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1.
Artigo em Inglês | MEDLINE | ID: mdl-34628005

RESUMO

BACKGROUND: United States population-level data on asthma morbidity and mortality are available primarily through state-level surveys. We hypothesize that significant county-level heterogeneity may be obscured by state-level data, thus impeding focused initiatives to improve asthma outcomes. OBJECTIVE: To assess heterogeneity in the prevalence of uncontrolled, severe, and severe uncontrolled asthma by examining state- and county-level morbidity reflected in large administrative claims datasets and identify relationships between pharmacotherapy-based morbidity and the Centers for Disease Control and Prevention's asthma mortality data. METHODS: Asthma prevalence and morbidity were identified using medical and pharmacy claims from the IQVIA Longitudinal Access and Adjudication Data database (7/2015-6/2018). Heatmaps ranked prevalence of severe uncontrolled asthma by deciles in all 50 states and the District of Columbia, plus 2935 counties. Mortality in states (2016) and 3147 counties (1999-2018) was similarly mapped and ranked and contrasted with claims-based morbidity. RESULTS: Among 4,506,527 individuals with asthma, 640,936 (14.2%) received agespecific therapy for severe asthma. Of those with severe asthma, 144,232 (22.5%) filled ≥2 annual courses of systemic steroids and were designated as having severe uncontrolled asthma. Most states with high mortality had relatively few patients with severe uncontrolled asthma. A significant correlation between mortality and morbidity and trends by urban/rural and metropolitan status were found at the county level. CONCLUSION: Intra-state heterogeneity in the morbidity and mortality of severe uncontrolled asthma at the county level is not evident in state-level analyses. Increased local awareness of systemic corticosteroid use as an indicator of uncontrolled asthma should prompt regional educational and public health efforts to improve outcomes.

2.
Thorax ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580195

RESUMO

INTRODUCTION: Asthma is a complex disease with heterogeneous expression/severity. There is growing interest in defining asthma endotypes consistently associated with different responses to therapy, focusing on type 2 inflammation (Th2) as a key pathological mechanism. Current asthma endotypes are defined primarily by clinical/laboratory criteria. Each endotype is likely characterised by distinct molecular mechanisms that identify optimal therapies. METHODS: We applied unsupervised (without a priori clinical criteria) principal component analysis on sputum airway cells RNA-sequencing transcriptomic data from 19 asthmatics from the Severe Asthma Research Program at baseline and 6-8 weeks follow-up after a 40 mg dose of intramuscular corticosteroids. We investigated principal components PC1, PC3 for association with 55 clinical variables. RESULTS: PC3 was associated with baseline Th2 clinical features including blood (rank-sum p=0.0082) and airway (rank-sum p=0.0024) eosinophilia, FEV1 change (Kendall tau-b R=-0.333 (-0.592 to -0.012)) and follow-up FEV1 albuterol response (Kendall tau-b R=0.392 (0.079 to 0.634)). PC1 with blood basophlia (rank-sum p=0.0191). The top 5% genes contributing to PC1, PC3 were enriched for distinct immune system/inflammation ontologies suggesting distinct subject-specific clusters of transcriptomic response to corticosteroids. PC3 association with FEV1 change was reproduced in silico in a comparable independent 14-subject (baseline, 8 weeks after daily inhaled corticosteroids (ICS)) airway epithelial cells microRNAome dataset. CONCLUSIONS: Transcriptomic PCs from this unsupervised methodology define molecular pharmacogenomic endotypes that may yield novel biology underlying different subject-specific responses to corticosteroid therapy in asthma, and optimal personalised asthma care. Top contributing genes to these PCs may suggest new therapeutic targets.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34536413

RESUMO

BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: By leveraging data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) and the Atopic Dermatitis Research Network (ADRN), we aim to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum (N=21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. For details, please see the Methods section in this article's Online Repository at www.jacionline.org. RESULTS: We identified six loci at genome-wide significance (P<5x10-9), including four loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, also identified in prior GWAS of atopic dermatitis and asthma. In the HLA allele association study, HLA-A*02:01 was associated with decreased tIgE (discovery P = 2x10-4, replication P = 5x10-4, discovery+replication P=4x10-7) and HLA-DQB1*03:02 was strongly associated with decreased tIgE in Hispanic/Latino ancestry populations (Hispanic/Latino discovery+replication P=8x10-8). CONCLUSION: We performed the largest GWAS and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.

5.
Lancet Respir Med ; 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34058148

RESUMO

BACKGROUND: We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease (COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation, progression, and early diagnosis of airways disease in COPD. METHODS: SPIROMICS was a multicentre, observational study in patients aged 40-80 years recruited from six clinical sites and additional subsites in the USA. In this analysis, MUC5AC and MUC5B were quantitated by stable isotope-labelled mass spectrometry in induced sputum samples from healthy never-smokers, ever-smokers at risk for COPD, and ever-smokers with COPD. Participants were extensively characterised using results from questionnaires, such as the COPD assessment test (CAT) and St George's Respiratory Questionnaire; quantitative CT, such as residual volume/total lung capacity ratio (RV/TLC) and parametric response mapping-functional small airway disease (PRM-fSAD); and pulmonary function tests, such as FEV1, forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF25-75%). Absolute concentrations of both MUC5AC and MUC5B were related to cross-sectional (baseline, initial visit) and 3-year follow-up longitudinal data, including lung function, small airways obstruction, prospective acute exacerbations, and smoking status as primary outcomes. This study is registered with ClinicalTrials.gov (NCT01969344). FINDINGS: This analysis included 331 participants (mean age 63 years [SEM 9·40]), of whom 40 were healthy never-smokers, 90 were at-risk ever-smokers, and 201 were ever-smokers with COPD. Increased MUC5AC concentrations were more reliably associated with manifestations of COPD than were MUC5B concentrations, including decreased FEV1 and FEF25-75%, and increased prospective exacerbation frequency, RV/TLC, PRM-fSAD, and COPD assessment scores. MUC5AC concentrations were more reactive to cigarette smoke exposure than were MUC5B concentrations. Longitudinal data from 3-year follow-up visits generated a multivariate-adjusted odds ratio for two or more exacerbations of 1·24 (95% CI 1·04-1·47, p=0·015) for individuals with high baseline MUC5AC concentration. Increased MUC5AC, but not MUC5B, concentration at baseline was a significant predictor of FEV1, FEV1/FVC, FEF25-75%, and CAT score decline during the 3-year follow-up. Moreover, current smokers in the at-risk group showed raised MUC5AC concentrations at initial visits and decreased lung function over 3 years. By contrast, former smokers in the at-risk group showed normal MUC5AC concentrations at the initial visit and preserved lung function over 3 years. INTERPRETATION: These data indicate that increased MUC5AC concentration in the airways might contribute to COPD initiation, progression, exacerbation risk, and overall pathogenesis. Compared with MUC5B, greater relative changes in MUC5AC concentrations were observed as a function of COPD severity, and MUC5AC concentration seems to be an objective biomarker to detect disease in at-risk and pre-COPD individuals. These data suggest that MUC5AC-producing pathways could be potential targets for future therapeutic strategies. Thus, MUC5AC could be a novel biomarker for COPD prognosis and for testing the efficacy of therapeutic agents. FUNDING: National Institutes of Health; National Heart, Lung, and Blood Institute.

6.
Genome Med ; 13(1): 66, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883027

RESUMO

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.


Assuntos
Brônquios , COVID-19/genética , Mucosa Respiratória , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Enzima de Conversão de Angiotensina 2/genética , Asma/genética , COVID-19/imunologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Expressão Gênica , Variação Genética , Humanos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/imunologia , Doença Pulmonar Obstrutiva Crônica/genética , Locos de Características Quantitativas , Fatores de Risco , Fumar/genética
7.
J Pers Med ; 11(3)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802355

RESUMO

Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV1). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV1, to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1ß ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores < -50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1ß induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics.

8.
PLoS One ; 16(3): e0245478, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33730034

RESUMO

BACKGROUND: The purpose of this study was to explore the association between perceived social support and COPD outcomes and to determine whether the associations are mediated by depressive symptoms. METHODS: Subjects with COPD who were enrolled as part of SPIROMICS were included in this analysis. Questionnaires relating to quality of life, symptom burden, and functional status were administered at annual clinic visits for over a 3 year period. In both cross-sectional and longitudinal analyses, we examined the association of social support as measured by the FACIT-F with COPD outcomes. Cross sectional analyses used multivariable linear or logistic regression, adjusting for covariates. For longitudinal analyses, generalized linear mixed models with random intercepts were used. Models were adjusted with and without depressive symptoms and mediation analyses performed. RESULTS: Of the 1831 subjects with COPD, 1779 completed the FACIT- F questionnaire. In adjusted cross-sectional analysis without depressive symptoms, higher perceived social support was associated with better quality of life, well-being, 6 minute walk distance, and less dyspnea. When also adjusting for depressive symptoms, all associations between social support and COPD outcomes were attenuated and no longer statistically significant. Mediation analysis suggested that depressive symptoms explained the majority (> = 85%) of the association between social support and measured COPD outcomes. Results of the longitudinal analysis were consistent with the cross-sectional analyses. There was no association between social support and odds of exacerbations. CONCLUSION: Higher social support was associated with better COPD outcomes across several measures of morbidity including quality of life, respiratory symptoms, and functional status. In addition, these associations were largely attenuated when accounting for depressive symptoms suggesting that the beneficial association of social support with COPD outcomes may be largely mediated by the association between social support and depression. TRIAL REGISTRATION: SPIROMICS was approved by Institutional Review Boards at each center and all participants provided written informed consent (clinicaltrials.gov: NCT01969344).


Assuntos
Depressão/etiologia , Doença Pulmonar Obstrutiva Crônica/psicologia , Apoio Social , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Dispneia/etiologia , Feminino , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Qualidade de Vida , Inquéritos e Questionários
9.
Artigo em Inglês | MEDLINE | ID: mdl-33713768

RESUMO

BACKGROUND: Genetic ancestry plays a role in asthma health disparities. OBJECTIVE: Our aim was to evaluate the impact of ancestry on and identify genetic variants associated with asthma, total serum IgE level, and lung function. METHODS: A total of 436 Peruvian children (aged 9-19 years) with asthma and 291 without asthma were genotyped by using the Illumina Multi-Ethnic Global Array. Genome-wide proportions of indigenous ancestry populations from continental America (NAT) and European ancestry from the Iberian populations in Spain (IBS) were estimated by using ADMIXTURE. We assessed the relationship between ancestry and the phenotypes and performed a genome-wide association study. RESULTS: The mean ancestry proportions were 84.7% NAT (case patients, 84.2%; controls, 85.4%) and 15.3% IBS (15.8%; 14.6%). With adjustment for asthma, NAT was associated with higher total serum IgE levels (P < .001) and IBS was associated with lower total serum IgE levels (P < .001). NAT was associated with higher FEV1 percent predicted values (P < .001), whereas IBS was associated with lower FEV1 values in the controls but not in the case patients. The HLA-DR/DQ region on chromosome 6 (Chr6) was strongly associated with total serum IgE (rs3135348; P = 3.438 × 10-10) and was independent of an association with the haplotype HLA-DQA1∼HLA-DQB1:04.01∼04.02 (P = 1.55 × 10-05). For lung function, we identified a locus (rs4410198; P = 5.536 × 10-11) mapping to Chr19, near a cluster of zinc finger interacting genes that colocalizes to the long noncoding RNA CTD-2537I9.5. This novel locus was replicated in an independent sample of pediatric case patients with asthma with similar admixture from Brazil (P = .005). CONCLUSION: This study confirms the role of HLA in atopy, and identifies a novel locus mapping to a long noncoding RNA for lung function that may be specific to children with NAT.

10.
Am J Respir Crit Care Med ; 204(3): 285-293, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33779531

RESUMO

Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways.Objectives: To measure whether AR and its ligands are associated with human asthma outcomes.Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (FeNO) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey).Measurements and Main Results: In SARP (n = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV1/FVC ratio (R2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R2 = 0.056, P = 0.016) and was negatively associated with FeNO (R2 = 0.178, P = 9.8 × 10-6) and NOS2 (nitric oxide synthase gene) expression (R2 = 0.281, P = 1.2 × 10-10). In SARP (n = 1,659), the Cleveland Clinic Health System (n = 32,527), and the NHANES (n = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV1 in both women and men.Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower FeNO in human asthma. The role of androgens should be considered in asthma management.


Assuntos
Asma/genética , Sulfato de Desidroepiandrosterona/sangue , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Mucosa Respiratória/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/sangue , Asma/fisiopatologia , Testes Respiratórios , Broncoscopia , Feminino , Volume Expiratório Forçado , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Qualidade de Vida , Fatores Sexuais , Capacidade Vital , Adulto Jovem
11.
J Allergy Clin Immunol ; 147(5): 1594-1601, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33667479

RESUMO

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.


Assuntos
Asma , Biomarcadores , Medicina de Precisão , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Projetos de Pesquisa
12.
Sci Rep ; 11(1): 4916, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649381

RESUMO

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and the traditional variables extracted from computed tomography (CT) images may not be sufficient to describe all the topological features of lung tissues in COPD patients. We employed an unsupervised three-dimensional (3D) convolutional autoencoder (CAE)-feature constructor (FC) deep learning network to learn from CT data and derive tissue pattern-clusters jointly. We then applied exploratory factor analysis (EFA) to discover the unobserved latent traits (factors) among pattern-clusters. CT images at total lung capacity (TLC) and residual volume (RV) of 541 former smokers and 59 healthy non-smokers from the cohort of the SubPopulations and Intermediate Outcome Measures in the COPD Study (SPIROMICS) were analyzed. TLC and RV images were registered to calculate the Jacobian (determinant) values for all the voxels in TLC images. 3D Regions of interest (ROIs) with two data channels of CT intensity and Jacobian value were randomly extracted from training images and were fed to the 3D CAE-FC model. 80 pattern-clusters and 7 factors were identified. Factor scores computed for individual subjects were able to predict spirometry-measured pulmonary functions. Two factors which correlated with various emphysema subtypes, parametric response mapping (PRM) metrics, airway variants, and airway tree to lung volume ratio were discriminants of patients across all severity stages. Our findings suggest the potential of developing factor-based surrogate markers for new COPD phenotypes.

13.
NPJ Biofilms Microbiomes ; 7(1): 14, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547327

RESUMO

Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF25-75). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.


Assuntos
Bactérias/classificação , Pulmão/microbiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , RNA Ribossômico 16S/genética , Análise de Sequência de RNA/métodos , Adulto , Idoso , Bactérias/isolamento & purificação , Líquido da Lavagem Broncoalveolar/microbiologia , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/microbiologia , Espirometria
14.
J Allergy Clin Immunol ; 148(1): 266-271.e2, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33609624

RESUMO

BACKGROUND: Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of benralizumab in the first year of BORA (year 2 of treatment) have been reported. OBJECTIVE: We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA. METHODS: Patients on benralizumab 30 mg every 4 weeks (Q4W) or every 8 weeks (Q8W) in SIROCCO/CALIMA continued their regimens in BORA (Q4W/Q4W and Q8W/Q8W, respectively), whereas placebo patients were rerandomized 1:1 to benralizumab (placebo/Q4W and placebo/Q8W, respectively) for 108 weeks. The primary outcome was safety; secondary outcomes included reduction in annual asthma exacerbation rate and change from baseline in prebronchodilator FEV1. RESULTS: Adolescents (N = 86) were treated with benralizumab Q8W (n = 61) or Q4W (n = 25); 69 completed treatment (Q8W: n = 51; Q4W: n = 18). For Q4W and Q8W regimens, rates of treatment-emergent adverse events were 68% (17 of 25) and 74% (45 of 61), respectively, rates of treatment-emergent adverse events (TEAEs) were 68% (17/25) and 74% (45/61), TEAEs leading to discontinuation were 4% (1/25) and 0%, serious AEs were 8% (2/25) and 7% (4/61), and no deaths occurred. In efficacy analyses, 69% (42 of 61) Q8W patients were exacerbation-free (placebo/Q8W: 62% [18 of 29], Q8W/Q8W: 75% [24 of 32]). Mean ± SD change in FEV1 at week 108 versus BORA baseline was 0.327 ± 0.452 L (placebo/Q8W) and 0.323 ± 0.558 L (Q8W/Q8W). CONCLUSIONS: Safety and efficacy profiles in this 2-year extension study (up to 3 years of benralizumab treatment in adolescents) were consistent with previous findings.


Assuntos
Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Eosinófilos/efeitos dos fármacos , Adolescente , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada/métodos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Eosinofilia Pulmonar/tratamento farmacológico
15.
Am J Respir Crit Care Med ; 203(7): 882-892, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33545021

RESUMO

Rationale: Some reports indicate longitudinal variability in sputum differential cell counts, whereas others describe stability. Highly variable sputum eosinophil percentages are associated with greater lung function loss than persistently elevated eosinophil percentages, but elevated neutrophils are linked to more severe asthma.Objectives: To examine sputum granulocyte stability or variability longitudinally and associations with important clinical characteristics.Methods: The SARP III (Severe Asthma Research Program III) cohort underwent comprehensive phenotype characterization at baseline and annually over 3 years. Adult subjects with acceptable sputum levels were assigned to one of three longitudinal sputum groups: eosinophils predominantly <2%, eosinophils predominantly ≥2%, or highly variable eosinophil percentages (>2 SDs determined from independent, repeated baseline eosinophil percentages). Subjects were similarly assigned to one of three longitudinal neutrophil groups with a 50% cut point.Measurements and Main Results: The group with predominantly <2% sputum eosinophils had the highest lung function (prebronchodilator FEV1% predicted, P < 0.01; FEV1/FVC ratio, P < 0.001) at baseline and throughout 3 years compared with other eosinophil groups. Healthcare use did not differ, although the highly variable eosinophil group reported more asthma exacerbations at Year 3. Longitudinal neutrophil groups showed few differences. However, a combination of predominantly ≥2% eosinophil and ≥50% neutrophil groups resulted in the lowest prebronchodilator FEV1% predicted (P = 0.049) compared with the combination with predominantly <2% eosinophils and<50% neutrophils.Conclusions: Subjects with predominantly ≥2% sputum eosinophils in combination with predominantly ≥50% neutrophils showed greater loss of lung function, whereas those with highly variable sputum eosinophils had greater healthcare use.


Assuntos
Asma/genética , Asma/fisiopatologia , Eosinófilos/química , Granulócitos/química , Inflamação/fisiopatologia , Pulmão/fisiopatologia , Escarro/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Testes de Função Respiratória , Índice de Gravidade de Doença
16.
Mitochondrion ; 58: 303-310, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33513442

RESUMO

Mitochondrial dysfunction has emerged to be associated with a broad spectrum of diseases, and there is an increasing demand for accurate detection of mitochondrial DNA (mtDNA) variants. Whole genome sequencing (WGS) has been the dominant sequencing approach to identify genetic variants in recent decades, but most studies focus on variants on the nuclear genome. Whole genome sequencing is also costly and time consuming. Sequencing specifically targeted for mtDNA is commonly used in the diagnostic settings and has lower costs. However, there is a lack of pairwise comparisons between these two sequencing approaches for calling mtDNA variants on a population basis. In this study, we compared WGS and mtDNA-targeted sequencing (targeted-seq) in analyzing mitochondrial DNA from 1499 participants recruited into the Severe Asthma Research Program (SARP). Our study reveals that targeted-sequencing and WGS have comparable capacity to determine genotypes and to call haplogroups and homoplasmies on mtDNA. However, there exists a large variability in calling heteroplasmies, especially for low-frequency heteroplasmies, which indicates that investigators should be cautious about heteroplasmies acquired from different sequencing methods. Further research is highly desired to improve variant detection methods for mitochondrial DNA.

17.
J Asthma ; : 1-10, 2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33492176

RESUMO

OBJECTIVE: : To improve understanding of real-world asthma treatment and inform physician education, we evaluated regional variation in asthma prevalence and oral corticosteroid (OCS) use across Germany. METHODS: : We developed a machine learning gradient-boosted tree model with IMS® Disease Analyzer electronic medical records, which cover 3% of German patients. This model had a 91% accuracy in predicting the presence of asthma and chronic obstructive pulmonary disease. We applied the model to the IMS® Longitudinal Prescription database, with 82% national coverage, to classify patients receiving treatment for airflow obstruction from October 2017-September 2018 in 63 regions in Germany. RESULTS: : Of 2.4 million individuals under statutory health insurance predicted to have asthma, 13.7%, 18.7%, 36.5%, 29.4%, and 1.7% received treatment classified as Global Initiative for Asthma (GINA) Steps 1, 2, 3, 4, and 5, respectively. Approximately 7-15% of those at GINA Steps 1-4 and 35% at Step 5 treatment received ≥1 acute OCS prescription (duration <10 days). Of patients receiving GINA Steps 1-4 and Step 5 treatments, 1-3% and 86%, respectively, received ≥1 high-dosage OCS prescription. Cumulative OCS dosage and percentages of patients receiving OCS differed substantially across regions, and regions with lower OCS use had greater use of biologic therapies. CONCLUSIONS: : Both acute and high OCS use varied regionally across Germany, with overall use suggesting patients are considerable risk of adverse effects and long-term health consequences.Supplemental data for this article can be accessed at publisher's website.

18.
J Allergy Clin Immunol ; 147(3): 894-909, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32795586

RESUMO

BACKGROUND: The Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium. OBJECTIVES: We sought to comprehensively investigate whole-genome sequence and RNA sequence from human bronchial epithelial cells to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program. METHODS: Expression quantitative trait loci analysis (n = 114), correlation analysis (n = 156) of gene expression and asthma phenotypes, and pathway analysis were performed in bronchial epithelial cells and replicated. Genetic association for asthma severity (426 severe vs 531 nonsevere asthma) and longitudinal asthma exacerbations (n = 273) was performed. RESULTS: Multiple SNPs in gasdermin B (GSDMB) associated with asthma severity (odds ratio, >1.25) and longitudinal asthma exacerbations (P < .05). Expression quantitative trait loci analyses identified multiple SNPs associated with expression levels of post-GPI attachment to proteins 3, GSDMB, or gasdermin A (3.1 × 10-9 

19.
Lancet Respir Med ; 9(1): 43-56, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32979986

RESUMO

BACKGROUND: Fevipiprant, an oral antagonist of the prostaglandin D2 receptor 2, reduced sputum eosinophils and improved lung function in phase 2 trials of patients with asthma. We aimed to investigate whether fevipiprant reduces asthma exacerbations in patients with severe asthma. METHODS: LUSTER-1 and LUSTER-2 were two phase 3 randomised, double-blind, placebo-controlled, parallel-group, replicate 52-week studies; LUSTER-1 took place at 174 clinical sites in 25 countries and LUSTER 2 took place at 169 clinical sites in 19 countries. Fevipiprant or placebo was added to Global Initiative for Asthma Steps 4 and 5 therapy in adolescents and adults with severe asthma. Patients aged 12 years or older with uncontrolled asthma on dual or triple asthma therapy were randomly assigned by use of interactive response technology to one of three treatment groups (once-daily fevipiprant 150 mg, fevipiprant 450 mg, or placebo) in a 1:1:1 ratio within each of the randomisation strata: peripheral blood eosinophil counts (<250 cells per µL or ≥250 cells per µL), patient age (<18 years or ≥18 years), and use or non-use of oral corticosteroids as part of their standard of care asthma therapy. The primary efficacy endpoint was the annualised rate of moderate to severe asthma exacerbations with 150 mg or 450 mg doses of fevipiprant once daily compared with placebo over 52 weeks, in patients with high blood eosinophil counts (≥250 cells per µL) and in the overall study population. All patients who underwent randomisation and received at least one dose of study medication were included in efficacy and safety analyses. These trials are registered with ClinicalTrials.gov, NCT02555683 (LUSTER-1) and NCT02563067 (LUSTER-2), and are complete and no longer recruiting. FINDINGS: Between Dec 11, 2015, and Oct 25, 2018, 894 patients were randomly assigned to fevipiprant 150 mg (n=301), fevipiprant 450 mg (n=295), or placebo (n=298) in LUSTER-1. Between Dec 3, 2015, and July 10, 2018, 877 patients were randomly assigned to fevipiprant 150 mg (n=296), fevipiprant 450 mg (n=294), or placebo (n=287) in LUSTER-2. In the high eosinophil population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 1·04 (95% CI 0·77-1·41) for fevipiprant 150 mg and 0·83 (0·61-1·14) for fevipiprant 450 mg, and in LUSTER-2 it was 0·69 (0·50-0·96) for fevipiprant 150 mg and 0·72 (0·52-1·01) for fevipiprant 450 mg. In the overall population, in LUSTER-1 the annualised rate ratio of moderate to severe exacerbations compared with placebo was 0·96 (95% CI 0·75-1·22) for fevipiprant 150 mg and 0·78 (0·61-1·01) for fevipiprant 450 mg and in LUSTER-2 it was 0·82 (0·62-1·07) for fevipiprant 150 mg and 0·76 (0·58-1·00) for fevipiprant 450 mg. In the overall pooled population of both studies, serious adverse events occurred in 53 (9%) patients in the fevipiprant 150 mg group, 50 (9%) in the fevipiprant 450 mg group, and 50 (9%) in the placebo group. Adverse events leading to death occurred in two (<1%) patients in the fevipiprant 450 mg group and three (<1%) in the placebo group. INTERPRETATION: Although neither trial showed a statistically significant reduction in asthma exacerbations after adjusting for multiple testing, consistent and modest reductions in exacerbations rates were observed in both studies with the 450 mg dose of fevipiprant. FUNDING: Novartis.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Ácidos Indolacéticos/uso terapêutico , Piridinas/uso terapêutico , Antiasmáticos/efeitos adversos , Método Duplo-Cego , Eosinófilos , Feminino , Hospitalização , Humanos , Ácidos Indolacéticos/efeitos adversos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Resultado do Tratamento
20.
Am J Respir Crit Care Med ; 203(7): 841-852, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33290668

RESUMO

Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function.Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline.Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to <1% gain/yr; and improvement, ≥1% gain/yr. Regression models were used to develop predictors of severe decline.Measurements and Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (derived by baseline subtraction) was related to the 4-year change in lung function or slope category in univariable models (P < 0.001). For each 5% decrement in the triamcinolone-induced difference the FEV1% predicted, there was a 50% increase in the odds of being in the severe decline group (odds ratio, 1.5; 95% confidence interval, 1.3-1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and body mass index.Conclusions: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk for a severe decline in lung function.


Assuntos
Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Asma/tratamento farmacológico , Asma/fisiopatologia , Broncodilatadores/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Infusões Parenterais , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Índice de Gravidade de Doença , Resultado do Tratamento
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