Beyond the Lung: Geriatric Conditions Afflict Community-Dwelling Older Adults With Self-Reported Chronic Obstructive Pulmonary Disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) predominantly affects older adults. However, the co-morbid occurrence of geriatric conditions has been understudied. OBJECTIVE: Characterize the prevalence of geriatric conditions among community-dwelling U.S. older adults with self-reported COPD. METHODS: We conducted a nationally representative, cross-sectional study of 3,005 U.S. community-dwelling older adults (ages 57-85 years) from the National Social Life, Health, and Aging Project (NSHAP). We evaluated the prevalence of select geriatric conditions (multimorbidity, functional disability, impaired physical function, low physical activity, modified frailty assessment, falls, polypharmacy, and urinary incontinence) and psychosocial measures (frequency of socializing, sexual activity in the last year, loneliness, cognitive impairment, and depressive symptoms) among individuals with self-reported COPD as compared to those without. Using multivariate logistic and linear regressions, we investigated the relationships between COPD and these geriatric physical and psychosocial conditions. MAIN RESULTS: Self-reported COPD prevalence was 10.7%, similar to previous epidemiological studies. Individuals with COPD had more multimorbidity [modified Charlson score 2.6 (SD 1.9) vs. 1.6 (SD 1.6)], more functional disability (58.1 vs. 29.6%; adjusted OR 3.1, 95% CI 2.3, 4.3), falls in the last year (28.4 vs. 20.8%; adjusted OR 1.4, 95% CI 1.01, 2.0), impaired physical function (75.8 vs. 56.6%; adjusted OR 2.1, 95% CI 1.1, 3.7), more frequently reported extreme low physical activity (18.7 vs. 8.1%; adjusted OR 2.3, 95% CI 1.5, 3.5) and higher frailty prevalence (16.0 vs. 2.7%; adjusted OR 6.3, 95% CI 3.0,13.0) than those without COPD. They experienced more severe polypharmacy (≥10 medications, 37.5 vs. 16.1%; adjusted OR 2.9, 95% CI 2.0, 4.2). They more frequently reported extreme social disengagement and were lonelier, but the association with social measures was eliminated when relationship status was accounted for, as those with COPD were less frequently partnered. They more frequently endorsed depressive symptoms (32.0 vs. 18.9%, adjusted OR 1.9, 95% CI 1.4, 2.7). There was no noted difference in cognitive impairment between the two populations. CONCLUSIONS: Geriatric conditions are common among community-dwelling older adults with self-reported COPD. A "beyond the lung" approach to COPD care should center on active management of geriatric conditions, potentially leading to improved COPD management, and quality of life.

A-to-I editing of miR-200b-3p in airway cells is associated with moderate-to-severe asthma.

BACKGROUND: Asthma is a chronic lung disease characterised by persistent airway inflammation. Altered microRNA (miRNA)-mediated gene silencing in bronchial epithelial cells (BECs) has been reported in asthma, yet adenosine deaminase acting on RNA (ADAR)-mediated miRNA editing in asthma remains unexplored. METHODS: We first identified adenosine to inosine (A-to-I) edited sites in miRNAs in BECs from 142 adult asthma cases and controls. A-to-I edited sites were tested for associations with asthma severity and clinical measures of asthma. Paired RNA sequencing data were used to perform pathway enrichments and test for associations with bioinformatically predicted target genes of the unedited and edited miRNAs. RESULTS: Of 19 A-to-I edited sites detected in these miRNAs, one site at position 5 of miR-200b-3p was edited less frequently in cases compared with controls (pcorrected=0.013), and especially compared with cases with moderate (pcorrected=0.029) and severe (pcorrected=3.9×10-4), but not mild (pcorrected=0.38), asthma. Bioinformatic prediction revealed 232 target genes of the edited miR-200b-3p, which were enriched for both interleukin-4 and interferon-γ signalling pathways, and included the SOCS1 (suppressor of cytokine signalling 1) gene. SOCS1 was more highly expressed in moderate (pcorrected=0.017) and severe (pcorrected=5.4×10-3) asthma cases compared with controls. Moreover, both miR-200b-3p editing and SOCS1 were associated with bronchoalveolar lavage eosinophil levels. CONCLUSIONS: Reduced A-to-I editing of position 5 of miR-200b-3p in lower airway cells from moderate-to-severe asthmatic subjects may lead to overexpression of SOCS1 and impaired cytokine signalling. We propose ADAR-mediated editing as an epigenetic mechanism contributing to features of moderate-to-severe asthma in adulthood.

Altered transcriptional and chromatin responses to rhinovirus in bronchial epithelial cells from adults with asthma.

There is a life-long relationship between rhinovirus (RV) infection and the development and clinical manifestations of asthma. In this study we demonstrate that cultured primary bronchial epithelial cells from adults with asthma (n = 9) show different transcriptional and chromatin responses to RV infection compared to those without asthma (n = 9). Both the number and magnitude of transcriptional and chromatin responses to RV were muted in cells from asthma cases compared to controls. Pathway analysis of the transcriptionally responsive genes revealed enrichments of apoptotic pathways in controls but inflammatory pathways in asthma cases. Using promoter capture Hi-C we tethered regions of RV-responsive chromatin to RV-responsive genes and showed enrichment of these regions and genes at asthma GWAS loci. Taken together, our studies indicate a delayed or prolonged inflammatory state in cells from asthma cases and highlight genes that may contribute to genetic risk for asthma.

Expression quantitative trait locus fine mapping of the 17q12-21 asthma locus in African American children: a genetic association and gene expression study.

BACKGROUND: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12-21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12-21 locus. METHODS: We first did a genetic association study and meta-analysis using 17q12-21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12-21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12-21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). FINDINGS: 17q12-21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p<0·0055 (for rs2305480_G, odds ratio [OR] 1·36 [95% CI 1·12-1·65], p=0·0014; and for rs8076131_A, OR 1·37 [1·13-1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [ß] 1·35 [95% CI 1·25-1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (ß 1·15 [1·08-1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLß 1·24 [1·15-1·32], p<0·0001; and for ORMDL3 (ß 1·19 [1·12-1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (ß 1·29 [1·15-1·44], p<0·0001). INTERPRETATION: Our study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12-21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus. FUNDING: National Institutes of Health, Office of the Director.

Ultrasensitive digital quantification of cytokines and bacteria predicts septic shock outcomes.

Quantification of pathogen and host biomarkers is essential for the diagnosis, monitoring, and treatment of infectious diseases. Here, we demonstrate sensitive and rapid quantification of bacterial load and cytokines from human biological samples to generate actionable hypotheses. Our digital assay measures IL-6 and TNF-α proteins, gram-negative (GN) and gram-positive (GP) bacterial DNA, and the antibiotic-resistance gene blaTEM with femtomolar sensitivity. We use our method to characterize bronchoalveolar lavage fluid from patients with asthma, and find elevated GN bacteria and IL-6 levels compared to healthy subjects. We then analyze plasma from patients with septic shock and find that increasing levels of IL-6 and blaTEM are associated with mortality, while decreasing IL-6 levels are associated with recovery. Surprisingly, lower GN bacteria levels are associated with higher probability of death. Applying decision-tree analysis to our measurements, we are able to predict mortality and rate of recovery from septic shock with over 90% accuracy.

Chemokine expression in the early response to injury in human airway epithelial cells.

Basal airway epithelial cells (AEC) constitute stem/progenitor cells within the central airways and respond to mucosal injury in an ordered sequence of spreading, migration, proliferation, and differentiation to needed cell types. However, dynamic gene transcription in the early events after mucosal injury has not been studied in AEC. We examined gene expression using microarrays following mechanical injury (MI) in primary human AEC grown in submersion culture to generate basal cells and in the air-liquid interface to generate differentiated AEC (dAEC) that include goblet and ciliated cells. A select group of ~150 genes was in differential expression (DE) within 2-24 hr after MI, and enrichment analysis of these genes showed over-representation of functional categories related to inflammatory cytokines and chemokines. Network-based gene prioritization and network reconstruction using the PINTA heat kernel diffusion algorithm demonstrated highly connected networks that were richer in differentiated AEC compared to basal cells. Similar experiments done in basal AEC collected from asthmatic donor lungs demonstrated substantial changes in DE genes and functional categories related to inflammation compared to basal AEC from normal donors. In dAEC, similar but more modest differences were observed. We demonstrate that the AEC transcription signature after MI identifies genes and pathways that are important to the initiation and perpetuation of airway mucosal inflammation. Gene expression occurs quickly after injury and is more profound in differentiated AEC, and is altered in AEC from asthmatic airways. Our data suggest that the early response to injury is substantially different in asthmatic airways, particularly in basal airway epithelial cells.

The metabolic footprint of the airway bacterial community in cystic fibrosis.

BACKGROUND: Progressive, chronic bacterial infection of the airways is a leading cause of death in cystic fibrosis (CF). Culture-independent methods based on sequencing of the bacterial 16S rRNA gene describe a distinct microbial community that decreases in richness and diversity with disease progression. Understanding the functional characteristics of the microbial community may aid in identifying potential therapies and may assist in management, but current methods are cumbersome. Here, we demonstrate the use of an oxidative metabolic assay as a complement to sequencing methods to describe the microbiome in the airways of patients with CF. METHODS: Expectorated sputum was collected from 16 CF subjects and 8 control subjects. The Biolog Gen III Microplate was used in a community-level physiological profiling (CLPP)-based assay to examine oxidative metabolic activity. 16S rRNA V4 amplicon sequencing was used to characterize the taxonomy and diversity of the samples. Correlations were then identified among the oxidative activity and taxonomy data. In an additional paired analysis, sputum from seven CF subjects were collected at two separate clinic visits and compared for oxidative activity, taxonomy, and diversity. RESULTS: Significant differences in oxidative metabolic activity, microbial taxonomy, and diversity were found between the CF and control sputum samples. Oxidative activity correlated positively with total genera but not with other measures of diversity or taxonomy, demonstrating that the metabolic assay complements the structural aspects of the microbiome. As expected, Pseudomonas was significantly enriched in CF samples, while Streptococcus and Prevotella were similarly abundant in both CF and control samples. Paired analysis of CF samples at separate clinic visits revealed comparable oxidative activity that correlated with similar stability in taxonomy and diversity. CONCLUSIONS: The CLPP assay used in this study complements existing sequencing methods to delineate the oxidative metabolic footprint of the CF airway bacterial community. This method may be useful to study the CF microbial community over time and with changes in disease state.

DNA methylation in lung cells is associated with asthma endotypes and genetic risk.

The epigenome provides a substrate through which environmental exposures can exert their effects on gene expression and disease risk, but the relative importance of epigenetic variation on human disease onset and progression is poorly characterized. Asthma is a heterogeneous disease of the airways, for which both onset and clinical course result from interactions between host genotype and environmental exposures, yet little is known about the molecular mechanisms for these interactions. We assessed genome-wide DNA methylation using the Infinium Human Methylation 450K Bead Chip and characterized the transcriptome by RNA sequencing in primary airway epithelial cells from 74 asthmatic and 41 nonasthmatic adults. Asthma status was based on doctor's diagnosis and current medication use. Genotyping was performed using various Illumina platforms. Our study revealed a regulatory locus on chromosome 17q12-21 associated with asthma risk and epigenetic signatures of specific asthma endotypes and molecular networks. Overall, these data support a central role for DNA methylation in lung cells, which promotes distinct molecular pathways of asthma pathogenesis and modulates the effects of genetic variation on disease risk and clinical heterogeneity.

Advances in Bronchial Thermoplasty.

Bronchial thermoplasty (BT) is a therapeutic intervention that delivers targeted thermal energy to the airway walls with the goal of ablating the smooth muscle in patients with severe persistent asthma. Since the publication of the original preclinical studies, three large randomized clinical trials evaluating its impact on asthma control have been performed. These trials have shown improvements in asthma-related quality of life and a reduction in asthma exacerbations following treatment with BT. However, there remains significant controversy regarding the true efficacy of BT and the interpretation of these studies, particularly the Asthma Intervention Research 2 trial. In this article, we will discuss these controversies and present the latest evidence on the use of BT in asthma, specifically the 5-year longitudinal evaluation of patients. In addition, we will discuss new insights into the histopathologic changes that occur in the airways following BT, as well as the feasibility of performing the procedure in patients with very severe asthma. We also will discuss the ongoing translational and clinical investigations regarding the underlying mechanism of action and methods to improve patient selection for this procedure.

A functional genomic model for predicting prognosis in idiopathic pulmonary fibrosis.

BACKGROUND: The course of disease for patients with idiopathic pulmonary fibrosis (IPF) is highly heterogeneous. Prognostic models rely on demographic and clinical characteristics and are not reproducible. Integrating data from genomic analyses may identify novel prognostic models and provide mechanistic insights into IPF. METHODS: Total RNA of peripheral blood mononuclear cells was subjected to microarray profiling in a training (45 IPF individuals) and two independent validation cohorts (21 IPF/10 controls, and 75 IPF individuals, respectively). To identify a gene set predictive of IPF prognosis, we incorporated genomic, clinical, and outcome data from the training cohort. Predictor genes were selected if all the following criteria were met: 1) Present in a gene co-expression module from Weighted Gene Co-expression Network Analysis (WGCNA) that correlated with pulmonary function (p < 0.05); 2) Differentially expressed between observed "good" vs. "poor" prognosis with fold change (FC) >1.5 and false discovery rate (FDR) < 2%; and 3) Predictive of mortality (p < 0.05) in univariate Cox regression analysis. "Survival risk group prediction" was adopted to construct a functional genomic model that used the IPF prognostic predictor gene set to derive a prognostic index (PI) for each patient into either high or low risk for survival outcomes. Prediction accuracy was assessed with a repeated 10-fold cross-validation algorithm and independently assessed in two validation cohorts through multivariate Cox regression survival analysis. RESULTS: A set of 118 IPF prognostic predictor genes was used to derive the functional genomic model and PI. In the training cohort, high-risk IPF patients predicted by PI had significantly shorter survival compared to those labeled as low-risk patients (log rank p < 0.001). The prediction accuracy was further validated in two independent cohorts (log rank p < 0.001 and 0.002). Functional pathway analysis revealed that the canonical pathways enriched with the IPF prognostic predictor gene set were involved in T-cell biology, including iCOS, T-cell receptor, and CD28 signaling. CONCLUSIONS: Using supervised and unsupervised analyses, we identified a set of IPF prognostic predictor genes and derived a functional genomic model that predicted high and low-risk IPF patients with high accuracy. This genomic model may complement current prognostic tools to deliver more personalized care for IPF patients.

Airway Inflammation after Bronchial Thermoplasty for Severe Asthma.

RATIONALE: Bronchial thermoplasty is an alternative treatment for patients with severe, uncontrolled asthma in which the airway smooth muscle is eliminated using radioablation. Although this emerging therapy shows promising outcomes, little is known about its effects on airway inflammation. OBJECTIVES: We examined the presence of bronchoalveolar lavage cytokines and expression of smooth muscle actin in patients with severe asthma before and in the weeks after bronchial thermoplasty. METHODS: Endobronchial biopsies and bronchoalveolar lavage samples from 11 patients with severe asthma were collected from the right lower lobe before and 3 and 6 weeks after initial bronchial thermoplasty. Samples were analyzed for cell proportions and cytokine concentrations in bronchoalveolar lavage and for the presence of α-SMA in endobronchial biopsies. MEASUREMENTS AND MAIN RESULTS: α-SMA expression was decreased in endobronchial biopsies of 7 of 11 subjects by Week 6. In bronchoalveolar lavage fluid, both transforming growth factor-ß1 and regulated upon activation, normal T-cell expressed and secreted (RANTES)/CCL5 were substantially decreased 3 and 6 weeks post bronchial thermoplasty in all patients. The cytokine tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in several cell types, was increased in concentration both 3 and 6 weeks post bronchial thermoplasty. CONCLUSIONS: Clinical improvement and reduction in α-SMA after bronchial thermoplasty in severe, uncontrolled asthma is associated with substantial changes in key mediators of inflammation. These data confirm the substantial elimination of airway smooth muscle post thermoplasty in the human asthmatic airway and represent the first characterization of significant changes in airway inflammation in the first weeks after thermoplasty.

Peripheral blood IRF1 expression as a marker for glucocorticoid sensitivity.

OBJECTIVE: Despite of the common usage of glucocorticoids (GCs), a significant portion of asthma patients exhibit GC insensitivity. This could be mediated by diverse mechanisms, including genomics. Recent work has suggested that measuring changes in gene expression may provide more predictive information about GC insensitivity than baseline gene expression alone, and that expression changes in peripheral blood may be reflective of those in the airway. METHODS: We performed in silico discovery using gene expression omnibus (GEO) data that evaluated GC effect on gene expression in multiple tissue types. Subsequently, candidate genes whose expression levels are affected by GC were examined in cell lines and in primary cells derived from human airway and blood. RESULTS: Through gene expression omnibus analysis, we identified interferon regulator factor 1 (IRF1), whose expression is affected by GC treatment in airway smooth muscle cells, normal human bronchial epithelial (NHBE) cells, and lymphoblastoid cell lines (LCLs). Significant IRF1 downregulation post GC exposure was confirmed in two cultured airway epithelial cell lines and primary NHBE cells (P<0.05). We observed large interindividual variation in GC-induced IRF1 expression changes among primary NHBE cells tested. Significant downregulation of IRF1 was also observed in six randomly selected LCLs (P<0.05), with variable degrees of downregulation among different samples. In peripheral blood mononuclear cells obtained from healthy volunteers, variable downregulation of IRF1 by GC was also shown. NFKB1, a gene whose expression is known to be downregulated by GC and the degree of downregulation of which is reflective of GC response, was used as a control in our study. IRF1 shows more consistent downregulation across tissue types when compared with NFKB1. CONCLUSION: Our results suggest that GC-induced IRF1 gene expression changes in peripheral blood could be used as a marker to reflect GC response in the airway.

Loss of sirtuin 1 (SIRT1) disrupts skin barrier integrity and sensitizes mice to epicutaneous allergen challenge.

BACKGROUND: Skin barrier integrity requires a highly coordinated molecular system involving the structural protein filaggrin (FLG). Mutational loss of the skin barrier protein FLG predisposes subjects to the development of atopic dermatitis (AD). OBJECTIVE: We sought to determine the role of sirtuin 1 (SIRT1) in skin barrier function, FLG expression, and development of AD. METHODS: Skin histology of mice with skin-specific SIRT1 deletion and wild-type control animals was examined by using hematoxylin and eosin staining. Protein and mRNA abundance was analyzed by means of immunoblotting, immunohistochemistry, immunofluorescence, and RT-PCR. Serum antibody levels were assessed by means of ELISA. RESULTS: Here we show that FLG is regulated by the protein deacetylase SIRT1 and that SIRT1 is critical for skin barrier integrity. Epidermis-specific SIRT1 ablation causes AD-like skin lesions in mice, and mice with epidermal SIRT1 deletion are sensitive to percutaneous challenge by the protein allergen ovalbumin. In normal human keratinocytes and mouse skin SIRT1 knockdown or genetic deletion downregulates FLG, and regulation of FLG expression by SIRT1 requires the deacetylase activity of SIRT1. SIRT1 also promotes activation of the aryl hydrocarbon receptor, and the aryl hydrocarbon receptor ligand restores FLG expression in SIRT1-inhibited cells. Compared with normal human skin, SIRT1 is downregulated in both AD and non-AD lesions. CONCLUSION: Our findings demonstrate a critical role of SIRT1 in skin barrier maintenance, open up new opportunities to use SIRT1 as a pharmacologic target, and might facilitate the development of mechanism-based agents for AD prevention and therapy.

A genome-wide survey of CD4(+) lymphocyte regulatory genetic variants identifies novel asthma genes.

BACKGROUND: Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. OBJECTIVE: We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4(+) lymphocytes for association with asthma. METHODS: eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. RESULTS: Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3/GSDMB variants with asthma (combined P = 2.9 × 10(-8)). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 (FADS2; P = .002), N-acetyl-α-D-galactosaminidase (NAGA; P = .0002), and Factor XIII, A1 (F13A1; P = .0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4(+) lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. CONCLUSIONS: Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma.

Interleukin-1 receptor-associated kinase M (IRAK-M) promotes human rhinovirus infection in lung epithelial cells via the autophagic pathway.

Human rhinovirus (HRV) is the most common viral etiology in acute exacerbations of asthma. However, the exact mechanisms underlying HRV infection in allergic airways are poorly understood. IL-13 increases interleukin-1 receptor associated kinase M (IRAK-M) and subsequently inhibits airway innate immunity against bacteria. However, the role of IRAK-M in lung HRV infection remains unclear. Here, we provide the first evidence that IRAK-M over-expression promotes lung epithelial HRV-16 replication and autophagy, but inhibits HRV-16-induced IFN-ß and IFN-λ1 expression. Inhibiting autophagy reduces HRV-16 replication. Exogenous IFN-ß and IFN-λ1 inhibit autophagy and HRV-16 replication. Our data indicate the enhancing effect of IRAK-M on epithelial HRV-16 infection, which is partly through the autophagic pathway. Impaired anti-viral interferon production may serve as a direct or an indirect (e.g., autophagy) mechanism of enhanced HRV-16 infection by IRAK-M over-expression. Targeting autophagic pathway or administrating anti-viral interferons may prevent or attenuate viral (e.g., HRV-16) infections in allergic airways.

Bronchial thermoplasty failure in severe persistent asthma: a case report.

INTRODUCTION: Bronchial thermoplasty (BT) is an emerging therapy for patients with severe persistent asthma who remain poorly controlled despite standard maximal medical therapy. Thermoplasty elicits asthma control over time by applying thermal radiofrequency energy to airways to ablate underlying smooth muscle. While this therapy is suggested to eliminate such smooth muscle permanently, no human studies have examined the possibility of treatment failure. CASE REPORT: We present a 62-year-old female with severe, refractory asthma symptoms who underwent BT without apparent complications. However, severe symptoms including multiple clinical exacerbations persisted despite BT treatment. Repeat endobronchial biopsy done six months after BT treatment demonstrated persistent smooth muscle hyperplasia in multiple airways that previously had been treated. The patient continued to have uncontrolled, refractory asthma despite multiple therapies. CONCLUSION: This case is the first to describe a failure of BT to reduce or eliminate airway smooth muscle in a patient with severe persistent asthma. It suggests the potential for treatment failure in the management of these patients after BT and highlights the need for further study of potential BT-refractory patients.