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Comparative effectiveness research (CER) is intended to address the expressed needs of patients, clinicians, and other stakeholders. Representatives of 54 stakeholder groups with an interest in chronic obstructive pulmonary disease (COPD) participated in workshops convened by the COPD Outcomes-based Network for Clinical Effectiveness and Research Translation (CONCERT) over a 2-year period. Year 1 focused on chronic care and care coordination. Year 2 focused on acute care and transitions in care between healthcare settings. Discussions and provisional voting were conducted via teleconferences and e-mail exchanges before the workshop. Final prioritization votes occurred after in-person discussions at the workshop. We used a modified Delphi approach to facilitate discussions and consensus building. To more easily quantify preferences and to evaluate the internal consistency of rankings, the Analytic Hierarchy Process was incorporated in Year 2. Results of preworkshop and final workshop voting often differed, suggesting that prioritization efforts relying solely on requests for topics from stakeholder groups without in-person discussion may provide different research priorities. Research priorities varied across stakeholder groups, but generally focused on studies to evaluate different approaches to healthcare delivery (e.g., spirometry for diagnosis and treatment, integrated healthcare strategies during transitions in care) rather than head-to-head comparisons of medications. This research agenda may help to inform groups intending to respond to CER funding opportunities in COPD. The methodologies used, detailed in the online supplement, may also help to inform prioritization efforts for CER in other health conditions. [ABSTRACT FROM AUTHOR]

Background: Hospitalized patients frequently misuse their respiratory inhalers, yet it is unclear what the most effective hospital-based educational intervention is for this population.Objective: To compare two strategies for teaching inhaler use to hospitalized patients with asthma or chronic obstructive pulmonary disease (COPD).Design: A Phase-II randomized controlled clinical trial enrolled hospitalized adults with physician diagnosed asthma or COPD.Participants: Hospitalized adults (age 18 years or older) with asthma or COPD.Interventions: Participants were randomized to brief intervention [BI]: single-set of verbal and written step-by-step instructions, or, teach-to-goal [TTG]: BI plus repeated demonstrations of inhaler use and participant comprehension assessments (teach-back).Main Measures: The primary outcome was metered-dose inhaler (MDI) misuse post-intervention (<75% steps correct). Secondary outcomes included Diskus® misuse, self-reported inhaler technique confidence and prevalence of 30-day health-related events.Key Results: Of 80 eligible participants, fifty (63%) were enrolled (BI n=26, TTG n=24). While the majority of participants reported being confident with their inhaler technique (MDI 70%, Diskus® 94%), most misused their inhalers pre-intervention (MDI 62%, Diskus® 78%). Post-intervention MDI misuse was significantly lower after TTG vs. BI (12.5 vs. 46%, p=0.01). The results for Diskus® were similar and approached significance (25 vs. 80%, p=0.05). Participants with 30-day acute health-related events were less common in the group receiving TTG vs. BI (1 vs. 8, p=0.02).Conclusions: TTG appears to be more effective compared with BI. Patients over-estimate their inhaler technique, emphasizing the need for hospital-based interventions to correct inhaler misuse. Although TTG was associated with fewer post-hospitalization health-related events, larger, multi-centered studies are needed to evaluate the durability and clinical outcomes associated with this hospital-based education. [ABSTRACT FROM AUTHOR]

Background: Previous studies of patients with bronchiectasis have found that the cause is idiopathic in the majority of cases, but these studies were done in homogeneous populations. We hypothesized that the etiology of bronchiectasis can be determined in a higher percentage of patients in a diverse US population and will differ significantly based on ethnicity.Methods: One hundred twelve patients with bronchiectasis confirmed by chest CT scan entered the study. Data from 106 patients were available for full evaluation. Clinical questionnaire, pulmonary function tests, sputum microbiology, laboratory data, and immune function testing were done. Results were analyzed by ethnicity and etiology.Results: Patients were 61.6% European American (EA), 26.8% African American (AA), 8.9% Hispanic American (HA), and 2.7% Asian American. A cause of bronchiectasis was determined in 93.3% of patients. In 63.2% of patients, bronchiectasis was caused by immune dysregulation, including deficiency (n = 18 [17%]), autoimmune disease (n = 33 [31.1%]), hematologic malignancy (n = 15 [14.2%]), and allergic bronchopulmonary aspergillosis (n = 1 [0.9%]). Rheumatoid arthritis was the cause of bronchiectasis in 28.6% of AA patients vs 6.2% of EA patients (P < .05). Hematologic malignancy was the etiology in 20.0% of the EA patients vs none of the AA patients (P = .02). A significantly higher percentage of HA patients had Pseudomonas aeruginosa in their sputum compared with AA and EA patients (P = .01).Conclusions: The etiology of bronchiectasis can be determined in the majority of patients in a heterogeneous US population and is most often due to immune dysregulation. Rheumatoid arthritis is more likely in AA patients than EA patients. HA patients are more likely to have P aeruginosa in their sputum. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Hospital admissions and emergency department (ED) visits have traditionally been used to assess the strength of association between environmental exposures, such as air pollution, and asthma morbidity. In the current study, we evaluate the use of short-acting beta-agonist (SABA) prescriptions as a surrogate marker for asthma exacerbation with respect to these more traditional markers. METHODS: Claims data for recipients covered by Illinois Medicaid with a diagnosis of asthma were obtained for fiscal-years 1996 through June 1998. Claims for short-acting bronchodilators and asthma-related ED visits and hospital admissions for 31,140 adults were identified. The odds ratio for the association of either an ED visit or hospital admission and an SABA prescription was calculated for time lags ranging from -28 to +28 days. Individual-subject heterogeneity and seasonal effects were corrected for using the Mantel-Haenszel method. RESULTS: After adjustment for individual and seasonal effects, there was a significant positive association between SABA prescriptions and ED visits or hospital admissions for asthma on any single day. In addition, a significant positive association was also found between the ED visits or hospital admissions occurring on the few days prior to an SABA prescription. No significant relation was found (after adjusting for subject and seasonal effects) between prescriptions and admissions when an SABA prescription date preceded that of a hospital admission or an ED visit. CONCLUSIONS: A very strong and significant association between ED visits or hospital admissions for asthma and SABA prescriptions was observed, which suggests that SABA prescription fills can be used as a marker for asthma morbidity. In addition, a temporal association exists between claims for ED visits or hospital admissions for asthma and SABA prescription claims when an ED visit or hospital admission precedes the SABA prescription. [ABSTRACT FROM AUTHOR]

Rationale: Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods: Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results: In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV 1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P  < 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM ( P  < 0.05). Conclusions: Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.

Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1, was downregulated in cases (q = 3.26 × 10 -9 ) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response (CEACAM5; p = 9.62 × 10 -16 and CPA3; p = 2.39 × 10 -14 ) and wound healing (FN1; p = 7.63 × 10 -9 ). Multi-omic analysis identifies FKBP5, a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes - increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response - that may play a critical role in asthma within the African Diaspora., (© 2024. The Author(s).)

Asthma is a heterogeneous, complex syndrome, and identifying asthma endotypes has been challenging. We hypothesize that distinct endotypes of asthma arise in disparate genetic variation and life-time environmental exposure backgrounds, and that disease comorbidity patterns serve as a surrogate for such genetic and exposure variations. Here, we computationally discover 22 distinct comorbid disease patterns among individuals with asthma (asthma comorbidity subgroups) using diagnosis records for >151 M US residents, and re-identify 11 of the 22 subgroups in the much smaller UK Biobank. GWASs to discern asthma risk loci for individuals within each subgroup and in all subgroups combined reveal 109 independent risk loci, of which 52 are replicated in multi-ancestry meta-analysis across different ethnicity subsamples in UK Biobank, US BioVU, and BioBank Japan. Fourteen loci confer asthma risk in multiple subgroups and in all subgroups combined. Importantly, another six loci confer asthma risk in only one subgroup. The strength of association between asthma and each of 44 health-related phenotypes also varies dramatically across subgroups. This work reveals subpopulations of asthma patients distinguished by comorbidity patterns, asthma risk loci, gene expression, and health-related phenotypes, and so reveals different asthma endotypes., (© 2022. The Author(s).)

Background: Cystic fibrosis (CF) is a multisystem disease that often requires otolaryngology care. Individuals with CF commonly have chronic rhinosinusitis but also present with hearing loss and dysphonia. Given these manifestations of CF, otolaryngologists are frequently involved in the care of patients with CF; however, there is limited consensus on optimal management of sinonasal, otologic, and laryngologic symptoms., Methods: The Cystic Fibrosis Foundation convened a multidisciplinary team of otolaryngologists, pulmonologists, audiologists, pharmacists, a social worker, a nurse coordinator, a respiratory therapist, two adults with CF, and a caregiver of a child with CF to develop consensus recommendations. Workgroups developed draft recommendation statements based on a systematic literature review, and a ≥80% consensus was required for acceptance of each recommendation statement., Results: The committee voted on 25 statements. Eleven statements were adopted recommending a treatment or intervention, while five statements were formulated recommending against a specific treatment or intervention. The committee recommended eight statements as an option for select patients in certain circumstances, and one statement did not reach consensus., Conclusion: These multidisciplinary consensus recommendations will help providers navigate decisions related to otolaryngology consultation, medical and surgical management of CF-CRS, hearing, and voice in individuals with CF. A collaborative and multidisciplinary approach is advocated to best care for our patients with CF. Future clinical research is needed utilizing standardized, validated outcomes with comprehensive reporting of patient outcome, effects of modulator therapies, and genetic characteristics to help continue to advance care, decrease morbidity, and improve the quality of life for individuals with CF., (© 2022 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Maternal asthma (MA) is among the most consistent risk factors for asthma in children. Possible mechanisms for this observation are epigenetic modifications in utero that have lasting effects on developmental programs in children of mothers with asthma. To test this hypothesis, we performed differential DNA methylation analyses of 398,186 individual CpG sites in primary bronchial epithelial cells (BECs) from 42 nonasthma controls and 88 asthma cases, including 56 without MA (NMA) and 32 with MA. We used weighted gene coexpression network analysis (WGCNA) of 69 and 554 differentially methylated CpGs (DMCs) that were specific to NMA and MA cases, respectively, compared with controls. WGCNA grouped 66 NMA-DMCs and 203 MA-DMCs into two and five comethylation modules, respectively. The eigenvector of one MA-associated module (turquoise) was uniquely correlated with 85 genes expressed in BECs and enriched for 36 pathways, 16 of which discriminated between NMA and MA using machine learning. Genes in all 16 pathways were decreased in MA compared with NMA cases (P = 7.1 × 10−3), a finding that replicated in nasal epithelial cells from an independent cohort (P = 0.02). Functional interpretation of these pathways suggested impaired T cell signaling and responses to viral and bacterial pathogens. The MA-associated turquoise module eigenvector was additionally correlated with clinical features of severe asthma and reflective of type 2 (T2)-low asthma (i.e., low total serum immunoglobulin E, fractional exhaled nitric oxide, and eosinophilia). Overall, these data suggest that MA alters diverse epigenetically mediated pathways that lead to distinct subtypes of severe asthma in adults, including hard-to-treat T2-low asthma.

Background: Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent., Methods: We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV 1 . We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p<1·6 × 10 -4 , and tested for replication using independent cohorts of individuals of African descent with asthma., Findings: We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 μg fluticasone plus salmeterol on chromosome 12 (odds ratio [OR local African ] 3·95, 95% CI 2·02-7·72, p=6·1 × 10 -5 ) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, OR allele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10 -5 ). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (OR local African 3·35, 1·98-5·67, p=6·8 × 10 -6 ) containing a locus adjacent to TPST2 (rs5752429, OR allele dose 0·21, 0·09-0·52, p=5·7 × 10 -4 ). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts., Interpretation: BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma., Funding: National Institutes of Health, National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests VEO reports consulting fees from Sanofi and fees for serving on independent data monitoring committees for Sanofi and Regeneron Pharmaceuticals. SJS reports receiving consulting fees, paid to his institution, from AstraZeneca, GlaxoSmithKline, Moderna, Propeller Health, Regeneron, and Sanofi, as well as a research grant from Propeller Health. ERB reports receiving consulting fees and donated drugs from Boehringer Ingelheim, donated drugs from Merck and Teva Pharmaceuticals, consulting fees from AstraZeneca, MedImmune, GlaxoSmithKline, Novartis, and Sanofi–Regeneron, and participating in trials as an employee of Wake Forest School of Medicine and the University of Arizona for AstraZeneca, MedImmune, Boehringer Ingelheim, Cephalon–Teva Pharmaceuticals, Genentech, GlaxoSmithKline, Johnson & Johnson (Janssen), Novartis, and Sanofi–Regeneron. VMC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. WP reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. DM reports receiving grant support and donated drugs from GlaxoSmithKline, Genentech, Vifor Pharma, Boehringer Ingelheim, and Teva Pharmaceuticals, grant support from Sanofi and AstraZeneca, fees for serving on a data and safety monitoring board from Novartis, and donated drugs from Merck. FDM reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, grant support from Johnson & Johnson, and consulting fees from Copeval and Commence. EH-L reports a fellowship from the Spanish Ministry of Science, Innovation, and Universities. MP-Y reports grants from the Spanish Ministry of Economy, Industry, and Competitiveness, the State Research Agency and the European Regional Development Funds from the European Union (MICIU/AEI/FEDER, UE), and grant support from GlaxoSmithKline, Spain. SJK reports receiving donated drugs from Merck–Organon, Genentech, GlaxoSmithKline, and Regeneron and owning stock in Merck. LBB reports receiving consulting fees and lecture fees from Aerocrine, GlaxoSmithKline, Genentech–Novartis, and AstraZeneca, advisory board fees and donated drugs from Merck, fees for serving on a data safety monitoring board from DBV Technologies, consulting fees, lecture fees, and donated drugs from Teva Pharmaceuticals and Boehringer Ingelheim, honoraria from WebMD–Medscape, advisory board fees and lecture fees from Sanofi–Regeneron, advisory board fees and consulting fees from Vectura, and advisory board fees from Circassia. MDC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, and consulting fees from Genentech and Novartis. JCC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. MC reports receiving grant support, lecture fees, and donated drugs from Boehringer Ingelheim, donated drugs from Merck, consulting fees, lecture fees, and donated drugs from Teva Pharmaceuticals, consulting fees and lecture fees from Boston Scientific and Genentech, consulting fees from Nuvaira, Aviragen, 4D Pharma, VIDA Diagnostics, Mallinckrodt Pharmaceuticals, Theravance, Therabron, and Vectura, grant support, consulting fees, and lecture fees from Sanofi-Aventis, grant support and lecture fees from AstraZeneca and GlaxoSmithKline, grant support from Chiesi and Novartis, and lecture fees from Regeneron Pharmaceuticals. LCD reports receiving grant support and consulting fees from AstraZeneca, and consulting fees from Sanofi–Regeneron. FH reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. DJJ reports grant support from GlaxoSmithKline, consulting fees from Novartis, Sanofi, Regeneron, Vifor Pharma, and AstraZeneca, and fees for serving on a data and safety monitoring board from Pfizer. NJ reports receiving honorarium for consulting from GlaxoSmithKline pharmaceuticals and Pulmocide. MK reports receiving grant support from Chiesi and Sanofi. JAK reports personal fees for independent data monitoring committee participation from Sanofi and research funding from the American Lung Association—Airway Clinical Research Centers Network. SCL reports grant funding from the American Lung Association—Airway Clinical Research Centers Network. RFL reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, and lecture fees from Thermo Fisher Scientific. JJL reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. NL reports receiving grant support, advisory board fees, and donated drugs from GlaxoSmithKline, grant support, consulting fees, and advisory board fees from AstraZeneca, consulting fees, advisory board fees, and donated drugs from Teva Pharmaceuticals, grant support from Genentech, grant support and advisory board fees from Sanofi–Regeneron, and donated drugs from Merck and Boehringer Ingelheim. WCM reports receiving grant support and donated drugs from Boehringer Ingelheim, donated drugs from Merck and Teva Pharmaceuticals, grant support and advisory board fees from AstraZeneca, GlaxoSmithKline, and Sanofi–Regeneron, and grant support from Novartis, Cumberland Pharmaceuticals, and Gossamer Bio. SPP reports receiving advisory board fees from AstraZeneca, GlaxoSmithKline, Mylan, Teva Pharmaceuticals, Sanofi–Regeneron, and Theravance, fees for serving as clinical trial adjudicator from Quintiles, fees for serving on a data and safety monitoring board from Genentech, fees for serving as chair of a data and safety monitoring board from Novartis, and honoraria from PRIME. JAP reports receiving donated drugs from Boehringer Ingelheim, Merck, Teva Pharmaceuticals, and GlaxoSmithKline. LJS reports receiving donated drugs from Boehringer Ingelheim and Teva Pharmaceuticals, and fees for serving on a data and safety monitoring board and donated drugs from Merck. JS reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, advisory board fees from PulmOne Advanced Medical Devices, advisory board fees, honoraria, and travel support from Regeneron–Sanofi–Genzyme, holding patents #6 090 618, #6 114 311, #6 284 743, #6 291 211, #6 297 221, #6 331 527, and #7 169 764 on a smooth-muscle gene promoter (SM22 alpha), holding pending patent PCT/US2014/032186 on a method for determining respiratory physiological parameters, holding pending patent 62/872,980 on remodilins for airway remodelling and organ fibrosis, and holding pending patent 62/828,122 on remodilins to prevent or treat cancer metastasis, glaucoma, and hypoxia. CAS reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. SW reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, grant support and consulting fees from AstraZeneca and Sanofi, and consulting fees from Pieris Pharmaceuticals. DAM reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. EI reports receiving grant support and consulting fees from AstraZeneca, Novartis, and Genentech, consulting fees from Regeneron Pharmaceuticals, Bird Rock Bio, Nuvelution Pharmaceuticals, Vitaeris, Sanofi Genzyme, Entrinsic Health Solutions, Pneuma Respiratory, 4D Pharma, Sienna Biopharmaceuticals, and Equillium, grant support, consulting fees, and donated drugs from Merck, Teva Pharmaceutical Industries, and GlaxoSmithKline, serving as a consultant for Vorso, receiving grant support and donated drugs from Vifor Pharma, Boehringer Ingelheim, and Teva Pharmaceuticals, grant support from Sanofi and AstraZeneca, and donated drugs from Circassia. MEW reports receiving grant support and consulting fees from AstraZeneca, Novartis, Sanofi, and GlaxoSmithKline, consulting fees from Regeneron Pharmaceuticals, Mylan, Genentech, Restorbio, Equillium, Boston Scientific, Genzyme, Gala Therapeutics, and Pulmatrix, fees for serving on a data and safety monitoring board from Sentien Biotechnologies, grant support, consulting fees, advisory board fees, and donated drugs from Teva Pharmaceuticals, consulting fees and donated drugs from Boehringer Ingelheim and Merck. MD, GAH, EJA CC, CE, AMF, DH, AM, ETN, SPS, MAS, SRW, EGB, and KB declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma., (© 2021. The Author(s).)

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 (p corrected =0.013), and especially compared with cases with moderate (p corrected =0.029) and severe (p corrected =3.9×10 -4 ), but not mild (p corrected =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 (p corrected =0.017) and severe (p corrected =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., Competing Interests: Conflict of interest: K.M. Magnaye has nothing to disclose. Conflict of interest: K.A. Naughton has nothing to disclose. Conflict of interest: J. Huffman has nothing to disclose. Conflict of interest: D.K. Hogarth reports personal fees and other (consultancy) from Auris, Eolo, Noah Medical, LX-Medical, Preora, Broncus and Prothea-X, personal fees for consultancy from Ambu, Johnson and Johnson, Oncocyte, Veracyte, Heritage Biologics, IDbyDNA, Level-Ex, Medtronic, Neurotronic, Olympus, PulmonX, AstraZeneca, Biodesix, Genetech, Grifols, Takeda, CSL and GSK, personal fees, nonfinancial support and other (consultancy) from Body Vision, other (consultancy) from Eon, VIDA and Viomics, other (stock holder) from Gravitas and Monogram Orthopedics, other (owner) from Med-Opsys, grants and personal fees for consultancy from Boston Scientific and Gala, personal fees for data monitoring committee work from InhibRX, outside the submitted work. Conflict of interest: E.T. Naureckas has nothing to disclose. Conflict of interest: S.R. White has nothing to disclose. Conflict of interest: C. Ober has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Patient and family participation in guideline development is neither standardized nor uniformly accepted in the guideline development community, despite the 2011 Institute of Medicine's Guidelines We Can Trust and the Guideline International Network's GIN-Public Toolkit recommendations. The Cystic Fibrosis Foundation has included patients and/or family members directly in guideline development since 2004. Over time, various strategies for increasing patient and family member participation have been implemented. Surveys of recent patient/family and clinical guidelines committee members have shown that inclusion of individuals with cystic fibrosis and their family members on guidelines committees has provided insight otherwise invisible to clinicians., (©Sarah E Hempstead, Kelsey Fredkin, Cade Hovater, Edward T Naureckas. Originally published in Journal of Participatory Medicine (http://jopm.jmir.org), 13.07.2020.)

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&#95;G, odds ratio [OR] 1·36 [95% CI 1·12-1·65], p=0·0014; and for rs8076131&#95;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 [β] 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 (β 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, eQTLβ 1·24 [1·15-1·32], p<0·0001; and for ORMDL3 (β 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 (β 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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The relationship between asthma, atopy, and underlying type 2 (T2) airway inflammation is complex. Although the bacterial airway microbiota is known to differ in asthmatic patients, the fungal and bacterial markers that discriminate T2-high (eosinophilic) and T2-low (neutrophilic/mixed-inflammation) asthma and atopy are still incompletely identified., Objectives: The aim of this study was to demonstrate the fungal microbiota structure of airways in asthmatic patients associated with T2 inflammation, atopy, and key clinical parameters., Methods: We collected endobronchial brush (EB) and bronchoalveolar lavage (BAL) samples from 39 asthmatic patients and 19 healthy subjects followed by 16S gene and internal transcribed spacer-based microbiota sequencing. The microbial sequences were classified into exact sequence variants. The T2 phenotype was defined by using a blood eosinophil count with a threshold of 300 cells/μL., Results: Fungal diversity was significantly lower in EB samples from patients with T2-high compared with T2-low inflammation; key fungal genera enriched in patients with T2-high inflammation included Trichoderma species, whereas Penicillium species was enriched in patients with atopy. In BAL fluid samples the dominant genera were Cladosporium, Fusarium, Aspergillus, and Alternaria. Using generalized linear models, we identified significant associations between specific fungal exact sequence variants and FEV 1 , fraction of exhaled nitric oxide values, BAL fluid cell counts, and corticosteroid use. Investigation of interkingdom (bacterial-fungal) co-occurrence patterns revealed different topologies between asthmatic patients and healthy control subjects. Random forest models with fungal classifiers predicted asthma status with 75% accuracy for BAL fluid samples and 80% accuracy for EB samples., Conclusions: We demonstrate clear differences in bacterial and fungal microbiota in asthma-associated phenotypes. Our study provides additional support for considering microbial signatures in delineating asthma phenotypes., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: The study sought to implement and assess the CommunityRx e-prescribing system to recruit research participants from a predominantly non-Hispanic Black community on Chicago's South Side., Materials and Methods: CommunityRx integrates with electronic medical record systems to generate a personalized list of health-promoting community resources (HealtheRx). Between December 2015 and December 2016, HealtheRxs distributed at outpatient visits to adults with asthma or chronic obstructive pulmonary disease also incentivized participation in a pulmonary research registry. Usual practices for registry recruitment continued in parallel., Results: Focus groups established acceptability and appropriateness among the target population. Pulmonary research registry recruitment information was included on 13 437 HealtheRxs. Forty-one (90% non-Hispanic Black) patients responded with willingness to participate and 9 (8 non-Hispanic Black) returned a signed consent required to enroll. Usual recruitment practices enrolled 4 registrants (1 non-Hispanic Black)., Discussion: Automating research recruitment using a community e-prescribing system is feasible., Conclusions: Implementation of an electronic medical record-integrated, community resource referral tool promotes enrollment of eligible underrepresented research participants; however, enrollment was low., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Asthmatic children who develop obesity through adolescence have poorer disease outcomes compared with those who do not. This study aimed to characterize the biology of childhood asthma complicated by adult obesity., Methods: Gene expression networks are powerful statistical tools for characterizing human disease that leverage the putative coregulatory relationships of genes to infer relevant biological pathways. Weighted gene coexpression network analysis of gene expression data was performed in whole blood from 514 adult asthmatic subjects. Then, module preservation and association replication analyses were performed in 418 subjects from two independent asthma cohorts (one pediatric and one adult)., Results: A multivariate model was identified in which three gene coexpression network modules were associated with incident obesity in the discovery cohort (each P < 0.05). Two module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-κB signaling, and Hedgehog signaling. The network structures of each of the obesity modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in subjects with obesity in both replication cohorts (each P < 0.05)., Conclusions: The gene coexpression network profiles thus implicate multiple interrelated pathways in the biology of an important endotype of asthma with obesity., (© 2018 The Obesity Society.)

Objective : Comprehensive, rapid, and accurate identification of patients with asthma for clinical care and engagement in research efforts is needed. The original development and validation of a computable phenotype for asthma case identification occurred at a single institution in Chicago and demonstrated excellent test characteristics. However, its application in a diverse payer mix, across different health systems and multiple electronic health record vendors, and in both children and adults was not examined. The objective of this study is to externally validate the computable phenotype across diverse Chicago institutions to accurately identify pediatric and adult patients with asthma. Methods : A cohort of 900 asthma and control patients was identified from the electronic health record between January 1, 2012 and November 30, 2014. Two physicians at each site independently reviewed the patient chart to annotate cases. Results : The inter-observer reliability between the physician reviewers had a κ-coefficient of 0.95 (95% CI 0.93-0.97). The accuracy, sensitivity, specificity, negative predictive value, and positive predictive value of the computable phenotype were all above 94% in the full cohort. Conclusions : The excellent positive and negative predictive values in this multi-center external validation study establish a useful tool to identify asthma cases in in the electronic health record for research and care. This computable phenotype could be used in large-scale comparative-effectiveness trials.

Rationale: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are a new class of medications targeting the underlying defect in CF. Ivacaftor (IVA) and IVA combined with lumacaftor (LUM; IVA/LUM) have been approved by the U.S. Food and Drug Administration (FDA) for use in patients with CF. However, the FDA label for these medications encompasses patient groups that were not studied as part of the drug approval process. CF clinicians, patients, and their families have recognized a need for recommendations to guide the use of these medications., Objective: Develop evidence-based guidelines for CFTR modulator therapy in patients with CF., Methods: A multidisciplinary committee of CF caregivers and patient representatives was assembled. A methodologist, an epidemiologist, a medical librarian, and a biostatistician were recruited to assist with the literature search, evidence grading, and generation of recommendations. The committee developed clinical questions using the Patient-Intervention-Comparison-Outcome format. A systematic review was conducted to find relevant publications. The evidence was then evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach, and recommendations were made based on this analysis., Results: For adults and children aged 6 years and older with CF due to gating mutations other than G551D or R117H, the guideline panel made a conditional recommendation for treatment with IVA. For those with the R117H mutation, the guideline panel made a conditional recommendation for treatment with IVA for 1) adults aged 18 years or older, and 2) children aged 6-17 years with a forced expiratory volume in 1 second (FEV 1 ) less than 90% predicted. For those with the R117H mutation, the guideline panel made a conditional recommendation against treatment with IVA for 1) children aged 12-17 years with an FEV 1 greater than 90% predicted, and 2) children less than 6 years of age. Among those with two copies of F508del, the guideline panel made a strong recommendation for treatment with IVA/LUM for adults and children aged 12 years and older with an FEV 1 less than 90% predicted; and made a conditional recommendation for treatment with IVA/LUM for 1) adults and children aged 12 years or older with an FEV 1 greater than 90% predicted, and 2) children aged 6-11 years., Conclusions: Using the GRADE approach, we have made recommendations for the use of CFTR modulators in patients with CF. These recommendations will be of help to CF clinicians, patients, and their families in guiding decisions regarding use of these medications.

Objectives: There is evidence to suggest that asthma pathogenesis is affected by both genetic and epigenetic variation independently, and there is some evidence to suggest that genetic-epigenetic interactions affect risk of asthma. However, little research has been done to identify such interactions on a genome-wide scale. The aim of this studies was to identify genes with genetic-epigenetic interactions associated with asthma., Methods: Using asthma case-control data, we applied a novel nonparametric gene-centric approach to test for interactions between multiple SNPs and CpG sites simultaneously in the vicinities of 18,178 genes across the genome., Results: Twelve genes, PF4, ATF3, TPRA1, HOPX, SCARNA18, STC1, OR10K1, UPK1B, LOC101928523, LHX6, CHMP4B, and LANCL1, exhibited statistically significant SNP-CpG interactions (false discovery rate = 0.05). Of these, three have previously been implicated in asthma risk (PF4, ATF3, and TPRA1). Follow-up analysis revealed statistically significant pairwise SNP-CpG interactions for several of these genes, including SCARNA18, LHX6, and LOC101928523 (p = 1.33E-04, 8.21E-04, 1.11E-03, respectively)., Conclusions: Joint effects of genetic and epigenetic variation may play an important role in asthma pathogenesis. Statistical methods that simultaneously account for multiple variations across chromosomal regions may be needed to detect these types of effects on a genome-wide scale., (© 2019 S. Karger AG, Basel.)

Rationale: Sleep disturbance frequently affects patients with chronic obstructive pulmonary disease (COPD), and is associated with reduced quality of life and poorer outcomes. Data indicate that smokers with preserved pulmonary function have clinical symptoms similar to those meeting spirometric criteria for COPD, but little is known about the driving factors for sleep disturbance in this population of emerging interest., Objectives: To compare the magnitude and correlates of sleep disturbance between smokers with preserved pulmonary function and those with airflow obstruction., Methods: Using cross-sectional data from the COPD Outcomes-Based Network for Clinical Effectiveness and Research Translation multicenter registry, we identified participants clinically identified as having COPD with a smoking history of at least 20 pack-years and either preserved pulmonary function or airflow obstruction. We quantified sleep disturbance by T-score measured in the sleep disturbance domain of the Patient-Reported Outcomes Information System questionnaire, and defined a minimum important difference as a T-score difference of two points. We performed univariate and multivariable linear regression to evaluate correlates within each group., Results: We identified 100 smokers with preserved pulmonary function and 476 with airflow obstruction. The sleep disturbance T-score was 4.1 points greater among individuals with preserved pulmonary function (95% confidence interval [CI], 2.0-6.3). In adjusted analyses, depression symptom T-score was associated with sleep disturbance in both groups (airflow obstruction: β, 0.61 points; 95% CI, 0.27-0.94; preserved pulmonary function: β, 0.25 points; 95% CI, 0.12-0.38). Of note, lower percent predicted FEV 1 was associated with greater sleep disturbance among those with preserved pulmonary function (β, -0.19 points; 95% CI, -0.31 to -0.07), whereas higher FEV 1 was associated with greater sleep disturbance among individuals with airflow obstruction (β, 0.06 points; 95% CI, 0.01-0.10)., Conclusions: Among smokers with clinically identified COPD, the severity of sleep disturbance is greater among those with preserved pulmonary function compared with those with airflow obstruction. Nonrespiratory symptoms, such as depression, were associated with sleep disturbance in both groups, whereas the relationship of sleep disturbance with FEV 1 differed.

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.

Background: Inhaled therapies are the cornerstone of pharmacologic management for COPD. Each device requires a unique series of steps to be most effective, making appropriate instruction in inhaler technique a key part of the management of COPD., Objectives: Examine characteristics of patients and devices associated with poor technique among patients with COPD., Methods: Cross-sectional study of subjects with COPD using at least one of: metered dose inhaler, Advair Diskus, Spiriva Handihaler, identified from the COPD Outcomes-based Network for Clinical Effectiveness and Research Translation (CONCERT) registry. Technique was assessed face-to-face using manufacturer-provided dummy inhalers, with standardized checklists for each device. We used logistic regression to model associations with poor inhaler technique, defined as an error in ≥20% of the steps, as a function of patient characteristics, with educational attainment the primary predictor., Results: 688 individuals meet eligibility criteria, 65.5% had poor technique for at least one device. In adjusted analyses, Black race was associated with poor technique (OR 3.25, 95%CI 1.86-5.67) while greater than high school education was associated with decreased odds of poor technique (OR 0.35, 95%CI 0.17-0.70 for trade school/some college, OR 0.25, 95%CI 0.11-0.61 for college or more, p ≤ 0.001 for test of linear trend). The percentage of errors varied between devices, with subjects making proportionally the most errors for MDIs., Conclusions: Poor inhaler technique is common among individuals with COPD, varies between devices, and is associated with race and educational attainment. Tailored educational interventions to teach inhaler technique should be part of the process of initiating and monitoring inhaled therapies., (Published by Elsevier Ltd.)

Rationale: Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches., Objectives: To identify molecular pathways and interrelated genes whose differential expression was associated with asthma control., Methods: We performed gene set enrichment analyses of asthma control in 1,170 adults with asthma, each with gene expression data derived from either whole blood (WB) or unstimulated CD4 + T lymphocytes (CD4), and a self-reported asthma control score representing either the preceding 6 months (chronic) or 7 days (acute). Our study comprised a discovery WB cohort (n = 245, chronic) and three independent, nonoverlapping replication cohorts: a second WB set (n = 448, acute) and two CD4 sets (n = 300, chronic; n = 77, acute)., Measurements and Main Results: In the WB discovery cohort, we found significant overrepresentation of genes associated with asthma control in 1,106 gene sets from the Molecular Signatures Database (false discovery rate, <5%). Of these, 583 (53%) replicated in at least one replication cohort (false discovery rate, <25%). Suboptimal control was associated with signatures of eosinophilic and granulocytic inflammatory signals, whereas optimal control signatures were enriched for immature lymphocytic patterns. These signatures included two related biologic processes related to activation by TREM-1 (triggering receptor expressed on myeloid cells 1) and lipopolysaccharide., Conclusions: Together, these results demonstrate the existence of specific, reproducible transcriptomic components in blood that vary with degree of asthma control and implicate a novel biologic target (TREM-1).

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., Competing Interests: J. Solway has been a scientific advisor for and has a financial interest in PulmOne Advanced Medical Devices Ltd., Israel, and received reimbursement for expenses. He served on the Respiratory Therapy Clinical Advisory Board for Hollister Inc., and for this received honoraria and was reimbursed for travel and meal expenses incurred during meetings. He has received a research grant from AstraZeneca Inc., from 2006 to 2014, that was administered through the University of Chicago. He has multiple patents concerning a smooth muscle gene promoter and one pending concerning a method to determine respiratory physiological parameters (6090618; 6114311; 6284743; 6291211; 6297221; 6331527; 7169764). He has consulted for Novartis Institute for Biomedical Research, for which he received an honorarium and travel reimbursement. He was a member of the scientific advisory board for Cytokinetics Inc., for which he received honoraria and travel reimbursement.

Rationale: Smoking cessation is the most important intervention for patients with chronic obstructive pulmonary disease (COPD). What leads smokers with COPD to quit smoking remains unknown., Objectives: We sought to examine the association between respiratory symptoms and other markers of COPD severity with intention to quit smoking among a cohort of patients with probable COPD., Methods: We conducted a cross-sectional study of subjects with COPD or fixed airflow obstruction clinically diagnosed on the basis of pulmonary function testing. The subjects were identified in the COPD Outcomes-based Network for Clinical Effectiveness and Research Translation multicenter registry. The primary outcome was the intention to quit smoking within the next 30 days (yes or no), which was examined using model building with multivariable logistic regression, clustered by study site., Measurements and Main Results: We identified 338 current smokers with COPD via the registry. Of these subjects, 57.4% (n = 194) had confirmed airflow obstruction based on pulmonary function testing. Nearly one-third (29.2%; n = 99) intended to quit smoking in the next 30 days. In adjusted analyses, compared with subjects without airflow obstruction based on pulmonary function testing, subjects with Global Initiative for Chronic Obstructive Lung Disease stage I/II COPD were more likely to be motivated to quit (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.37-2.49), with no association found for subjects with Global Initiative for Chronic Obstructive Lung Disease stage III/IV disease. Among the entire cohort, frequent phlegm (OR, 2.10; 95% CI, 1.22-3.64), cough (OR, 1.74; 95% CI, 1.01-2.99), wheeze (OR, 1.73; 95% CI, 1.09-3.18), and higher modified Medical Research Council dyspnea score (OR, 1.26 per point; 95% CI, 1.13-1.41) were associated with increased odds of intending to quit smoking. Low self-reported health was associated with decreased odds of intending to quit (OR, 0.75; 95% CI, 0.62-0.92)., Conclusions: Frequent cough, phlegm, wheeze, and shortness of breath were associated with intention to quit smoking in the next 30 days, with a less clear relationship for severity of illness graded by pulmonary function testing and self-rated health. These findings can be used to inform the content of tobacco cessation interventions to provide a more tailored approach for patients with respiratory diseases such as COPD.

Background: The lung has a diverse microbiome that is modest in biomass. This microbiome differs in asthmatic patients compared with control subjects, but the effects of clinical characteristics on the microbial community composition and structure are not clear., Objectives: We examined whether the composition and structure of the lower airway microbiome correlated with clinical characteristics of chronic persistent asthma, including airflow obstruction, use of corticosteroid medications, and presence of airway eosinophilia., Methods: DNA was extracted from endobronchial brushings and bronchoalveolar lavage fluid collected from 39 asthmatic patients and 19 control subjects, along with negative control samples. 16S rRNA V4 amplicon sequencing was used to compare the relative abundance of bacterial genera with clinical characteristics., Results: Differential feature selection analysis revealed significant differences in microbial diversity between brush and lavage samples from asthmatic patients and control subjects. Lactobacillus, Pseudomonas, and Rickettsia species were significantly enriched in samples from asthmatic patients, whereas Prevotella, Streptococcus, and Veillonella species were enriched in brush samples from control subjects. Generalized linear models on brush samples demonstrated oral corticosteroid use as an important factor affecting the relative abundance of the taxa that were significantly enriched in asthmatic patients. In addition, bacterial α-diversity in brush samples from asthmatic patients was correlated with FEV1 and the proportion of lavage eosinophils., Conclusion: The diversity and composition of the bronchial airway microbiome of asthmatic patients is distinct from that of nonasthmatic control subjects and influenced by worsening airflow obstruction and corticosteroid use., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Dyspnea is a common symptom in patients hospitalized with acute cardiopulmonary diseases. Routine assessment of dyspnea severity is recommended by clinical guidelines based on the evidence that patients are not treated consistently for dyspnea relief., Objective: To evaluate attitudes and beliefs of hospitalists regarding the assessment and management of dyspnea., Design: Cross-sectional survey., Settings: Nine hospitals in the United States., Measurements: Survey questions assessed the following domains regarding dyspnea: importance in clinical care, potential benefits and challenges of implementing a standardized assessment, current approaches to assessment, and how awareness of severity affects management. A 5-point Likert scale was used to assess the respondent's level of agreement; strongly agree and agree were combined into a single category., Results: Of the 255 hospitalists invited to participate, 69.8% completed the survey; 77.0% agreed that dyspnea relief is an important goal when treating patients with cardiopulmonary conditions. Approximately 90% of respondents stated that awareness of dyspnea severity influences their decision to intensify treatment, to pursue additional diagnostic testing, and the timing of discharge. Of the respondents, 61.0% agreed that standardized assessment of dyspnea should be part of the vital signs, and 64.6% agreed that awareness of dyspnea severity influences their decision to prescribe opioids. Hospitalists who appreciated the importance of dyspnea in clinical practice were more likely to support the implementation of a standardized scale., Conclusions: Most hospitalists believe that routine assessment of dyspnea severity would enhance their clinical decision making and patient care. Measurement and documentation of dyspnea severity may represent an opportunity to improve dyspnea management., (© 2015 Society of Hospital Medicine.)

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-β1 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.

Description: The Cystic Fibrosis (CF) Foundation developed clinical care guidelines for the prevention of Pseudomonas aeruginosa infection, the treatment of initial P. aeruginosa infection, and the use of bronchoscopy to obtain routine airway cultures in individuals with CF., Methods: A multidisciplinary committee developed questions about the prevention and treatment of initial P. aeruginosa infection and the use of bronchoscopy to obtain routine airway cultures. The outcome measure of interest was cultures without P. aeruginosa growth. Systematic reviews of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were conducted in May 2012 and August 2013. Searches combined controlled vocabulary terms and text words for CF and terms relevant to each question. The entire committee reviewed the evidence, and final recommendation statements were graded using the U.S. Preventive Services Task Force system. Recommendation 1: The CF Foundation strongly recommends inhaled antibiotic therapy for the treatment of initial or new growth of P. aeruginosa from an airway culture (certainty of net benefit, high; estimate of net benefit, substantial; grade of recommendation, A). The favored antibiotic regimen is inhaled tobramycin (300 mg twice daily) for 28 days. Recommendation 2: The CF Foundation recommends against the use of prophylactic antipseudomonal antibiotics to prevent the acquisition P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, zero; grade of recommendation, D). Recommendation 3: The CF Foundation recommends routine oropharyngeal cultures rather than bronchoalveolar lavage cultures obtained by bronchoscopy in individuals with CF who cannot expectorate sputum to determine if they are infected with P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, moderate; grade of recommendation, B).

Rationale: Clinical trials in chronic obstructive pulmonary disease (COPD) usually require evidence of airflow obstruction and clinical risk factors. International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes or patient-reported physician diagnoses are often used for epidemiologic studies and performance improvement programs., Objectives: To evaluate agreement between these case definitions for COPD and to assess the comparability of study populations identified as having COPD not using the clinical trial reference standard., Methods: We recruited patients from the COPD Outcomes-based Network for Clinical Effectiveness and Research Translation multicenter clinical registry in a cross-sectional study. Demographics, clinical, and post-bronchodilator spirometry data were collected at an in-person study visit. The kappa statistic (κ) was used to evaluate agreement. A multivariable logistic regression model was used to identify patient characteristics associated with meeting the trial reference standard., Measurements and Main Results: A total of 998 (82.8%) of 1,206 study participants met at least one case definition for COPD (of the 998: 91% using ICD-9 codes, 73% using patient-reported physician diagnosis, 56% using trial reference standard); agreement between case definitions was poor (κ = 0.20-0.26). Lack of airflow obstruction was the principal (89%) reason patients identified as having COPD did not meet the trial reference standard. Patients who were black (vs. white), obese (vs. normal weight), or had depression (vs. not) were less likely to meet the trial reference standard (odds ratio [95% CI], 0.37 [0.26-0.53], 0.51 [0.34-0.75], 0.53 [0.40-0.71], respectively)., Conclusions: Findings highlight concerns about the applicability of findings in clinical trials to patients meeting other case definitions for COPD.

Background: The Patient Reported Outcomes Measurement Information System 43-item short form (PROMIS-43) and the five-level EQ-5D (EQ-5D-5L) are recently developed measures of health-related quality of life (HRQL) that have potentially broad application in evaluating treatments and capturing burden of respiratory-related diseases. The aims of this study were: (1) to examine their psychometric properties in patients with chronic obstructive pulmonary disease (COPD), and (2) to identify dimensions of HRQL that differ and do not differ by lung function., Methods: We conducted a multi-center, cross-sectional study ("COPD Outcomes-based Network for Clinical Effectiveness & Research Translation" [CONCERT]). We analyzed patients who met spirometric criteria for COPD, and completed EQ-5D-5L and PROMIS questionnaires. Disease severity was graded based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. Pulmonary function test, PROMIS-43, EQ-5D (index score and EQ-Visual Analog Scale [EQ-VAS]), six minute walk test (6MWT), and three dyspnea scales (mMRC, Borg, FACIT-Dyspnea) were administered. Validity and reliability of EQ-5D-5L and PROMIS-43 were examined, and differences in HRQL by GOLD grade were assessed., Results: Data from 670 patients with COPD were analyzed (mean age 68.5 years; 58% male). More severe COPD was associated with more problems with mobility, self-care and usual activities (all p-values <0.01) according to EQ-5D-5L. Related domains on EQ-5D-5L, PROMIS and clinical measures were moderately (r = 0.30-0.49) to strongly (r ≥ 0.50) correlated. A statistically significant trend of decreasing HRQL with more severe lung functions was observed for EQ-5D-5L index scores, EQ-VAS scores, and PROMIS physical function and social roles., Conclusions: Results supported the validity of EQ-5D-5L and PROMIS-43 in COPD patients, and indicate that physical function and social activities decrease with level of lung function by GOLD grade, but not pain, mental health, sleep or fatigue as reported by patients.

Background: Infliximab, a chimeric, monoclonal, anti-TNF antibody has been shown to be safe and efficacious for refractory sarcoidosis, we investigated whether adalimumab, a fully human, anti-TNF monoclonal antibody, is similarly safe and efficacious in refractory pulmonary sarcoidosis., Methods: An open-label, single-center study was conducted in 11 patients with refractory pulmonary sarcoidosis. Patients received adalimumab 40 mg weekly for 45 weeks, with a final follow-up at Week 52. The primary endpoint was the percent change in predicted forced vital capacity (FVC) at 24 weeks. Secondary efficacy parameters included the 6-minute walk test (6MWT), Borg dyspnea score, and Physician's (PGA) and Patient's (PaGA) Global Assessments. A successful outcome of the study was defined as reduction in immunosuppressive therapy (prednisone to 10 mg or less), improvement in FVC of 5% or greater, improvement in 6-minute walk test distance (6MWD) of 50 meter or greater at the end of weeks 24 and 52., Results: Eleven patients received adalimumab and had 24-week follow-ups. Only ten patients had a Week 52 evaluation. FVC stabilized in seven patients, and four patients showed improvement in FVC. Five patients had improved 6MWD, and nine had lower Borg dyspnea scores. PGA and PaGA improved at weeks 24 and 52 for all patients (P&lt;0.008 for all comparisons). Among 11 patients who underwent adalimumab treatment, 9 (82%) and 8(80%) had a successful outcome at the end of 24 and 52 weeks respectively. No severe adverse incidents were reported., Conclusions: In this small, open-label study, adalimumab improved refractory pulmonary sarcoidosis and was well tolerated (ClinicalTrials.gov identifier NCT00311246).

There is renewed interest in non-cystic fibrosis bronchiectasis, which is a cause of significant morbidity in adults and can be diagnosed by high-resolution chest computed tomography scan. No longer mainly a complication after pulmonary infection with Mycobacterium tuberculosis, diverse disease processes and mechanisms have been demonstrated to result in the chronic cough, purulent sputum production, and airway dilation that characterize this disease. Improved understanding of the role of mucus stasis in causing bacterial colonization has led to increased emphasis on the use of therapies that enhance airway clearance. Inhalational antibiotics reduce the bacterial burden associated with a worse outcome. Low-dose, chronic macrolide therapy has been shown to decrease exacerbation frequency and airway inflammation. For the first time, a number of therapies for non-cystic fibrosis bronchiectasis are undergoing testing in clinical research trials designed specifically for this population. This concise clinical review focuses on the major etiologies, diagnostic testing, microbiology, and management of patients with adult non-cystic fibrosis bronchiectasis. Systematic evaluation identifies a specific cause in the majority of patients and may affect subsequent treatment. We outline current therapies and review the data that support their use.

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.

Background: We previously reported an interaction between maternal asthma and the child's HLA-G genotype on the child's subsequent risk for asthma. The implicated single nucleotide polymorphism at +3142 disrupted a target site for the microRNA (miR)-152 family. We hypothesized that the interaction effect might be mediated by these miRs., Objective: The objective of this study was to test this hypothesis in adults with asthma who are a subset of the same subjects who participated in our earlier family-based studies., Methods: We measured soluble HLA-G (sHLA-G) concentrations in bronchoalveolar lavage fluid (n = 36) and plasma (n = 57) from adult asthmatic subjects with and without a mother with asthma, and HLA-G and miR-152 family (miR-148a, miR-148b, and miR-152) transcript levels in airway epithelial cells from the same subjects., Results: miR-148b levels were significantly increased in airway epithelial cells from asthmatic subjects with an asthmatic mother compared with those seen in asthmatic subjects without an asthmatic mother, and +3142 genotypes were associated with sHLA-G concentrations in bronchoalveolar lavage fluid among asthmatic subjects with an asthmatic mother but not among those with a nonasthmatic mother. Neither effect was observed in the plasma (sHLA-G) or white blood cells (miRNA)., Conclusion: These combined results are consistent with +3142 allele-specific targeting of HLA-G by the miR-152 family and support our hypothesis that miRNA regulation of sHLA-G in the airway is influenced by both the asthma status of the subject's mother and the subject's genotype. Moreover, we demonstrate that the effects of maternal asthma on the gene regulatory landscape in the airways of the mother's children persist into adulthood., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Rationale: Cystic fibrosis (CF) is an autosomal recessive disease characterized by abnormal airways secretions, chronic endobronchial infection, and progressive airway obstruction. The use of medications to slow the progression of lung disease has led to significant improvement in survival. An evidence review of chronic medications for CF lung disease was performed in 2007 to provide guidance to clinicians in evaluating and selecting appropriate treatment for individuals with this disease. We have undertaken a new review of the literature to update the recommendations, including consideration of new medications and additional evidence on previously reviewed therapies. A multidisciplinary committee of experts in CF pulmonary care was established to review the evidence for use of chronic medications for CF lung disease and make treatment recommendations. Published evidence for chronic lung therapies was systematically reviewed and resulting treatment recommendations were graded based on the United States Preventive Services Task Force scheme. These guidelines provide up-to-date evidence of safety and efficacy of chronic treatments of CF lung disease, including the use of novel therapies that have not previously been included in CF pulmonary guidelines.

Objective: Bronchial thermoplasty (BT) can provide relief for patients with severe, uncontrolled asthma despite maximal medical therapy. However, it is unclear whether BT is safe in patients with very severe airflow obstruction., Methods: We performed BT in eight patients with severe asthma as defined by Expert Panel Report 3 (EPR-3) guidelines who were poorly controlled despite step 5 therapy. Data were available on each subject for 1 year prior to and 15-72 weeks following BT., Results: The mean (±SEM) pre-bronchodilator forced expiratory volume in one second (FEV(1)) prior to BT was 51.8 ± 8.6% of predicted, and the mean (±SEM) number of hospitalizations for asthma in the year prior to BT was 2.9 ± 1.2. No subject had an unexpected severe adverse event due to BT. Among the eight patients with follow-up of at least 15 weeks, there was no significant decline in FEV(1) (p = .4)., Conclusion: We suggest that BT may be safe for asthma patients with severe airflow obstruction and higher hospitalization rates than previously reported.

Background: Objective measurement of airflow obstruction by spirometry is an essential part of the diagnosis of asthma or COPD. During exacerbations, the feasibility and utility of spirometry to confirm the diagnosis of asthma or chronic obstructive pulmonary disease (COPD) are unclear. Addressing these gaps in knowledge may help define the need for confirmatory testing in clinical care and quality improvement efforts. This study was designed to determine the feasibility of spirometry and to determine its utility to confirm the diagnosis in patients hospitalized with a physician diagnosis of asthma or COPD exacerbation., Methods: Multi-center study of four academic healthcare institutions. Spirometry was performed in 113 adults admitted to general medicine wards with a physician diagnosis of asthma or COPD exacerbation. Two board-certified pulmonologists evaluated the spirometry tracings to determine the proportion of patients able to produce adequate quality spirometry data. Findings were interpreted to evaluate the utility of spirometry to confirm the presence of obstructive lung disease, according to the 2005 European Respiratory Society/American Thoracic Society recommendations., Results: There was an almost perfect agreement for acceptability (κ = 0.92) and reproducibility (κ =0.93) of spirometry tracings. Three-quarters (73%) of the tests were interpreted by both pulmonologists as being of adequate quality. Of these adequate quality tests, 22% did not present objective evidence of obstructive lung disease. Obese patients (BMI ≥30 kg/m2) were more likely to produce spirometry tracings with no evidence of obstructive lung disease, compared to non-obese patients (33% vs. 8%, p = 0.007)., Conclusions: Adequate quality spirometry can be obtained in most hospitalized adults with a physician diagnosis of asthma or COPD exacerbation. Confirmatory spirometry could be a useful tool to help reduce overdiagnosis of obstructive lung disease, especially among obese patients.

Background: Acute exacerbations of COPD (AE-COPD) are a leading cause of hospitalizations in the United States. To estimate the burden of disease (eg, prevalence and cost), identify opportunities to improve care quality (eg, performance measures), and conduct observational comparative effectiveness research studies, various algorithms based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes have been used to identify patients with COPD. However, the validity of these algorithms remains unclear., Methods: We compared the test characteristics (sensitivity, specificity, positive predictive value, and negative predictive value) of four different coding algorithms for identifying patients hospitalized for an exacerbation of COPD with chart review (reference standard) using a stratified probability sample of 200 hospitalizations at two urban academic medical centers. Sampling weights were used when calculating prevalence and test characteristics., Results: The prevalence of COPD exacerbations (based on the reference standard) was 7.9% of all hospitalizations. The sensitivity of all ICD-9-CM algorithms was very low and varied by algorithm (12%-25%), but the negative predictive value was similarly high across algorithms (93%-94%). The specificity was > 99% for all algorithms, but the positive predictive value varied by algorithm (81%-97%)., Conclusions: Algorithms based on ICD-9-CM codes will undercount hospitalizations for AE-COPD, and as many as one in five patients identified by these algorithms may be misidentified as having a COPD exacerbation. These findings suggest that relying on ICD-9-CM codes alone to identify patients hospitalized for AE-COPD may be problematic.

Background: High frequency chest wall oscillation (HFCWO) is used for airway mucus clearance. The objective of this study was to evaluate the use of HFCWO early in the treatment of adults hospitalized for acute asthma or chronic obstructive pulmonary disease (COPD)., Methods: Randomized, multi-center, double-masked phase II clinical trial of active or sham treatment initiated within 24 hours of hospital admission for acute asthma or COPD at four academic medical centers. Patients received active or sham treatment for 15 minutes three times a day for four treatments. Medical management was standardized across groups. The primary outcomes were patient adherence to therapy after four treatments (minutes used/60 minutes prescribed) and satisfaction. Secondary outcomes included change in Borg dyspnea score (≥ 1 unit indicates a clinically significant change), spontaneously expectorated sputum volume, and forced expired volume in 1 second., Results: Fifty-two participants were randomized to active (n = 25) or sham (n = 27) treatment. Patient adherence was similarly high in both groups (91% vs. 93%; p = 0.70). Patient satisfaction was also similarly high in both groups. After four treatments, a higher proportion of patients in the active treatment group had a clinically significant improvement in dyspnea (70.8% vs. 42.3%, p = 0.04). There were no significant differences in other secondary outcomes., Conclusions: HFCWO is well tolerated in adults hospitalized for acute asthma or COPD and significantly improves dyspnea. The high levels of patient satisfaction in both treatment groups justify the need for sham controls when evaluating the use of HFCWO on patient-reported outcomes. Additional studies are needed to more fully evaluate the role of HFCWO in improving in-hospital and post-discharge outcomes in this population., Trial Registration: ClinicalTrials.gov: NCT00181285.

Individuals with asthma living in the inner city experience increased asthma morbidity and mortality compared to the US average. The Controlling Asthma in America's Cities Project's Chicago site used a multifaceted approach to improve asthma care. The diverse scope of this project's interventions necessitated the use of novel methods to assess the effect of these interventions on the entire study area. Asthma-related medication-dispensing data were obtained from a large pharmacy chain for prescriptions filled in calendar years 2004-2006 for all individuals aged 5-17 years living in Chicago who filled at least four asthma-related medications within a 12-month period. Inhaled corticosteroid (ICS) use was considered inadequate if an individual had four or more dispensings of a short-acting beta-agonist without at least four dispensings of an ICS agent. Logistic regression was used to compare adequate ICS use in individuals within the intervention area with ICS use in the remainder of the city, after controlling for gender, insurance status, race, and poverty. A significant difference in adequate ICS use was found in years 2 (2005) and 3 (2006) of the project for individuals aged 5-9 in the intervention area (odds ratios for adequate ICS use-year 2, 1.26; CI, 1.04-1.53, p = 0.04; year 3, 1.30; CI, 1.08-1.55, p = 0.008) compared to individuals aged 5-9 in the remainder of the city. There was no similar significant difference in the 10-17 age group. These findings suggest an effect of a large multifaceted asthma intervention in improving medication use in the targeted age group. This methodology might also prove useful in the future for assessing the effect of similar interventions.