The gastrointestinal (GI) tract provides an intriguing organ for considering the eosinophil's role in health and disease. The normal GI tract, except for the esophagus, is populated by eosinophils ...that are present throughout the mucosa, raising the possibility that eosinophils participate in innate mechanisms of defense. However, data from clinical studies associates increased numbers of eosinophils with inflammatory GI diseases, prompting concerns that eosinophils may have a deleterious effect on the gut. We present clinical features of 4 disease processes that have been associated with eosinophilia and suggest areas requiring investigation as to their clinical significance and scientific relevance.
Purpose of Review
This review seeks to understand novel avenues for eosinophilic GI disease management. Biomarkers offer a unique and non-invasive approach to tracking EoE disease progression. While ...no biomarkers have definitively met the diagnostic criteria for eosinophilic GI diseases, some biomarkers have been shown to be associated with disease activity. Here, we examine the potential of recently studied biomarkers.
Recent Findings
Current research shows advancements in blood, luminal fluid, and breath testing. Particular areas of interest include mRNA analyses, protein fingerprinting, amplicon sequence variants (ASVs), T cells and IgE receptors, eosinophilic cationic proteins, cytokines, and nitric oxide exhalation.
Summary
Preliminary results showed that mucosal biomarkers, directly captured from the esophagus, may reflect the best representation of biopsy-based results, in contrast to biomarkers obtained from indirect or peripheral (blood, breath) methods. However, this is based on limited clinical studies without sufficient numbers to evaluate true diagnostic accuracy. Large-scale randomized trials are needed to fully ascertain both the optimal sampling technique and the specific biomarkers that reflect diagnostic status of the disease.
During the last decade, clinical practice saw a rapid increase of patients with esophageal eosinophilia who were thought to have gastroesophageal reflux disease (GERD) but who did not respond to ...medical and/or surgical GERD management. Subsequent studies demonstrated that these patients had a “new” disease termed eosinophilic esophagitis (EE). As recognition of EE grew, so did confusion surrounding diagnostic criteria and treatment. To address these issues, a multidisciplinary task force of 31 physicians assembled with the goal of determining diagnostic criteria and making recommendations for evaluation and treatment of children and adults with suspected EE. Consensus recommendations were based upon a systematic review of the literature and expert opinion. EE is a clinicopathological disease characterized by (1) Symptoms including but not restricted to food impaction and dysphagia in adults, and feeding intolerance and GERD symptoms in children; (2) ≥ 15 eosinophils/HPF; (3) Exclusion of other disorders associated with similar clinical, histological, or endoscopic features, especially GERD. (Use of high dose proton pump inhibitor treatment or normal pH monitoring). Appropriate treatments include dietary approaches based upon eliminating exposure to food allergens, or topical corticosteroids. Since EE is a relatively new disease, the intent of this report is to provide current recommendations for care of affected patients and defining gaps in knowledge for future research studies.
The literature related to eosinophilic gastritis (EG), gastroenteritis (EGE), and colitis (EC) is limited. We aimed to characterize rates of diagnosis, clinical features, and initial treatments for ...patients with EG, EGE, and EC.
In this retrospective study, data were collected from 6 centers in the Consortium of Eosinophilic Gastrointestinal Researchers from 2005 to 2016. We analyzed demographics, time trends in diagnosis, medical history, presenting symptoms, disease overlap, and initial treatment patterns/responses.
Of 373 subjects (317 children and 56 adults), 38% had EG, 33% EGE, and 29% EC. Rates of diagnosis of all diseases increased over time. There was no male predominance, and the majority of subjects had atopy. Presenting symptoms were similar between diseases with nausea/vomiting and abdominal pain, the most common. One hundred fifty-four subjects (41%) had eosinophilic inflammation outside of their primary disease location with the esophagus the second most common gastrointestinal (GI) segment involved. Multisite inflammation was more common in children than in adults (68% vs 37%; P < 0.001). Initial treatment patterns varied highly between centers. One hundred-nine subjects (29%) had follow-up within 6 months, and the majority had clinical, endoscopic, and histologic improvements.
In this cohort, EG, EGE, and EC were diagnosed more frequently over time, and inflammation of GI segments outside the primary disease site co-occurrence of atopy was common with a lack of male predominance. Symptoms were similar between diseases, and initial treatment strategies were highly variable. Future investigation should assess the cause of the increased prevalence of eosinophilic GI disorders and prospectively assess outcomes to establish treatment algorithms.
Background Eosinophilic esophagitis is a chronic allergic disease with insufficient treatment options. Results from animal studies suggest that IL-5 induces eosinophil trafficking in the esophagus. ...Objective We sought to evaluate the effect of reslizumab, a neutralizing antibody against IL-5, in children and adolescents with eosinophilic esophagitis. Methods Patients with symptom severity scores of moderate or worse and an esophageal biopsy specimen with 24 or more intraepithelial eosinophils per high-power field were randomly assigned to receive infusions of 1, 2, or 3 mg/kg reslizumab or placebo at weeks 0, 4, 8, and 12. The coprimary efficacy measures were changes in peak esophageal eosinophil count and the physician’s global assessment score at week 15 (end of therapy). Results Two-hundred twenty-six patients received study medication. Median reductions from baseline to the end of therapy in peak esophageal eosinophil counts were 59%, 67%, 64%, and 24% in the 1, 2, and 3 mg/kg reslizumab (all P < .001) and placebo groups, respectively. All treatment groups, including the placebo group, showed improvements in physician’s global assessment scores; the differences between the reslizumab and placebo groups were not statistically significant. The most common adverse events in the reslizumab groups were headache, cough, nasal congestion, and upper respiratory tract infection. One patient in each reslizumab group and 2 in the placebo group had serious adverse events; none were considered related to the study medication. Conclusion Reslizumab significantly reduced intraepithelial esophageal eosinophil counts in children and adolescents with eosinophilic esophagitis. However, improvements in symptoms were observed in all treatment groups and were not associated with changes in esophageal eosinophil counts.
To review and highlight the unappreciated roles of eosinophils suggested by recent studies.
The literature, unpublished observations, and insights by the authors.
Basic studies of mouse models and ...patient-based clinical studies of disease.
Eosinophils are often thought of as destructive end-stage effector cells primarily linked to parasite host defense and dysregulated immune responses associated with allergic diseases, such as asthma. However, recent studies (ie, research focused on mechanisms of action and translational studies examining disease/inflammatory pathways) are suggesting far more complex roles for eosinophils. The goal of this review is 3-fold. (1) The authors examine the dynamic history of eosinophils and how physicians over time used this information to formulate defining hypotheses. Particular emphasis is placed on recent studies challenging the parochial view of host defense in favor of roles maintaining homeostasis through immune modulation and tissue remodeling/repair. (2) They discuss diagnostic approaches to assess eosinophils in clinical settings as a means of disease identification and subsequently as a measurement of disease severity. (3) They examine how contemporary views of eosinophils and their perceived roles in diseases have led to specific therapeutic strategies. The emphasis is to review the successes and failures of these strategies as the basis of formulating future clinical studies targeting eosinophils as potential therapies of disease.
Despite the complexities of eosinophil-mediated activities and the less than overwhelming success of initial attempts targeting these cells, eosinophils remain a potentially important focal target of disease diagnosis and subsequent treatment strategies.
Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new studies have been reported recently that describe EoE management. An expert panel was convened by the ...American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a technical review to be used as the basis for an updated clinical guideline. This technical review was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Eighteen focused EoE management questions were considered, with 15 answered using the GRADE framework and 3 with a narrative summary. There is moderate certainty in the evidence that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to <15 per high-power field over a short-term treatment period of 4–12 weeks, but very low certainty about the effects of using topical glucocorticosteroids as maintenance therapy. Multiple dietary strategies may be effective in reducing esophageal eosinophil counts to <15 per high-power field over a short-term treatment period, with moderate certainty for elemental diets, low certainty for empiric 2-, 4-, and 6-food elimination diets, and very low certainty that allergy-based testing dietary eliminations have a higher failure rate compared to empiric diet elimination. There is very low certainty for the effect of proton pump inhibitors in patients with esophageal eosinophilia. Although esophageal dilation appears to be relatively safe, there is no evidence that it reduces esophageal eosinophil counts. There is very low certainty in the effects of multiple other medical treatments for EoE: anti–interleukin-5 therapy, anti–interleukin-13 therapy, anti-IgE therapy, montelukast, cromolyn, and anti-TNF therapy.
The microbiome has been implicated in the pathogenesis of a number of allergic and inflammatory diseases. The mucosa affected by eosinophilic esophagitis (EoE) is composed of a stratified squamous ...epithelia and contains intraepithelial eosinophils. To date, no studies have identified the esophageal microbiome in patients with EoE or the impact of treatment on these organisms. The aim of this study was to identify the esophageal microbiome in EoE and determine whether treatments change this profile. We hypothesized that clinically relevant alterations in bacterial populations are present in different forms of esophagitis.
In this prospective study, secretions from the esophageal mucosa were collected from children and adults with EoE, Gastroesophageal Reflux Disease (GERD) and normal mucosa using the Esophageal String Test (EST). Bacterial load was determined using quantitative PCR. Bacterial communities, determined by 16S rRNA gene amplification and 454 pyrosequencing, were compared between health and disease.
Samples from a total of 70 children and adult subjects were examined. Bacterial load was increased in both EoE and GERD relative to normal subjects. In subjects with EoE, load was increased regardless of treatment status or degree of mucosal eosinophilia compared with normal. Haemophilus was significantly increased in untreated EoE subjects as compared with normal subjects. Streptococcus was decreased in GERD subjects on proton pump inhibition as compared with normal subjects.
Diseases associated with mucosal eosinophilia are characterized by a different microbiome from that found in the normal mucosa. Microbiota may contribute to esophageal inflammation in EoE and GERD.
To evaluate the impact of type and dose of swallowed topical steroids (STS) and concurrent steroid therapy on the development and resolution of adrenal insufficiency (AI) in pediatric eosinophilic ...esophagitis (EoE).
We performed a retrospective case-control study of pediatric EoE subjects in a single tertiary care center, who were treated with STS for at least 3 months and diagnosed with AI based on a peak stimulated cortisol level of <18 µg/dL (500 nmol/L). Steroid forms and doses, and endoscopy data were collected at the time of AI diagnosis and AI resolution or the last known evaluation. Steroid formulations were converted to a fluticasone-equivalent dose for analysis.
Thirty-two EoE subjects with AI were identified, and 20 had AI resolution, including 12 who remained on lower dose STS. Eight of the 32 patients were also treated with extended-release budesonide (ER budesonide), which resulted in a 7-fold higher total daily steroid dose, and thus were analyzed separately. When the 24 cases that were not on ER budesonide were compared to the 81 controls, no difference was found in the STS dose nor total daily steroid dose, although the inhaled steroid dose had marginal significance. Peak eosinophil counts tended to increase when STS doses were decreased, except in subjects on ER budesonide at AI diagnosis.
Altering the total daily steroid regimen can lead to resolution of AI in patients with EoE, though this may come at the expense of disease control.
PDF
