eosinophils in health and disease. Adv Immunol 78:291–328. https://doi.org/10.1016/s0065-2776(01)78007-8
Dellon ES, Kim HP, Sperry SLW et al (2014) A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic disease. Gastrointest Endosc 79:577–85.e4. https://doi.org/10.1016/j.gie.2013.10.027
Schoepfer AM, Safroneeva E, Bussmann C, Kuchen T, Portmann S, Simon H–U, Straumann A (2013) Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner. Gastroenterology 145:1230–1236.e2. https://doi.org/10.1053/j.gastro.2013.08.015
Molina-Infante J, Bredenoord AJ, Cheng E et al (2016) Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut 65:524–531. https://doi.org/10.1136/gutjnl-2015-310991
Dellon ES, Liacouras CA, Molina-Infante J, Furuta GT, Spergel JM, Zevit N, Spechler SJ, Attwood SE, Straumann A, Aceves SS, Alexander JA, Atkins D, Arva NC, Blanchard C, Bonis PA, Book WM, Capocelli KE, Chehade M, Cheng E, Collins MH, Davis CM, Dias JA, di Lorenzo C, Dohil R, Dupont C, Falk GW, Ferreira CT, Fox A, Gonsalves NP, Gupta SK, Katzka DA, Kinoshita Y, Menard-Katcher C, Kodroff E, Metz DC, Miehlke S, Muir AB, Mukkada VA, Murch S, Nurko S, Ohtsuka Y, Orel R, Papadopoulou A, Peterson KA, Philpott H, Putnam PE, Richter JE, Rosen R, Rothenberg ME, Schoepfer A, Scott MM, Shah N, Sheikh J, Souza RF, Strobel MJ, Talley NJ, Vaezi MF, Vandenplas Y, Vieira MC, Walker MM, Wechsler JB, Wershil BK, Wen T, Yang GY, Hirano I, Bredenoord AJ (2018) Updated international consensus diagnostic criteria for eosinophilic esophagitis: Proceedings of the AGREE conference. Gastroenterology. 155:1022–1033.e10. https://doi.org/10.1053/j.gastro.2018.07.009
Lucendo AJ, Arias A, de Rezende LC, Yagüe-Compadre JL, Mota-Huertas T, González-Castillo S, Cuesta RA, Tenias JM, Bellón T (2011) Subepithelial collagen deposition, profibrogenic cytokine gene expression, and changes after prolonged fluticasone propionate treatment in adult eosinophilic esophagitis: a prospective study. J Allergy Clin Immunol 128:1037–1046. https://doi.org/10.1016/j.jaci.2011.08.007
Mishra A, Wang M, Pemmaraju VR, Collins MH, Fulkerson PC, Abonia JP, Blanchard C, Putnam PE, Rothenberg ME (2008) Esophageal remodeling develops as a consequence of tissue specific IL-5-induced eosinophilia. Gastroenterology 134:204–214. https://doi.org/10.1053/j.gastro.2007.10.002
Straumann A, Bussmann C, Zuber M, Vannini S, Simon HU, Schoepfer A (2008) Eosinophilic esophagitis: analysis of food impaction and perforation in 251 adolescent and adult patients. Clin Gastroenterol Hepatol 6:598–600. https://doi.org/10.1016/j.cgh.2008.02.003
Safroneeva E, Balsiger L, Hafner D, Kuehni CE, Zwahlen M, Trelle S, Godat S, Biedermann L, Greuter T, Vavricka S, Straumann A, Schoepfer AM (2018) Adults with eosinophilic oesophagitis identify symptoms and quality of life as the most important outcomes. Aliment Pharmacol Ther 48:1082–1090. https://doi.org/10.1111/apt.15000
Liacouras CA, Wenner WJ, Brown K, Ruchelli E (1998) Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr 26:380–385
Faubion WA, Perrault J, Burgart LJ et al (1998) Treatment of eosinophilic esophagitis with inhaled corticosteroids. J Pediatr Gastroenterol Nutr 27:90–93
Schaefer ET, Fitzgerald JF, Molleston JP, Croffie JM, Pfefferkorn MD, Corkins MR, Lim JD, Steiner SJ, Gupta SK (2008) Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children. Clinical Gastroenterology and Hepatology : the official clinical practice journal of the American Gastroenterological Association 6:165–173. https://doi.org/10.1016/j.cgh.2007.11.008
Greuter T, Bussmann C, Safroneeva E, Schoepfer AM, Biedermann L, Vavricka SR, Straumann A (2017) Long-term treatment of eosinophilic esophagitis with swallowed topical corticosteroids: development and evaluation of a therapeutic concept. Am J Gastroenterol 112:1527–1535. https://doi.org/10.1038/ajg.2017.202
Dellon ES, Woosley JT, Arrington A et al (2020) Rapid recurrence of eosinophilic esophagitis activity after successful treatment in the observation phase of a randomized, double-blind, double-dummy trial. Clin Gastroenterol Hepatol 18:1483–1492.e2. https://doi.org/10.1016/j.cgh.2019.08.050
Straumann A, Lucendo AJ, Miehlke S, Vieth M, Schlag C, Biedermann L, Vaquero CS, Ciriza de los Rios C, Schmoecker C, Madisch A, Hruz P, Hayat J, von Arnim U, Bredenoord AJ, Schubert S, Mueller R, Greinwald R, Schoepfer A, Attwood S, Tack J, Miehlke S, Bajbouj M, Brückner S, Fibbe C, Haag S, Schmöcker C, Hartmann D, Lammert F, Madisch A, Reinshagen M, Schubert S, von Arnim U, Börner N, Witzemann D, Caca K, Albert J, Zeuzem S, Wiedbrauck F, Messmann H, Bredenoord AJ, Verdonk R, Wolfhagen F, Villarin AL, Vaquero CS, de los Ríos CC, Juan AP, Martinez IP, Sanchez-Migallon JR, Andrés JB, Aisa ÁP, Straumann A, Hruz P, Schoepfer A, Biedermann L, Hayat J, Dhar A (2020) Budesonide orodispersible tablets maintain remission in a randomized, placebo-controlled trial of patients with eosinophilic esophagitis. Gastroenterology. 159:1672–1685.e5. https://doi.org/10.1053/j.gastro.2020.07.039
Spechler SJ, Genta RM, Souza RF (2007) Thoughts on the complex relationship between gastroesophageal reflux disease and eosinophilic esophagitis. Am J Gastroenterol 102:1301–1306. https://doi.org/10.1111/j.1572-0241.2007.01179.x
Laserna-Mendieta EJ, Casabona S, Savarino E et al (2020) Efficacy of therapy for eosinophilic esophagitis in real-world practice. Clin Gastroenterol Hepatol 18:2903–2911.e4. https://doi.org/10.1016/j.cgh.2020.01.024
Netzer P, Gschossmann JM, Straumann A, Sendensky A, Weimann R, Schoepfer AM (2007) Corticosteroid-dependent eosinophilic oesophagitis: azathioprine and 6-mercaptopurine can induce and maintain long-term remission. Eur J Gastroenterol Hepatol 19:865–869. https://doi.org/10.1097/MEG.0b013e32825a6ab4
Straumann A, Conus S, Grzonka P, Kita H, Kephart G, Bussmann C, Beglinger C, Smith DA, Patel J, Byrne M, Simon HU (2010) Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut 59:21–30. https://doi.org/10.1136/gut.2009.178558
Assa’ad AH, Gupta SK, Collins MH et al (2011) An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology 141:1593–1604. https://doi.org/10.1053/j.gastro.2011.07.044
Spergel JM, Rothenberg ME, Collins MH et al (2012) Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol 129:456-63–463.e1-3. https://doi.org/10.1016/j.jaci.2011.11.044
Hirano I, Collins MH, Assouline-Dayan Y et al (2019) RPC4046, a monoclonal antibody against IL13, reduces histologic and endoscopic activity in patients with eosinophilic esophagitis. Gastroenterology 156:592–603.e10. https://doi.org/10.1053/j.gastro.2018.10.051
Hirano I, Dellon ES, J d H et al (2020) Efficacy of dupilumab in a phase 2 randomized trial of adults with active eosinophilic esophagitis. Gastroenterology 158:111–122.e10. https://doi.org/10.1053/j.gastro.2019.09.042
Kelly KJ, Lazenby AJ, Rowe PC et al. (1995) Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. 2011 DDW Abstract Supplement 109: 1503–1512
Simon D, Cianferoni A, Spergel JM, Aceves S, Holbreich M, Venter C, Rothenberg ME, Terreehorst I, Muraro A, Lucendo AJ, Schoepfer A, Straumann A, Simon HU (2016) Eosinophilic esophagitis is characterized by a non-IgE-mediated food hypersensitivity. Allergy 71:611–620. https://doi.org/10.1111/all.12846
Arias A, González-Cervera J, Tenias JM, Lucendo AJ (2014) Efficacy of dietary interventions for inducing histologic remission in patients with eosinophilic esophagitis: a systematic review and meta-analysis. Gastroenterology 146:1639–1648. https://doi.org/10.1053/j.gastro.2014.02.006
Kagalwalla AF, Sentongo TA, Ritz S, Hess T, Nelson SP, Emerick KM, Melin–Aldana H, Li BUK (2006) Effect of six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clin Gastroenterol Hepatol 4:1097–1102. https://doi.org/10.1016/j.cgh.2006.05.026
Gonsalves N, Yang G-Y, Doerfler B et al (2012) Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology 142:1451-9.e1–quiz e14-5. https://doi.org/10.1053/j.gastro.2012.03.001
Molina-Infante J, Arias Á, Alcedo J, Garcia-Romero R, Casabona-Frances S, Prieto-Garcia A, Modolell I, Gonzalez-Cordero PL, Perez-Martinez I, Martin-Lorente JL, Guarner-Argente C, Masiques ML, Vila-Miravet V, Garcia-Puig R, Savarino E, Sanchez-Vegazo CT, Santander C, Lucendo AJ (2018) Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: The 2-4-6 Study. J Allergy Clin Immunol 141:1365–1372. https://doi.org/10.1016/j.jaci.2017.08.038
Schoepfer AM, Gonsalves N, Bussmann C, Conus S, Simon HU, Straumann A, Hirano I (2010) Esophageal dilation in eosinophilic esophagitis: effectiveness, safety, and impact on the underlying inflammation. Am J Gastroenterol 105:1062–1070. https://doi.org/10.1038/ajg.2009.657
Safroneeva E, Straumann A, Coslovsky M et al (2016) Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis. Gastroenterology 150:581–590.e4. https://doi.org/10.1053/j.gastro.2015.11.004
Straumann A, Blanchard C, Radonjic-Hoesli S, Bussmann C, Hruz P, Safroneeva E, Simon D, Schoepfer AM, Simon HU (2016) A new eosinophilic esophagitis (EoE)-like disease without tissue eosinophilia found in EoE families. Allergy 71:889–900. https://doi.org/10.1111/all.12879
Greuter T, Collins MH, Bussmann C et al. (2018) Sa1118 - eosinophilic esophagitis-like disease with lack of significant esophageal eosinophilia: description of a new disease entity. 2011 DDW Abstract Supplement 154: S-246. https://doi.org/10.1016/S0016-5085(18)31199-5
Rubio CA, Sjödahl K, Lagergren J (2006) Lymphocytic esophagitis: a histologic subset of chronic esophagitis. Am J Clin Pathol 125:432–437
Rouphael C, Gordon IO, Thota PN (2017) Lymphocytic esophagitis: still an enigma a decade later. World J Gastroenterol 23:949–956. https://doi.org/10.3748/wjg.v23.i6.949
Xue Y, Suriawinata A, Liu X, Li Z, Gabbard S, Rothstein R, Lacy B, Lisovsky M (2015) Lymphocytic esophagitis with CD4 T-cell-predominant intraepithelial lymphocytes and primary esophageal motility abnormalities: a potential novel clinicopathologic entity. Am J Surg Pathol 39:1558–1567. https://doi.org/10.1097/PAS.0000000000000493
Pasricha S, Gupta A, Reed CC, Speck O, Woosley JT, Dellon ES (2016) Lymphocytic esophagitis: an emerging clinicopathologic disease associated with dysphagia. Dig Dis Sci 61:2935–2941. https://doi.org/10.1007/s10620-016-4230-2
Cohen S, Saxena A, Waljee AK, Piraka C, Purdy J, Appelman H, McKenna B, Elmunzer BJ, Singal AG (2012) Lymphocytic esophagitis: a diagnosis of increasing frequency. J Clin Gastroenterol 46:828–832. https://doi.org/10.1097/MCG.0b013e3182500de8
Purdy JK, Appelman HD, Golembeski CP, McKenna BJ (2008) Lymphocytic esophagitis: a chronic or recurring pattern of esophagitis resembling allergic contact dermatitis. Am J Clin Pathol 130:508–513. https://doi.org/10.1309/D3PCF6D6YYMQRX9A
Sonnenberg A, Turner KO, Genta RM (2018) Associations of microscopic colitis with other lymphocytic disorders of the gastrointestinal tract. Clin Gastroenterol Hepatol 16:1762–1767. https://doi.org/10.1016/j.cgh.2018.03.002
Hirano I, Chan ES, Rank MA, Sharaf RN, Stollman NH, Stukus DR, Wang K, Greenhawt M, Falck-Ytter YT, Chachu KA, Day L, Lebwohl B, Muniraj T, Patel A, Peery AF, Shah R, Singh H, Singh S, Spechler SJ, Sultan S, Su GL, Thrift AP, Weiss JM, Weizman AV, Bernstein JA, Dinakar C, Golden DBK, Khan DA, Lieberman J, Oppenheimer J, Shaker M, Wallace DV, Wang J, Hirano I, Falck-Ytter YT, Rank MA, Stollman NH, Wang K, Stukus DR, Greenhawt M, Sharaf RN, Chan ES, Furuta G, Dellon E, Spergel J, Aceves S, Greenhawt M, Falck-Ytter Y, Rank MA, Sharaf R (2020) AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines for the Management of Eosinophilic Esophagitis. Gastroenterology 158:1776–1786. https://doi.org/10.1053/j.gastro.2020.02.038
Dellon ES, Gonsalves N, Hirano I, Furuta GT, Liacouras CA, Katzka DA (2013) ACG clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol 108:679–692; quiz 693. https://doi.org/10.1038/ajg.2013.71
Mishra A, Hogan SP, Lee JJ, Foster PS, Rothenberg ME (1999) Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J Clin Invest 103:1719–1727. https://doi.org/10.1172/JCI6560
Woodruff SA, Masterson JC, Fillon S, Robinson ZD, Furuta GT (2011) Role of eosinophils in inflammatory bowel and gastrointestinal diseases. J Pediatr Gastroenterol Nutr 52:650–661. https://doi.org/10.1097/MPG.0b013e3182128512
Katzka DA, Pandolfino JE, Kahrilas PJ (2020) Phenotypes of gastroesophageal reflux disease: where Rome, Lyon, and Montreal meet. Clin Gastroenterol Hepatol 18:767–776. https://doi.org/10.1016/j.cgh.2019.07.015
Molina-Infante J, Ferrando-Lamana L, Mateos-Rodríguez JM, Pérez-Gallardo B, Prieto-Bermejo AB (2008) Overlap of reflux and eosinophilic esophagitis in two patients requiring different therapies: a review of the literature. World J Gastroenterol 14:1463–1466. https://doi.org/10.3748/wjg.14.1463
Hori K, Watari J, Fukui H et al (2014) Do endoscopic features suggesting eosinophilic esophagitis represent histological eosinophilia? Dig Endosc 26:156–163. https://doi.org/10.1111/den.12091
Rodrigo S, Abboud G, Oh D, DeMeester SR, Hagen J, Lipham J, DeMeester TR, Chandrasoma P (2008) High intraepithelial eosinophil counts in esophageal squamous epithelium are not specific for eosinophilic esophagitis in adults. Am J Gastroenterol 103:435–442. https://doi.org/10.1111/j.1572-0241.2007.01594.x
Dellon ES, Gibbs WB, Fritchie KJ, Rubinas TC, Wilson LA, Woosley JT, Shaheen NJ (2009) Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease. Clin Gastroenterol Hepatol 7:1305–1313. https://doi.org/10.1016/j.cgh.2009.08.030
Ravi K, Talley NJ, Smyrk TC, Katzka DA, Kryzer L, Romero Y, Arora AS, Alexander JA (2011) Low grade esophageal eosinophilia in adults: an unrecognized part of the spectrum of eosinophilic esophagitis? Dig Dis Sci 56:1981–1986. https://doi.org/10.1007/s10620-011-1594-1
Moawad FJ, Schoepfer AM, Safroneeva E et al (2014) Eosinophilic oesophagitis and proton pump inhibitor-responsive oesophageal eosinophilia have similar clinical, endoscopic and histological findings. Aliment Pharmacol Ther 39:603–608. https://doi.org/10.1111/apt.12636
Lucendo AJ, Arias Á, Molina-Infante J (2016) Efficacy of proton pump inhibitor drugs for inducing clinical and histologic remission in patients with symptomatic esophageal eosinophilia: a systematic review and meta-analysis. Clinical Gastroenterology and Hepatology : the official clinical practice journal of the American Gastroenterological Association 14:13–22.e1. https://doi.org/10.1016/j.cgh.2015.07.041
Laserna-Mendieta EJ, Casabona S, Guagnozzi D, Savarino E, Perelló A, Guardiola-Arévalo A, Barrio J, Pérez-Martínez I, Lund Krarup A, Alcedo J, de la Riva S, Rey-Iborra E, Santander C, Arias Á, Lucendo AJ, the EUREOS EoE CONNECT Research group (2020) Efficacy of proton pump inhibitor therapy for eosinophilic oesophagitis in 630 patients: results from the EoE connect registry. Aliment Pharmacol Ther 52:798–807. https://doi.org/10.1111/apt.15957
Cotton CC, Betancourt R, Randall C, Perjar I, Bookhout C, Woosley JT, Shaheen NJ, Dellon ES (2020) A model using clinical and endoscopic characteristics identifies patients at risk for eosinophilic esophagitis according to updated diagnostic guidelines. Clin Gastroenterol Hepatol. https://doi.org/10.1016/j.cgh.2020.06.068
Quaglietta L, Coccorullo P, Miele E et al (2007) Eosinophilic oesophagitis and coeliac disease: is there an association? Aliment Pharmacol Ther 26:487–493. https://doi.org/10.1111/j.1365-2036.2007.03388.x
Verzegnassi F, Bua J, de Angelis P, Dall'Oglio L, di Leo G, Ventura A (2007) Eosinophilic oesophagitis and coeliac disease: is it just a casual association? Gut 56:1029–1030. https://doi.org/10.1136/gut.2006.117986
Ooi CY, Day AS, Jackson R, Bohane TD, Tobias V, Lemberg DA (2008) Eosinophilic esophagitis in children with celiac disease. J Gastroenterol Hepatol 23:1144–1148. https://doi.org/10.1111/j.1440-1746.2007.05239.x
Thompson JS, Lebwohl B, Reilly NR, Talley NJ, Bhagat G, Green PHR (2012) Increased incidence of eosinophilic esophagitis in children and adults with celiac disease. J Clin Gastroenterol 46:e6–e11. https://doi.org/10.1097/MCG.0b013e318221aefd
Dharmaraj R, Hagglund K, Lyons H (2015) Eosinophilic esophagitis associated with celiac disease in children. BMC Res Notes 8:263. https://doi.org/10.1186/s13104-015-1256-z
Lucendo AJ, Arias Á, Tenias JM (2014) Systematic review: the association between eosinophilic oesophagitis and coeliac disease. Aliment Pharmacol Ther 40:422–434. https://doi.org/10.1111/apt.12859
Jensen ET, Eluri S, Lebwohl B, Genta RM, Dellon ES (2015) Increased risk of esophageal eosinophilia and eosinophilic esophagitis in patients with active celiac disease on biopsy. Clin Gastroenterol Hepatol 13:1426–1431. https://doi.org/10.1016/j.cgh.2015.02.018
Ludvigsson JF, Aro P, Walker MM, Vieth M, Agréus L, Talley NJ, Murray JA, Ronkainen J (2013) Celiac disease, eosinophilic esophagitis and gastroesophageal reflux disease, an adult population-based study. Scand J Gastroenterol 48:808–814. https://doi.org/10.3109/00365521.2013.792389
Hommeida S, Alsawas M, Murad MH, Katzka DA, Grothe RM, Absah I (2017) The association between celiac disease and eosinophilic esophagitis: Mayo experience and meta-analysis of the literature. J Pediatr Gastroenterol Nutr 65:58–63. https://doi.org/10.1097/MPG.0000000000001499
Smolander M, Nurminen S, Repo M et al (2020) Prevalence and clinical significance of esophageal abnormalities in children with celiac disease. Dis Esophagus 33. https://doi.org/10.1093/dote/doaa033
Lucendo AJ, Arias Á, Pérez-Martínez I, López-Vázquez A, Ontañón-Rodríguez J, González-Castillo S, de Rezende LC, Rodrigo L (2011) Adult patients with eosinophilic esophagitis do not show an increased frequency of the HLA-DQ2/DQ8 genotypes predisposing to celiac disease. Dig Dis Sci 56:1107–1111. https://doi.org/10.1007/s10620-010-1383-2
Ari A, Morgenstern S, Chodick G, Matar M, Silbermintz A, Assa A, Mozer-Glassberg Y, Rinawi F, Nachmias-Friedler V, Shamir R, Zevit N (2017) Oesophageal eosinophilia in children with coeliac disease. Arch Dis Child 102:825–829. https://doi.org/10.1136/archdischild-2016-311944
D’Haens G, Rutgeerts P, Geboes K et al (1994) The natural history of esophageal Crohn’s disease: three patterns of evolution. Gastrointest Endosc 40:296–300. https://doi.org/10.1016/s0016-5107(94)70059-1
Goldstein NS, Amin M (2010) Upper gastrointestinal tract in inflammatory bowel disease. Surg Pathol Clin 3:349–359. https://doi.org/10.1016/j.path.2010.05.004
Ahrens R, Waddell A, Seidu L, Blanchard C, Carey R, Forbes E, Lampinen M, Wilson T, Cohen E, Stringer K, Ballard E, Munitz A, Xu H, Lee N, Lee JJ, Rothenberg ME, Denson L, Hogan SP (2008) Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis. J Immunol 181:7390–7399. https://doi.org/10.4049/jimmunol.181.10.7390
Dubucquoi S, Janin A, Klein O, Desreumaux P, Quandalle P, Cortot A, Capron M, Colombel JF (1995) Activated eosinophils and interleukin 5 expression in early recurrence of Crohn’s disease. Gut 37:242–246. https://doi.org/10.1136/gut.37.2.242
Ruuska T, Vaajalahti P, Arajärvi P, Mäki M (1994) Prospective evaluation of upper gastrointestinal mucosal lesions in children with ulcerative colitis and Crohn’s disease. J Pediatr Gastroenterol Nutr 19:181–186. https://doi.org/10.1097/00005176-199408000-00007
Horjus Talabur Horje CS, Meijer J, Rovers L, van Lochem EG, Groenen MJM, Wahab PJ (2016) Prevalence of Upper gastrointestinal lesions at primary diagnosis in adults with inflammatory bowel disease. Inflamm Bowel Dis 22:1896–1901. https://doi.org/10.1097/MIB.0000000000000786
Abuquteish D, Putra J (2019) Upper gastrointestinal tract involvement of pediatric inflammatory bowel disease: a pathological review. World J Gastroenterol 25:1928–1935. https://doi.org/10.3748/wjg.v25.i16.1928
Decker GAG, Loftus EV, Pasha TM et al (2001) Crohn’s disease of the esophagus: clinical features and outcomes. Inflamm Bowel Dis 7:113–119. https://doi.org/10.1097/00054725-200105000-00006
Fan YC, Steele D, Kochar B et al (2018) Increased prevalence of esophageal eosinophilia in patients with inflammatory bowel disease. Inflamm Intest Dis 3:180–186. https://doi.org/10.1159/000497236
Limketkai BN, Shah SC, Hirano I, Bellaguarda E, Colombel JF (2019) Epidemiology and implications of concurrent diagnosis of eosinophilic oesophagitis and IBD based on a prospective population-based analysis. Gut. 68:2152–2160. https://doi.org/10.1136/gutjnl-2018-318074
Sonnenberg A, Turner KO, Genta RM (2020) Comorbid occurrence of eosinophilic esophagitis and inflammatory bowel disease. Clin Gastroenterol Hepatol 19:613–615.e1. https://doi.org/10.1016/j.cgh.2020.02.015
Frieling T, Heise J, Kreysel C, Blank M, Hemmerlein B, Beccu L, Kuhlbusch-Zicklam R (2019) Eosinophile Ösophagitis und Achalasie – nur eine Koinzidenz? (Eosinophilic esophagitis and achalasia - just a coincidence?). Z Gastroenterol 57:151–155. https://doi.org/10.1055/a-0808-5043
Tøttrup A, Fredens K, Funch-Jensen P et al (1989) Eosinophil infiltration in primary esophageal achalasia. A possible pathogenic role. Dig Dis Sci 34:1894–1899. https://doi.org/10.1007/BF01536708
Lucendo AJ, Castillo P, Martín-Chávarri S et al (2007) Manometric findings in adult eosinophilic oesophagitis: a study of 12 cases. Eur J Gastroenterol Hepatol 19:417–424. https://doi.org/10.1097/MEG.0b013e328010bd69
Martín Martín L, Santander C, Lopez Martín MC et al (2011) Esophageal motor abnormalities in eosinophilic esophagitis identified by high-resolution manometry. J Gastroenterol Hepatol 26:1447–1450. https://doi.org/10.1111/j.1440-1746.2011.06770.x
Nennstiel S, Bajbouj M, Becker V et al (2016) High-resolution manometry in patients with eosinophilic esophagitis under topical steroid therapy-a prospective observational study (HIMEOS-study). Neurogastroenterol Motil 28:599–607. https://doi.org/10.1111/nmo.12753
Franco DL, Ruff K, Mertz L, Lam-Himlin DM, Heigh R (2014) Eosinophilic granulomatosis with polyangiitis and diffuse gastrointestinal involvement. Case Rep Gastroenterol 8:329–336. https://doi.org/10.1159/000369129
Lecouffe-Desprets M, Groh M, Bour B et al (2016) Eosinophilic gastrointestinal disorders associated with autoimmune connective tissue disease. Joint Bone Spine 83:479–484. https://doi.org/10.1016/j.jbspin.2015.11.006
Mir O, Nazal E-M, Cohen P, Vignaux O, Krivitzky A, Christoforov B, Jian R, Mouthon L, Guillevin L (2007) Esophageal involvement as an initial manifestation of Churg-Strauss syndrome. Presse Med 36:57–60. https://doi.org/10.1016/j.lpm.2006.10.014
Mignogna MD, Lo Muzio L, Galloro G et al (1997) Oral pemphigus: clinical significance of esophageal involvement: report of eight cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:179–184. https://doi.org/10.1016/s1079-2104(97)90067-6
Gue S, Huang G, Moore L, Hammond P, Boros CA (2017) Pemphigus vulgaris and eosinophilic esophagitis in a 13-year-old boy: case report and review of the literature. Pediatr Dermatol 34:e80–e84. https://doi.org/10.1111/pde.13086
Ghoneim S, Shah A, Calderon A (2019) Esophageal Nikolsky’s sign: a rare finding in a patient with bullous pemphigoid. Case Rep Gastroenterol 13:445–449. https://doi.org/10.1159/000503898
McFarlane M, Azam A, Snead D, Disney B (2019) Oesophageal pemphigoid: a rare cause of dysphagia. Clin J Gastroenterol 12:25–28. https://doi.org/10.1007/s12328-018-0897-6
Hopp RJ, Lewis E, Kunnath SD (2017) Do pinworms cause eosinophilic esophagitis? J Allergy Ther 08. https://doi.org/10.4172/2155-6121.1000247
Rezapour M, Agarwal N (2017) You are what you eat: a case of nematode-induced eosinophilic esophagitis. ACG Case Rep J 4:e13. https://doi.org/10.14309/crj.2017.13
Kinoshita Y, Oouchi S, Fujisawa T (2019) Eosinophilic gastrointestinal diseases - pathogenesis, diagnosis, and treatment. Allergol Int 68:420–429. https://doi.org/10.1016/j.alit.2019.03.003
Egan M, Furuta GT (2018) Eosinophilic gastrointestinal diseases beyond eosinophilic esophagitis. Ann Allergy Asthma Immunol 121:162–167. https://doi.org/10.1016/j.anai.2018.06.013
Gonsalves N (2019) Eosinophilic gastrointestinal disorders. Clin Rev Allergy Immunol 57:272–285. https://doi.org/10.1007/s12016-019-08732-1
Simon H-U, Rothenberg ME, Bochner BS, Weller PF, Wardlaw AJ, Wechsler ME, Rosenwasser LJ, Roufosse F, Gleich GJ, Klion AD (2010) Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol 126:45–49. https://doi.org/10.1016/j.jaci.2010.03.042
Takahashi K, Sato H, Tominaga K, Kohisa J, Ikarashi S, Hayashi K, Miuzno K, Hashimoto S, Yokoyama J, Terai S (2018) Gastrointestinal: a case of hypereosinophilic syndrome with esophageal involvement. J Gastroenterol Hepatol 33:1817. https://doi.org/10.1111/jgh.14312
Watanabe M, Matsui N, Hamada S et al (2004) A rare case of idiopathic hypereosinophilic syndrome involving the oral cavity associated with the esophagus and gastrointestinal tract. Intern Med 43:336–339. https://doi.org/10.2169/internalmedicine.43.336
Zimmermann D, Criblez DH, Dellon ES et al (2016) Acute Herpes simplex viral esophagitis occurring in 5 immunocompetent individuals with eosinophilic esophagitis. ACG Case Rep J 3:165–168. https://doi.org/10.14309/crj.2016.38
Fritz J, Lerner D, Suchi M (2018) Herpes simplex virus esophagitis in immunocompetent children: a harbinger of eosinophilic esophagitis? J Pediatr Gastroenterol Nutr 66:609–613. https://doi.org/10.1097/MPG.0000000000001748
Erkman J, Vaynblat A, Thomas K et al (2018) Airway and esophageal eosinophils in children with severe uncontrolled asthma. Pediatr Pulmonol 53(12):1598–1603
Eid RC, Palumbo ML, Laidlaw TM, Buchheit KM, Cahill KN (2019) A retrospective analysis of esophageal eosinophilia in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol Pract 7(4):1338–1340
Villa N, El-Serag HB, Younes M, Ertan A (2013) Esophageal eosinophilia after radiofrequency ablation for Barrett's esophagus. Dis Esophagus 26(7):674–677
Owens VL, Katzka DA, Lutzke LS, Wang KK, Smyrk TC (2012) Endoscopic ablative therapy for Barrett's esophagus: a potential cause of eosinophilic esophagitis. Dis Esophagus 25(1):33–39
Halsey KD, Arora M, Bulsiewicz WJ et al (2013) Eosinophilic infiltration of the esophagus following endoscopic ablation of Barrett's neoplasia. Dis Esophagus 26(2):113–116
Daneshpouy M, Socie G, Lemann M, Rivet J, Gluckman E, Janin A (2002) Activated eosinophils in upper gastrointestinal tract of patients with graft-versus-host disease. Blood 99(8):3033–3040
Wright BL, Fernandez-Becker NQ, Kambham N et al (2020) Gastrointestinal eosinophil responses in a longitudinal. Randomized Trial of Peanut Oral Immunotherapy, Clin Gastroenterol Hepatol
Ma X, Xu Q, Zheng Y et al (2015) Prevalence of esophageal eosinophilia and eosinophilic esophagitis in adults: a population-based endoscopic study in Shanghai China. Dig Dis Sci 60(6):1716–1723
Ishibashi F, Fukushima K, Onizuka R, Tanaka R (2020) Risk of progression to eosinophilic esophagitis in patients with asymptomatic esophageal eosinophilia: A retrospective pilot study. JGH Open 4(3):422–428
Ronkainen J, Talley NJ, Aro P et al (2007) Prevalence of oesophageal eosinophils and eosinophilic oesophagitis in adults: the population-based Kalixanda study. Gut 56(5):615–620
Schreiner P, Biedermann L (2020) Greuter T. Wright BL, Straumann A. How to approach adult patients with asymptomatic esophageal eosinophilia. Dis Esophagus
Funding
Open Access funding provided by Universität Zürich.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is a contribution to the special issue on: Eosinophils - Guest Editor: Hans-Uwe Simon
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Biedermann, L., Straumann, A., Greuter, T. et al. Eosinophilic esophagitis—established facts and new horizons. Semin Immunopathol 43, 319–335 (2021). https://doi.org/10.1007/s00281-021-00855-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-021-00855-y