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1.
Artigo em Norueguês | MEDLINE | ID: mdl-31592602
2.
PLoS One ; 14(9): e0222449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31527888

RESUMO

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are debilitating events and spur disease progression. Infectious causes are frequent; however, it is unknown to what extent exacerbations are caused by larger shifts in the airways' microbiota. The aim of the current study was to analyse the changes in microbial composition between stable state and during exacerbations, and the corresponding immune response. METHODS: The study sample included 36 COPD patients examined at stable state and exacerbation from the Bergen COPD Cohort and Exacerbations studies, and one patient who delivered sputum on 13 different occasions during the three-year study period. A physician examined the patients at all time points, and sputum induction was performed by stringent protocol. Only induced sputum samples were used in the current study, not spontaneously expectorated sputum. Sputum inflammatory markers (IL-6, IL-8, IL-18, IP-10, MIG, TNF-α) and antimicrobial peptides (AMPs, i.e. LL-37/hCAP-18, SLPI) were measured in supernatants, whereas target gene sequencing (16S rRNA) was performed on corresponding cell pellets. The microbiome bioinformatics platform QIIME2TM and the statistics environment R were applied for bioinformatics analyses. RESULTS: Levels of IP-10, MIG, TNF-α and AMPs were significantly different between the two disease states. Of 36 sample pairs, 24 had significant differences in the 12 most abundant genera between disease states. The diversity was significantly different in several individuals, but not when data was analysed on a group level. The one patient case study showed longitudinal dynamics in microbiota unrelated to disease state. CONCLUSION: Changes in the sputum microbiota with changing COPD disease states are common, and are accompanied by changes in inflammatory markers. However, the changes are highly individual and heterogeneous events.

3.
Int J Chron Obstruct Pulmon Dis ; 14: 1639-1655, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413559

RESUMO

Rationale: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 is based on an ABCD assessment tool of symptoms and exacerbation history and grade 1-4 of airflow limitation severity, facilitating classification either into 4 groups (ABCD) or 16 groups (1A-4D). We aimed to compare the GOLD 2011, GOLD 2017 ABCD, and GOLD 2017 1A-4D classifications in terms of their distribution and prediction of mortality and hospitalizations. Methods: In the GenKOLS study, 912 COPD patients with FEV1 less than 80% of the predicted answered questionnaires and performed lung function testing in 2003-2005. The patients were recruited from a hospital patient registry (n=662) and from the general population (n=250), followed up until 2011 with respect to all-cause and respiratory mortality, and all-cause and respiratory hospitalizations. We performed logistic regression and receiver operating curve (ROC) analyses for the different classifications with estimations of area under the curve (AUC) for comparisons. Results: Mean age at baseline was 60 years (SD 11), 55% were male. Mean duration of follow-up was 91 months. By GOLD 2011, 21% were classified as group A, 29% group B, 6% group C, and 43% as group D, corresponding percentages for GOLD 2017 were: 25%, 52%, 3%, and 20%. The GOLD 2011 classification had higher AUC values than the GOLD 2017 group ABCD classification for respiratory mortality and hospitalization, but after inclusion of airflow limitation severity in GOLD 2017 groups 2A-4D, AUC values were significantly higher with GOLD 2017. Conclusion: In a clinically relevant sample of COPD patients, the GOLD 2017 classification doubles the prevalence of group B and halves the prevalence of groups C and D as compared to the GOLD 2011 classification. The prediction of respiratory mortality and respiratory hospitalization was better for GOLD 2017 2A-4D taking airflow limitation severity into account, as compared to GOLD 2017 ABCD and GOLD 2011.

5.
Respir Med ; 152: 81-88, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31128615

RESUMO

BACKGROUND: COPD patients have an increased risk of developing lung cancer, but the underlying mechanisms are poorly understood. We aimed to identify risk factors for lung cancer in patients from the Bergen COPD Cohort Study. METHODS: We compared 433 COPD patients with 279 healthy controls, all former or current smokers. All COPD patients had FEV1<80% and FEV1/FVC-ratio<0.7. Baseline predictors were sex, age, spirometry, body composition, smoking history, emphysema assessed by CT, chronic bronchitis, prior exacerbation frequency, Charlson Comorbidity Score, inhalation medication and 44 serum/plasma inflammatory biomarkers. Patients were followed up for 9 years recording incidence of lung cancer. Cox-regression models were fitted for the statistical analyses. The biomarkers were evaluated using principal component analysis. RESULTS: 28 COPD patients and 3 controls developed lung cancer, COPD patients had a significantly higher risk of developing lung cancer, (HR 5.0; 95% CI 1.5-17.1, p < 0.01, adjusted values). Among COPD patients, emphysema (HR 4.4; 1.7-10.8, p < 0.01) and obesity (HR 3.3; 1.3-8.5, p = 0.02) were associated with a higher cancer rate. Use of inhaled steroids was associated with a lower rate (HR 0.4; 0.2-0.9, p = 0.03). Smoking status, pack-years smoked or levels of systemic inflammatory markers, except for interferon gamma-induced protein 10, did not affect the lung cancer rate in patients with COPD. CONCLUSION: Patients with COPD have a higher lung cancer rate compared to healthy controls adjusted for smoking. The presence of emphysema and obesity in COPD predicted a higher lung cancer risk in COPD patients. Systemic inflammation was not associated with increased lung cancer risk.

6.
J Allergy Clin Immunol ; 144(1): 70-82, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30928653

RESUMO

BACKGROUND: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. OBJECTIVE: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. METHODS: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. RESULTS: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. CONCLUSION: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30998987

RESUMO

BACKGROUND: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. OBJECTIVE: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. METHODS: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17-high and IL-13-high asthma phenotypes. RESULTS: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17-high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and ß-defensin. CONCLUSION: The IL-17-high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

9.
COPD ; 16(1): 8-17, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30870059

RESUMO

The CODEX index was developed and validated in patients hospitalized for COPD exacerbation to predict the risk of death and readmission within one year after discharge. Our study aimed to validate the CODEX index in a large external population of COPD patients with variable durations of follow-up. Additionally, we aimed to recalculate the thresholds of the CODEX index using the cutoffs of variables previously suggested in the 3CIA study (mCODEX). Individual data on 2,755 patients included in the COPD Cohorts Collaborative International Assessment Plus (3CIA+) were explored. A further two cohorts (ESMI AND EGARPOC-2) were added. To validate the CODEX index, the relationship between mortality and the CODEX index was assessed using cumulative/dynamic ROC curves at different follow-up periods, ranging from 3 months up to 10 years. Calibration was performed using univariate and multivariate Cox proportional hazard models and Hosmer-Lemeshow test. A total of 3,321 (87.8% males) patients were included with a mean ± SD age of 66.9 ± 10.5 years, and a median follow-up of 1,064 days (IQR 25-75% 426-1643), totaling 11,190 person-years. The CODEX index was statistically associated with mortality in the short- (≤3 months), medium- (≤1 year) and long-term (10 years), with an area under the curve of 0.72, 0.70 and 0.76, respectively. The mCODEX index performed better in the medium-term (<1 year) than the original CODEX, and similarly in the long-term. In conclusion, CODEX and mCODEX index are good predictors of mortality in patients with COPD, regardless of disease severity or duration of follow-up.

10.
Nat Genet ; 51(3): 481-493, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804560

RESUMO

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.


Assuntos
Predisposição Genética para Doença/genética , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fumar/genética
11.
Nat Genet ; 51(3): 494-505, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804561

RESUMO

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.


Assuntos
Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Asma/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fibrose Pulmonar/genética , Fumar/genética
12.
Am J Respir Cell Mol Biol ; 60(5): 523-531, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30694715

RESUMO

DlCO is a widely used pulmonary function test in clinical practice and a particularly useful measure for assessing patients with chronic obstructive pulmonary disease (COPD). We hypothesized that elucidating genetic determinants of DlCO could lead to better understanding of the genetic architecture of COPD. We estimated the heritability of DlCO using common genetic variants and performed genome-wide association analyses in four cohorts enriched for subjects with COPD (COPDGene [Genetic Epidemiology of COPD], NETT [National Emphysema Treatment Trial], GenKOLS [Genetics of Chronic Obstructive Lung Disease study], and TESRA [Treatment of Emphysema With a Gamma-Selective Retinoid Agonist study]) using a combined European ancestry white dataset and a COPDGene African American dataset. We assessed our genome-wide significant and suggestive associations for DlCO in previously reported genome-wide association studies of COPD and related traits. We also characterized associations of known COPD-associated variants and DlCO. We estimated the SNP-based heritability of DlCO in the European ancestry white population to be 22% (P = 0.0004). We identified three genome-wide significant associations with DlCO: variants near TGFB2, CHRNA3, and PDE11A loci (P < 5 × 10-8). In addition, 12 loci were suggestively associated with DlCO in European ancestry white (P < 1 × 10-5 in the combined analysis and P < 0.05 in both COPDGene and GenKOLS), including variants near NEGR1, CADM2, PCDH7, RETREG1, DACT2, NRG1, ANKRD18A, KRT86, NTN4, ARHGAP28, INSR, and PCBP3. Some DlCO-associated variants were also associated with COPD, emphysema, and/or spirometric values. Among 25 previously reported COPD loci, TGFB2, CHRNA3/CHRNA5, FAM13A, DSP, and CYP2A6 were associated with DlCO (P < 0.001). We identified several genetic loci that were significantly associated with DlCO and characterized effects of known COPD-associated loci on DlCO. These results could lead to better understanding of the heterogeneous nature of COPD.

13.
Clin Respir J ; 13(2): 114-119, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30597746

RESUMO

INTRODUCTION: Based on the National Lung Cancer Screening Trial (NLST), guidelines on screening programs for lung cancer have recommended low-dose computed tomography (LDCT). De Torres et al made a score for COPD patients (COPD-LUCSS) to improve their selection criteria. OBJECTIVE: To examine and compare the discriminating value of both scores in a community-based cohort of COPD patients. METHODS: Four hundred and twenty-two ever-smokers with COPD from the GenKOLS study in Bergen were merged with the Cancer Registry of Norway. We divided the patients into groups of high and low risk according to the COPD-LUCSS and the NLST criteria. Cox regression and logistic regression were used to analyse the associations between the scores and lung cancer. We used Harrell's C and area under the curve (AUC) to estimate discriminating values and to compare the models. RESULTS: Hazard ratio for the high risk vs the low risk in the COPD-LUCSS was 3.0 (1.4-6.5 95% CI), P < 0.01. Hazard ratio for the NLST criteria was 2.2 (95% CI 1.1-4.5), P < 0.05. Harrell's C was 0.63 for the COPD-LUCSS and 0.59 for the NLST selection criteria. AUC was 0.61 for COPD-LUCSS and 0.59 for NLST criteria. Comparing tests showed no differences (P = 0.76). CONCLUSION: Although the COPD-LUCSS and the NLST criteria were associated with increased risk of lung cancer, the AUC and Harrell's C values showed that these models have poor discriminating abilities in our cohort of COPD patients. The COPD-LUCSS was not significantly better than the NLST criteria.


Assuntos
Neoplasias Pulmonares/diagnóstico , Programas de Rastreamento/métodos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Tomografia Computadorizada por Raios X/métodos , Idoso , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Fumar/efeitos adversos
14.
J Allergy Clin Immunol ; 143(5): 1811-1820.e7, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30529449

RESUMO

BACKGROUND: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using "omics" technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes. OBJECTIVES: We aimed (1) to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses) and (2) to assess the stability of eNose-derived phenotypes in relation to within-patient clinical and inflammatory changes. METHODS: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability. RESULTS: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNose-driven clusters (n = 26/33/19) were revealed, showing differences in circulating eosinophil (P = .045) and neutrophil (P = .017) percentages and ratios of patients using oral corticosteroids (P = .035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P = .045). CONCLUSIONS: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma.

15.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(3): 224-233, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30528790

RESUMO

INTRODUCTION: Disturbances in onset and resolution of inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. Dietary polyunsaturated fatty acids (PUFAs) can be converted into lipid mediators here collectively named oxylipins. These include classical eicosanoids, but also pro-resolving mediators. A balanced production of pro-inflammatory and pro-resolving oxylipins is of importance for adequate inflammatory responses and subsequent return to homeostasis. OBJECTIVES: Here we investigated if PUFA metabolism is disturbed in COPD patients. METHODS: Free PUFA and oxylipin levels were measured in induced sputum samples from the Bergen COPD cohort and COPD exacerbation study using liquid chromatography-mass spectrometry. Additionally, effects of whole cigarette smoke on PUFA metabolism in air-liquid interface cultures of primary bronchial epithelial cells were assessed. RESULTS: Significantly lower levels of free alpha-linolenic acid, linoleic acid and eicosapentaenoic acid (EPA) were detected in sputum from stable COPD patients compared to controls. During acute exacerbation (AE), levels of free arachidonic acid and docosapentaenoic acid were higher than in stable COPD patients. Furthermore, levels of omega-3 EPA- and docosahexaenoic acid-derived oxylipins were lower in sputum from stable COPD patients compared to controls. Cyclooxygenase-2-converted mediators were mostly increased during AE. In vitro studies additionally showed that cigarette smoke exposure may also directly contribute to altered epithelial PUFA metabolism, and indirectly by causing airway epithelial remodelling. CONCLUSIONS: Our findings show significant differences in PUFA metabolism in COPD patients compared to controls, further changed during AE. Airway epithelial remodelling may contribute to these changes. These findings provide new insight in impaired inflammatory resolution in COPD.


Assuntos
Ácidos Graxos Insaturados/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Escarro/metabolismo , Ácido Araquidônico/metabolismo , Fumar Cigarros/efeitos adversos , Fumar Cigarros/metabolismo , Dieta , Ácido Eicosapentaenoico/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Ácidos Graxos Insaturados/fisiologia , Feminino , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Oxilipinas/metabolismo , Mucosa Respiratória/metabolismo , Fumantes , Escarro/química , Ácido alfa-Linoleico
16.
BMC Pulm Med ; 18(1): 187, 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30522466

RESUMO

BACKGROUND: Lung hyperinflation contributes to dyspnea, morbidity and mortality in chronic obstructive pulmonary disease (COPD). The inspiratory-to-total lung capacity (IC/TLC) ratio is a measure of lung hyperinflation and is associated with exercise intolerance. However, knowledge of its effect on longitudinal change in the 6-min walk distance (6MWD) in patients with COPD is scarce. We aimed to study whether the IC/TLC ratio predicts longitudinal change in 6MWD in patients with COPD. METHODS: This prospective cohort study included 389 patients aged 40-75 years with clinically stable COPD in Global Initiative for Chronic Obstructive Lung Disease stages II-IV. The 6MWD was measured at baseline, and after one and 3 years. We performed generalized estimating equation regression analyses to examine predictors for longitudinal change in 6MWD. Predictors at baseline were: IC/TLC ratio, age, gender, pack years, fat mass index (FMI), fat-free mass index (FFMI), number of exacerbations within 12 months prior to inclusion, Charlson index for comorbidities, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and light and hard self-reported physical activity. RESULTS: Reduced IC/TLC ratio (p < 0.001) was a statistically significant predictor for decline in 6MWD. With a 0.1-unit decrease in baseline IC/TLC ratio, the annual decline in 6MWD was 12.7 m (p < 0.001). Study participants with an IC/TLC ratio in the upper quartiles maintained their 6MWD from baseline to year 3, while it was significantly reduced for the patients with an IC/TLC ratio in the lower quartiles. Absence of light and hard physical activity, increased age and FMI, decreased FEV1 and FVC, more frequent exacerbations and higher Charlson comorbidity index were also predictors for lower 6MWD at any given time, but did not predict higher rate of decline over the timespan of the study. CONCLUSION: Our findings demonstrated that patients with less lung hyperinflation at baseline maintained their functional exercise capacity during the follow-up period, and that it was significantly reduced for patients with increased lung hyperinflation.

17.
BMC Pulm Med ; 18(1): 195, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30572869

RESUMO

BACKGROUND: Evidence from several studies show poor guideline adherence to COPD treatment, but no such study has been undertaken in Norway. The objectives of this study, was to estimate and compare the guideline adherence to COPD treatment in general population-based and hospital-recruited COPD patients, and find possible predictors of guideline adherence. METHODS: From the prospective, observational EconCOPD-study, we analysed guideline adherence for 90 population-based COPD cases compared to 245 hospital-recruited COPD patients. Overall guideline adherence was defined as correct pharmacological treatment, and influenza vaccination the preceding year, and having received smoking cessation advice. Multivariate logistic regression analysis was performed with the dichotomous outcome overall guideline adherence adjusting for relevant variables. RESULTS: The overall guideline adherence for population-based COPD cases was 6.7%, significantly lower than the 29.8% overall guideline-adherence amongst hospital-recruited COPD patients. Adherence to pharmacological treatment guidelines was 10.0 and 35.5%, for the two recruitment sources, respectively. GOLD-stage 3 to 4 was associated with significantly better guideline adherence compared to GOLD-stage 2 (OR (95% CI) 18.9 (8.37,42.7)). The unadjusted difference between the two recruitment sources was completely explained by degree of airflow obstruction. CONCLUSION: Overall guideline adherence was very low for both recruitment sources. We call for increased attention from authorities and healthcare personnel to improve the quality of care given to this patient group.


Assuntos
Aconselhamento Diretivo/estatística & dados numéricos , Fidelidade a Diretrizes/estatística & dados numéricos , Influenza Humana/prevenção & controle , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade da Assistência à Saúde , Vacinação/estatística & dados numéricos , Idoso , Feminino , Hospitais , Humanos , Vacinas contra Influenza , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/reabilitação , Índice de Gravidade de Doença , Abandono do Hábito de Fumar
19.
PLoS One ; 13(9): e0203874, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30240401

RESUMO

Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker information enabling characterization of these subjects. We investigated oxidative stress in severe asthma subjects by analysing urinary 8-iso-PGF2α and the mRNA-expression of the main pro-oxidant (NOX2; NOSs) and anti-oxidant (SODs; CAT; GPX1) enzymes in the airways of SAs/ex and SAn. All the severe asthma U-BIOPRED subjects were further divided into current smokers with severe asthma (CSA), ex-smokers with severe asthma (ESA) and non-smokers with severe asthma (NSA) to deepen the effect of active smoking. Clinical data, urine and sputum were obtained from severe asthma subjects. A bronchoscopy to obtain bronchial biopsy and brushing was performed in a subset of subjects. The main clinical data were analysed for each subset of subjects (urine-8-iso-PGF2α; IS-transcriptomics; BB-transcriptomics; BBr-transcriptomics). Urinary 8-iso-PGF2α was quantified using mass spectrometry. Sputum, bronchial biopsy and bronchial brushing were processed for mRNA expression microarray analysis. Urinary 8-iso-PGF2α was increased in SAs/ex, median (IQR) = 31.7 (24.5-44.7) ng/mmol creatinine, compared to SAn, median (IQR) = 26.6 (19.6-36.6) ng/mmol creatinine (p< 0.001), and in CSA, median (IQR) = 34.25 (24.4-47.7), vs. ESA, median (IQR) = 29.4 (22.3-40.5), and NSA, median (IQR) = 26.5 (19.6-16.6) ng/mmol creatinine (p = 0.004). Sputum mRNA expression of NOX2 was increased in SAs/ex compared to SAn (probe sets 203922_PM_s_at fold-change = 1.05 p = 0.006; 203923_PM_s_at fold-change = 1.06, p = 0.003; 233538_PM_s_at fold-change = 1.06, p = 0.014). The mRNA expression of antioxidant enzymes were similar between the two severe asthma cohorts in all airway samples. NOS2 mRNA expression was decreased in bronchial brushing of SAs/ex compared to SAn (fold-change = -1.10; p = 0.029). NOS2 mRNA expression in bronchial brushing correlated with FeNO (Kendal's Tau = 0.535; p< 0.001). From clinical and inflammatory analysis, FeNO was lower in CSA than in ESA in all the analysed subject subsets (p< 0.01) indicating an effect of active smoking. Results about FeNO suggest its clinical limitation, as inflammation biomarker, in severe asthma active smokers. These data provide evidence of greater systemic oxidative stress in severe asthma smokers as reflected by a significant changes of NOX2 mRNA expression in the airways, together with elevated urinary 8-iso-PGF2α in the smokers/ex-smokers group. Trial registration ClinicalTrials.gov-Identifier: NCT01976767.

20.
Sci Rep ; 8(1): 14439, 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30262855

RESUMO

The polygenic nature of complex diseases offers potential opportunities to utilize network-based approaches that leverage the comprehensive set of protein-protein interactions (the human interactome) to identify new genes of interest and relevant biological pathways. However, the incompleteness of the current human interactome prevents it from reaching its full potential to extract network-based knowledge from gene discovery efforts, such as genome-wide association studies, for complex diseases like chronic obstructive pulmonary disease (COPD). Here, we provide a framework that integrates the existing human interactome information with experimental protein-protein interaction data for FAM13A, one of the most highly associated genetic loci to COPD, to find a more comprehensive disease network module. We identified an initial disease network neighborhood by applying a random-walk method. Next, we developed a network-based closeness approach (CAB) that revealed 9 out of 96 FAM13A interacting partners identified by affinity purification assays were significantly close to the initial network neighborhood. Moreover, compared to a similar method (local radiality), the CAB approach predicts low-degree genes as potential candidates. The candidates identified by the network-based closeness approach were combined with the initial network neighborhood to build a comprehensive disease network module (163 genes) that was enriched with genes differentially expressed between controls and COPD subjects in alveolar macrophages, lung tissue, sputum, blood, and bronchial brushing datasets. Overall, we demonstrate an approach to find disease-related network components using new laboratory data to overcome incompleteness of the current interactome.

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