Objetivo: Traduzir e adaptar para o português falado no Brasil a escala Dyspnoea-12. Fornecer dados de validação da escala para pacientes com DPOC e hipertensão pulmonar (HP). Métodos: A versão em inglês da escala Dyspnoea-12 sofreu processo clássico de tradução, até obtenção de versão definitiva em português denominada Dispneia-12-Pt. A escala Dispneia-12-Pt foi aplicada a 51 pacientes com DPOC (33 homens; idade: 66,4±8,1 anos; VEF1: 48,7±17,2%) e 15 com HP de diferentes etiologias (12 mulheres; idade: 45,8±12,7 anos; pressão sistólica da artéria pulmonar: 88±33,2 mmHg). Os voluntários responderam a escala de dispneia do Medical Research Council(MRC), o índice de dispneia basal (IDB), a escala hospitalar de ansiedade e depressão, questionário respiratório de Saint George (QRSG), avaliação funcional respiratória e teste da caminhada dos seis minutos (TC6min). Sessenta voluntários responderam a escala uma segunda vez, duas semanas após a primeira avaliação. Resultados: No grupo DPOC a escala Dispneia-12-Pt apresentou correlações significantes com as escalas MRC (r=0,4641; p=0,0006), IDB (r=0,515; p <0,0001), QRSG (r=0,8113; p<0,0001), ansiedade (r=0,4714; p=0,0005), depressão (0,4139; p=0,0025) e distância percorrida no TC6min (r=0,3293; p=0,0255). No grupo com HP a escala mostrou correlações significantes com as escalas MRC (r=0,5774; p=0,0242), QRSG (r=0,6907; p=0,0044), distância percorrida no TC6min (r=0,7193; p=0,0025) e difusão do monóxido de carbono (r=0,564; p=0,0447). O alfa de Cronbach para os voluntários analisados em um único grupo foi 0,927 e o coeficiente de correlação intraclasse 0,8456. Conclusões: A escala Dispneia-12-Pt apresenta propriedades biométricas aceitáveis e pode ser empregada em pacientes brasileiros com dispneia de diferentes etiologias. / Objective: To translate and to adapt for the Portuguese spoken in Brazil the scale Dyspnoea-12. To obtain validation data, regarding the use of this scale in patients with COPD and pulmonary hypertension (PH). Methods: The English version of the scale Dyspnoea-12 received a formal translation process and the final version was called Dispneia-12-Pt. The latter was applied to 51 COPD patients (33 men; age: 66.4±8.1 years; FEV1: 48.7±17.2 % pred) and 15 subjects with PH from different etiologies (12 women; age: 45.8±12.7 years; systolic pulmonary arterial pressure: 88±33.2 mmHg). The volunteers also answered the Medical Research Council dyspnea scale (MRC), the basal dyspnea index (DBI), the hospital scale of anxiety and depression, the Saint George Respiratory Questionnaire (SGRQ), respiratory functional evaluation and the six minute walk test (6 MWT). Sixty volunteers also answered the Dispneia-12-Pt scale about two weeks after the first evaluation. Results: In the COPD group the Dispneia-12-Br showed significant correlations with the scales MRC (r=0.4641; p=0.0006), BDI (0.515; p<0.0001), SGRQ (r=0.8113; p<0.0001), anxiety (r=0.4714; p=0.0005), depression (0.4139; p=0.0025) and walked distance in the 6 MWT (r=0.3293; p= 0.0255). In the HP group the scale showed significant correlations with the scales MRC (r=0.5774; p=0.0005), SGRQ (r=0.6907; p=0.0044), walked distance in the 6 MWT (0.7193; p=0.0025) and carbon dioxide diffusion capacity (r=0.564; p=0.0447). Cronbach´s alpha calculated for all volunteers evaluated as a whole was 0.927 while the intraclass correlation coefficient was 0.8456. Conclusions: The Dispneia-12-Pt exhibits acceptable biometric properties and may be used as a tool in Brazilian patients with dyspnea of different etiologies.

Lung cancer is the leading cause of death from cancer in the world. First, we hypothesized that microRNA expression is altered in the bronchial epithelium of patients with lung cancer and that incorporating microRNA expression into an existing mRNA biomarker may improve its performance. Using bronchial brushings collected from current and former smokers, we profiled microRNA expression via small RNA sequencing for 347 patients with available mRNA data. We found that four microRNAs were under-expressed in cancer patients compared to controls (p<0.002, FDR<0.2). We explored the role of these microRNAs and their gene targets in cancer. In addition, we found that adding a microRNA feature to an existing 23-gene biomarker significantly improves its performance (AUC) in a test set (p<0.05). Next, we generalized the biomarker discovery process, and developed a visualization tool for biomarker selection. We built upon an existing biomarker discovery pipeline and created a web-based interface to visualize the performance of multiple predictors. The “visualization” component is the key to sorting through a thousand potential biomarkers, and developing clinically useful molecular predictors. Finally, we explored the molecular events leading to the development of COPD and ILD, two heterogeneous diseases with high mortality. We hypothesized that integrative genetic and expression networks can help identify drivers and elucidate mechanisms of genetic susceptibility. We utilized 262 lung tissue specimens profiled with microRNA sequencing, microarray gene expression and SNP chip genotyping. Next, we built condition specific integrative networks using a causality inference test for predicting SNP-microRNA-mRNA associations, where the microRNA is a predicted mediator of the SNP’s effect on gene expression. We identified the microRNAs predicted to affect the most genes within each network. Members of miR-34/449 family, known to promote airway differentiation by repressing the Notch pathway, were among the top ranked microRNAs in COPD and ILD networks, but not in the non-disease network. In addition, the miR-34/449 gene module was enriched among genes that increase in expression over time when airway basal cells are differentiated at an air-liquid interface and among genes that increase in expression with the airway wall thickening in patients with emphysema. / 2019-07-31T00:00:00Z

Emphysema, a subset of COPD, occurs due to an abnormal inflammatory response to noxious gases or particles leading an influx of immunologic cells. Recent studies have demonstrated endothelial dysfunction in COPD subjects and are suggestive of a vascular phenotype present in COPD that is not fully characterized. We hypothesize that processes affecting the pulmonary vasculature lead to early changes important in the pathogenesis of COPD. This work focuses on the use of multidetector-row computed tomography (MDCT)-based measures of pulmonary blood flow (PBF), mean transit time (MTT) and pulmonary vascular volume (TPVV) to gain new insights into vasculature-related changes present in COPD. As a precursor to using perfusion MDCT imaging to phenotype lung disease, we demonstrated good regional correlation of PBF measurements obtained with MDCT imaging and fluorescent microspheres (FMS) at a FMS piece size resolution of 1.9 cm3 and regional volume level of 8-10 cm3. Additionally, we developed an ex vivo perfusion system, and applied quantitative image analysis techniques to study the lung preparation's stability over 120 minutes. We further validated CT-based PBF and MTT measurements by demonstrating physiologically appropriate responses to a range of flow rates with this new system. Finally, quantitative MDCT-based measurements were used to characterize a novel phenotype of emphysema and test hypotheses regarding vasculature-related changes in smokers and COPD subjects. We demonstrated increased heterogeneity in regional MTT and PBF measurements in smokers with preclinical emphysema compared with smokers with normal lung function and imaging studies and nonsmokers. This data is supportive of the notion that inflammatory-based vascular responses to hypoxia are occurring in smokers susceptible to COPD, but are successfully blocked in smokers without signs of emphysema. A new CT-based measure, TPVV, was studied and we demonstrate its association with total lung volume and body size metrics. TPVV measurements correlated with measures of COPD severity. A trend linking increased TPVV with increased endothelial dysfunction was observed, suggesting that pathological changes of COPD have an effect on the pulmonary vasculature. This work demonstrates the importance of functional information that can compliment structural, anatomical information to answer questions based on the lung physiology and pathological disease processes.

Chronic Obstructive Pulmonary Disease (COPD), a growing health concern, is the fourth leading cause of death in the United States. While people habituated to smoking constitute the highest COPD susceptible population, people exposed to air pollution or other lung irritants also form a major group of potential COPD patients. COPD is a progressive disease that is characterized by the combination of chronic bronchitis, small airway obstruction, and emphysema that causes an overall decrease in the lung elasticity affecting the lung tissue. The current gold standard method to diagnose COPD is by pulmonary function tests (PFT) which measures the extent of COPD based on the lung volumes and is further classified into five severity stages. PFT measurements are insensitive to early stages of COPD and also its lack of reproducibility makes it hard to rely on, in assessing the disease progression. Alternatively, Pulmonary CT scans are considered as a major diagnostic tool in analyzing the COPD and CT measures are also closely related to the pathological extent of the disease. Quantification of COPD using features derived from CT images has been proven effective. The most common features are density based and texture based. We propose a new set of features called lung biomechanical features which capture the regional lung tissue deformation patterns during the respiratory cycle. We have tested these features on 75 COPD subjects and 15 normal subjects. We have done classification of COPD/Non COPD on the dataset using the three feature sets and also performed the classification all these subjects to their corresponding severity stage. It is shown that the lung biomechanical features were also able to classify COPD subjects with a good AUC. It is also shown that, by combining the best features from each feature set, there is an improvement in the classifier performance. Multiple regression analysis is performed to find the correlation between the CT derived features and PFT measurements.

Chronic obstructive pulmonary disease (COPD) is a growing health concern associated with high morbidity and mortality, and is currently the third-ranked cause of death in the United States. COPD is characterized by airflow limitation that is not fully reversible and includes chronic bronchitis, functional small airway disease, and emphysema. The interrelationship between emphysema and airway disease in COPD makes it a highly complex and heterogeneous disorder. Appropriate diagnosis of COPD is vital to administer targeted therapy strategies that can improve patient’s quality of life and reduce the frequency of COPD associated exacerbations. Although spirometry or pulmonary function tests are currently the gold standard for the diagnosis and staging of the disease, their lack of reproducibility and minimal information on regional characterization of the lung tissue destruction makes it hard to rely on to phenotype COPD population and predict disease progression. Quantification of COPD, as done by computed tomography (CT) methods has seen significant advancements, helping us understand the complex pathophysiology of this disease. The prospective and established techniques that are derived from CT imaging such as densitometry, texture, airway, and pulmonary vasculature-based analyses have been successful in regional characterization of emphysema related lung tissue destruction and airway disease related morphological changes in COPD patients. Although, these measures enriched our diagnostic and treating capability of COPD, they lack information on patient specific alterations in lung mechanics and regional parenchymal stresses. This valuable information can be achieved through the use of image registration protocols. Our main goal of this research work is to examine and evaluate the role of lung mechanical measures derived from CT image registration techniques in COPD diagnosis, phenotyping, and progression.

Background: Endotoxin is a lipopolysaccharide located on the outer membrane of the cell wall of Gram-negative bacteria that is widespread in the environment. Although domestic endotoxin has been found to be associated with asthma and wheeze, its association with chronic obstructive pulmonary disease (COPD) is unclear. It is also unknown how environmental exposures influence the relationship between endotoxin and asthma and very few studies have investigated the effectiveness of interventions in reducing endotoxin in the homes of people with asthma. Goals: The goals of this dissertation were to examine 1) the association of house dust endotoxin with chronic bronchitis or emphysema, two phenotypes of COPD, 2) the influence on the relationship between endotoxin and asthma outcomes of environmental factors such as exposure to dog and cat in homes, climate regions, as well as co-exposure to ambient air pollution, and 3) the effectiveness of an environmental intervention in reducing home endotoxin and asthma symptoms in rural Iowa children with asthma. Methods: For the first two goals of this dissertation, data from the 2005-2006 National Health and Nutrition Examination Survey (NHANES) was used. Dust sampled from the bedroom floor and bedding of 6,963 children and adult participants was evaluated for endotoxin at the University of Iowa Pulmonary Toxicology facility using a kinetic chromogenic Limulus amebocyte lysate assay. Data on asthma outcomes and chronic bronchitis or emphysema (CBE) was collected using questionnaires. Home exposure to dog and cat was considered by pet ownership and levels of dog (Canis familiaris 1) and cat (Feline domesticus 1) allergens in house dust. Annual average particulate matter ≤2.5 µm (PM2.5), ozone (O3), and nitrogen dioxide (NO2) concentrations at participants’ residential location were estimated using the Community Multiscale Air Quality (CMAQ) and Downscaler (DS) models. In the third goal, data from the Louisa Environmental Intervention Project (LEIP) study which included schoolchildren 5-14 years-old with active asthma from Louisa and Keokuk counties in rural Iowa was analyzed. The households were block-randomized to receive extensive (education + professional cleaning) or educational intervention. Environmental sampling and questionnaire administration were done at baseline and during three follow-up visits. Results: In the NHANES, the median concentration of endotoxin in house dust was 16.2 EU/mg. In adjusted analysis, house dust endotoxin (log10-endotoxin) was associated with increased odds of CBE diagnosis (OR: 1.27, 95% CI: 1.00-1.61) and chronic bronchitis symptoms (OR: 1.78, 95% CI: 1.01-3.12). Sensitization to inhalant allergens modified the relationship between log10-endotoxin and CBE diagnosis (P(interaction)=0.001), with stronger associations observed in sensitized participants (OR: 2.46, 95% CI: 1.72-3.50). The association of endotoxin with asthma outcomes was different with climate regions of the U.S. Endotoxin was associated with higher prevalence of wheeze outcomes in the past 12 months in subarctic/very cold/cold regions (OR: 1.48, 95% CI:1.19-1.85) and in hot-humid regions (OR: 1.66, 95% CI:1.04-2.65). In hot-humid regions, endotoxin was positively associated with current asthma (OR: 1.56, 95% CI:1.11-2.18), but negatively with sensitization to any inhalant allergens (OR: 0.83, 95% CI:0.74-0.92). Exposure to dog and cat allergens enhanced endotoxin association with current asthma (OR: 2.00, 95% CI: 1.04-3.83, P(interaction)=0.012) and wheeze in the past 12 months (OR: 1.88, 95% CI: 1.32-2.66, P(interaction)=0.016). House dust endotoxin co-exposure with PM2.5 (CMAQ) was synergistically associated with emergency room visits for asthma in the past 12 months (OR: 5.01, 95% CI: 2.54-9.87) in general. In children, a synergistic association was found for co-exposure to house dust endotoxin and NO2 with the outcome (OR: 3.45, 95% CI: 1.65-7.18). In LEIP, 104 asthmatic children from 89 homes were included in the study. In the main analysis, extensive compared to the educational intervention was associated with decreased endotoxin load in farm homes (P-value of main effect for intervention <0.0001) and with less frequent nighttime asthma symptoms (Intervention x visit interaction P-value = 0.044). In exploratory analysis, endotoxin load reduction from baseline was associated with less daytime wheeze (OR: 0.59, 95%CI: 0.38-0.91) and daytime cough (OR: 0.62, 95% CI: 0.40-0.97). Conclusions: House dust endotoxin is associated with obstructive pulmonary diseases. The association of endotoxin with asthma outcomes is stronger in cold regions of the U.S. and is enhanced by exposure to pet allergens and co-exposure to ambient air pollutants such as PM2.5 and NO2 in children. The LEIP study demonstrated that extensive cleaning interventions can be effective at reducing endotoxin in the homes children with asthma and can alleviate their symptoms.

<p>ABSTRACT</p><p>Nontypable Haemophilus influenzae is a common cause of otitis, sinusitis and conjunctivitis. It is the most common bacterial pathogen associated with chronic obstructive pulmonary disease (COPD). Studies have shown that nonpathogenic Haemophilus haemolyticus are often mistaken for Haemophilus influenzae due to an absent hemolytic reaction on blood agar. Distinguishing H. haemolyticus from H. influenzae is important to prevent unnecessary antibiotic use, and to understand the role of H. influenzae in clinical infections. In this study, PCR-primers for amplifying 16S rDNA sequences were used to set up a method for distinguishing H. haemolyticus from H. influenzae. The aim was to use the method for analyzing apparent H. influenzae strains, to investigate if some strains were in fact H. haemolyticus. However, because of problems with unspecific primerannealing,no conclusions could be drawn regarding misclassification of H. haemolyticus.</p><p>Moraxella catarrhalis is the second most common bacterial pathogen associated with COPD. It also causes otitis and sinusitis. An important virulence factor of M. catarrhalis is the outer membrane protein Moraxella catarrhalis IgD-binding protein (MID). One part of the protein; MID764-913 , has been shown to function as an adhesin, and this part has been fragmented to further investigate its adhesive properties. The aim of this second, independent study, was to express some of these proteinfragments by cloning in E. coli. The time spent on this project was too short, and no proteins could be expressed duing this period.</p>

This thesis examined associations between ecological indicators of residential radon and fine particulate matter air pollution (PM2.5) and lung cancer mortality using data from the American Cancer Society Cancer Prevention Study-II (CPS-II) prospective cohort. Nearly 1.2 million CPS-II participants were recruited in 1982. Mean county-level residential radon concentrations were linked to study participants according to ZIP code information at enrollment (mean (SD) = 53.5 (38.0) Bq/m3). Cox proportional hazards regression models were used to obtain adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for lung cancer mortality associated with radon. After necessary exclusions, a total of 811,961 participants in 2,754 counties were retained for analysis. A significant positive linear trend was observed between categories of radon concentrations and lung cancer mortality (p = 0.02). A 15% (95% CI 1 - 31%) increase in the risk of lung cancer mortality was observed per each 100 Bq/m3 radon. Radon was also positively associated with chronic obstructive pulmonary disease mortality (HR per each 100 Bq/m3 = 1.13, 95% CI 1.05 - 1.21). No clear associations were observed between radon and non-respiratory mortality. In lifelong never smokers (n = 188,699), each 10 µg/m3 increase in mean metropolitan statistical area PM2.5 concentrations was associated with a 15-27% increase in the risk of lung cancer death which strengthened among individuals with a history of asthma or any prevalent chronic lung disease at enrollment (p for interaction < 0.05). There was no association between PM2.5 and mortality from non-malignant respiratory disease. In conclusion, this thesis observed significant positive associations between ecological indicators of residential radon and PM2.5 concentrations and lung cancer mortality. These findings further support efforts to reduce radon concentrations in homes to the lowest possible level and strengthens the evidence that ambient concentrations of PM2.5 measured in recent decades are associated with small but measurable increases in lung cancer mortality. Further research is needed to better understand possible complex inter-relationships between environmental risk factors, chronic lung disease, and lung cancer.

Introduction: This study explored the health behaviour of older adults with COPD. Objectives included: 1) to explore the process of successfully managing COPD; 2) to identify health behaviour strategies utilized; 3) to identify factors influencing health behaviour change; 4) to understand the impact of pulmonary rehabilitation (PR). Methods: Eleven community-dwelling older adults were interviewed following PR. Interviews were coded and analyzed using constant comparative analysis, comparing and contrasting incoming data with emerging theory. Findings: Two distinct models were developed representing participants’ experience with COPD and health behaviour change: Struggling with Living: Life with COPD before Pulmonary Rehabilitation; and Carrying on with Living: Life with COPD following Pulmonary Rehabilitation. Conclusions: Older adults with COPD engaged in a limited repertoire of health behaviour strategies which were relatively ineffectual prior to participation in PR. PR had a major impact on health behaviour strategies, and on the external and personal factors influencing health behaviour.

Introduction: This study explored the health behaviour of older adults with COPD. Objectives included: 1) to explore the process of successfully managing COPD; 2) to identify health behaviour strategies utilized; 3) to identify factors influencing health behaviour change; 4) to understand the impact of pulmonary rehabilitation (PR). Methods: Eleven community-dwelling older adults were interviewed following PR. Interviews were coded and analyzed using constant comparative analysis, comparing and contrasting incoming data with emerging theory. Findings: Two distinct models were developed representing participants’ experience with COPD and health behaviour change: Struggling with Living: Life with COPD before Pulmonary Rehabilitation; and Carrying on with Living: Life with COPD following Pulmonary Rehabilitation. Conclusions: Older adults with COPD engaged in a limited repertoire of health behaviour strategies which were relatively ineffectual prior to participation in PR. PR had a major impact on health behaviour strategies, and on the external and personal factors influencing health behaviour.