Food-specific antibodies in oesophageal secretions: association with trigger foods in eosinophilic oesophagitis.

BACKGROUND: Food antigens are clearly implicated in the induction and persistence of eosinophilic oesophagitis. Dietary elimination to identify triggers is tedious and expensive. Alternatives that can mitigate cost and improve patient quality of life during this process are needed. AIMS: To test the hypothesis that antibodies against foods that trigger eosinophilic oesophagitis are secreted into the oesophageal lumen where they can be collected by oesophageal brushings. METHODS: We evaluated food-specific immune responses within brushings in 68 patients undergoing endoscopy (12 controls, 13 resolved eosinophilic oesophagitis and 43 active eosinophilic oesophagitis). Seventeen participants identified their trigger foods via food elimination diets. Immunoglobulin A and immunoglobulin G4 antibodies against the four most common eosinophilic oesophagitis food triggers were measured using the ImmunoCAP assay in the oesophageal brushings. Food-specific antibody values were compared between active eosinophilic oesophagitis, resolved eosinophilic oesophagitis and controls. RESULTS: Patients with active eosinophilic oesophagitis (>15 eosinophils/hpf) demonstrated increased immunoglobulin A and immunoglobulin G4 levels to common eosinophilic oesophagitis triggers compared to controls (327 ± 380 vs 150 ± 130 for immunoglobulin A, and 1534 ± 3346 vs 178 ± 123 for immunoglobulin G4, P < 0.003). Specific trigger foods were associated with elevated immunoglobulin A and immunoglobulin G4 responses compared to foods that did not trigger oesophageal eosinophilia (733 ± 469 vs 142 ± 64, P < 0.001 immunoglobulin A and 2620 ± 3228 vs 526 ± 1050, P < 0.001 immunoglobulin G4). CONCLUSIONS: Food-specific antibodies are easily collected along the oesophageal lumen of eosinophilic oesophagitis patients. Further studies are needed to validate our preliminary findings to determine whether these antibodies can be used to guide elimination diet therapy.

Incidence and Prevalence of Pediatric Eosinophilic Esophagitis in Utah Based on a 5-Year Population-Based Study.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is often detected in children and is considered to be a rare disease, with prevalence values reported to be below 60 cases per 100,000 persons. To determine whether the incidence of EoE in children in Utah exceeds estimates from regional reports, we calculated incidence and prevalence values over a 5-year period. METHODS: Using consensus guidelines for the diagnosis of EoE, we reviewed pathology records from the Intermountain Healthcare pathology database, from July 1, 2011 through June 31, 2016. We collected data on 10,619 pediatric patients with available esophageal biopsy results, and identified cases of esophageal eosinophilia (>14 eosinophils in a high-power microscopy field in an endoscopic biopsy). An EoE case required the presence of esophageal eosinophilia, symptoms of esophageal dysfunction, and the absence of co-morbid conditions that may cause esophageal eosinophilia. Annual pediatric EoE incidence and prevalence values were calculated per 100,000 children, based on averaged pediatric population estimates from census figures of Utah in 2010 and 2016. RESULTS: We identified 1281 unique pediatric patients who met criteria for esophageal eosinophilia. Of those, 1060 patients met criteria for newly diagnosed EoE. Over the 5-year period studied, the average annual pediatric EoE incidence in Utah was 24 cases per 100,000 children. The prevalence in year 5 of the study was 118 cases per 100,000 children. CONCLUSION: In a population-based study of children in Utah, we found the incidence and prevalence of pediatric EoE to be higher than previously reported. This could be due to the prominence of EoE risk factors in this region, as well as Utah's searchable medical record system that allows for reliable case ascertainment. Further studies of this type could increase disease awareness, prompting early referral to pediatric gastroenterologists and trials to strengthen evidence-based, algorithmic approaches to EoE diagnosis and treatment in children.

Post-transplantation Development of Food Allergies.

PURPOSE OF REVIEW: The development of food allergies is increasingly being recognized as a post-solid organ transplant complication. In this article, we review the spectrum of post-transplant food allergy development and the proposed mechanisms for de novo food allergies and the clinical significance they pose. RECENT FINDINGS: The development of new food allergies is disproportionately associated with pediatric liver transplants, where it occurs in up to 38% of select populations. The mechanism of food allergy development is not completely understood; however, it is likely promoted by unbalanced immune suppression. De novo food allergy development is a common complication of solid organ transplants with the highest risk occurring in pediatric liver transplant recipients. There are likely multiple mechanisms for food allergy development including passive transfer of membrane-bound IgE and lymphocytes from donor to recipient, as well as loss of food tolerance and active development of new food allergies. The optimal management of food allergies following organ transplants has not been well researched but may include changing the immune suppression regimen if the food allergy does not resolve without intervention.

Population-based familial aggregation of eosinophilic esophagitis suggests a genetic contribution.

BACKGROUND: Prior familial clustering studies have observed an increased risk of eosinophilic esophagitis (EoE) mostly among first-degree relatives, suggesting a genetic contribution to EoE, and twin studies have suggested a powerful contribution from environmental factors. OBJECTIVE: This study sought to clarify the contribution of genetic factors to EoE through estimation of familial aggregation and risk of EoE in extended relatives. METHODS: The Utah Population Database, a population-based genealogy resource linked to electronic medical records for health care systems across the state of Utah, was used to identify EoE cases and age, sex, and birthplace-matched controls at a 5:1 ratio. Logistic regression was used to determine the odds of EoE among relatives of EoE probands compared with the odds of EoE among relatives of controls. RESULTS: There were 4,423 EoE cases and 24,322 controls. The population-attributable risk of EoE was 31% (95% CI, 28% to 34%), suggesting a relatively strong genetic contribution. Risks of EoE were significantly increased among first-degree relatives (odds ratio [OR], 7.19; 95% CI, 5.65-9.14), particularly first-degree relatives of EoE cases diagnosed <18 years of age (OR, 16.3; 95% CI, 9.4-28.3); second-degree relatives (OR, 1.99; 95% CI, 1.49-2.65); and first cousins (OR, 1.35; 95% CI, 1.03-1.77), providing evidence of a genetic contribution. However, spouses of EoE probands were observed to be at increased risk of EoE (OR, 2.86; 95% CI, 1.31-6.25), suggesting either positive assortative mating or a shared environmental contribution to EoE. CONCLUSIONS: This study supports a significant genetic contribution to EoE as evidenced by increased risk of EoE in distant relatives.

Risk of Autoimmunity in EoE and Families: A Population-Based Cohort Study.

OBJECTIVES: Recent genome-wide association studies have suggested possible genetic associations between eosinophilic esophagitis (EoE) and genes associated with autoimmunity. No studies to date have looked at potential genetic association of EoE with specific autoimmune diseases by evaluating such diagnoses within family members. Investigate the risk of specific autoimmune disease within EoE probands and their extended family members. METHODS: The Utah Population Database offers a unique opportunity to link medical records from over 85% of Utah's population to genealogy records representing Utah. We searched for associations of specific autoimmune diseases in probands diagnosed with EoE and their extended family members (e.g., first cousins). Comparisons were made to age- and sex-matched controls and their respective families at a 5:1 ratio. RESULTS: Excess risk for multiple autoimmune conditions was detected in subjects with a diagnosis of EoE. Celiac, Crohn's, ulcerative colitis (UC), rheumatoid arthritis, IgA deficiency, CVID, multiple sclerosis (MS), and Hashimoto's thyroiditis were found at increased risk in first-degree relatives of EoE subjects. UC, systemic sclerosis, and MS had nominally significant associations within second-degree family members of EoE subjects; and, in reverse analysis, probands and their families with the above three conditions were at an increased risk for EoE suggesting shared genetic factors with EoE. CONCLUSIONS: Patients with EoE have an increased risk of multiple autoimmune diseases. Possible shared genetic etiologies were observed between EoE and UC, systemic sclerosis, and MS. Practitioners should be aware of these comorbid associations and query all EoE patients and family members for symptoms of these diseases.

Role of Matrix Metalloproteinases-1 and -2 in Interleukin-13-Suppressed Elastin in Airway Fibroblasts in Asthma.

Elastin synthesis and degradation in the airway and lung parenchyma contribute to airway mechanics, including airway patency and elastic recoil. IL-13 mediates many features of asthma pathobiology, including airway remodeling, but the effects of IL-13 on elastin architecture in the airway wall are not known. We hypothesized that IL-13 modulates elastin expression in airway fibroblasts from subjects with allergic asthma. Twenty-five subjects with mild asthma (FEV1, 89 ± 3% predicted) and 30 normal control subjects (FEV1, 102 ± 2% predicted) underwent bronchoscopy with endobronchial biopsy. Elastic fibers were visualized in airway biopsy specimens using Weigert's resorcin-fuchsin elastic stain. Airway fibroblasts were exposed to IL-13; a pan-matrix metalloproteinase (MMP) inhibitor (GM6001); specific inhibitors to MMP-1, -2, -3, and -8; and combinations of IL-13 with MMP inhibitors in separate conditions in serum-free media for 48 hours. Elastin (ELN) expression as well as MMP secretion and activity were quantified. Results of this study show that elastic fiber staining of airway biopsy tissue was significantly associated with methacholine PC20 (i.e., the provocative concentration of methacholine resulting in a 20% fall in FEV1 levels) in patients with asthma. IL-13 significantly suppressed ELN expression in asthmatic airway fibroblasts as compared with normal control fibroblasts. The effect of IL-13 on ELN expression was significantly correlated with postbronchodilator FEV1/FVC in patients with asthma. MMP inhibition significantly stimulated ELN expression in patients with asthma as compared with normal control subjects. Specific inhibition of MMP-1 and MMP-2, but not MMP-3 or MMP-8, reversed the IL-13-induced suppression of ELN expression. In asthma, MMP-1 and MMP-2 mediate IL-13-induced suppression of ELN expression in airway fibroblasts.

Management of acute attacks of hereditary angioedema: role of ecallantide.

Hereditary angioedema (HAE) is characterized as an episodic swelling disorder with autosomal dominant inheritance. Clinical features include nonpitting edema of external or mucosal body surfaces, and patients often present with swelling of the extremities, abdominal pain, and swelling of the mouth and throat, which can lead to asphyxiation. Patients with HAE classically have no associated urticaria, which is often referred to as nonhistaminergic angioedema. Treatment for HAE involves long-term prophylaxis, short-term prophylaxis, and management of acute attacks. Up until the past few years, acute HAE episodes were predominately treated with supportive measures. Three classes of medications have recently been approved by the US Food and Drug Administration (FDA) for the management of acute HAE attacks. Ecallantide, a recombinant protein that acts as a reversible inhibitor of kallikrein, is currently indicated for acute attacks of HAE in those aged ≥12 years. In two randomized, double-blind, placebo-controlled, multicenter trials, EDEMA3 and EDEMA4, patients treated with 30 mg of ecallantide demonstrated statistically significant improvement in symptoms compared to those on placebo. In addition to its use as treatment for HAE, ecallantide has been used off label in the management of nonhistaminergic angioedema, not due to HAE. Ecallantide has shown promise in the treatment of these other forms; however, data are limited to mainly case reports at this time. Ecallantide is generally a safe and well-tolerated medication; however, based on reports of anaphylaxis, ecallantide does contain a black box warning. Due to the risk of anaphylaxis, ecallantide cannot be self-administered and must be given by a health care professional. Overall, ecallantide is a safe and effective medication for the treatment of acute attacks of HAE.

Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-ß1 in airway fibroblasts in asthma.

Airway remodelling is a feature of asthma that contributes to loss of lung function. One of the central components of airway remodelling is subepithelial fibrosis. Interleukin (IL)-13 is a key T-helper 2 cytokine and is believed to be the central mediator of allergic asthma including remodelling, but the mechanism driving the latter has not been elucidated in human asthma. We hypothesised that IL-13 stimulates collagen type-1 production by the airway fibroblast in a matrix metalloproteinase (MMP)- and transforming growth factor (TGF)-ß1-dependent manner in human asthma as compared to healthy controls. Fibroblasts were cultured from endobronchial biopsies in 14 subjects with mild asthma and 13 normal controls that underwent bronchoscopy. Airway fibroblasts were treated with various mediators including IL-13 and specific MMP-inhibitors. IL-13 significantly stimulated collagen type-1 production in asthma compared to normal controls. Inhibitors of MMP-2 significantly attenuated collagen production in asthma but had no effect in normal controls. IL-13 significantly increased total and active forms of TGF-ß1, and this activation was blocked using an MMP-2 inhibitor. IL-13 activated endogenous MMP-2 in asthma patients as compared to normal controls. In an ex vivo model, IL-13 potentiates airway remodelling through a mechanism involving TGF-ß1 and MMP-2. These effects provide insights into the mechanism involved in IL-13-directed airway remodelling in asthma.

Chronic obstructive pulmonary disease: safety and tolerability of hyperpolarized 129Xe MR imaging in healthy volunteers and patients.

PURPOSE: To evaluate the safety and tolerability of inhaling multiple 1-L volumes of undiluted hyperpolarized xenon 129 ((129)Xe) followed by up to a 16-second breath hold and magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained. Forty-four subjects (19 men, 25 women; mean age, 46.1 years ± 18.8 [standard deviation]) were enrolled, consisting of 24 healthy volunteers, 10 patients with chronic obstructive pulmonary disease (COPD), and 10 age-matched control subjects. All subjects received three or four 1-L volumes of undiluted hyperpolarized (129)Xe, followed by breath-hold MR imaging. Oxygen saturation, heart rate and rhythm, and blood pressure were continuously monitored. These parameters, along with respiratory rate and subjective symptoms, were assessed after each dose. Subjects' serum biochemistry and hematology were recorded at screening and at 24-hour follow-up. A 12-lead electrocardiogram (ECG) was obtained at these times and also within 2 hours prior to and 1 hour after (129)Xe MR imaging. Xenon-related symptoms were evaluated for relationship to subject group by using a χ(2) test and to subject age by using logistic regression. Changes in vital signs were tested for significance across subject group and time by using a repeated-measures multivariate analysis of variance test. RESULTS: The 44 subjects tolerated all xenon inhalations, no subjects withdrew, and no serious adverse events occurred. No significant changes in vital signs (P > .27) were observed, and no subjects exhibited changes in laboratory test or ECG results at follow-up that were deemed clinically important or required intervention. Most subjects (91%) did experience transient xenon-related symptoms, most commonly dizziness (59%), paresthesia (34%), euphoria (30%), and hypoesthesia (30%). All symptoms resolved without clinical intervention in 1.6 minutes ± 0.9. CONCLUSION: Inhalation of hyperpolarized (129)Xe is well tolerated in healthy subjects and in those with mild or moderate COPD. Subjects do experience mild, transient, xenon-related symptoms, consistent with its known anesthetic properties.

Airway fibroblasts in asthma manifest an invasive phenotype.

RATIONALE: Invasive cell phenotypes have been demonstrated in malignant transformation, but not in other diseases, such as asthma. Cellular invasiveness is thought to be mediated by transforming growth factor (TGF)-ß1 and matrix metalloproteinases (MMPs). IL-13 is a key T(H)2 cytokine that directs many features of airway remodeling through TGF-ß1 and MMPs. OBJECTIVES: We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-ß1 and MMPs in asthma compared with normal controls. METHODS: Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV(1): 90 ± 3.6% pred) and 17 normal control subjects (FEV(1): 102 ± 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-ß1 neutralizing antibody or pan-MMP inhibitor (GM6001) was added to the lower chamber as a chemoattractant. Flow cytometry and immunohistochemistry were performed in a subset of subjects to evaluate IL-13 receptor levels. MEASUREMENTS AND MAIN RESULTS: IL-13 significantly stimulated invasion in asthmatic airway fibroblasts, compared with normal control subjects. Inhibitors of both TGF-ß1 and MMPs blocked IL-13-induced invasion in asthma, but had no effect in normal control subjects. At baseline, in airway tissue, IL-13 receptors were expressed in significantly higher levels in asthma, compared with normal control subjects. In airway fibroblasts, baseline IL-13Rα2 was reduced in asthma compared with normal control subjects. CONCLUSIONS: IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-ß1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.

An overview of novel therapies for acute hereditary angioedema.

Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by nonpitting edema of external or mucosal body surfaces. Patients often present with swelling of the extremities, abdominal pain, and swelling of the mouth and throat, which can at times lead to asphyxiation. The disease is caused by a mutation in the gene encoding the complement C1-inhibitor protein, which leads to unregulated production of bradykinin. Long-term therapy has depended on the use of attenuated androgens or plasmin inhibitors but in the US there was, until recently, no specific therapy for acute attacks. As well, many patients with hereditary angioedema in the US were either not adequately controlled on previously available therapies or required doses of medications that exposed them to the risk of serious adverse effects. Five companies have completed or are currently conducting phase III clinical trials in the development of specific therapies to terminate acute attacks or to be used as prophylaxis. These products are based on either replacement therapy with purified plasma-derived or recombinant C1-inhibitor, or inhibition of the kinin-generating pathways with a recombinant plasma kallikrein inhibitor or bradykinin type 2 receptor antagonist. Published studies thus far suggest that all of these products are likely to be effective. These new therapies will likely lead to a totally new approach in treating hereditary angioedema.

Pharmacotherapy of severe asthma.

Severe asthma is a complex and heterogeneous phenotype where management can be challenging. While many patients with severe asthma respond to high-dose inhaled corticosteroids in combination with a long-acting beta-agonist, there remains a significant subset of patients that require oral corticosteroids to control symptoms. Alternative therapies are needed to help reduce the need for continuous oral corticosteroids; however, there are currently very few effective options. Several new alternatives to oral corticosteroids have been evaluated in severe asthma as add-on to conventional therapy. These include macrolide antibiotics, omalizumab, tumor necrosis factor-alpha inhibitors, cytokine receptor antagonists, and bronchial thermoplasty. The challenge with these entities is determining the appropriate phenotype of severe asthma where effectiveness is demonstrated, given the significant heterogeneity of the disease. Therefore, there is a crucial need to better understand the mechanisms and pathophysiology of severe asthma so more effective immunomodulators and biologic therapies can emerge.

A comparison of brand-name drug prices between Canadian-based Internet pharmacies and major U.S. drug chain pharmacies.

BACKGROUND: Many Americans have been purchasing their medications from online Canadian pharmacies. Although it is commonly perceived that medications are less expensive in Canada than in the United States, little research has been done to quantify this difference. OBJECTIVE: To compare the prices of retail brand-name medications between Canadian Internet pharmacies and major U.S. drug chain pharmacies with online pricing. DESIGN: Cross-sectional study. SETTING: 12 Canadian Internet pharmacies and 3 major online U.S. drug chain pharmacies. MEASUREMENTS: The authors calculated the per unit and annual savings (in U.S. dollars) for an American if he or she were to buy the 44 brand-name medications most commonly purchased through the Internet from Canadian Internet pharmacies instead of from an online U.S. drug chain pharmacy. RESULTS: Americans can save a mean of approximately 24% per unit of drug if they purchase their medications from Canadian Internet pharmacies instead of from major online U.S. drug chain pharmacies. Forty-one of the 44 brand-name medications examined were less expensive in Canada. The medications offering the largest mean yearly savings were Zyprexa (olanzapine) (Eli Lilly, Indianapolis, Indiana) (1159 dollars), Actos (pioglitazone) (Eli Lilly, Indianapolis, Indiana) (852 dollars), and Nexium (esomeprazole) (AstraZeneca, Wilmington, Delaware) (772 dollars). Only 3 medications, all in the erectile dysfunction category, were more expensive in Canada. LIMITATIONS: Potential savings may vary because of temporal fluctuations in drug prices. CONCLUSIONS: Brand-name medications are often substantially less expensive when purchased from Canadian Internet pharmacies instead of from major online U.S. drug chain pharmacies.