Figure - available from: Frontiers in Immunology
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(A) Endoscopic picture of the esophagus showing mild longitudinal furrows (e.g., yellow arrow) and mild edema. (B) Endoscopic picture of the distal esophagus with mild edema. (C) Esophagitis Endoscopic Reference Score (EREFS) distributed over the proximal esophagus (PE), middle esophagus (ME), and distal esophagus (DE). E, edema; R, rings; Ex, exudate; F, furrows; S, strictures.
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Rationale: Oral immunotherapy (OIT) is an emerging treatment for food allergy. While desensitization is achieved in most subjects, many experience gastrointestinal symptoms and few develop eosinophilic gastrointestinal disease. It is unclear whether these subjects have subclinical gastrointestinal eosinophilia (GE) at baseline. We aimed to evaluate...
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Background
The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with PeanuT (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents.
Objective
ARC004, the open-label follow-on study to PALISADE, used five dosing cohorts to explore PTAH treatment beyond 1 y...
Citations
... Therefore, the baseline status of the esophagus in these patients prior to OIT is typically unknown. This issue is further emphasized by a recent demonstration that 24% of food allergic adult individuals entering peanut-OIT had baseline esophageal eosinophilia utilizing the low criteria of > 5 eosinophils/HPF and 14% utilizing the criteria of ≥ 15 eos/HPF [54]. Furthermore, in a group of children (median age of 8 years) with persistent milk allergy and a history of anaphylaxis, 34 out of 89 (38.2%) of patients had esophageal eosinophilia (> 15 eos/HPF) [55]. ...
Gastrointestinal adverse events are common during oral immunotherapy (OIT) for food allergy and range from immediate IgE-mediated reactions to non-anaphylactic clinical presentations. This review aims to summarize recent findings on non-anaphylactic eosinophil-associated gastrointestinal adverse events during OIT. Two clinical presentations of non-anaphylactic eosinophil-associated gastrointestinal adverse events during OIT are identified, each with a different paradigm for treatment, and distinguished by their time of onset. In the first clinical entity, characterized by its onset early in the course of treatment, patients present with abdominal pain, nausea, and/or vomiting. The symptoms become evident typically within weeks to months of starting OIT. These symptoms, however, are not temporally related to the time of dose administration, as in the case of immediate IgE-mediated anaphylactic reactions. While esophageal biopsies, when performed, can demonstrate eosinophilic esophagitis (EoE), baseline esophageal eosinophilia has also been observed in food allergic patients prior to OIT. A potential non-invasive biomarker, the peripheral absolute eosinophil count (AEC), often rises during these reactions and subsides after dose reduction and subsequent resolution of symptoms. OIT can usually then be resumed, albeit at a slower pace, without a recurrence of symptoms. Risk factors for development of symptoms early during OIT include a high starting dose and a baseline AEC of greater than 600. The second, and much less frequently encountered, non-anaphylactic gastrointestinal adverse event related to OIT, presents months to years after initiating OIT. In this latter group, patients present with the classical clinical symptoms and endoscopic findings of EoE. In contrast to the acute onset group, peripheral eosinophilia is usually not observed in these cases. This OIT-associated EoE has shown good response to standard EoE treatment approaches of proton pump inhibitors or swallowed steroids. Most patients with eosinophil-associated adverse reactions are able to continue OIT and remain desensitized. Treatment approaches depend on the specific subtype of these reactions and relate to the stages of OIT treatment.
... In a substudy of adult patients undergoing peanut OIT, endoscopies were performed before therapy initiation, at the end of buildup, and during maintenance therapy. The substudy demonstrated that 24% of patients had preexisting esophageal eosinophilia without symptoms suggestive of EoE, 19 with a transient increase in esophageal eosinophilia noted during buildup that resolved during maintenance without intervention in most patients. Only 1 patient developed EoE. ...
Eosinophilic esophagitis (EoE) has been reported secondary to aeroallergen sublingual immunotherapy (SLIT) and food allergen oral immunotherapy. Gastrointestinal symptoms with food allergen SLIT are uncommon, with no prior reports of cases of food allergen SLIT inducing EoE. Here we report a patient who developed EoE secondary to food and aeroallergen SLIT therapy that resolved with SLIT cessation.
... Asymptomatic GI eosinophilia often coexists with FA, with published rates of 24% to 43%, 42,43 and it is histologically comparable to EoE. 44 FA may develop in individuals with EoE during periods of food elimination, 45 and conversely, EoE and asymptomatic GI eosinophilia may develop following successful oral challenge, introduction of a previously avoided IgE-mediated food allergen, and OIT. 46,47 A pilot study investigating 20 adults undergoing peanut OIT in the POISED cohort found that OITinduced GI eosinophilia is usually transient and asymptomatic, with 1 adult developing EoE. ...
... 51 Eosinophil counts do not normally rise above 5 eosinophils per hpf (eos/ hpf) in the esophagus, 30 eos/hpf in the stomach, 52 and 26 eos/ hpf in the duodenum. 42 Elevation of eosinophil counts in the GI tract with the presence of clinical symptoms suggests the presence of EGIDs, 53 including EoE, eosinophilic gastritis (EoG), and eosinophilic enteritis (EoN), which affect 52, 54 5.1, 55 and 28 54 people per 100,000, respectively. ...
Continuing insight into the molecular mechanisms of atopic disorders has enabled the development of biologics to precisely target these diseases. Food allergy (FA) and eosinophilic gastrointestinal disorders (EGIDs) are driven by similar inflammatory molecular mechanisms and exist along the same atopic disease spectrum. Therefore, many of the same biologics are being investigated to target key drivers of mechanisms shared across the disease states. The enormous potential of biologics for the treatment of FA and EGIDs is highlighted by the significant increases in the number of ongoing clinical trials (more than 30) evaluating their use in these disease states, as well as by the recent US Food and Drug Administration approval of dupilumab for the treatment of eosinophilic esophagitis. Here we discuss past and current research into the use of biologics in FA and EGIDs and their potential role in improving treatment options in the future, with the need to have biologics widely clinically available.
... Some patients have pathological criteria in favor of EO on digestive biopsies without symptoms suggestive of the disease. 63 In young children, food refusal, abdominal pain, and recurrent nausea and vomiting may be warning signs of EO, whereas in older children or adolescents, dysphagia is the most suggestive symptom. In cases of suspicion of EO, the diagnosis is confirmed by carrying out a digestive endoscopy with esophageal biopsies. ...
Oral immunotherapy (OIT) is now recognized as an alternative active treatment to strict food avoidance in certain patients with IgE-mediated food allergy. Studies have confirmed the efficacy of OIT to desensitize children with allergy to cow's milk, eggs, and peanuts. The benefits, risks, and constraints of OIT are becoming increasingly well understood. However, there is no consensual criteria to select patients to whom OIT could be proposed, and many issues remain to address including the definitions of desensitization and long-term efficacy, the assessment of patient's experience in real life, the optimization of buildup and maintenance protocols, and the utility of multiple food OIT. The recent authorization by medical agency concerning the first medicine for peanut OIT is a step forward towards higher standardization in the practice of OIT. This article summarizes in comprehensive narrative format data on efficacy, tolerance, impact on quality of life and adverse effects of OIT and discuss elements to consider in clinical practice before starting OIT.
... Therefore, it is impossible to know if EoE is a new disease that developed during OIT or OIT reveals a preexisting esophageal eosinophilia. As far as we know, there is only one prospective study conducted in 21 adults who completed a symptom questionnaire before OIT (29) . Those patients with gastrointestinal symptoms had an EGD and 60% had histology compatible with EoE (29) . ...
... As far as we know, there is only one prospective study conducted in 21 adults who completed a symptom questionnaire before OIT (29) . Those patients with gastrointestinal symptoms had an EGD and 60% had histology compatible with EoE (29) . In our study, approximately onethird of children diagnosed with EoE retrospectively reported infrequent mild abdominal pain or reflux. ...
Objectives:
Oral immunotherapy (OIT) an effective treatment for children with persistent food allergy, has concerns about its safety, including Eosinophilic Esophagitis (EoE). The aim of this study was to evaluate the prevalence of EoE in a large cohort of children who underwent OIT in our center. and to determine if there were any clinical, endoscopic or histologic differences depending on the food employed for the OIT.
Methods:
A retrospective study was performed over a 15-year period (2005-2020). Children who underwent cow's milk (CM), egg and/or peanut OIT and developed EoE were included.
Results:
607 OIT were carried out (277 CM-OIT, 322 egg-OIT and 8 peanut-OIT). Seventeen patients (2.8%) had a confirmed histologic diagnosis of EoE with a higher prevalence for patients who underwent CM-OIT (3.9%) than egg-OIT (2.2%). Symptoms suggestive of EoE and a confirmed diagnosis occurred at median times of 25 months and 36 months respectively after the build-up phase of the OIT was completed. Choking, abdominal pain and dysphagia were the most frequent symptoms and lamina propria fibrosis was observed in 41.2% of patients. No significant differences in clinical symptoms, endoscopic or histologic findings between patients under CM or egg-OIT were found. One third of patients reported mild symptoms suggestive of EoE before the OIT.
Conclusions:
EoE appears to be a rare but important adverse event that can occur even years after OIT. Validated questionnaires to screen EoE before the OIT and in the follow-up of these patients may be the main tool for an early diagnosis.An infographic is available for this article at: http://links.lww.com/MPG/C952.
... In addition, slides were stained by EPX IHC using a mouse monoclonal anti-EPX antibody (Lee, Jacobsen, MM.85.2.11) (9). To eliminate the need for a correction factor, EPX staining within a hpf (0.307 mm 2 ) was quantified using automated image analysis (3,10) and reported as EPX positivity (EPX-positive pixels/total tissue pixels). The hpf with the most EPX staining was selected manually. ...
Background:
We aimed to assess the diagnostic utility of eosinophil peroxidase (EPX) staining on Cytosponge™ (CS) samples in eosinophilic esophagitis (EoE).
Methods:
Esophageal biopsy (BX) samples from adult EoE subjects were assessed using peak eosinophils per high-power field (eos/hpf), EPX, and the EoE Histologic Scoring System (EoEHSS). EPX staining and eos/hpf were compared (BX vs. CS).
Results:
CS EPX positivity correlated with eos/hpf (CS [r=0.82, P<0.0001]; BX [r=0.65, P<0.0001]) and EoEHSS (grade [r=0.62, P<0.00001]; stage [r=0.61, P<0.0001]). CS EPX identified active EoE subjects (AUC=0.86, P<0.0001).
Discussion:
The correlation of CS EPX with eosinophilic inflammation and histologic disease severity supports its diagnostic utility in EoE.
... Furthermore, significant oesophageal eosinophilia has been reported in allergic patients prior to the beginning of OIT. 8 Eosinophilia is usually transient and not associated with clinical symptoms. The long-term effects of asymptomatic eosinophilia are not established, but progression to structural disease that will cause symptomatic disease is possible. ...
... Further, in those developing eosinophilia in the esophagus during POIT, the occurrence was largely asymptomatic and resolved with continued POIT. 36,37 These studies highlight that eosinophilia can be common in allergic individuals. The true incidence of EoE is unknown because it requires clinical symptoms and histological confirmation. ...
Oral immunotherapy (OIT) in pediatric patients provides an alternative option to the current standard of care in food allergy, which is allergen avoidance and reactive treatment. Because patients are exposed to one or more food allergens during treatment, OIT is associated with adverse events and can be a cumbersome process for children, their caregivers, and clinicians. However, there have been an overwhelming number of studies that show high efficacy in both single- and multi-allergen OIT, and that quality of life is greatly improved for both patients and their families after undergoing immunotherapy. This review discusses clinical considerations for OIT in pediatrics, including efficacy and safety, practical management, and future directions of treatment.
... A single-center adult peanut OIT study found that 3 of 21 (14%) patients who underwent gastroscopy before starting OIT had more than 15 eos/hpf, associated with mild endoscopic findings. 55 All were asymptomatic and would have been otherwise undiagnosed. In addition, some patients develop significant eosinophilia while remaining asymptomatic and the best way to manage these patients is not clear. ...
Treatment of food allergy is a rapidly changing landscape with arguably, the most significant advancement in recent years, the transition of oral immunotherapy (OIT) to clinical practice. As an innovation, OIT is a phase of rapidly increasing demand, particularly for some allergens such as peanut, egg and milk which have substantial evidence of efficacy. However significant questions remain about how to best treat multiple food allergies and less common food allergies and how to optimize long-term safety and efficacy. This review summarizes the currently available resources for integrating food allergy OIT into clinical practice and focuses on the multiple remaining unmet needs such as providing an approach for OIT to food allergens for which there is no or limited evidence; practical issues related to food allergy treatment particularly when it is not going well; long-term outcomes and follow-up after OIT; and strategies to help meet the impending increase in demand.
... Of note, the amount of eosinophilia may also be associated with peak allergy season and geographic location. A study showed that 9 of 21 asymptomatic adults with peanut allergy had gastric and/or duodenal eosinophilia (based on cut-offs of >12 eos/hpf in the antrum and > 26 eos/hpf in the duodenum) [35]. Previous studies showed that duodenal eosinophil levels were higher in adult patients with functional dyspepsia compared to healthy control patients, but this was not demonstrated in gastric eosinophils [36]. ...
Purpose of Review
Eosinophilic gastritis/gastroenteritis (EG/EGE) are rare eosinophilic infiltrative disorders in children and adults that fall under the umbrella term eosinophilic gastrointestinal disorders (EGIDs). EGIDs also include eosinophilic esophagitis (EoE) and eosinophilic colitis. In this article, we present the current literature regarding the clinical presentation, diagnostic criteria, and management of EG/EGE.
Recent Findings
The underlying complex pathophysiology remains unknown, yet hypersensitivity response is a central component. Unlike EoE, standardized diagnostic criteria are lacking but, promising research employing tissue-based and blood-based methods of diagnosis have been reported. Non-EoE EGIDs are more challenging to treat than EoE. More than a third of patients may achieve spontaneous remission. Still, most will require dietary elimination and/or pharmaceutical interventions, mainly corticosteroids, but also biologics (monoclonal antibodies against IL-4, IL-5, TNFα, integrin α4β7, and IgE), mast-cell stabilizers, leukotriene (LT)-receptor antagonists, and antihistamines. Promising research suggests the role of AK002, an anti-siglec antibody, in clinical and histological improvement.
Summary
Given the rarity and underdiagnosis of EG/EGE, different natural progression compared to EoE, heterogeneous clinical manifestations, and probable normal endoscopic appearance, it is vital to maintain a high suspicion index in atopic patients, obtain at least 5–6 random biopsies from each site for gastro/duodenal eosinophilic infiltrate with the subsequent exclusion of inflammatory, allergic and infectious differential diagnoses to increase the yield of an accurate diagnosis. Corticosteroids remain the mainstay of treatment, often requiring long-term use. Steroid-sparing agents remain experimental. Goals of therapy move beyond clinical remission but lack evidence to support histological remission.
