The effects of extrafine beclometasone/formoterol (BDP/F) on lung function, dyspnea, hyperinflation, and airway geometry in COPD patients: novel insight using functional respiratory imaging

Background: The efficacy of inhaled corticosteroids (ICS) in moderately severe COPD patients remains unclear. At the same time, the use of extrafine particles in COPD patients is a topic of ongoing research. Objectives: This study assessed the effect of ICS in steroid-naive mild COPD patients and the effect of reducing the ICS dose in more severe COPD patients previously using ICS when switching to an extrafine particle BDP/F formulation (Foster using Modulite technology, Chiesi Pharmaceutici, Parma, Italy). Methods: Novel functional respiratory imaging (FRI) methods, consisting of multi-slice CT scans and Computational Fluid Dynamics, were used in combination with conventional pulmonary function tests and patient reported outcomes. Results: The study showed that the administration of extrafine BDP/F after 4-6 h led to a significant improvement in lung function parameters and hyperinflation as determined by spirometry, body plethysmography, and functional respiratory imaging. After 6 months of treatment, it was observed that, compared to baseline, the hyperinflation on lobar level at total lung capacity was significantly reduced (-1.19 +/- 7.19 %p, p=0.009). In addition, a significant improvement in SGRQ symptom score was noted in the entire patient population. Patients who improved in terms of hyperinflation also improved their MMRC dyspnea score. CFD indicated a difference in regional deposition between extrafine and non-extrafine formulations with -11% extrathoracic deposition and up to +4% lobe deposition for the extrafine formulation. Conclusions: The study showed that the administration of extrafine BDP/F improved lung function parameters and hyperinflation. Patients previously treated with ICS remained stable despite the lower dose, while ICS naive patients improved in terms of lobar hyperinflation. FRI seems to be a sensitive biomarker to detect clinically relevant changes that are not detected by spirometry. The next step is to confirm these findings in a controlled trial

Oscillatory Positive Expiratory Pressure (OPEP) therapy in COPD

People with chronic obstructive pulmonary disease (COPD) commonly have a productive cough due to mucus hypersecretion. Clearing mucus from the chest can be difficult, as lung hyperinflation, respiratory muscle dysfunction and premature airway collapse impede the ability to generate an effective cough. Airway Clearance Techniques (ACTs) with the use of oscillating positive expiratory pressure (OPEP) devices can be added to the usual care for sputum clearance. However, assessment of the effect of OPEP devices is so far based on short-term studies with low-grade evidence and there is a lack of information regarding their long-term impact and effectiveness. In this thesis, I have four results chapters to discuss this gap. First, using accepted systematic review methodology to rigorously examine the current evidence on the use of OPEP devices for the treatment of cough and sputum clearance in patients with COPD who frequently produce sputum. Second, conduct a randomised clinical trial (acronym: O-COPD) to evaluate the impact of an OPEP device (the Acapella) on the health-related quality of life in patients with COPD over three-months. Third, study cough characteristics and its relationship to overnight sleep disturbances. Fourth, evaluate the impact of an OPEP device (the Acapella) on cough frequency and sleep actigraphy in a subset of the O-COPD group. In summary, results from the O-COPD trial, coupled with the systematic review, can address the concerns raised regarding the long-term effectiveness of OPEP devices in treating sputum aspects in stable COPD patients. COPD patients with sputum production who received OPEP treatment for three months, compared to the usual care, demonstrated better disease management and improvement in general and cough-related quality of life (LCQ). The findings suggest that adding the OPEP device is effective in optimising the usual care and, perhaps, can be the new mode of usual care in managing cough and sputum production in COPD patients. Larger and longer clinical trials are required to guide the long-term use of OPEP and patient selection.Open Acces

Quantitative pulmonary imaging using computed tomography and magnetic resonance imaging

Measurements of lung function, including spirometry and body plethesmography, are easy to perform and are the current clinical standard for assessing disease severity. However, these lung functional techniques do not adequately explain the observed variability in clinical manifestations of disease and offer little insight into the relationship of lung structure and function. Lung imaging and the image-based assessment of lung disease has matured to the extent that it is common for clinical, epidemiologic and genetic investigation to have a component dedicated to image analysis. There are several exciting imaging modalities currently being used for the non-invasive study of lung anatomy and function. In this review, we will focus on two of them; X-ray computed tomography and magnetic resonance imaging. Following a brief introduction of each method, we detail some of the most recent work being done to characterize smoking-related lung disease and the clinical applications of such knowledge

Efeito da reabilitação respiratória na microbiota pulmonar detetada na saliva de doentes com DPOC

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of mortality worldwide. Pulmonary Rehabilitation (PR), a comprehensive intervention that includes several components, one of which is exercise training, is the most cost-effective therapy for patients with COPD. Exercise training increases ventilation and oxygen uptake, which most likely influences airway microbiota. However, how this influence occurs is still poorly understood. This study aimed to study the impact of RR on pulmonary microbiota in patients with COPD by exploring the microbial composition, alpha and beta diversity. Sociodemographic, anthropometric, clinical and saliva samples (once a month) were collected from a group of patients over a period of ~ 9 months (~ 3 months before RR, 3 months during RR and 3 months after RR) and in another patient group for a period of 6 months (without RR). Saliva microbiota was characterized by 16s rRNA sequencing and analyzed using the QIIME2 pipeline. Twenty-five patients with COPD who underwent PR (19♂, 73±6y, FEV1pp 48±15) and 5 patients who never had PR (5♂, 75±6y, FEV1pp 48±13) participated in the study. A significant increase of Proteobacteria phylum and Neisseria genus from pre-PR to PR period was observed. LEfSe showed that pre-PR comparing with during PR, samples’ microbiotas are enriched in the genera Pseudomonas and Shingomonas and during PR samples’ microbiotas are enriched in Neisseria and Alloscardovia. When comparing the periods during PR with post-PR, LEfSe pointed Granulicatella and Acinetobacter as being enriched during PR period and Staphylococcus, Selenomonas and Pasteurellaceae family as being enriched in the post-PR period. Comparing pre-PR with post-PR periods, LEfSe pointed Granulicatella, Sphingomonas, Pseudomonas and Enhydrobacter as being enriched in the pre-PR period and Pasteurellaceae family as being enriched in the post-PR period. No significant differences were observed in alfa diversity when comparing the different periods. LME model showed that time has a significant impact in alfa-diversity and that the interaction between PR and time passage are mainly contributing for microbiota dynamics, in non-phylogenetic metrics. PERMANOVA showed that microbiota does not converge per period. In conclusion, PR does not seem to significantly alter the structure of microbiota (alpha diversity) but changes composition. In general, alpha diversity is influenced by the passage of time and not by PR. Beta-diversity analyses showed that there is no microbiota convergence during or after PR. In non-phylogenetic metrics, microbiota dissimilarity is impacted by interaction between PR and time passage.A doença pulmonar obstrutiva crónica (DPOC) é a terceira principal causa de mortalidade no mundo. A Reabilitação Respiratória (RR), uma intervenção compreensiva que, inclui várias componentes sendo uma delas o exercício físico, é a terapia mais custo-efetiva para os doentes com DPOC. O exercício físico aumenta a ventilação e captação de oxigénio, o que provavelmente influencia a microbiota das vias aéreas. No entanto, a forma como esta influência ocorre é ainda pouco compreendida. Este estudo teve como objetivo estudar o impacto da RR na microbiota pulmonar em doentes com DPOC explorando a composição microbiana, alfa e beta diversidade. Foram recolhidos dados sociodemográficos, antropométricos, clínicos e amostras de saliva (uma vez por mês) num grupo de doentes durante um período de ~9 meses (~3 meses antes da RR, 3 meses durante a RR e 3 meses após a RR) e noutro grupo de doentes durante um período de 6 meses (sem RR). A microbiota da saliva foi caracterizada pelo sequenciamento de 16s rRNA e analisada usando o pipeline QIIME2. Participaram no estudo 25 doentes com DPOC que realizaram RR (19♂, 73±6y, FEV1pp 48±15) e 5 doentes que nunca realizaram RR (5♂, 75±6y, FEV1pp 48±13). Observou-se um aumento significativo do filo Proteobacteria e do género Neisseria do período pré-RR para durante a RR. O LefSe mostrou que a microbiota das amostras do periodo pré-RR em comparação com o período durante a RR são enriquecidas nos géneros Pseudomonas e Shingomonas e a microbiota das amostras do período RR em comparação com o período pré-RR são enriquecidas em Neisseria e Alloscardovia. Comparando entre os períodos RR e pós-RR, o LEfSe apontou os géneros Granulicatella e Acinetobacter como sendo enriquecidas nas amostras do período RR e os géneros Staphylococcus, Selenomonas e a família Pasteurellaceae como sendo enriquecida no período pós-RP. Comparando o pré-PR com o período pós-PR, LEfSe apontou os géneros Granulicatella, Sphingomonas, Pseudomonas e Enhydrobacter como sendo enriquecidas no período pré-PR e a família Pasteurellaceae como sendo enriquecida no período pós-PR. Não foram observadas diferenças significativas na alfa-diversidade comparando os diferentes períodos. O modelo LME mostrou que o tempo tem um impacto significativo na alfa-diversidade e que a interação entre a RR e passagem no tempo contribui para a dinâmica da microbiota, em métricas não filogenéticas. A PERMANOVA mostrou que a microbiota não converge por período. Em conclusão, a RR não parece alterar significativamente a estrutura da microbiota (alfa-diversidade), mas sim a sua composição. Em geral, a alfa-diversidade é influenciada pela passagem do tempo e não pela RR. As análises da beta-diversidade mostram que não há convergência da microbiota durante nem apos a RR. Em métricas não filogenéticas, a dissemelhança da microbiota é influenciada pela interação entre a RR e a passagem do tempo.Mestrado em Biomedicina Molecula

Exploring Pulmonary Rehabilitation Strategies for those with Respiratory Conditions

Effective rehabilitation strategies are paramount to improve physiological and psychological health in pulmonary disease. The aim of this thesis was to investigate traditional and alternative pulmonary rehabilitation strategies in those with chronic respiratory disease. Chapter Four found that traditional pulmonary rehabilitation (PR) was physiologically and psychologically effective, regardless of respiratory disease, with socioeconomic status being a key determinant of adherence. Chapter Five investigated the feasibility and acceptability of IMT. Children aged 10.8 ± 0.8 years with Cystic Fibrosis (CF) enjoyed the IMT intervention, perceiving improvements in their physical ability and psychosocial health. The care team highlighted that future interventions needed to be longer and to monitor engagement and adherence. Chapter Six assessed the effectiveness of an alternative rehabilitation strategy, using a four-week inspiratory muscle training (IMT) intervention, on lung function and heart rate variability in children with CF aged 10.8 ± 1.1 years. There were significant and clinically meaningful increases in respiratory muscle strength, a clinically meaningful decrease in sympathetic modulation, and decreases in respiratory symptoms. Subsequently, utilising the formative, physiological and psychological findings derived from Chapters Five and Six, an eight-week IMT intervention with live biofeedback, performed at 80% maximal inspiratory pressure, three times a week was implemented, with an eight-week optional IMT top-up. Overall, Chapter Seven found that eight weeks of IMT elicited significant increases in respiratory muscle strength, aerobic capacity and in CF-specific questionnaire domains in children (11.0 ± 2.2 years) with CF, which were maintained following the eight-week top-up period. Chapter Eight demonstrated significant improvements in inspiratory muscle strength and endurance after eight weeks, with sustained improvements in physiological health after 16-weeks in adults with bronchiectasis (64.5 ± 10.3 years). CF and bronchiectasis participants demonstrated high levels of adherence and reported competency and autonomy. Overall, IMT may be an effective and feasible alternative to pulmonary rehabilitation

Clot microatructure (dt) as a blomarker and measurement of thrombogenlcity in Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)

Introduction: Chronic obstructive pulmonary disease is an inflammatory condition of the lungs characterised by irreversible airway obstruction and impairment of gas exchange. Acute exacerbation is associated with an increased incidence of venous thromboembolism. The main aim of the study was to investigate whether patients with acute exacerbation were thrombogenic utilising the functional biomarker of clot microstructure, the fractal dimension (df). Methodology: The study recruited 30 stable patients from the chest clinic and 85 patients with acute exacerbation from the Emergency Department of a tertiary teaching hospital. One sample of blood was taken from stable group. Acute exacerbation group had four sampling points at 0 hours, 4-6 hours, 24 hours and 3-7 days. Results: The biomarker, df was significantly elevated in patients presenting with acute exacerbation when compared to stable group (1.71 ± 0.06 vs 1.69 ± 0.05, p=0.03). There was no significant increase in df across the four time points (p=0.28) in the acute exacerbation group. All inflammatory markers and fibrinolytic markers such as D-dimer were significantly higher in acute exacerbation group. Those who died during admission in the acute exacerbation group had significantly elevated df when compared to those who survived (1.76 ± 0.03 vs 1.71 ± 0.06, p=0.02) and binary regression analysis showed that df was a significant predictor of mortality (p=0.024). Conclusions: Patients with chronic obstructive pulmonary disease during exacerbation had denser and tighter clot microstructure as demonstrated by significantly elevated df when compared to stable group indicating that they were thrombogenic. This was due to profound inflammatory response and increased fibrin production. However, with appropriate treatments and prophylactic anticoagulation, there was no further increase in df which might explain low incidence of venous thromboembolism during admissions. Therefore, df is a useful biomarker that measures thrombogenicity, effect of treatment and predicts mortality in patients with acute exacerbation

Effect on smoking quit rate of telling patients their lung age: the Step2quit randomised controlled trial

Objective To evaluate the impact of telling patients their estimated spirometric lung age as an incentive to quit smoking.Design Randomised controlled trial.Setting Five general practices in Hertfordshire, England.Participants 561 current smokers aged over 35.Intervention All participants were offered spirometric assessment of lung function. Participants in intervention group received their results in terms of "lung age" (the age of the average healthy individual who would perform similar to them on spirometry). Those in the control group received a raw figure for forced expiratory volume at one second (FEV1). Both groups were advised to quit and offered referral to local NHS smoking cessation services.Main outcome measures The primary outcome measure was verified cessation of smoking by salivary cotinine testing 12 months after recruitment. Secondary outcomes were reported changes in daily consumption of cigarettes and identification of new diagnoses of chronic obstructive lung disease.Results Follow-up was 89%. Independently verified quit rates at 12 months in the intervention and control groups, respectively, were 13.6% and 6.4% (difference 7.2%, P=0.005, 95% confidence interval 2.2% to 12.1%; number needed to treat 14). People with worse spirometric lung age were no more likely to have quit than those with normal lung age in either group. Cost per successful quitter was estimated at 280 pound ((euro) 365, $556). A new diagnosis of obstructive lung disease was made in 17% in the intervention group and 14% in the control group; a total of 16% (89/561) of participants.Conclusion Telling smokers their lung age significantly improves the likelihood of them quitting smoking, but the mechanism by which this intervention achieves its effect is unclear.Trial registration National Research Register N0096173751