Plasma microRNAs as biomarkers in hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disease with variable expression. In some families with identical genetic abnormalities, the expression can range from several attacks per month to no attacks at all. It is hypothesized that post-transcriptional gene regulation accounts for the variable expression of the disease. OBJECTIVE: To identify candidate microRNAs (miRNAs) that could play a role in HAE by determining whether miRNAs are differentially expressed in patients with HAE vs non-HAE individuals and whether expression profiles are tracked with severity. METHODS: This study compared serum miRNA expression in patients with HAE vs non-HAE using RNA sequencing. Associations between miRNA expression and HAE severity were assessed in patients with mild disease (<6 attacks a year) vs severe disease (>1 attack per month). The functions of candidate miRNAs were analyzed using in silico methods. RESULTS: There were robust miRNA expression differences between patients with HAE and non-HAE controls. A cluster analysis identified subgroups of patients with HAE having unique miRNA profiles that tracked with frequency of attacks. Two miRNAs, miR-99b-5p and miR-127-3p, were differentially expressed between mild and severe HAE (adjusted P < .05). In silico analysis revealed a function of differentially expressed miRNAs in regulation of C1 esterase inhibitor, kininogen, the bradykinin B2 receptor, and adherens junction function. CONCLUSION: Candidate microRNAs were identified that could distinguish patients with and without HAE and may be used to identify phenotypes of HAE.

Identification of biologic-responsive phenotypes in elderly people with eosinophilic asthma.

Background: Asthma in the elderly is not as well studied as in younger age groups. Age-related immunosenescence may result in diminished TH2 inflammation, which raises a question about whether asthma in elderly patients responds well to anti-TH2 asthma biologics. Objective: We sought to determine whether asthma in elderly people has different TH2 biomarkers and clinical features compared to nonelderly people, and if disease in the 2 age groups responds differently to anti-TH2 biologics. We also aimed to identify treatment-responsive phenotypes with clinical and biomarker features that could be used to predict best response to biologics. Methods: A retrospective chart review was conducted for 56 patients (30 elderly [age ≥62 years] and 26 nonelderly [ages 18-59 years] subjects) with severe asthma treated with dupilumab or benralizumab. Differences in baseline characteristics and response to treatment were analyzed. A hierarchical cluster analysis was also performed to identify treatment-responsive phenotypes. Significance threshold was P = .05 for all analyses. Results: Baseline characteristics and TH2 biomarkers (blood eosinophil level, total IgE, aeroallergen sensitivity) were similar between elderly and nonelderly subjects. The disease in both groups responded well to biologics (improvement in ACT scores, decreased exacerbations, decreased need for prednisone), but no significant response difference was found based on age groups. Cluster analysis identified 3 phenotypes, as follows: cluster 1, youngest age, moderate eosinophil levels, lowest total IgE, few environmental allergies, and least response to biologics; cluster 2, intermediate age, lowest eosinophil level, highest IgE level, many environmental allergies, and an intermediate response to biologics; and cluster 3, oldest ages, highest eosinophil levels, high total IgE, few environmental allergies, and best response to biologics. These results confirm trends seen in another study utilizing cluster analyses showing that subjects with highest levels of IgE and eosinophils responded better to biologic treatment for asthma. Conclusion: Elderly people with asthma should be considered for biologic therapy no differently than younger people. There may be subgroups of patients with different biologic responses based on age, allergenicity, IgE, and eosinophil levels that could be used to predict treatment response.

Penicillin Allergy: Mechanisms, Diagnosis, and Management.

Allergy to penicillin can occur via any of the 4 types of Gel-Coombs hypersensitivity reactions, producing distinct clinical histories and physical examination findings. Treatments include penicillin discontinuation, and depending on the type of reaction, epinephrine, antihistamines, and/or glucocorticoids. Most beta-lactams may be safely used in penicillin-allergic patients, with the possible exception of first-generation and second-generation cephalosporins. Penicillin testing includes skin testing, patch testing, and graded challenge. The selection of the type of testing depends on the clinical setting, equipment availability, and type of hypersensitivity reaction. Desensitization may be used in some cases where treatment with penicillins is essential.

Salivary microRNAs in pediatric eosinophilic esophagitis.

Background: Diagnosis and management of eosinophilic esophagitis (EoE) occur via esophagogastroduodenoscopy with tissue biopsy. Objective: We sought to determine if salivary microribonucleic acid (miRNA) levels could differentiate children with EoE, serving as a noninvasive biomarker. Methods: Saliva was collected from children undergoing esophagogastroduodenoscopy (N = 291). miRNA analysis was conducted on 150 samples: EoE (n = 50), no pathologic alteration (n = 100). RNA was quantified with high throughput sequencing and aligned to build hg38 of the human genome using sequencing and alignment software. Quantile normalized levels of robustly expressed miRNAs (raw counts > 10 in 10% of samples) were compared across EoE and non-EoE groups with Wilcoxon rank sum testing. miRNA biomarker candidates were selected based on variable importance projection (VIP) scoring with partial least squared discriminant analysis (VIP > 1.5). Ability of these miRNAs to differentiate EoE status was assessed via logistic regression. Putative biologic targets for the miRNA candidates were determined in miRNA pathway analysis software. Results: Of the 56 salivary miRNAs reliably detected, miR-205-5p displayed the largest difference between EoE and non-EoE groups (V = 1623, adjusted p = 0.029). Six miRNAs (miR-26b-5p, miR-27b-3p, Let-7i-5p, miR-142-5p, miR-30a-5p, miR-205-5p) displayed elevated VIP scores (>1.5) and were able to differentiate EoE samples on logistic regression analysis with 70% sensitivity and 68% specificity. These six miRNAs demonstrated significant enrichment for gene targets involved in valine, leucine, and isoleucine biosynthesis (p = 0.0012), 2-oxycarboxylic acid metabolism (p = 0.043), and steroid hormone biosynthesis (p = 0.048). Conclusions: Salivary miRNAs represent a noninvasive, biologically relevant measure that may aid disease monitoring of EoE.

Prior authorization delays biologic initiation and is associated with a risk of asthma exacerbations.

Background: Biologics are effective treatments for patients with severe allergic disease. Impacts of delays in the prior authorization process on clinical outcomes has not been studied. Objective: The objective was to quantify the times for approval and filling of biologics, and whether patients were at risk of exacerbations during this time frame. Methods: The times for insurance approval and pharmacy filling of biologics (omalizumab, benralizumab, mepolizumab, dupilumab) in 80 subjects with severe asthma (n = 60) or urticaria (n = 20) from our clinic were reviewed. We compared the impact of clinical features, insurance, specialty pharmacy on fill times, and quantified exacerbations and prednisone use while awaiting biologic initiation. Results: The mean ± standard deviation (SD) time (days) from submission of a prescription to the first dose available for injection was 44.0 ± 23.2 days. This was composed of the mean ± SD time for insurance approval (21.5 ± 19.6 days) and the mean ± SD time for a specialty pharmacy to fill the medication (22.8 ± 14.1 days). There was no significant difference between the times for diagnosis (asthma versus urticaria), specific biologic, or insurance. The "buy and bill" system was faster than filling via a specialty pharmacy (mean ± SD, 7.3 ± 8.5 days versus 23.3 ± 21.3 days, respectively, p < 0.001). Clinical features of patients with fast versus slow approval times was not significantly different. The subjects with asthma were at high risk of exacerbations and need for prednisone while awaiting initiation of the biologics; 28 of 59 patients (47%) required prednisone, with an mean cumulative dose of 483.2 ± 273.7 mg per person. Conclusion: The prior authorization process for biologics was slow, and the subjects were at high risk of exacerbations during this time. The system needs to be improved to expedite approval and initiation of these medications.

Effects of Inhaled Corticosteroids and Particle Size on Risk of Obstructive Sleep Apnea: A Large Retrospective Cohort Study.

Background: Inhaled corticosteroids (ICS) produce local effects on upper airway dilators that could increase the risk of developing obstructive sleep apnea (OSA). Given that the particle size of ICS changes their distribution, the particle size of ICS may impact the risk of developing OSA. Objectives: In this large retrospective study, we explore the relationship of ICS use and OSA in patients with asthma. In addition, we seek to determine if this relationship is affected by the particle size of ICS. Methods: Using electronic health records, we established a cohort of 29,816 asthmatics aged 12 and older with a diagnosis of asthma documented by ICD-9 or ICD-10 codes between January 2011 and August 2016. We performed analyses of variance and multivariate logistic regression analysis to determine the effects ICS on the diagnosis of OSA with sub-analysis by particle size of ICS. Results: Uncontrolled asthmatics showed increased odds of receiving a diagnosis of OSA whether when looking at ACT scores (adjusted odds ratio (aOR) 1.60, 95% CI 1.32-1.94) or PFT results (aOR 1.45, 95% CI 1.19-1.77). Users of ICS also had increased odds of OSA independent of asthma control (aOR 1.58, 95% CI 1.47-1.70). Notably, users of extra-fine particle ICS did not have significantly increased odds of having OSA compared to non-users of ICS (aOR 1.11, 95% CI 0.78-1.58). Conclusions: Use of ICS appears to be an independent risk factor for OSA. Notably, extra-fine particle size ICS do not appear to be associated with an increased risk of OSA.

MiR-4668 as a Novel Potential Biomarker for Eosinophilic Esophagitis.

INTRODUCTION: Eosinophilic esophagitis (EoE) is a clinico-pathological diagnosis characterized by esophageal dysfunction and eosinophilic infiltration of the esophagus. Demonstration of esophageal eosinophilia (more than 15 eosinophils/hpf) in biopsy specimen obtained by esophagogastroduodenoscopy (EGD) continues to be the gold standard for diagnosis and monitoring of response to therapy. There is a growing necessity for non-invasive biomarkers that can accurately diagnose this condition and assess response to therapy. While microRNAs (miRNA) are being investigated in allergic diseases, including EoE, not many studies have explored the role of salivary miRNAs in EoE. MiR-4668-5p is a particularly interesting candidate, as it is predicted to regulate TGF-beta signaling and has not previously been identified as a target in any allergy disease. We sought to further investigate the role of miR-4668 as a biomarker to characterize and monitor response to treatment with swallowed topical glucocorticoids. METHODS: After IRB approval, twenty-two adult patients with EoE were randomly enrolled to provide a saliva sample before and after 2 months of swallowed fluticasone therapy. Differences of miRNA expression before and after treatment were analyzed by paired T-test. A significance cutoff of <0.05 was used for all analyses. RESULTS: Expression of miR-4668 was higher in EoE vs. non-EoE subjects. The level of miR-4668 decreased in all subjects except one, with a mean fold change 0.49 ± 0.25. There was an association between miRNA expression and number of positive aeroallergens. The miR-4668 high group had a higher number of positive aeroallergen tests, while the miR-4668 low group had a greater number of subjects with drug allergies. CONCLUSIONS: In this study, we identified that salivary miRNAs may serve as biomarkers to characterize EoE and response to topical corticosteroids. We specifically identified miR-4668 as a novel potential biomarker, which was not previously discovered as a target in EoE or any other allergic disease.

Tristetraprolin targets Nos2 expression in the colonic epithelium.

Tristetraprolin (TTP), encoded by the Zfp36 gene, is a zinc-finger protein that regulates RNA stability primarily through association with 3' untranslated regions (3' UTRs) of target mRNAs. While TTP is expressed abundantly in the intestines, its function in intestinal epithelial cells (IECs) is unknown. Here we used a cre-lox system to remove Zfp36 in the mouse epithelium to uncover a role for TTP in IECs and to identify target genes in these cells. While TTP was largely dispensable for establishment and maintenance of the colonic epithelium, we found an expansion of the proliferative zone and an increase in goblet cell numbers in the colon crypts of Zfp36ΔIEC mice. Furthermore, through RNA-sequencing of transcripts isolated from the colons of Zfp36fl/fl and Zfp36ΔIEC mice, we found that expression of inducible nitric oxide synthase (iNos or Nos2) was elevated in TTP-knockout IECs. We demonstrate that TTP interacts with AU-rich elements in the Nos2 3' UTR and suppresses Nos2 expression. In comparison to control Zfp36fl/fl mice, Zfp36ΔIEC mice were less susceptible to dextran sodium sulfate (DSS)-induced acute colitis. Together, these results demonstrate that TTP in IECs targets Nos2 expression and aggravates acute colitis.

Long-term assessment of aspirin desensitization shows successful bridging with non-aspirin nonsteroidal anti-inflammatory drugs for procedures.

Background: Aspirin (ASA) desensitization and continuous daily ASA therapy is the criterion standard treatment for ASA-exacerbated respiratory disease (AERD). However, the optimal maintenance dosage of ASA and safety of "bridging" patients with AERD and with alternative cyclooxygenase-1 inhibitors for surgery have not been determined and require further investigation. Objective: This study was designed to compare the long-term effects of different maintenance doses of ASA and to assess the success of bridging subjects with AERD for surgery without losing desensitization. Methods: We retrospectively assessed 36 subjects with AERD who successfully underwent ASA desensitization from 2011 to 2017. We performed comprehensive medical record reviews and subsequent telephone interviews with a questionnaire. Results: Of 36 subjects, the average age was 52.8 years, with an average of 3.2 years since desensitization, and 65% were women. The subjects reported a decrease in frequency of nasal symptoms (p < 0.001), asthma symptoms (p = 0.016), and sinus infections (p < 0.001) after desensitization. Improvements were reported in sense of smell, taste, quality of sleep, and quality of life (p < 0.001) in all dosage groups. Thirteen subjects required stopping of ASA for surgeries. Six subjects (46%) were bridged with ibuprofen on an average of 5.9 days before surgery and restarted ASA on an average of 1.3 days after surgery, with no incidence of major adverse events or loss of desensitization. Seven subjects (54%) were not bridged, with three subjects restarting ASA after surgery without symptoms and four subjects losing desensitization. Conclusion: There did not seem to be a difference of benefits between 325 mg once or twice a day compared with 650 mg once or twice a day, but our small subject numbers made this conclusion difficult to prove. Desensitization improved subjective reporting on sleep quality as well as quality of life. Bridging the subjects with AERD who required surgery by using ibuprofen seemed to be safe and effective in maintaining ASA desensitization.

miR-511-3p protects against cockroach allergen-induced lung inflammation by antagonizing CCL2.

miR-511-3p, encoded by CD206/Mrc1, was demonstrated to reduce allergic inflammation and promote alternative (M2) macrophage polarization. Here, we sought to elucidate the fundamental mechanism by which miR-511-3p attenuates allergic inflammation and promotes macrophage polarization. Compared with WT mice, the allergen-challenged Mrc1-/- mice showed increased airway hyperresponsiveness (AHR) and inflammation. However, this increased AHR and inflammation were significantly attenuated when these mice were pretransduced with adeno-associated virus-miR-511-3p (AAV-miR-511-3p). Gene expression profiling of macrophages identified Ccl2 as one of the major genes that was highly expressed in M2 macrophages but antagonized by miR-511-3p. The interaction between miR-511-3p and Ccl2 was confirmed by in silico analysis and mRNA-miR pulldown assay. Further evidence for the inhibition of Ccl2 by miR-511-3p was given by reduced levels of Ccl2 in supernatants of miR-511-3p-transduced macrophages and in bronchoalveolar lavage fluids of AAV-miR-511-3p-infected Mrc1-/- mice. Mechanistically, we demonstrated that Ccl2 promotes M1 macrophage polarization by activating RhoA signaling through Ccr2. The interaction between Ccr2 and RhoA was also supported by coimmunoprecipitation assay. Importantly, inhibition of RhoA signaling suppressed cockroach allergen-induced AHR and lung inflammation. These findings suggest a potentially novel mechanism by which miR-511-3p regulates allergic inflammation and macrophage polarization by targeting Ccl2 and its downstream Ccr2/RhoA axis.

Isolation and profiling of plasma microRNAs: Biomarkers for asthma and allergic rhinitis.

Chronic inflammatory diseases can be particularly challenging to diagnose and characterize, as inflammatory changes in tissue may not be present in blood. There is a crucial need to develop non-invasive biomarkers that would be useful in diagnosing disease and selecting medical therapies. For example, there are no blood tests to diagnose asthma, a common inflammatory lung disease. MicroRNA (miRNA) expression profiling in blood is emerging as a potentially sensitive and useful biomarker of many diseases. In particular, we have characterized a cost-effective PCR-based array technology to measure and profile circulating miRNAs in the plasma of patients with allergic rhinitis and asthma. Here, we describe the methods to isolate, quantify, and analyze miRNAs in the plasma of human subjects as well as ways to determine their diagnostic utility.

Generalized rash and pruritus in a 58-year-old woman.

Although allergists often evaluate rashes associated with allergic, IgE mediated etiologies, it is important to consider a wide range of differential diagnoses that includes inflammatory, infectious, and autoimmune etiologies. The case of a 58-year-old woman with a 1-year history of progressive pruritic rash that did not improve with topical creams and steroids is presented. The patient did not state any other symptoms, and a physical examination was notable for a widespread rash. After a detailed evaluation of the rash, a differential diagnosis was made, and results of a skin biopsy confirmed a specific diagnosis. Even in the context of a medical history of atopy, one must consider nonallergic causes of rash, including abnormal presentations of systemic conditions. It is important to determine the specific etiology of the rash because this will dictate treatment and prognosis and/or complications of the disease associated with the skin manifestations.

MicroRNA-146a is induced by inflammatory stimuli in airway epithelial cells and augments the anti-inflammatory effects of glucocorticoids.

BACKGROUND: MicroRNAs (miRNAs) are emerging as central regulators of inflammation, but their role in asthma and airway epithelial cells is not well studied. Glucocorticoids are the cornerstone of therapy in asthma and other inflammatory disease, yet their mechanisms of action are not completely elucidated, and it is not clear whether miRNAs modulate their effects. OBJECTIVE: We aimed to identify miRNAs that regulate cytokine and chemokine expression in airway epithelial cells and whether these miRNAs are subject to the effects of glucocorticoids. METHODS AND RESULTS: MicroRNAomic analyses of immortalized, normal human bronchial epithelial cells identified 7 miRNAs that were altered by inflammatory cytokine treatment and 22 that were regulated by glucocorticoids (n = 3 for each treatment condition). MiR-146a emerged as a central candidate, whose expression was induced by TNF-α and repressed by glucocorticoids. Its role as a candidate in asthmatic inflammation was supported by expression profiling in human asthmatics, which showed that plasma miR-146a expression was elevated in asthma and associated with measures related to worse asthma outcomes, including elevated blood eosinophil counts, higher asthma control questionnaire scores, and need for higher doses of inhaled glucocorticoids. However, transfection of miR-146a in A549 cells treated with TNF-α +/- glucocorticoids produced an anti-inflammatory effect and increased efficacy of glucocorticoids. CONCLUSIONS: We propose a model whereby miR-146a is induced by inflammatory conditions as a feedback mechanism to limit inflammation. Exogenous administration of miR-146a augmented the effects of glucocorticoids and could be a novel therapeutic strategy to enhance efficacy of these medications.

Effects of allergic stimulation and glucocorticoids on miR-155 in CD4+ T-cells.

RATIONALE: MicroRNAs (miRNAs) are emerging as important regulators of allergic inflammation and potential therapeutic targets. We sought to identify which miRNAs are expressed in CD4+ T-cells and determine whether allergic stimuli or glucocorticoids alter their expression. METHODS: After IRB approval, blood was collected from dust mite (DM) allergic rhinitis subjects (n=20), non-allergic controls (n=8), and asthmatics (n=16). Peripheral blood mononuclear cells were incubated with dust mite extract (DME), diluent control, or DME + dexamethasone (0.1 µM). CD4+ T-cells were collected by magnetic bead column, and RNA was isolated by guanidinium/phenol-chloroform extraction. MicroRNA expression was measured using Nanostring microarray and quantitative real time PCR (qPCR). RESULTS: We identified 196 miRNAs that were stably expressed in circulating CD4+ T-cells. Allergen stimulation of CD4+ T-cells with DME differentially induced miR-155 expression in cells of DM-allergic subjects as compared to non-allergic subjects. Induction of miR-155 expression was also observed with anti-CD3/anti-CD28 simulation and phorbol-12-Myristate-13-Acetate (PMA) treatment, and further augmented by calcium inophore and bromocyclic AMP in the latter treatment. The level of miR-155 expression was positively associated with expression of the TH2 cytokines IL-5 and IL-13. Inhibition of miR-155 in Jurkat T-cells inhibited the production of these cytokines. Glucocorticoids attenuated the effects of dust mite allergen, raising the possibility that inhibition of this miRNA could be a mechanism through which glucocorticoids exhibit their anti-inflammatory effects. The CD4+ T-cells had a higher level of miR-155 expression in asthma compared to in allergic rhinitis and non-asthmatics. The inhibitory effects of glucocorticoids on CD4+ T-cell miR-155 expression were lost in severe asthmatics. CONCLUSION: Mir-155 is differentially expressed in allergic T-cells exposed to DM extract compared to in non-allergic cells and it is inhibited by glucocorticoids. MiR-155 may play a role in mediating allergic inflammation in T-cells and could be an anti-inflammatory target of steroids. This pathway may be de-regulated in severe asthma.

miR-155 Modulates Cockroach Allergen- and Oxidative Stress-Induced Cyclooxygenase-2 in Asthma.

Exposure to cockroach allergen is a strong risk factor for developing asthma. Asthma has been associated with allergen-induced airway epithelial damage and heightened oxidant stress. In this study, we investigated cockroach allergen-induced oxidative stress in airway epithelium and its underlying mechanisms. We found that cockroach extract (CRE) could induce reactive oxygen species (ROS) production, particularly mitochondrial-derived ROS, in human bronchial epithelial cells. We then used the RT2 Profiler PCR array and identified that cyclooxygenase-2 (COX-2) was the most significantly upregulated gene related to CRE-induced oxidative stress. miR-155, predicted to target COX-2, was increased in CRE-treated human bronchial epithelial cells, and was showed to regulate COX-2 expression. Moreover, miR-155 can bind COX-2, induce COX-2 reporter activity, and maintain mRNA stability. Furthermore, CRE-treated miR-155-/- mice showed reduced levels of ROS and COX-2 expression in lung tissues and PGE2 in bronchoalveolar lavage fluid compared with wild-type mice. These miR-155-/- mice also showed reduced lung inflammation and Th2/Th17 cytokines. In contrast, when miR-155-/- mice were transfected with adeno-associated virus carrying miR-155, the phenotypic changes in CRE-treated miR-155-/- mice were remarkably reversed, including ROS, COX-2 expression, lung inflammation, and Th2/Th17 cytokines. Importantly, plasma miR-155 levels were elevated in severe asthmatics when compared with nonasthmatics or mild-to-moderate asthmatics. These increased plasma miR-155 levels were also observed in asthmatics with cockroach allergy compared with those without cockroach allergy. Collectively, these findings suggest that COX-2 is a major gene related to cockroach allergen-induced oxidative stress and highlight a novel role of miR-155 in regulating the ROS-COX-2 axis in asthma.

Mannose receptor modulates macrophage polarization and allergic inflammation through miR-511-3p.

BACKGROUND: Mannose receptor (MRC1/CD206) has been suggested to mediate allergic sensitization and asthma to multiple glycoallergens, including cockroach allergens. OBJECTIVE: We sought to determine the existence of a protective mechanism through which MRC1 limits allergic inflammation through its intronic miR-511-3p. METHODS: We examined MRC1-mediated cockroach allergen uptake by lung macrophages and lung inflammation using C57BL/6 wild-type (WT) and Mrc1-/- mice. The role of miR-511-3p in macrophage polarization and cockroach allergen-induced lung inflammation in mice transfected with adeno-associated virus (AAV)-miR-511-3p (AAV-cytomegalovirus-miR-511-3p-enhanced green fluorescent protein) was analyzed. Gene profiling of macrophages with or without miR-511-3p overexpression was also performed. RESULTS: Mrc1-/- lung macrophages showed a significant reduction in cockroach allergen uptake compared with WT mice, and Mrc1-/- mice had an exacerbated lung inflammation with increased levels of cockroach allergen-specific IgE and TH2/TH17 cytokines in a cockroach allergen-induced mouse model compared with WT mice. Macrophages from Mrc1-/- mice showed significantly reduced levels of miR-511-3 and an M1 phenotype, whereas overexpression of miR-511-3p rendered macrophages to exhibit a M2 phenotype. Furthermore, mice transfected with AAV-miR-511-3p showed a significant reduction in cockroach allergen-induced inflammation. Profiling of macrophages with or without miR-511-3p overexpression identified 729 differentially expressed genes, wherein expression of prostaglandin D2 synthase (Ptgds) and its product PGD2 were significantly downregulated by miR-511-3p. Ptgds showed a robust binding to miR-511-3p, which might contribute to the protective effect of miR-511-3p. Plasma levels of miR-511-3p were significantly lower in human asthmatic patients compared with nonasthmatic subjects. CONCLUSION: These studies support a critical but previously unrecognized role of MRC1 and miR-511-3p in protection against allergen-induced lung inflammation.

Differential effects of obesity on eosinophilic vs. non-eosinophilic asthma subtypes.

OBJECTIVE: Asthma is a heterogeneous disease composed of multiple disease subtypes. Obesity may worsen asthma, although the mechanism is poorly understood and its effects on different subtypes are not well characterized. We sought to determine whether obesity affects eosinophilic asthma differently from non-eosinophilic asthma. METHODS: Charts of 196 persistent asthmatics were reviewed. Subjects were categorized according to BMI (obese ≥ 30 kg/m2) and blood eosinophilia based on two different cutoffs (≥200 or ≥400 cells/µl): eosinophilic, non-obese (E-NO), eosinophilic, obese (E-O), non-eosinophilic, non-obese (NE-NO), and non-eosinophilic, obese (NE-O). We analyzed clinical parameters across these groups to determine associations with obesity and/or eosinophilia. RESULTS: Obesity was highly prevalent in our population (50.5%, 99/196). The majority of asthmatics were female (75.5%), though the ratio was lower in the E-NO group (56%). The NE-NO group was associated with lowest asthma severity, lower atopy, and less medication use. Regardless of eosinophilia, obesity was associated with higher inhaled corticosteroid doses and lower FVC% predicted than their non-obese counterparts. Obesity was associated with reduced FEV1% only in the non-eosinophilic group. Eosinophilia was also associated with reduced FEV1% in the non-obese subjects, but FEV1% was not further reduced in the E-O group compared to the E-NO and NE-O groups. Similar findings were observed regardless of whether the blood eosinophil cutoff was 200 or 400 cells/ µl. CONCLUSION: Multiple clinical features of asthma are adversely affected by obesity, which may affect eosinophilic and non-eosinophilic subtypes differently.

Effect of topical beclomethasone on inflammatory markers in adults with eosinophilic esophagitis: A pilot study.

BACKGROUND: Topical corticosteroids have proven efficacy in the treatment of eosinophilic esophagitis (EoE) and are considered the cornerstone of therapy. OBJECTIVE: To evaluate the effect of topical beclomethasone dipropionate (BDP) therapy on clinical outcomes, esophageal eosinophilia, and other markers of inflammation in patients with EoE. METHODS: Nine subjects with a biopsy-proven diagnosis of EoE were enrolled. In a cross-over design, the subjects were randomly assigned to a sequence of BDP and placebo. Treatment periods were 8 weeks, with a 4-week washout period. The subjects had endoscopic biopsies and blood tests at baseline and after each treatment period. They were instructed to maintain a diary of symptoms. Immuno-histochemical studies were performed for interleukins IL-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and transforming growth factor (TGF) beta. Reverse transcription polymerase chain reaction was performed for IL-3, IL-4, IL-5, IL-10, IL-13, IL-17F, IL-25, IL-33, chemokine ligands (CCL)2, CCL5, CCL11, GM-CSF, and TGF-beta levels. The mast cell tryptase (MCT) level was measured in esophageal tissues. RESULTS: BDP led to a significantly larger decrease in esophageal eosinophilia compared with placebo, but there was no significant change in peripheral eosinophilia and high-sensitivity C-reactive protein between the two groups. The study was not powered enough for us to report a significant improvement in clinical symptoms. There was a significant decrease in tissue IL-13 and MCT levels from baseline to the end of treatment between the treatment and placebo groups. Mean fold decreases in cytokine expression between the baseline and treatment groups were observed for IL-17F, IL-25, CCL2, and CCL5. CONCLUSION: Treatment with topical BDP was associated with significant decrease in esophageal eosinophilia, MCT and IL-13. BDP is a potential alternative to fluticasone propionate and budesonide for treatment of EoE. Larger studies are needed to validate these findings.

Childhood Polyarthritis As Early Manifestation of Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy Syndrome.

Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) is a rare disorder of immune dysregulation caused by mutations in the autoimmune regulator (AIRE) gene. Individuals affected with APECED develop a clinical syndrome characterized by ectodermal abnormalities, autoantibody production, and organ-specific autoimmune manifestations. Inflammatory arthritis is usually not described as a part of the syndrome, and only sporadic cases are reported. We describe the case of a preschool-age girl who presented with hypoparathyroidism, hepatitis, interstitial pneumonitis, and chronic polyarthritis at 4 years of age and was found to have two compound heterozygous disease-associated mutations in the AIRE gene. We also conducted a literature review of the main characteristics of inflammatory arthritis in APECED patients. Our case and review demonstrate that (1) inflammatory arthritis, although rare, can be an early manifestation of APECED; (2) the diagnosis of APECED should be considered if mucocutaneous candidiasis, multiple organ-specific autoimmune manifestations, polyendocrinopathy, especially hypoparathyroidism or adrenal failure, or ectodermal dystrophy accompany joint symptoms; and (3) genotyping interpretation should take into account that mutations are found in the 14 exons of the gene, compound heterozygosity is common, and in some cases, only one or no mutated alleles are found.