Tiotropium Respimat inhaler and the risk of death in COPD

Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo.

The TORCH (towards a revolution in COPD health) survival study protocol

Only long-term home oxygen therapy has been shown in randomised controlled trials to increase survival in chronic obstructive pulmonary disease (COPD). There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators, alone or in combination, on mortality in patients with COPD, despite their known benefit in reducing symptoms and exacerbations. The "TOwards a Revolution in COPD Health" (TORCH) survival study is aiming to determine the impact of salmeterol/fluticasone propionate (SFC) combination and the individual components on the survival of COPD patients. TORCH is a multicentre, randomised, double-blind, parallel-group, placebo-controlled study. Approximately 6,200 patients with moderate-to-severe COPD were randomly assigned to b.i.d. treatment with either SFC (50/500 microg), fluticasone propionate (500 microg), salmeterol (50 microg) or placebo for 3 yrs. The primary end-point is all-cause mortality; secondary end-points are COPD morbidity relating to rate of exacerbations and health status, using the St George's Respiratory Questionnaire. Other end-points include other mortality and exacerbation end-points, requirement for long-term oxygen therapy, and clinic lung function. Safety end-points include adverse events, with additional information on bone fractures. The first patient was recruited in September 2000 and results should be available in 2006. This paper describes the "TOwards a Revolution in COPD Health" study and explains the rationale behind it.

S21 Culture Independent Identification Of Bacterial Communities In The Respiratory Tract Of Patients With Copd, Healthy Non-smokers And Healthy Smokers

Introduction and aims: The role bacteria play in the development and progression of Chronic Obstructive Pulmonary Disease (COPD) is unclear. We used culture-independent methods to describe differences and/or similarities in microbial communities in the lower airways of patients with COPD, healthy non-smokers and smokers.

Methods: Bronchial wash samples were collected from patients with COPD (GOLD 1–3; n = 18), healthy non-smokers (HV; n = 11) and healthy smokers (HS; n = 8). Samples were processed using the Illumina MiSeq platform. The Shannon-Wiener Index (SW) of diversity, lung obstruction (FEV1/FVC ratio) and ordination by Non-Metric Multidimensional Scaling (NMDS) on Bray-Curtis dissimilarity indices were analysed to evaluate how samples were related. Principal component analysis (PCA) was performed to assess the effect specific taxa had within each cohort. Characteristics of each cohort are shown in Table 1.

Results: There was no difference in taxa richness between cohorts (range: 69–71; p = 0.954). Diversity (SW Index) was significantly lower in COPD samples compared to samples from HV and HS (p = 0.009 and p = 0.033, respectively). There was no significant difference between HV and HS (p = 0.186). The FEV1/FVC ratio was significantly lower for COPD compared to HV (p = 9*10–8) and HS (p = 2*10–6), respectively. NMDS analysis showed that communities belonging to either of the healthy groups were more similar to each other than they were to samples belonging to the COPD group. PCA analysis showed that members of Streptococcus sp. and Haemophilus sp. had the largest effect on the variance explained in COPD. In HS, Haemophilus sp., Fusobaterium sp., Actinomyces sp., Prevotella sp. and Veillonella sp. had the largest effect on the variance explained, while in HV Neisseria sp., Porphyromonas sp., Actinomyces sp., Atopobium sp., Prevotella and Veillonella sp. had the largest effect on the variance explained.

Conclusions: The study demonstrates that microbial communities in the lower airways of patients with COPD are significantly different from that seen in healthy comparison groups. Patients with COPD had lower microbial diversity than either of the healthy comparison groups, higher relative abundance of members of Streptococcus sp. and lower relative abundance of a number of key anaerobes.Characteristics

Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4)

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components. These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.

Antitussive drugs--past, present, and future

Cough remains a serious unmet clinical problem, both as a symptom of a range of other conditions such as asthma, chronic obstructive pulmonary disease, gastroesophageal reflux, and as a problem in its own right in patients with chronic cough of unknown origin. This article reviews our current understanding of the pathogenesis of cough and the hypertussive state characterizing a number of diseases as well as reviewing the evidence for the different classes of antitussive drug currently in clinical use. For completeness, the review also discusses a number of major drug classes often clinically used to treat cough but that are not generally classified as antitussive drugs. We also reviewed a number of drug classes in various stages of development as antitussive drugs. Perhaps surprising for drugs used to treat such a common symptom, there is a paucity of well-controlled clinical studies documenting evidence for the use of many of the drug classes in use today, particularly those available over the counter. Nonetheless, there has been a considerable increase in our understanding of the cough reflex over the last decade that has led to a number of promising new targets for antitussive drugs being identified and thus giving some hope of new drugs being available in the not too distant future for the treatment of this often debilitating symptom.

Pooled analysis of tiotropium Respimat® pharmacokinetics in cystic fibrosis

Tiotropium is the first bronchodilator to be studied systematically in cystic fibrosis (CF). We investigated whether any intrinsic or extrinsic factors affected pharmacokinetic (PK) parameters of inhaled tiotropium delivered by Respimat® in adults and children with CF. Tiotropium PK in patients with CF was compared with that of healthy volunteers and patients with chronic obstructive pulmonary disease (COPD). This pooled analysis summarizes the PK parameters of inhaled tiotropium Respimat® across 9 early- and late-phase trials involving 27 healthy volunteers (1 trial), 409 patients with CF (3 trials), and 281 patients with COPD (5 trials). Patients with CF aged 5 to 11, 12 to 17, and ≥18 years had similar tiotropium plasma concentrations (geometric mean C_{0.083,ss,norm}: 2.22pg/mL/μg; not determined for patients aged <5 years). The fraction excreted unchanged in the urine was 3.4-fold lower for patients aged 0.4 to <5 years than for those aged 5 to 11 years (fe_0-4,ss: 1.19% vs 4.09%). Tiotropium PK parameters were similar between CF patients and COPD patients.

Relationship between Azithromycin Susceptibility and Administration Efficacy for Nontypeable Haemophilus influenzae Respiratory Infection

Nontypeable Haemophilus influenzae (NTHI) is an opportunistic pathogen that is an important cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). COPD is an inflammatory disease of the airways, and exacerbations are acute inflammatory events superimposed on this background of chronic inflammation. Azithromycin (AZM) is a macrolide antibiotic with antibacterial and anti-inflammatory properties and a clinically proven potential for AECOPD prevention and management. Relationships between AZM efficacy and resistance by NTHI and between bactericidal and immunomodulatory effects on NTHI respiratory infection have not been addressed. In this study, we employed two pathogenic NTHI strains with different AZM susceptibilities (NTHI 375 [AZM susceptible] and NTHI 353 [AZM resistant]) to evaluate the prophylactic and therapeutic effects of AZM on the NTHI-host interplay. At the cellular level, AZM was bactericidal toward intracellular NTHI inside alveolar and bronchial epithelia and alveolar macrophages, and it enhanced NTHI phagocytosis by the latter cell type. These effects correlated with the strain MIC of AZM and the antibiotic dose. Additionally, the effect of AZM on NTHI infection was assessed in a mouse model of pulmonary infection. AZM showed both preventive and therapeutic efficacies by lowering NTHI 375 bacterial counts in lungs and bronchoalveolar lavage fluid (BALF) and by reducing histopathological inflammatory lesions in the upper and lower airways of mice. Conversely, AZM did not reduce bacterial loads in animals infected with NTHI 353, in which case a milder anti-inflammatory effect was also observed. Together, the results of this work link the bactericidal and anti-inflammatory effects of AZM and frame the efficacy of this antibiotic against NTHI respiratory infection.

Interventions to increase physical activity in patients with COPD: A comprehensive review

It is unknown how interventions aimed at increasing physical activity (PA), other than traditional pulmonary rehabilitation, are structured and whether they are effective in increasing PA in chronic obstructive pulmonary disease (COPD). The primary aim of this review was to outline the typical components of PA interventions in patients with COPD. This review followed the PRISMA guidelines. A structured literature search of relevant electronic databases from inception to April 2014 was undertaken to outline typical components and examine outcome variables of PA interventions in patients with COPD. Over 12000 articles were screened and 20 relevant studies involving 31 PA interventions were included. Data extracted included patient demographics, components of the PA intervention, PA outcome measures and effects of the intervention. Quality was assessed using the PEDro and CASP scales. There were 13 randomised controlled trials and three randomised trials (PEDro score 5-7/10) and four cohort studies (CASP score 5/10). Interventions varied in duration, number of participant/researcher contacts and mode of delivery. The most common behaviour change techniques included information on when and where (n = 26/31) and how (n = 22/31) to perform PA behaviour and self-monitoring (n = 18/31). Significant between-group differences post-intervention in favour of the PA intervention, compared to a control group or to other PA interventions, in one or more PA assessments were found in 7/16 studies. All seven studies used walking as the main type of PA/exercise. In conclusion, although the components of PA interventions were variable, there is some evidence that PA interventions have the potential to increase PA in patients with COPD

Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

Therapies that are safe, effective, and not vulnerable to developing resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an antimicrobial approach alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by using host-directed drugs. In this study, we identified and evaluated the efficacy of a panel of host-directed drugs against respiratory infection by nontypeable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing cell whole-genome expression profiling and identified a repertoire of host target candidates that were pharmacologically modulated. Based on the proposed relationship between NTHi intracellular location and persistence, we hypothesized that drugs perturbing host pathways used by NTHi to enter epithelial cells could have antimicrobial potential against NTHi infection. Interfering drugs were tested for their effects on bacterial and cellular viability, on NTHi-epithelial cell interplay, and on mouse pulmonary infection. Glucocorticoids and statins lacked in vitro and/or in vivo efficacy. Conversely, the sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi, and the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts intracellularly and in the lungs of infected mice. PDE4 inhibition is currently prescribed in COPD, and resveratrol is an attractive geroprotector for COPD treatment. Together, these results expand our knowledge of NTHi-triggered host subversion and frame the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection.

Translating proteomics into environmental health : biomarkers discovery for tobacco smoke-induced biological damage

Tese de doutoramento, Biologia (Biologia Molecular), Universidade de Lisboa, Faculdade de Ciências, 2015

Intervenção nutricional numa população hospitalizada em função do risco e estado nutricional

Relatório de estágio de mestrado, Nutrição Clínica, Universidade de Lisboa, Faculdade de Medicina, 2015

Fractional-order impulse response of the respiratory system

This paper presents the measurement, frequency-response modeling and identification, and the corresponding impulse time response of the human respiratory impedance and admittance. The investigated adult patient groups were healthy, diagnosed with chronic obstructive pulmonary disease and kyphoscoliosis, respectively. The investigated children patient groups were healthy, diagnosed with asthma and cystic fibrosis, respectively. Fractional order (FO) models are identified on the measured impedance to quantify the respiratory mechanical properties. Two methods are presented for obtaining and simulating the time-domain impulse response from FO models of the respiratory admittance: (i) the classical pole-zero interpolation proposed by Oustaloup in the early 90s, and (ii) the inverse discrete Fourier Transform (DFT). The results of the identified FO models for the respiratory admittance are presented by means of their average values for each group of patients. Consequently, the impulse time response calculated from the frequency response of the averaged FO models is given by means of the two methods mentioned above. Our results indicate that both methods provide similar impulse response data. However, we suggest that the inverse DFT is a more suitable alternative to the high order transfer functions obtained using the classical Oustaloup filter. Additionally, a power law model is fitted on the impulse response data, emphasizing the intrinsic fractal dynamics of the respiratory system.

Is multidimensional scaling suitable for mapping the input respiratory impedance in subjects and patients?

This paper presents the application of multidimensional scaling (MDS) analysis to data emerging from noninvasive lung function tests, namely the input respiratory impedance. The aim is to obtain a geometrical mapping of the diseases in a 3D space representation, allowing analysis of (dis)similarities between subjects within the same pathology groups, as well as between the various groups. The adult patient groups investigated were healthy, diagnosed chronic obstructive pulmonary disease (COPD) and diagnosed kyphoscoliosis, respectively. The children patient groups were healthy, asthma and cystic fibrosis. The results suggest that MDS can be successfully employed for mapping purposes of restrictive (kyphoscoliosis) and obstructive (COPD) pathologies. Hence, MDS tools can be further examined to define clear limits between pools of patients for clinical classification, and used as a training aid for medical traineeship.

A Review of National Guidelines for Management of COPD in Europe

The quality of care can be improved by the development and implementation of evidence-based treatment guidelines. Different national guidelines for chronic obstructive pulmonary disease (COPD) exist in Europe and relevant differences may exist among them.This was an evaluation of COPD treatment guidelines published in Europe and Russia in the past 7 years. Each guideline was reviewed in detail and information about the most important aspects of patient diagnosis, risk stratification and pharmacotherapy was extracted following a standardised process. Guidelines were available from the Czech Republic, England and Wales, Finland, France, Germany, Italy, Poland, Portugal, Russia, Spain and Sweden. The treatment goals, criteria for COPD diagnosis, consideration of comorbidities in treatment selection and support for use of long-acting bronchodilators, were similar across treatment guidelines. There were differences in measures used for stratification of disease severity, consideration of patient phenotypes, criteria for the use of inhaled corticosteroids and recommendations for other medications (e.g. theophylline and mucolytics) in addition to bronchodilators.There is generally good agreement on treatment goals, criteria for diagnosis of COPD and use of long-acting bronchodilators as the cornerstone of treatment among guidelines for COPD management in Europe and Russia. However, there are differences in the definitions of patient subgroups and other recommended treatments.

Análise comparativa das readmissões hospitalares nas Unidades Locais de Saúde (ULS) e nos Hospitais

RESUMO - Introdução: Os modelos organizacionais de saúde baseados na gestão integrada de cuidados têm permitido melhorar os resultados em saúde. A taxa de readmissão hospitalar (um indicador de resultados) tem diminuído nas instituições que adotaram aquele modelo de gestão. Em Portugal, a criação das Unidades Locais de Saúde, representa a adoção de um modelo baseado na gestão integrada entre os cuidados de saúde hospitalares, primários e continuados, pelo que importa comparar a taxa de readmissões hospitalares entre os hospitais com esse modelo e os restantes Hospitais. Metodologia: Determinaram-se as readmissões não planeadas a 30 dias nos hospitais públicos portugueses do Continente durante 2013, segundo a metodologia do Centers for Medicare and Medicaid Service, que usa um algoritmo que identifica as readmissões que são habitualmente planeadas e podem ocorrer no prazo de 30 dias após a alta hospitalar. Foi calculada a taxa anual de readmissão por tipo de hospital e a sua frequência por género, faixa etária e para indivíduos com insuficiência cardíaca, doença pulmonar obstrutiva crónica, diabetes mellitus e hipertensão arterial. Resultados: Dos 692.211 episódios de internamento de 2013, 6,0% corresponderam a readmissões hospitalares não planeadas a 30 dias. Os episódios de internamento nas Unidades Locais de Saúde foram 72.725, sendo 6,6% readmitidos. Nos restantes Hospitais foram 619.486, sendo 6,0% readmitidos. A taxa de readmissão registada nos indivíduos do sexo masculino foi superior à do sexo feminino nas Unidades Locais de Saúde (7,6% vs. 6,0%) e nos restantes Hospitais (6,7% vs. 5,4%), não sendo esta diferença estatisticamente significativa (p> 0,05). Foram identificadas diferenças estatisticamente significativas (p <0,05) nas taxas de readmissão por faixa etária, sendo as pessoas com 65 anos ou mais as que apresentaram a maior taxa de readmissão nas Unidades Locais de Saúde (10,3%) e nos restantes Hospitais (10,0%). Quando analisadas as readmissões por patologia, nas Unidades Locais de Saúde os doentes com doença pulmonar obstrutiva crónica foram os que apresentaram a maior taxa de readmissão (17,5%) e os doentes com insuficiência cardíaca os que apresentaram a maior taxa de readmissão para os restantes Hospitais (16,4%). Conclusão: Em termos gerais, a frequência das readmissões nas Unidades Locais de Saúde é superior à dos restantes Hospitais. Os resultados obtidos podem indicar dificuldades na operacionalização do modelo de gestão adotado pelas Unidades Locais de Saúde, nomeadamente falhas na coordenação dos cuidados entre os diferentes níveis de prestação de cuidados.