Dissertations / Theses on the topic 'Chronic obstructive pulmonary disease patients'

It is estimated that within a few years chronic obstructive pulmonary disease (COPD) will be the third leading cause of death worldwide. The morbidity and mortality associated with COPD are due, in part to acute exacerbation episodes (AECOPD), mainly caused by microbial pathogens such as Haemophilus influenzae, Streptococcus pneumoniae and Pseudomonas aeruginosa. Moreover, COPD is the main underlying disease associated with pneumococcal pneumonia episodes. This thesis describes four studies performed to gain insights into the role of pneumococci and their closely-related species S. pseudopneumoniae in causing acute exacerbation and pneumonia episodes in COPD patients. In the first study, a total of 188 sputum samples were obtained from AECOPD episodes occurring in severe COPD patients during a 1-year period. Samples were quantitatively cultured; of them, S. pneumoniae was isolated in 31 (16.5%) episodes and S. pseudopneumoniae in 9 (4.8%) episodes. S. pneumoniae was the third most frequent cause after Pseudomonas aeruginosa (28.8%) and Haemophilus influenzae (19.7%). There are major differences in the invasiveness potential of pneumococci, depending on their serotype and genotype. Indeed, in our second study (from 2001 to 2008) we found an association of certain serotypes, and their related genotypes, with different pneumococcal infections. Serotypes 4 (ST2474), 5 (Colombia5-ST289) and 8 (Netherlands8-ST53) were associated with bacteraemic pneumonia, serotypes 1 (Sweden1-ST306) and 3 (Netherlands3-ST180 and ST2603) with bacteraemic and non-bacteraemic pneumonia, and serotypes 16F (ST3016F), 11A and non-typeable pneumococci with AECOPD episodes (P<0.05). Finally, in our experience, serotype 3 pneumococcus was the most frequent cause of pneumonia and acute exacerbations in COPD patients. Moreover, the implementation of pneumococcal conjugate vaccine PCV7 for children in 2001 in Spain has been shown to be highly effective in reducing invasive pneumococcal disease in children, and in adults as well due to the phenomenon of herd protection. This effect was also observed among pneumococci causing acute exacerbations in adults: PCV7 serotypes decreased from 39.4% in the 2001-04 period to 11.2% in the 2009-12 period. In parallel, the prevalence of multi-drug resistant serotypes 15A and 6C has dramatically increased in recent years. For this reason, although the resistance rates of β-lactams decreased over time, macrolides and multi-drug resistance remained stable throughout the study period. The presence of bacteria colonizing the lower airways of most severe COPD patients results in bronchial epithelial injury and increases morbidity among these patients. In the third study (1995-2010 period), it was found that a third of recurrent pneumococcal acute exacerbations were relapses (caused by a pre-existing strain), mainly associated with serotypes 9V and 19F (P<0.02). This suggests an important role for capsular type in pneumococcal persistence. In view of these results, we analysed the impact of antimicrobial consumption in the development of pneumococcal resistance to β-lactams and fluoroquinolones in 13 patients with a long-time persistence of pneumococci (average time: 582 days, SD ±362). Changes in quinolone-resistant determining regions (QRDR) involved in fluoroquinolone resistance were frequently observed in persistent strains after fluoroquinolone treatment; however, the penicillin-binding protein (PBP) sequences were stable over time, even though all but two patients received multiple courses of β-lactam treatment. These results suggest that an optimal combination of pbp genes is maintained to compensate for the fitness cost imposed by additional changes in these genes. Despite the genetic stability of these persistent strains, S. pneumoniae is naturally transformable and is able to acquire exogenous DNA, resulting in a dynamic and complex epidemiology of pneumococcal diseases. This genetic diversity was also observed among the 36 S. pseudopneumoniae strains analysed. Altogether, our studies can help to improve the understanding of the dynamics of S. pneumoniae and S. pseudopneumoniae populations causing disease in COPD patients.
En aquesta tesis, es van dur a terme quatre estudis amb l’objectiu d’aprofundir en el paper de S. pneumoniae com a causant d’exacerbacions agudes i pneumònia en pacients amb MPOC. En el primer estudi, es van sembrar quantitativament un total de 188 mostres d’esput obtingudes durant episodis d’EAMPOC en pacients amb MPOC avançat, durant un any d’estudi (febrer 2010 - febrer 2011). S. pneumoniae es va aïllar en 31 (16.5%) episodis i fou la tercera causa d’exacerbació, després de Pseudomonas aeruginosa (28.8%) i Haemophilus influenzae (19.7%). En el segon estudi es va trobar una diferent associació d’alguns serotipus i del seus genotipus relacionats, en pacients amb MPOC amb diferents infeccions pneumocòcciques (període 2001-2008). El serotipus 3 va ser la causa més freqüent de pneumònia i d’EAMPOC, però els serotipus 4 (ST2474), 5 (Colombia5-ST289) i 8 (Netherlands8-ST53) es varen associar amb pneumònia bacterièmica; serotipus 1 (Sweden1-ST306) i 3 (Netherlands3-ST180 i ST2603) es varen associar amb pneumònia tant bacterièmica com no bacterièmica; mentre serotipus 16F (ST3016F), 11A i els pneumococs no-tipificables es varen associar amb EAMPOC (P<0.05). Degut a la implementació de la vacuna conjugada PCV7, els serotipus inclosos en la vacuna han disminuït del 39.4% en el període 2001-2004 a 11.2% en el període 2008-2012. Paral•lelament a aquest descens, els serotipus 15A i 6C han augmentat dramàticament en els últims anys. Per aquesta raó, la multiresistència s’ha mantingut estable durant tot el període d’estudi. En el tercer estudi (1995-2010), es va observar que un terç dels episodis d’EAMPOC recurrents, varen ser causats per una soca preexistent, principalment serotipus 9V i 19F (P<0.05), considerant-se recaigudes. Aquest fet suggereix un paper important del tipus capsular en la persistència. Finalment, es va analitzar l’impacte del consum d’antimicrobians en el desenvolupament de resistència en 13 pacients colonitzats per pneumococc (temps mitjà: 582 dies, DS ±362). Es van observar canvis en les QRDRs de les soques d’aquells pacients que van rebre tractament amb fluoroquinolones. En canvi, les PBPs de les soques persistents van romandre estables tot i els múltiples tractaments amb β-lactàmics que van rebre els pacients. En total, els estudis presentats han millorat el coneixement de la dinàmica de les poblacions de S. pneumoniae i S. pseudopneumoniae en pacients amb MPOC.

Thesis (M.S.)--Wake Forest University. Dept. of Health and Exercise Science, 2009.
Title from electronic thesis title page. Thesis advisor: Michael J. Berry. Includes bibliographical references (p. 49-54).

This study was designed to gain an understanding of the family experience when an adult member has chronic obstructive pulmonary disease (COPD). It is recognized that illness within the family affects the well-being of the family unit and the health of all members. To understand the impact of COPD upon the family, however, the literature provides only knowledge of the experience of the individual who has COPD and the spouse, not that of the family unit. Thus, the purpose of this study was to describe and explain the COPD experience from the perspective of the family unit. A qualitative method, phenomenology, was chosen for this investigation. Data were collected through semi-structured interviews with eight families who shared their experiences. From the content analysis of these data, three themes that were common throughout the families' accounts were identified and developed to describe and explain family life with COPD. The first theme, disease-dictated family life, describes four aspects of a common lifestyle that is imposed on the family by the characteristics of COPD. The second theme, isolation, describes the isolation that accompanies the illness experience, for the family group and the individual members within the group. The final theme, family work, describes the four primary challenges the families face and the coping strategies they use to deal with them. These findings revealed that COPD acts as an intense stressor within the family, requiring extensive family work to cope with COPD in a way that maintains the well-being of the family unit. Furthermore, it was found that living with COPD in many ways inhibits the resources within the family and those external sources of support that foster the family's ability to manage the stress associated with living with COPD. The implications for nursing practice and nursing research were delineated in light of the research findings.
Applied Science, Faculty of
Nursing, School of
Graduate

Background: Although physical activity is key to improve prognosis in patients with chronic obstructive pulmonary disease (COPD), information to tailor interventions individually is still required. This thesis aims to understand physical activity progression and explore its determinants in COPD patients. Methods: We used baseline and 12-month data from 643 COPD patients with stable mild-to very severe disease from two European multicenter studies. We assessed: physical activity (Dynaport MoveMonitor), physical activity experience (Clinical visit-PROactive physical activity in COPD [C-PPAC]), functional exercise capacity (6-minutes walk distance [6MWD]), as well as sociodemographic, interpersonal, environmental, clinical and psychological variables. Results: (1) The natural progression in physical activity over time was heterogeneous and three distinct patterns could be identified: Inactive, Active Improvers and Active Decliners. While Inactive patients related to worse scores for clinical COPD characteristics, Active Improvers and Decliners could not be predicted at baseline; (2) Higher population density and long-term NO2 exposure were associated with lower physical activity, while a steeper slope of the terrain related to better exercise capacity; (3) twelve-month completion of a behavioral physical activity intervention was determined by previous physical activity habits as well as interpersonal and environmental facilitators, while response to the intervention was related to diverse factors associated with motivation to change to an active lifestyle. Conclusions: This thesis shows that the natural progression of physical activity in COPD patients is heterogeneous and highlights that environmental, interpersonal and psychological factors are important determinants of physical activity behaviour in COPD patients, beyond clinical factors.
Antecedentes: Aunque la actividad física es clave para mejorar el pronóstico en pacientes con enfermedad pulmonar obstructiva crónica (EPOC), todavía no se dispone de información que permita adaptar las intervenciones de manera individualizada. El objetivo de la presente tesis es comprender la progresión de la actividad física y explorar sus determinantes en pacientes con EPOC. Métodos: Utilizamos datos basales y de seguimiento (12 meses) de 643 pacientes con EPOC estable de estadio leve a muy grave, procedentes de dos estudios europeos multicéntricos. Evaluamos: actividad física (Dynaport MoveMonitor), experiencia de actividad física (Clinical visit-PROactive physical activity in COPD [C-PPAC]), capacidad funcional de ejercicio (distancia caminada en la prueba de la marcha de 6 minutos [6MWD]) y variables sociodemográficas, interpersonales, ambientales, clínicas y psicológicas. Resultados: (1) La progresión natural de la actividad física a lo largo del tiempo fue heterogénea y se pudieron identificar tres patrones distintos: inactivo, activo que aumenta y activo que reduce. Mientras que el patrón de pacientes inactivo se relacionaba con peores características clínicas de la EPOC, no se pudo predecir la evolución de los activos a aumentar o reducir; (2) la mayor densidad de población y la exposición a largo plazo al NO2 se asociaron desfavorablemente con la actividad física, mientras que una mayor pendiente del terreno se relacionó con una mejor capacidad de ejercicio; (3) la compleción a los 12 meses con una intervención de actividad física conductual estuvo determinada por los hábitos de actividad física previos, así como por facilitadores interpersonales y ambientales, mientras que la respuesta a la intervención se relacionó con diversos factores asociados a la motivación para cambiar a un estilo de vida activo. Conclusiones: Esta tesis muestra que la progresión natural de la actividad física en los pacientes con EPOC es heterogénea y destaca que los factores ambientales, interpersonales y psicológicos son importantes determinantes de la actividad física en los pacientes con EPOC, más allá de los factores clínicos. Resum Antecedents: Malgrat el paper clau de l’activitat física per millorar el pronòstic en pacients amb malaltia pulmonar obstructiva crònica (MPOC), encara no disposem d’informació que permeti individualitzar les intervencions. L’objectiu d’aquesta tesi és entendre la progressió de l’activitat física i explorar-ne els determinants en pacients amb MPOC.

Early avoidable 30-day post discharge readmission among patients diagnosed with chronic obstructive pulmonary disease (COPD) is associated with poor transition care processes. The purpose of this project was to analyze organizational system processes for admission and discharge transition care of patients diagnosed with COPD to identify key intervention strategies that could decrease the rate of 30-day post-discharge readmission by 1%. The project used the transitional care model as the framework to target specific care transition needs and create patient-centered, supportive, evidence-based relationships among the patient, the providers, the community, and the health care system to identify key intervention strategies for implementation. A retrospective chart review was conducted of transitional care management and care coordination practices of providers of patients diagnosed with COPD. Analysis of the data revealed that the local regional organization used a single, generic, computerized discharge planning and care transition process for patients diagnosed with COPD. As a result, missed opportunities to target a patient's specific care needs led to higher rates of readmission. The implications of the findings of this project for social change include identification of evidence-based recommendations and practices that could influence clinician practices and improve patient outcomes and the quality of health care delivery.

The problem of this study is to determine the vitamin B-6 status of patients who have chronic obstructive pulmonary disease (COPD). Erythrocyte aspartate transaminase assay was the method for measuring vitamin B-6 status. The vitamin B-6 status was examined in thirty subjects (ten COPD subjects and twenty control subjects). An unpaired t-test was used to compare the vitamin B-6 status of the COPD group versus the control group. Four determinants (percentage stimulation, ratio of basal to stimulated activity, basal activity, and stimulated activity) were used to determine vitamin B-6 status in both groups of subjects. Percentage stimulation and ratio of basal to stimulated activity were not significantly different (control group versus COPD group) at the .05 level. However, two of ten COPD subjects had values for percentage stimulation that were two standard deviations above the mean, indicating a poor B-6 status. In contrast, basal activity and stimulated activity of erythrocyte aspartate transaminase were found to be significantly lower at the .05 level in the COPD group than the control group. Therefore, the COPD subjects as a group had some biochemical characteristics of a lower level of vitamin B-6 than the controls.

Background: Exertional breathlessness and fatigue are common disabling symptoms of patients with Chronic Obstructive Pulmonary Disease (COPD) and Chronic Heart Failure (CHF). The mechanisms behind these symptoms are similar including skeletal muscle dysfunction. Exercise training at least partially reverses the skeletal muscle abnormalities and improves exercise performance and health related quality of life in both conditions. Pulmonary rehabilitation, with exercise training as a core component, is an integral part of the management of COPD, but a service for CHF has not developed in the same way. The hypothesis, for the main studies described in this thesis, was that the successful model of pulmonary rehabilitation could be applied to patients with CHF and patients with COPD and CHF could be beneficially trained together. Methods: Two main studies were undertaken; 1) a randomised controlled trial of pulmonary rehabilitation (PR) vs. normal care (NC) in patients with CHF 2) a comparative observational study of PR between COPD and CHF. Alongside these studies, the outcome measures commonly used for COPD were applied to patients with CHF. Two pilot studies were performed investigating the effect of exercise training on other systemic manifestations of COPD and CHF. Results: Patients with CHF made significant improvements in exercise performance and health status with PR compared to NC. The improvements were similar to those seen in the patients with COPD. Measures of exercise performance and health status were applied successfully to patients with CHF. Conclusions: Patients with COPD and CHF can be successfully trained together demonstrating the feasibility of generic exercise rehabilitation for exertional breathlessness. Further work would need to investigate whether combined exercise programmes for COPD and CHF provides economies of scale for both populations. The work in this thesis highlights the possibility of organising services for chronic disease around a disability rather than an individual disease.

The overall aim of this thesis was to describe subjects with chronic obstructive pulmonary disease (COPD) from different perspectives. Focus was on patients at the time of diagnosis, impact of the disease in comparison to other chronic diseases, factors associated with good health and quality of life (QoL), and diagnostic spirometry in clinical practice. Methods: Qualitative method, grounded theory, was used to analyse patients´ perspectives at the time of diagnosis in a primary care setting (n=10). Public health surveys in the general population were used to compare chronic diseases (n=10,755) and analyse factors associated with health outcomes in COPD (n=1,475). Medical records and spirometry reports, from primary and secondary care, were analysed to assess diagnosis of COPD in clinical practice (n=533). Results: In clinical practice, 70% of patients at the time of diagnosis of COPD lacked spirometry results confirming the diagnosis. Factors related to consequences of smoking, shame and restrictions in physical activity (PA) in particular, were described by patients at the time of diagnosis of COPD. In general subjects with COPD (84%), rheumatoid arthritis (74%) and diabetes mellitus (72%) had an activity level considered too low to maintain good health. In COPD, the most important factor associated with good health and quality of life was a high level of PA. Odds ratios (OR (95%CI)) varied from 1.90 (1.47-2.44) to 7.57 (4.57-12.55) depending on the degree of PA, where subjects with the highest PA level had the best health and QoL. Conclusions: Subjects with COPD need to be diagnosed at an early stage, and health professionals should be aware that feelings of shame could delay patients from seeking care and thus obtaining a diagnosis. The use of spirometry and the diagnostic quality should be emphasised. In patients with COPD greater attention should be directed on increasing the physical activity level, as patients with a low level of physical activity display worse health and quality of life.

The overall aims of the studies were to investigate the effects of different training modalities on exercise capacity and health-related quality of life (HRQoL) in patients with moderate or severe COPD and, further, to explore two of the physical tests used in pulmonary rehabilitation.

In study I, the 12-minute walking distance (12MWD) did not increase on retesting in patients with exercise-induced hypoxemia (EIH) whereas 12MWD increased significantly on retesting in the non-EIH patients. In study II, we found that the incremental shuttle walking test was as good a predictor of peak exercise capacity (W peak) as peak oxygen uptake (VO₂ peak) is. In study III, we investigated the effects of two different combination training programmes when training twice a week for eight weeks. One programme was mainly based on endurance training (group A) and the other on resistance training and callisthenics (group B). W peak and 12MWD increased in group A but not in group B. HRQoL, anxiety and depression were unchanged in both groups. Ratings of perceived exertion at rest were significantly lower in group A than in group B after training and during 12 months of follow-up. Twelve months post-training, 12MWD was back to baseline in group A, but significantly shorter than at baseline in group B. Thus, a short endurance training intervention delayed decline in 12MWD for at least one year. Patients with moderate and severe COPD responded to training in the same way. In study IV, both interval and continuous endurance training increased W peak, VO₂ peak, peak exhaled carbon dioxide (VCO₂ peak) and 12MWD. Likewise, HRQoL, dyspnoea during activities of daily life, anxiety and depression improved similarly in both groups. At a fixed, submaximal workload (isotime), the interval training reduced oxygen cost and ventilatory demand significantly more than the continuous training did.

Malnutrition, as evidenced by low weight for height, low triceps skinfold thickness and low midarm muscle circumference, is prevalent among COPD patients. A stepped decline in nutritional status has been postulated as a mechanism for malnutrition wherein patients progressively suffer weight loss with each COPD exacerbation. A randomized clinical trial of continuous enteral nutrition could not successfully address whether or not the stepped decline in weight can be prevented. Despite this, sixteen patients admitted for a COPD exacerbation, participated in an observational prospective study wherein anthropometric, biochemical, dynamometric, respiratory, general well-being and energy consumption measures were obtained. Twelve patients had body weights below 90% of ideal weight. The mean energy intake was 107% $ pm$ 30 of estimated resting energy expenditure. Measures were repeated to assess changes during hospitalization. Weight change was a poor indicator of nutritional status. Midarm muscle circumference and handgrip strength appear to be useful as nutritional status indicators among unstable hospitalized COPD patients. Changes in handgrip strength and midarm muscle circumference were closely linked (r =.78, p $<$ 0.0005) and tended to decrease over the course of hospitalization despite clinical improvement. In the absence of adequate nutrition, COPD patients have at least as much risk of developing iatrogenic malnutrition as are other hospitalized medical patients.

The Regie de 1'assurance maladie du Quebec (RAMQ) health insurance databases have been demonstrated to be a valuable research tool for certain illnesses. The purpose of this study was to examine which data from the RAMQ administrative database could be used to accurately diagnose COPD patients, and classify their severity and comorbidity. Methods . Patients with physician-diagnosed COPD were selected using hospital discharge and outpatient records. Information collected from medical chart was compared to information on the same patients from medical service and prescription drug databases. Results. The ICD-9 respiratory diagnostic codes were found to have a sensitivity of 93% identifying COPD in 151 cases and 94% specificity within a group of similar-aged asthmatic patients. The number of prednisone prescriptions over one year accurately separated severe from moderate patients. As well, diagnostic codes showed moderate reliability for indicating the presence of comorbidity. Conclusions. The diagnostic codes of the medical service database were accurate at identifying COPD patients and the prescription drug data was useful for classifying their severity.

Mestrado em Biologia Molecular e Celular
Microbiome is a community of microorganisms living in a particular environment that englobes all microorganisms with their genes and environmental interactions. The human microbiome plays a pivotal role in human physiology and metabolism being associated to development, nutrition, immunity, and resistance to pathogens and has recognized implications for health and disease. Chronic Obstructive Pulmonary Disease (COPD) is a pulmonary disease characterized by persistent and progressive and nonreversible airflow obstruction. The role of bacteria as a potential pathogenic and etiologic factor in COPD has been a topic of debate for many years. It is thought that lung colonization by particular bacterial strains, in patients with COPD, is responsible for the chronic bronchitis phenotype, increased risk of exacerbations, and loss of lung function. Even though saliva is one of the most easily collectable samples, few studies have been conducted to characterize the saliva microbiome in patients with COPD and even fewer to identify biomarkers that might be informative for disease onset and progression. The aim of this study was to implement the methodology to study the saliva microbiome in patients suffering with COPD, to understand the dynamics of saliva microbiome in the setting of an exacerbation and how the microbiome evolve after that. For that a metagenomic approach was carried out, using the sequencing of the 16S rRNA gene, to analyze 17 samples from 7 patients with COPD, collected at 3 different time points, i.e. at exacerbation, 2 weeks after exacerbation, and at clinical full recovery. In this study, we found microbial shifts in the samples collected at different time points. We also detected high sample variability, especially between samples collected from different individuals. These results suggest that saliva might me a good source of biomarkers for COPD management and may represent an improvement to the implementation of personalized medicine in this population. However, more and larger studies must be conducted.
Microbioma é definido como sendo uma comunidade de microrganismos presente num dado ambiente, que engloba todos os microorganismos com seus genes e interações ambientais. O microbioma humano desempenha um papel importante na fisiologia humana e no seu metabolismo, estando associado ao desenvolvimento, nutrição, imunidade e resistência a agentes patogénicos com implicações na saúde e doença. A doença pulmonar obstrutiva crónica (DPOC) é uma doença pulmonar caracterizada por uma obstrução das vias aéreas persistente progressiva e não reversível. O papel das bactérias como potencial fator patogénico e etiológico na DPOC tem sido tema de debate nos últimos anos. Pensa-se que a colonização dos pulmões por determinadas bactérias, em pacientes com DPOC, é responsável pelo aumento do risco de exacerbações e perda de função pulmonar. Embora a saliva seja uma das amostras mais facilmente recolhida, são ainda poucos os estudos para caracterizar o microbioma da saliva em pacientes com DPOC, e ainda menos para identificar nele biomarcadores informativos sobre o diagnóstico e progressão desta doença. O objetivo deste estudo foi implementar a metodologia que permita estudar o microbioma da saliva em pacientes com DPOC, compreender a dinâmica do microbioma da saliva no contexto de uma exacerbação e como o microbioma evolui depois disso. Para isso, utilizou-se uma abordagem metagenómica utilizando a sequenciação do gene 16S rRNA, para analisar 17 amostras de 7 pacientes com DPOC, recolhidas em 3 momentos diferentes, i.e. em exacerbação, 2 semanas após a exacerbação e após recuperação clínica. Neste estudo foram encontradas e serão descritas diferenças na composição microbiana das amostras colhidas em tempos diferentes. Verificou-se também uma grande variabilidade nos resultados, com grandes diferenças entre as amostras colhidas de diferentes pacientes. Estes resultados sugerem que a saliva pode ser uma boa fonte de biomarcadores para a DPOC e poderá representar um avanço para a implementação da medicina personalizada nesta população. No entanto mais estudos com amostras alargadas são ainda necessários. Contudo, mais estudos deverão ser realizados.

Chronic obstructive pulmonary disease (COPD) requiring long-term oxygen therapy (LTOT) is an incurable lung disease often complicated by other comorbidities. Research is limited for hospitalized COPD exacerbations with LTOT and palliative care services. The purpose of this quantitative research study was to determine the correlation between palliative care interventions and COPD patient outcomes specific to an intensive care unit (ICU) stay, invasive mechanical ventilator support, physician orders for cardiopulmonary resuscitation (CPR) code status, and hospital discharge to hospice care. The theoretical base for this study was Donabedian's quality improvement theory. The quasi-experimental, nonequivalent groups design divided COPD hospitalized patient sample into 2 groups, those with and those without palliative care, for comparison. An independent-samples t test, one-way MANOVA, and follow-up univariate ANOVAS was done to compare the means of ICU days and ventilator days; a cross tabulation, chi-square test of independence, and Fisher exact test was done to compare code status and place of hospital discharge. The mean number of the ICU days and ventilator days for palliative care patients was significantly higher than patients who did not receive palliative care. A significant interaction was found for palliative care and code status change from CPR to no CPR; however, data relating to palliative care and hospital discharge to hospice was insignificant. In conclusion, palliative care does not reduce costs by limiting the number of days spent in an ICU or the number of days on invasive mechanical ventilation; although, it may have an important role in the code status order change from CPR to no CPR to align with the patient's end of life care preference.

The primary aim of this thesis was to develop a better understanding of the physiology and perceptual responses associated with the performance of continuous (CE) and intermittent exercise (IE) in patients with moderate chronic obstructive pulmonary disease (COPD). A secondary aim was to examine factors that could potentially limit exercise tolerance in COPD patients, particularly in relation to the dynamics of the cardiovascular system and muscle metabolism. The results of the four studies conducted to achieve these aims are presented in this thesis. In Study 1, the physiological, metabolic and perceptual responses to an acute bout of IE and CE were examined in 10 individuals with moderate COPD. Each subject completed an incremental exercise test to exhaustion on a cycle ergometer. Subjects then performed IE (1 min exercise: 1 min rest ratio) and CE tests at 70% of peak power in random order on separate days. Gas exchange, heart rate, plasma lactate concentration, ratings of breathlessness, inspiratory capacity and the total amount of work completed were measured during each exercise test. Subjects were able to complete a significantly greater amount of work during IE (71 ± 32 kJ) compared with CE (31 ± 24 kJ). Intermittent exercise was associated with significantly lower values for oxygen uptake, expired ventilation and plasma lactate concentration when compared with CE. Subjects also reported a significantly lower rating of breathlessness during IE compared to CE. The degree of dynamic lung hyperinflation (change in end-expiratory lung volume) was lower during IE (0.23 ± 0.07 L) than during CE (0.52 ± 0.13 L). The results suggest that IE may be superior to CE as a mode of training for patients with COPD. The greater amount of total work performed and the lower measured physiological responses attained with intermittent exercise could potentially allow greater training adaptations to be achieved in individuals with more limited lung function. The purpose of Study 2 was to compare the adaptations to 8 wk of supervised intermittent and continuous cycle ergometry training, performed at the same relative intensity and matched for total work completed, in patients with COPD. Nineteen subjects with moderate COPD were stratified according to age, gender, and pulmonary function, and then randomly assigned to either an IE (1 min exercise: 1 min rest ratio) or CE training group. Subjects trained 3 d per week for 8 wk and completed 30 min of exercise. Initial training intensity, i.e., the power output applied during the CE bouts and during the exercise interval of the IE bouts, was determined as 50% of the peak power output achieved during incremental exercise and was increased by 5% each week after 2 wk of training. The total amount of work performed was not significantly different (P=0.74) between the CE (750 ± 90 kJ) and IE (707 ± 92 kJ) groups. The subjects who performed IE (N=9) experienced significantly lower levels of perceived breathlessness and lower limb fatigue during the exercise-training bouts than the group who performed CE (N=10). However, exercise capacity (peak oxygen uptake) and exercise tolerance (peak power output and 6-min walk distance) improved to a similar extent in both training groups. During submaximal constant-load exercise, the improved (faster) phase II oxygen uptake kinetic response with training was independent of exercise mode. Furthermore, training-induced reductions in submaximal exercise heart rate, carbon dioxide output, expired ventilation and blood lactate concentrations were not different between the two training modes. Exercise training also resulted in an equivalent reduction for both training modes in the degree of dynamic hyperinflation observed during incremental exercise. Thus, when total work performed and relative intensity were the same for both training modes, 8 wk of CE or IE training resulted in similar functional improvements and physiological adaptations in patients with moderate COPD. Study 3 examined the relationship between exercise capacity (peak oxygen uptake) and lower limb vasodilatory capacity in 9 patients with moderate COPD and 9 healthy age-matched control subjects. While peak oxygen uptake was significantly lower in the COPD patients (15.8 ± 3.5 mL·min-1·kg-1) compared to the control subjects (25.2 ± 3.5 mL·kg-1·min-1), there were no significant differences between groups in peak calf blood flow or peak calf conductance measured 7 s post-ischemia. Peak oxygen uptake was significantly correlated with peak calf blood flow and peak conductance in the control group, whereas there was no significant relationship found between these variables in the COPD group. However, the rate of decay in blood flow following ischemia was significantly slower (p less than 0.05) for the COPD group (-0.036 ± 0.005 mL·100 mL-1·min-1·s-1) when compared to the control group (-0.048 ± 0.015 mL·100 mL-1·min-1·s-1). The results of this study suggest that the lower peak exercise capacity in patients with moderate COPD is not related to a loss in leg vasodilatory capacity. Study 4 examined the dynamics of oxygen uptake kinetics during high-intensity constant-load cycling performed at 70% of the peak power attained during an incremental exercise test in 7 patients with moderate COPD and 7 healthy age-matched controls. The time constant of the primary component (phase II) of oxygen uptake was significantly slower in the COPD patients (82 ± 8 s) when compared to healthy control subjects (44 ± 4 s). Moreover, the oxygen cost per unit increment in power output for the primary component and the overall response were significantly higher in patients with COPD than in healthy control subjects. A slow component was observed in 5 of the 7 patients with COPD (49 ± 11 mL·min-1), whereas all of the control subjects demonstrated a slow component of oxygen uptake (213 ± 35 mL·min-1). The slow component comprised a significantly greater proportion of the total oxygen uptake response in the healthy control group (18 ± 2%) than in the COPD group (10 ± 2%). In the COPD patients, the slow component amplitude was significantly correlated with the decrease in inspiratory capacity (r = -0.88, P less than 0.05; N=5), indicating that the magnitude of the slow component was larger in individuals who experienced a greater degree of dynamic hyperinflation. This study demonstrated that most patients with moderate COPD are able to exercise at intensities high enough to elicit a slow component of oxygen uptake during constant-load exercise. The significant correlation observed between the slow component amplitude and the degree of dynamic hyperinflation suggests that the work of breathing may contribute to the slow component in patients with COPD.

The primary aim of this thesis was to develop a better understanding of the physiology and perceptual responses associated with the performance of continuous (CE) and intermittent exercise (IE) in patients with moderate chronic obstructive pulmonary disease (COPD). A secondary aim was to examine factors that could potentially limit exercise tolerance in COPD patients, particularly in relation to the dynamics of the cardiovascular system and muscle metabolism. The results of the four studies conducted to achieve these aims are presented in this thesis. In Study 1, the physiological, metabolic and perceptual responses to an acute bout of IE and CE were examined in 10 individuals with moderate COPD. Each subject completed an incremental exercise test to exhaustion on a cycle ergometer. Subjects then performed IE (1 min exercise: 1 min rest ratio) and CE tests at 70% of peak power in random order on separate days. Gas exchange, heart rate, plasma lactate concentration, ratings of breathlessness, inspiratory capacity and the total amount of work completed were measured during each exercise test. Subjects were able to complete a significantly greater amount of work during IE (71 ± 32 kJ) compared with CE (31 ± 24 kJ). Intermittent exercise was associated with significantly lower values for oxygen uptake, expired ventilation and plasma lactate concentration when compared with CE. Subjects also reported a significantly lower rating of breathlessness during IE compared to CE. The degree of dynamic lung hyperinflation (change in end-expiratory lung volume) was lower during IE (0.23 ± 0.07 L) than during CE (0.52 ± 0.13 L). The results suggest that IE may be superior to CE as a mode of training for patients with COPD. The greater amount of total work performed and the lower measured physiological responses attained with intermittent exercise could potentially allow greater training adaptations to be achieved in individuals with more limited lung function. The purpose of Study 2 was to compare the adaptations to 8 wk of supervised intermittent and continuous cycle ergometry training, performed at the same relative intensity and matched for total work completed, in patients with COPD. Nineteen subjects with moderate COPD were stratified according to age, gender, and pulmonary function, and then randomly assigned to either an IE (1 min exercise: 1 min rest ratio) or CE training group. Subjects trained 3 d per week for 8 wk and completed 30 min of exercise. Initial training intensity, i.e., the power output applied during the CE bouts and during the exercise interval of the IE bouts, was determined as 50% of the peak power output achieved during incremental exercise and was increased by 5% each week after 2 wk of training. The total amount of work performed was not significantly different (P=0.74) between the CE (750 ± 90 kJ) and IE (707 ± 92 kJ) groups. The subjects who performed IE (N=9) experienced significantly lower levels of perceived breathlessness and lower limb fatigue during the exercise-training bouts than the group who performed CE (N=10). However, exercise capacity (peak oxygen uptake) and exercise tolerance (peak power output and 6-min walk distance) improved to a similar extent in both training groups. During submaximal constant-load exercise, the improved (faster) phase II oxygen uptake kinetic response with training was independent of exercise mode. Furthermore, training-induced reductions in submaximal exercise heart rate, carbon dioxide output, expired ventilation and blood lactate concentrations were not different between the two training modes. Exercise training also resulted in an equivalent reduction for both training modes in the degree of dynamic hyperinflation observed during incremental exercise. Thus, when total work performed and relative intensity were the same for both training modes, 8 wk of CE or IE training resulted in similar functional improvements and physiological adaptations in patients with moderate COPD. Study 3 examined the relationship between exercise capacity (peak oxygen uptake) and lower limb vasodilatory capacity in 9 patients with moderate COPD and 9 healthy age-matched control subjects. While peak oxygen uptake was significantly lower in the COPD patients (15.8 ± 3.5 mL·min-1·kg-1) compared to the control subjects (25.2 ± 3.5 mL·kg-1·min-1), there were no significant differences between groups in peak calf blood flow or peak calf conductance measured 7 s post-ischemia. Peak oxygen uptake was significantly correlated with peak calf blood flow and peak conductance in the control group, whereas there was no significant relationship found between these variables in the COPD group. However, the rate of decay in blood flow following ischemia was significantly slower (p less than 0.05) for the COPD group (-0.036 ± 0.005 mL·100 mL-1·min-1·s-1) when compared to the control group (-0.048 ± 0.015 mL·100 mL-1·min-1·s-1). The results of this study suggest that the lower peak exercise capacity in patients with moderate COPD is not related to a loss in leg vasodilatory capacity. Study 4 examined the dynamics of oxygen uptake kinetics during high-intensity constant-load cycling performed at 70% of the peak power attained during an incremental exercise test in 7 patients with moderate COPD and 7 healthy age-matched controls. The time constant of the primary component (phase II) of oxygen uptake was significantly slower in the COPD patients (82 ± 8 s) when compared to healthy control subjects (44 ± 4 s). Moreover, the oxygen cost per unit increment in power output for the primary component and the overall response were significantly higher in patients with COPD than in healthy control subjects. A slow component was observed in 5 of the 7 patients with COPD (49 ± 11 mL·min-1), whereas all of the control subjects demonstrated a slow component of oxygen uptake (213 ± 35 mL·min-1). The slow component comprised a significantly greater proportion of the total oxygen uptake response in the healthy control group (18 ± 2%) than in the COPD group (10 ± 2%). In the COPD patients, the slow component amplitude was significantly correlated with the decrease in inspiratory capacity (r = -0.88, P less than 0.05; N=5), indicating that the magnitude of the slow component was larger in individuals who experienced a greater degree of dynamic hyperinflation. This study demonstrated that most patients with moderate COPD are able to exercise at intensities high enough to elicit a slow component of oxygen uptake during constant-load exercise. The significant correlation observed between the slow component amplitude and the degree of dynamic hyperinflation suggests that the work of breathing may contribute to the slow component in patients with COPD.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Physiotherapy and Exercise Science
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Rationale: Chronic obstructive pulmonary disease (COPD) is not only a common lung disease but is a major cause of morbidity and mortality worldwide. Pulmonary rehabilitation (PR) helps optimize function and independence by increasing exercise capacity, reducing symptoms and improving health related quality of life (HRQL). Exercise training is certainly a key component of the PR programs; however, many of its aspects still need to be better defined such as optimal exercise assessment and training modality for these patients. The general purpose of this thesis was to generate new knowledge that could contribute to new strategies for exercise assessment and training in patients with COPD. Methods and results: This thesis is comprised of four independent studies. Thigh muscle strength, endurance and fatigue were compared between 42 patients with moderate to severe COPD and 53 healthy controls (Study I). Impaired thigh muscle strength and endurance in patients with COPD was found, except for muscle strength in knee extension in male patients. Female patients had higher fatigue index than female controls while no difference was found between male patients and controls. The six-minute walk test (6MWD) performed on a non-motorized treadmill (6MWD-T) was compared with the 6MWD performed in a corridor (6MWD-C) in 16 healthy elderly subjects (Study II). They performed twelve tests (six 6MWD-C and six 6MWD-T) on two different days in a randomized order. An average discrepancy was found between the two methods with the subjects walking a shorter distance on the non-motorized treadmill. However, the results showed good test-retest reliability between days and test repetitions. A systematic review (Study III) was done of studies that investigated the effects of an arm training program in patients with COPD. The findings of this review indicated that there is evidence that an arm training program improves arm exercise capacity, but its effects on dyspnea, arm fatigue and healthy-related quality of life is unclear. Finally, a two-armed randomized controlled trial examined the effects of an arm training program on arm function, arm exercise capacity, muscle strength, symptoms and HRQL in patients with COPD (Study IV). The groups were randomized to arm training or sham. Compared with the changes observed in the control group, the magnitude of change in the intervention group was greater for arm function, arm exercise capacity and muscle strength. There was no difference between groups in HRQL or symptoms. Conclusions: Upper extremity resistance training improves arm exercise capacity, arm function and muscle strength in patients with COPD. Training and assessment of upper and lower limb muscles should be included into PR programs. The 6MWD performed on a non-motorized treadmill may offer an alternative option to the standard 6MWD when a 30-meter corridor is not available.

Objective: The main goal of this study is to compare the Quality of Life (QoL) of Chronic Obstructive Pulmonary Disease (COPD) patients between three different regions: the United Arab Emirates (UAE), the United Kingdom (UK) and Morocco. Another aim of this research is to assess the predictive factors correlated to the QoL and study the extent of their involvement as well as any possible interaction between them. It is also designed to compare the QoL of control group (healthy individuals) among the same countries. Methods: A total of 1800 subjects were recruited including stable COPD patients (n=430), and a control group (n=1370) from the UK, Morocco and the UAE. St George’s Respiratory Questionnaire (SGRQ) was the instrument used to evaluate the QoL, while Mahler Dyspnoea Index was used to assess the dyspnoea. Lung functions were measured by a standardised Vitalograph spirometer, while a hand grip dynamometer was used to measure the muscle strength. Data was analysed using ANOVA Post Hoc test to compare the QoL between the centres and linear regression analysis used to assess the effect of various variables upon the QoL scores components. Extra questions were asked to the patients to study their awareness of their condition and its management, which have been tested using chi-square statistical method. Results: Our results show that differences in the QoL between the countries exist. The UK had better overall QoL than Morocco and the UAE, with no significant difference between genders. How well total SGRQ scores were predicted by BMI, dyspnoea index, total muscle grip and pulmonary function were assessed and the results indicated that age, total muscle grip, FVC% predicted, and dyspnoea index are significantly associated with the QoL. Regarding the control groups, our results indicated that there was a highly significant difference in all variables between the three countries. Conclusion: Muscle grip, age, dyspnoea and FVC% predicted are good predictors of QoL in COPD patients. Patients’ QoL deteriorates with older age and increased dyspnoea. COPD patients with poor QoL experience muscle weakness and poor lung function. There was clearly a difference between the QoL of COPD patients in the three regions and the reason behind this is mainly due to the socio-economic status and the health care system followed in each country rather than the demographic location.

Patients with chronic obstructive pulmonary disease (COPD) develop limb muscle atrophy partly due to proteasomal activation. Whether autophagy, a proteolysis pathway involved in organelles recycling, is also induced in limb muscles of COPD patients remains unclear. We investigate whether autophagy is induced in limb muscles of COPD patients and identify the mechanisms of initiation and maintenance of autophagy in these patients. Two studies were performed. Study 1 was aimed at counting autophagosome formation using electron microscopy in the vastus lateralis and tibialis anterior of control subjects and COPD patients. Study 2 was aimed at detecting LC3B protein lipidation (marker of autophagosome formation) and autophagy-related gene expression in the vastus lateralis of control subjects and COPD patients. Proteasome activation, oxidative stress and AKT, mTOR and AMPK pathway activation were also monitored. Autophagosome numbers were significantly greater in limb muscles of COPD patients compared to control subjects. LC3B protein lipidation and expression of autophagy-related genes in the vastus lateralis of COPD patients were significantly higher than control subjects. LC3B protein lipidation correlated negatively with thigh cross sectional areas and FEV1/FVC ratios. Autophagy induction was associated with inhibition of AKT and mTOR pathways and upregulation of AMPK and FOXO1 transcription factor expressions and with the development of oxidative stress in muscles of COPD patients. These results indicate that autophagy is significantly induced in limb muscles of COPD patients and the level of autophagy correlates with the severity of muscle atrophy and lung disease.
Les patients souffrant de la Broncho-pneumopathie chronique obstructive (BPCO) développent de l'atrophie musculaire des membres causée en partie par l'activation de la protéasome. L'implication de l'autophagie, une méthode de protéolyse utilisée pour le recyclage des organites, dans le développement de l'atrophie musculaire des patients de la BPCO n'est pas encore certaine. Nous investiguons si l'autophagie est induite dans l'atrophie musculaire des membres des patients de la BPCO et nous identifions le mécanisme de l'initiation et de la maintenance de l'autophagie dans ces patients. Deux études ont été conduites. La première étude visait à compter le nombre d'autophagosomes formés dans le vastus lateralis et le tibialis antérieur des patients contrôle et des patients de la BPCO en utilisant le microscope électronique. La deuxième étude consistait de la détection de la lipidation de la protéine LC3B (un marquer de formation d'autophagosome) et de mesuré l'expression de gènes liés a l'autophagie dans le vastus lateralis et le tibialis antérieur des patients contrôle et des patients de la BPCO. L'activation de la protéasome, le stresse oxydatif ainsi que l'activation des systèmes de l'AKT, mTOR et l'AMPK ont été surveillés. Le nombre d'autophagosome était largement augmenté dans les muscles des patients de la BPCO comparé aux contrôles. La lipidation de la protéine LC3B ainsi que l'expression des gènes de l'autophagie dans la vastus lateralis des patients de la BPCO étaient largement plus élevées comparé aux contrôles. Une corrélation inverse existe entre la lipidation de la protéine LC3B et l'aire de la section des cuisses et le rapport du FEV1/FVC (coefficient de Tiffeneau) des patients. L'induction de l'autophagie était associée avec l'inhibition des systèmes d'AKT et mTOR et l'augmentation de l'expression de l'AMPK et FOXO1. De plus, l'induction de l'autophagie correspondait avec le stress oxydatif dans les muscles des patients de la BPCO. Ces résultats indiquent que l'autophagie est induite significativement dans les muscles des membres des patients de la BPCO et que le niveau d'autophagie suit la sévérité d'atrophie des muscles et de la maladie du poumon.

This thesis explores the subjective experiences of patients and carers living with chronic obstructive pulmonary disease (COPD), a degenerative respiratory condition. It aims to improve understanding of the illness trajectory experienced by sufferers as they respond to the physical and psychological impact of COPD on their body, self- identity, relationships and daily living. The illness COPD is poorly recognised by health policy makers, the media, health professionals and patients alike, despite being predicted to become the third leading cause of death worldwide by 2020. Even less is known about the lived experience of COPD as perceived by the individuals themselves. A qualitative approach based on symbolic interactionism was employed to collect and analyse narrative data obtained from a purposive sample of 53 patients with moderate to severe COPD and 15 family carers. Exploration of the illness trajectory through narratives recounted by patients and carers highlighted the impact of COPD on their lives. The study identified conceptual illness phases experienced by patients as: the early days, adapting to changes in self and lifestyle, the daily struggle and living with severe COPD: fears and facing the future. Individuals revealed how they perceived their disabled body, dependency on others, and the cumulative life losses they experienced, together with feelings of vulnerability, as contributing to a sense of altered self and identity. The illness phases were reflected in the role of the relative who moved through the transitional phases from being a caring relative to a care-giving relative, caring through crisis periods, and eventually becoming a full-time carer. The study provides insights into the perceived issues and concerns of patients and carers living with the consequences of COPD. It may provide lessons for health professionals, which will contribute to more appropriate and acceptable healthcare to support patients with COPD and their carers.

Thesis (Ph. D.)--Ohio State University, 2005.
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To date, there is a scant amount of research on the long-term benefits of exercise training for individuals with moderate to severe chronic obstructive pulmonary disease. The purpose of this study was to evaluate standardized outcomes of a six-month maintenance pulmonary rehabilitation program to determine maintenance of functional capacity. Twenty-three subjects (sixteen men, seven women) diagnosed with clinical COPD ages 30-82 (65 + 12 years) participated in the retrospective study. The subjects were referred to an eight-week comprehensive pulmonary rehabilitation program after which upon twelve subjects continued onto a maintenance program. Eleven subjects chose not to participate in the maintenance program and were given a home exercise program and were encouraged to remain active. Hemodynamic, functional, and educational measures were taken prior to entry, upon completion of the hospital program, and again six-months post-program. Outcome tests were standardized using the Indiana Society of Cardiovascular and Pulmonary Rehabilitation Outcomes Manual. Significant differences were found between the maintenance and non-maintenance groups for systolic blood pressure in resting, exercise, and recovery measures at six monthsreevaluation. Differences in oxygen saturation were also found to reach significance between the two groups during recovery from the six-minute walk test. Interestingly, duration of exercise was found to be statistically significant between the two groups as well as emergency room visits and physician visits within the last six months. The maintenance group tended to have fewer emergency room and physician visits in addition to having self-reported higher durations of exercise. In conclusion, maintenance pulmonary rehabilitation programs have been shown to maintain physical activity levels for COPD patients and as a result, fewer quality of life consequences specifically the number of hospital admissions and emergency room visits.
School of Physical Education

Background: In chronic obstructive pulmonary disease (COPD), understanding the problem of poor patient participation in evidence-based self-management (SM) and pulmonary rehabilitation (PR) programmes (together referred to as SM support programmes) is critical. This thesis aimed to improve understanding of poor patient participation and retention in these programmes; how participation might be improved; and how might patients be better supported with their SM. Methods: Using the Medical Research Council guidance on complex interventions this thesis (1) quantified the 'actual' patient participation and completion rates; (2) explained, using theory, the factors that influenced participation in studies of SM support including the programmes among chronic disease and COPD patients; and (3) explored patient and expert stakeholders' perspectives on the reasons for non-participation in SM support programmes, how participation might be improved, how might patients be supported with their SM. Results: (1) Among 56 studies, high study participation rates and completion rates were seen however, the incomplete reporting of participant flow confused the problem of participation. (2) Among 31 studies, participation among patients with chronic disease including COPD was shown to be influenced by their 'attitude' and 'perceived social influence/subjective norms'; 'illness' and 'intervention perceptions'. (3) From 38 interviewees, besides patients' beliefs, non-participation was also influenced by resignation and denial of the illness; health systems; and programme organisational factors. Professionals building relationships and supporting patients with their SM alongside programme organisational improvements might encourage patient participation in SM and the programmes. Conclusions Patient participation is a complex behaviour, besides socio-behavioural factors, participation behaviour can by influenced by a mix of several health system and programme organisational factors. Changing the behaviour of health professionals and indeed the wider health system, towards normalising a patient partnership approach, with implementation of SM support in routine care might help more patients to consider participation in their care and improve patient participation in COPD SM support programmes.

Antecedents i objectius: La malaltia pulmonar obstructiva crònica (MPOC) és una malaltia respiratòria de les vies aèries inferiors que es caracteritza per la presència de limitació al flux aeri poc reversible. Com a conseqüència de la malaltia els pacients amb MPOC presenten una reducció de la seva capacitat d’exercici. Així mateix, sovint s’observa una pèrdua progressiva de la capacitat d’exercici al llarg del temps, tal i com es descriu a la teoria del cercle viciós de la dispnea-inactivitat en la MPOC. És sabut que la pèrdua longitudinal de capacitat d’exercici és un important factor predictiu de mortalitat en aquets pacients. Per aquest motiu, és important identificar factors de risc associats amb aquesta pèrdua. L’objectiu d’aquesta tesi és aprofundir en el coneixement sobre els determinats i els efectes de la pèrdua de capacitat d’exercici en els pacients amb MPOC. Mètodes: La recerca portada a terme en el marc d’aquesta tesi doctoral es basa en el projecte “Caracterització fenotípica i evolució de la MPOC (Estudi PAC-MPOC)”. Es van recollir variables clíniques i funcionals en un total de 342 pacients amb MPOC en fase estable. La distància caminada a la prova de marxa de 6 minuts (6MWD) es va mesurar en el moment basal i 18-24 mesos més tard. La informació relacionada amb els ingressos hospitalaris esdevinguts durant el seguiment es va obtenir de registres centralitzats. Es van portar a terme anàlisis de regressió lineal múltiple per tal d’estudiar els factors predictius de la pèrdua en la 6MWD. Així mateix, es va portar a terme una revisió sistemàtica de la literatura per tal d’identificar models conceptuals per al cercle viciós de la dispnea-inactivitat a la MPOC i es van utilitzar models estructurals per tal de validar-los amb dades longitudinals de l’estudi PAC-MPOC. Resultats: Vam observar que el quocient entre la capacitat inspiratòria i la capacitat pulmonar total (IC/TLC) i la dispnea eren les variables basals que predeien la pèrdua de capacitat d’exercici a la nostra cohort; i que els ingressos hospitalaris que esdevenien durant el seguiment s’associaven amb una major pèrdua de capacitat d’exercici. D’altra banda, vam identificar 9 diagrames que expliquen el cercle viciós de la dispnea-inactivitat a la MPOC, però cap d’ells semblava ser vàlid a partir de les nostres dades. Proposem un model alternatiu que té present la informació esmentada en models conceptuals previs, contempla el paper central de la limitació en la capacitat d’exercici i presenta una adequada bondat d’ajust. Conclusions: A partir de la recerca portada a terme a aquesta tesi doctoral, es conclou que la hiperinsuflació pulmonar estàtica, la dispnea i els ingressos hospitalaris són importants factors predictius de la pèrdua de capacitat d’exercici a pacients amb MPOC. A més, la limitació de la capacitat d’exercici sembla que té un paper important en el cercle viciós de la dispnea-inactivitat descrit a la MPOC. Aquests resultats poden ser d’interès a l’hora de guiar intervencions terapèutiques, com la rehabilitació pulmonar, destinades a prevenir l’empitjorament de la capacitat d’exercici i frenar el cercle viciós de la malaltia en els pacients amb MPOC.
Background and objective: Chronic obstructive pulmonary disease (COPD) is characterised by poorly reversible airflow limitation and reduced exercise capacity. Moreover, exercise capacity is a strong predictor of mortality and it often declines over time, as theoretically described in the vicious circle of dyspnoea-inactivity. Therefore, it is important to identify risk factors for exercise capacity decline in COPD. The objective of this thesis is to understand the determinants and effects of exercise capacity decline in patients with COPD. Methods: The research conducted in the frame of this thesis is based on the population of the Phenotype and Course of COPD (PAC-COPD) study cohort. Clinical and functional variables were collected for 342 clinically stable COPD patients. The 6-minute walk distance (6MWD) was determined at baseline and at a second visit 18 to 24 months later. Information on hospitalisations during follow-up was obtained from centralised administrative databases. Multivariate linear regression was used to assess factors related to 6MWD decline. We also conducted a systematic review to identify previously published conceptual models for the dyspnoea-inactivity vicious circle in COPD and used structural equation models to validate them with longitudinal PAC-COPD data. Results: We observed that inspiratory capacity-to-total lung capacity (IC/TLC) ratio and dyspnoea were the baseline variables that predicted exercise capacity decline in our COPD cohort; and that all-cause hospital admissions during follow-up, particularly if frequent, were significantly related to a higher decline in exercise capacity. None of the 9 diagrams identified in the literature explaining the dyspnoea-inactivity vicious circle in COPD were supported by our data. We propose an alternative model, taking into account previous models and evidence from the literature. This model, with a central role of exercise capacity limitation, provides significant associations among variables and appropriate goodness of fit when validated with repeated PAC-COPD data. Conclusions: From the research conducted in the present thesis, we conclude that static lung hyperinflation, dyspnoea and hospital admissions are important predictors of exercise capacity decline in COPD patients. Exercise capacity limitation has a central role in the dyspnoea-inactivity vicious circle proposed in COPD. These results may help to guide early therapeutic interventions, such as pulmonary rehabilitation, to prevent exercise capacity deterioration and interrupt the disease vicious circle in COPD patients.

Antecedents: La Malaltia Pulmonar Obstructiva Crònica (MPOC) és una de les principals causes de mortalitat i discapacitat a nivell mundial. L'activitat física és un dels pocs factors modificables que desacceleren l'evolució de la MPOC. No obstant, la dosi i les característiques de l'activitat física responsables de la desacceleració són encara desconegudes. En conseqüència, els objectius d'aquesta tesi són avançar i perfeccionar la metodologia i els instruments per avaluar l'activitat física realitzada pels malalts amb MPOC, aprofundir en el coneixement sobre les característiques i els patrons de la seva activitat física i determinar quines característiques de l'activitat física milloren el pronòstic dels malalts amb MPOC. Mètodes: Han participat 177 individus amb MPOC estable seleccionats de 8 hospitals a Espanya (94% homes, edat mitjana±DE 71±8 anys, volum expiratori forçat en 1 s 52±16% i índex de massa corporal 29±5 kg·m-2). L'activitat física va ser mesurada per un acceleròmetre (SenseWear® Pro2 Armband) i per un qüestionari (Yale Physical Activity Survey, YPAS). Les variables sociodemogràfiques (edat, sexe, estat civil, nivell educatiu, nivell socioeconòmic, situació laboral i hàbit tabàquic) i les variables clíniques (limitació al flux d'aire, hiperinsuflació pulmonar, díspnea, intercanvi de gasos, inflamació sistèmica i local, composició corporal, comorbiditats, qualitat de vida i capacitat d'exercici), es van obtenir utilitzant instruments validats i seguint les normes internacionals. La informació sobre l'evolució de la malaltia (els ingressos hospitalaris i la mortalitat) es va obtenir dels registres dels governs. Resultats: (Objectiu 1) El YPAS és una eina vàlida per a la detecció precoç de la inactivitat dels individus amb MPOC [àrea sota la corba ROC (95% IC) = 0.71 (0,63-0,79)]. (Objectiu 2) El 97% dels individus amb MPOC són capaços de realitzar episodis de 10 minuts d'activitat física moderada-vigorosa. Més del 50% dels individus amb MPOC compleixen amb les recomanacions de l'Organització Mundial de la Salut sobre l'activitat física per a la gent gran. La quantitat d'activitat física, la proporció d'aquesta activitat realitzada en episodis de 10 minuts i la freqüència d'aquests episodis va disminuir amb l'augment de la gravetat de la MPOC. (Objectiu 3) La quantitat i la intensitat de l'activitat física són determinants independents de l'evolució de la MPOC. El risc d'hospitalització per MPOC és un 20% menor per cada 1000 passos diaris addicionals realitzats en baixa intensitat. No obstant, una major quantitat de passos diaris a una alta intensitat mitjana no influeix en el risc d'hospitalització per MPOC (HR = 1.01; p = 0,919). Conclusions: El YPAS és una eina vàlida per a la detecció precoç dels individus amb MPOC físicament inactius. Els pacients amb MPOC greu i molt greu realitzen menys episodis i quantitat d'activitat física, i tenen menor la ràtio entre episodis i quantitat que en aquells en estat lleu i moderat. Una major quantitat d'activitat física de baixa intensitat redueix el risc d'hospitalització per MPOC.
Antecedentes: La Enfermedad Pulmonar Obstructiva Crónica (EPOC) es una de las principales causas de mortalidad y discapacidad a nivel mundial. La actividad física es uno de los pocos factores modificables que desaceleran la evolución de la EPOC. Sin embargo, la dosis y las características de la actividad física responsables de la desaceleración son todavía desconocidas. En consecuencia, los objetivos de esta tesis son avanzar y perfeccionar la metodología e instrumentos para evaluar la actividad física realizada por los enfermos con EPOC, profundizar en el conocimiento sobre las características y patrones de su actividad física y determinar qué características de la actividad física mejoran el pronóstico de los enfermos con EPOC. Métodos: Han participado 177 individuos con EPOC estable seleccionados de 8 hospitales en España (94% hombre, edad media±DE 71±8 años, volumen espiratorio forzado predicho en 1 s 52±16% e índice de masa corporal 29±5 kg·m-2). La actividad física fue medida por un acelerómetro (SenseWear® Pro2 Armband) y por un cuestionario (Yale Physical Activity Survey, YPAS). Las variables sociodemográficas (edad, sexo, estado civil, nivel educativo, nivel socioeconómico, situación laboral y hábito tabáquico) y las variables clínicas (limitación al flujo aereo, hiperinsuflación pulmonar, disnea, intercambio de gases, inflamación sistémica y local, composición corporal, comorbilidades, calidad de la vida y capacidad de ejercicio), se obtuvieron utilizando instrumentos validados y siguiendo las normas internacionales. La información sobre la evolución de la enfermedad (ingresos hospitalarios y mortalidad) se obtuvo de los registros gubernamentales. Resultados: (Objetivo 1) El YPAS es una herramienta válida para la detección precoz de la inactividad de los individuos con EPOC [área bajo la curva ROC (95% IC) = 0.71 (0.63-0.79)]. (Objetivo 2) El 97% de los individuos con EPOC son capaces de realizar episodios de 10 minutos de actividad física moderada-vigorosa. Más del 50% de los individuos con EPOC cumplen con la recomendación de la Organización Mundial de la Salud sobre actividad física para las personas mayores. La cantidad de actividad física, la proporción de ésta realizada en episodios de 10 minutos y la frecuencia de estos episodios disminuyó con el aumento de la gravedad de la EPOC. (Objetivo 3) La cantidad y la intensidad de la actividad física son determinantes independientes de la evolución de la EPOC. El riesgo de hospitalización por EPOC es un 20% menor por cada 1000 pasos adicionales realizados en baja intensidad media. Sin embargo, una mayor cantidad de pasos diarios a una alta intensidad media no influye en el riesgo de hospitalización por EPOC (HR = 1.01; p = 0,919). Conclusiones: El YPAS es una herramienta válida para la detección precoz de los individuos con EPOC físicamente inactivos. Los pacientes con EPOC grave y muy grave realizan menos episodios y cantidad de actividad física, y tienen menor el ratio entre episodios y cantidad que en aquellos en estado leve y moderado. Una mayor cantidad de actividad física de baja intensidad reduce el riesgo de hospitalización por EPOC.
Background: Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of worldwide mortality and disability. Physical activity is one of the few modifiable factors that decelerate COPD evolution. Nonetheless, the dose and characteristics of physical activity responsible of the deceleration are still unknown. In consequence, the aims of this thesis are to move forward and refine the methodology and instruments to evaluate the physical activity of COPD individuals, go in depth in the knowledge about the characteristics and the pattern of their physical activity, and determine which physical activity characteristics improve the prognosis of COPD patients. Methods: 177 individuals with stable COPD selected from 8 hospitals in Spain have participated (94% male, mean±SD age 71±8 years, forced expiratory volume in 1 s 52±16% predicted and body mass index 29±5 kg·m-2). Physical activity was measured with an accelerometer (SenseWear® Pro2 Armband) and with a questionnaire (Yale Physical Activity Survey, YPAS). The sociodemographic (age, sex, civil status, educational level, socioeconomic status, employment status, and tobacco habit) and clinical variables (airflow limitation, lung hyperinflation, dyspnoea, gas exchange, local and systemic inflammation, body composition, comorbidities, quality of life, and exercise capacity), were obtained using validated tools and following international standards. Information about the evolution of the disease (Hospital Admissions and Mortality) was obtained from government registries. Results: (Objective 1) The YPAS is a valid tool for the detection of COPD individuals’ inactivity [the area under the ROC curve is 0.71 (95% CI: 0.63–0.79)]. (Objective 2) The 97% of COPD individuals are able to perform 10-minutes bouts of moderate-to-vigorous physical activity. More than 50% of the COPD individuals met the World Health Organization recommendation of physical activity for the elderly. The quantity of physical activity, the percentage of activity done in bouts and the frequency of bouts decreased with increasing COPD severity. (Objective 3) The quantity and the intensity of physical activity are independent determinants of the COPD evolution. Every additional 1000 daily steps at low-average intensity reduce by 20% the risk of COPD hospitalisation. However, a greater quantity of daily steps at high-average intensity does not influence the risk of COPD hospitalisation (HR 1.01, p=0.919). Conclusion: The YPAS is a valid instrument for the early screening of COPD patients who run the risk of sedentarism. Patients with severe and very severe COPD perform fewer bouts and less quantity of physical activity, and have lower ratio between bouts and quantity than those in mild and moderate stages. Higher quantity of low-intensity physical activity reduces the risk of COPD hospitalization.

Background: Patients with chronic obstructive pulmonary disease (COPD) are known to have an increased risk of ischemic heart disease. Persistently elevated resting heart rate and arterial stiffness, two common clinical manifestations in COPD, are known determinants of myocardial ischemia as well as predictors of cardiovascular events. Controversies exist on the effect of pulmonary rehabilitation on these ischemic heart disease risk factors. No study has explored the effect of pulmonary rehabilitation on the resting heart rate - arterial stiffness relationship in COPD. Objectives and Methods: The overall objectives of this dissertation were to provide a comprehensive investigation of the resting heart rate and arterial stiffness in patients with COPD, and explore the impact of pulmonary rehabilitation on their relationship in this population. We describe the association between resting heart rate and prior myocardial infarction in patients with chronic lung disease attending pulmonary rehabilitation (Chapter 2). We test the reliability of resting heart rate and arterial stiffness measurements in COPD patients (Chapters 3 and 4). We determine the association between resting heart rate and arterial stiffness (Chapter 5), and explore the potential beneficial effects of standard pulmonary rehabilitation on resting heart rate and/or arterial stiffness in COPD (Chapter 6). Summary of findings: We showed that an elevated resting heart rate is a potential indicator of prior myocardial infarction in patients with chronic lung disease (Chapter 2). Resting heart rate and arterial stiffness measurements have excellent and substantial reliability, respectively, under a standardized procedure in COPD patients (Chapters 3 and 4). The association between resting heart rate and arterial stiffness in control subjects is not present in patients with COPD (Chapter 5). Standard pulmonary rehabilitation in COPD reduces arterial stiffness, but not resting heart rate, and does not impact the resting heart rate - arterial stiffness relationship (Chapter 6). Conclusions: This dissertation provides new knowledge on resting heart rate and arterial stiffness, as well as on the potential beneficial effects of pulmonary rehabilitation on these two ischemic heart disease risk factors in COPD patients.
Medicine, Faculty of
Graduate

The neutrophil is central to the development of COPD. To enter lung, neutrophils must migrate accurately from the circulation to inflamed tissue. It is unclear which migratory stimuli are important and whether COPD neutrophils vary in their migratory behaviour, either to controls or patients with similar lung disease. COPD sputum and plasma samples were collected on 11 occasions over one month. Significant correlations were demonstrated between the inflammatory biomarkers and between inflammatory biomarkers and markers of disease. IL-8 correlated most strongly both with other inflammatory mediators, neutrophil counts and indices of disease. Neutrophils from healthy older subjects migrated with maintained speed but reduced accuracy to IL-8. Differences could not be accounted for by surface receptor expression or shedding, but inhibition of CXCR2 gave young neutrophils and old migratory phenotype, suggesting altered downstream signalling. COPD neutrophils migrated with increased speed and reduced accuracy compared with control groups. They formed less pseudopodia when migrating, and had reduced surface expression of CXCR1 and CXCR2. Inhibitory studies suggested that CXCR2 was the predominant receptor in migration to biological samples. Treating COPD cells with a PI3 Kinase inhibitor differentially altered their migration, reducing speed but increasing accuracy, so that cells now resembled those from controls.

This thesis investigated lifestyle characteristics including cigarette smoking, alcohol consumption, dietary supplements intake, physical activity, and urinary incontinence status for Japanese patients with chronic obstructive pulmonary disease (COPD). Field studies were conducted in the middle of Japan. The study was conducted using a cross-sectional survey and all patients were recruited from the outpatient departments of six hospitals in three districts/prefectures, namely, Aichi, Gifu, and Kyoto. Three hundred referred COPD patients diagnosed by respiratory physicians were recruited in 2006. Inclusion criteria were (i) aged between 50 and 75 years; and (ii) had COPD as the primary functionally limiting illness which was diagnosed within the past four years. Diagnosis of COPD was confirmed by spirometry with FEV1/FVC < 70%, where FEV1 = forced expiratory volume in one second and FVC = forced vital capacity. A structured questionnaire was administered to collect information on lifestyle characteristics. All interviews, averaging 40 minutes, took place in the hospital outpatient departments. Clinical characteristics, height, weight and presence of any co-morbidity (e.g. diabetes, hypertension, cardiovascular disease), were retrieved from medical records.A total of 278 eligible participants (244 men and 34 women) were available for analysis. The majority were men (88%) with mean age 66.5 (SD 6.7) years and mean body mass index (BMI) 21.9 (SD 3.6). Most of them were married (84%), had high school or below education (80%) and retired (55%). In relation to cigarette smoking, 62 (53 male and 9 female) participants (22.5%) were current smokers of whom the great majority (89%) smoked daily. Only six (2.1%) participants were never smokers. The prevalence of smoking by time from diagnosis was: 24.5% (< 1 year), 20.6% (1-2 years), and 18.9% (2-4 years). Continuous smoking was inversely associated with age (odds ratio (OR) = 0.94, 95% confidence interval (CI) 0.90-0.98), BMI (OR = 0.88, 95% CI 0.80-0.97) and disease severity vii (OR = 0.29, 95% CI 0.12-0.74 for severe COPD and OR = 0.29, 95% CI 0.09-0.92 for very severe COPD). For alcohol consumption, 158 (150 male and 8 female) patients (56.8%) drank alcohol regularly on at least a monthly basis, the majority of them (73.4%) being daily drinkers. Beer was the most preferred alcoholic beverage drank (30.9%). Alcohol intake appeared to be positively associated with the habit of adding soy sauce to foods, whereas dyspnoea of patients posed significant limitations for them to drink alcoholic beverages.Also, female patients tended to have lower alcohol consumption levels than male patients. Regarding dietary supplements, 117 (101 male and 16 female) participants (42.1%) were dietary supplement users, but the prevalence for female patients (47.1%) was higher than male patients (41.4%). Younger patients (≤ 60 years) and those with severe COPD had relatively low proportion of users (27.3% and 28.9%, respectively). Dietary supplementation was found to be affected by age (p = 0.04), COPD severity (p = 0.03) and presence of co-morbidity (p = 0.03). Older patients over 60 years were more likely to take dietary supplements (OR = 2.44, 95% CI 1.03-5.80), whereas severe COPD patients (OR = 0.41, 95% CI 0.18-0.95) and those with a co-morbidity (OR = 0.54, 95% CI 0.32-0.94) tended not to use. With respect to physical activity of COPD patients, 198 (175 male and 23 female) of them (77%) participated in physical activities on at least weekly basis, but only 22% and 4% engaged in moderate and vigorous activities, respectively. Over 2/3 of them walked at least weekly. Regression analysis showed that perceived life-long physical activity involvement appeared to be positively associated with total physical activity, whereas patients with very severe COPD tended to have significantly lower total physical activity levels.Besides COPD severity, both age and smoking exhibited a negative impact on walking. It is evident that walking activities decreased among very severe patients, current smokers and those in advanced age. The prevalence of urinary incontinence was 12.6% (10% for men and 32% for women). The most common occurrence of urine loss was before reaching the toilet (54%) followed by coughing/sneezing (23%). While urge incontinence was reported viii by 63% of male incontinent patients, 82% of female incontinent patients experienced stress incontinence. Incontinence was more likely among female patients (OR = 8.7, 95% CI 3.2-23.4) and older patients over 70 years (OR = 2.3, 95% CI 1.0-5.2). COPD severity was also found to be a significant factor (p = 0.007), with very severe patients at slightly higher risk of urinary incontinence (OR = 1.1, 95% CI 0.3-3.5) than mild COPD patients, though the relationship appeared not to be linear across the severity classifications. It is alarming to find mild and moderate COPD patients continue to smoke. The implementation of a co-ordinated tobacco control program immediately post diagnosis is needed for the effective pulmonary rehabilitation of COPD patients. The high alcohol consumption by COPD patients is also alarming. Alcohol control programs targeting male patients should be promoted during pulmonary rehabilitation in order to minimise the harm due to excessive drinking. Dietary supplements are popular for patients with COPD especially among older patients.The findings are important to clinical trials and experimental interventions advocating nutritional supplementation therapy for pulmonary rehabilitation. Patients with COPD had lower physical activity levels than the general elderly population. Older patients with very severe COPD and those who currently smoke should be targeted for intervention and encouraged to increase their participation in physical activity so as to maintain their health and well being. The high prevalence yet underreporting of urinary incontinence suggested that education and regular assessment are needed after COPD diagnosis. Appropriate exercise and treatment tailored for the specific type of incontinence incurred should be incorporated within the rehabilitation program of COPD patients. To maintain a healthy lifestyle and to achieve optimal outcomes during the pulmonary rehabilitation of COPD patients, the identified factors should be taken into consideration and health awareness programs should be promoted in conjunction with respiratory physicians and allied health professionals.

This thesis investigated lifestyle characteristics including cigarette smoking, alcohol consumption, dietary supplements intake, physical activity, and urinary incontinence status for Japanese patients with chronic obstructive pulmonary disease (COPD). Field studies were conducted in the middle of Japan. The study was conducted using a cross-sectional survey and all patients were recruited from the outpatient departments of six hospitals in three districts/prefectures, namely, Aichi, Gifu, and Kyoto. Three hundred referred COPD patients diagnosed by respiratory physicians were recruited in 2006. Inclusion criteria were (i) aged between 50 and 75 years; and (ii) had COPD as the primary functionally limiting illness which was diagnosed within the past four years. Diagnosis of COPD was confirmed by spirometry with FEV1/FVC < 70%, where FEV1 = forced expiratory volume in one second and FVC = forced vital capacity. A structured questionnaire was administered to collect information on lifestyle characteristics. All interviews, averaging 40 minutes, took place in the hospital outpatient departments. Clinical characteristics, height, weight and presence of any co-morbidity (e.g. diabetes, hypertension, cardiovascular disease), were retrieved from medical records.
A total of 278 eligible participants (244 men and 34 women) were available for analysis. The majority were men (88%) with mean age 66.5 (SD 6.7) years and mean body mass index (BMI) 21.9 (SD 3.6). Most of them were married (84%), had high school or below education (80%) and retired (55%). In relation to cigarette smoking, 62 (53 male and 9 female) participants (22.5%) were current smokers of whom the great majority (89%) smoked daily. Only six (2.1%) participants were never smokers. The prevalence of smoking by time from diagnosis was: 24.5% (< 1 year), 20.6% (1-2 years), and 18.9% (2-4 years). Continuous smoking was inversely associated with age (odds ratio (OR) = 0.94, 95% confidence interval (CI) 0.90-0.98), BMI (OR = 0.88, 95% CI 0.80-0.97) and disease severity vii (OR = 0.29, 95% CI 0.12-0.74 for severe COPD and OR = 0.29, 95% CI 0.09-0.92 for very severe COPD). For alcohol consumption, 158 (150 male and 8 female) patients (56.8%) drank alcohol regularly on at least a monthly basis, the majority of them (73.4%) being daily drinkers. Beer was the most preferred alcoholic beverage drank (30.9%). Alcohol intake appeared to be positively associated with the habit of adding soy sauce to foods, whereas dyspnoea of patients posed significant limitations for them to drink alcoholic beverages.
Also, female patients tended to have lower alcohol consumption levels than male patients. Regarding dietary supplements, 117 (101 male and 16 female) participants (42.1%) were dietary supplement users, but the prevalence for female patients (47.1%) was higher than male patients (41.4%). Younger patients (≤ 60 years) and those with severe COPD had relatively low proportion of users (27.3% and 28.9%, respectively). Dietary supplementation was found to be affected by age (p = 0.04), COPD severity (p = 0.03) and presence of co-morbidity (p = 0.03). Older patients over 60 years were more likely to take dietary supplements (OR = 2.44, 95% CI 1.03-5.80), whereas severe COPD patients (OR = 0.41, 95% CI 0.18-0.95) and those with a co-morbidity (OR = 0.54, 95% CI 0.32-0.94) tended not to use. With respect to physical activity of COPD patients, 198 (175 male and 23 female) of them (77%) participated in physical activities on at least weekly basis, but only 22% and 4% engaged in moderate and vigorous activities, respectively. Over 2/3 of them walked at least weekly. Regression analysis showed that perceived life-long physical activity involvement appeared to be positively associated with total physical activity, whereas patients with very severe COPD tended to have significantly lower total physical activity levels.
Besides COPD severity, both age and smoking exhibited a negative impact on walking. It is evident that walking activities decreased among very severe patients, current smokers and those in advanced age. The prevalence of urinary incontinence was 12.6% (10% for men and 32% for women). The most common occurrence of urine loss was before reaching the toilet (54%) followed by coughing/sneezing (23%). While urge incontinence was reported viii by 63% of male incontinent patients, 82% of female incontinent patients experienced stress incontinence. Incontinence was more likely among female patients (OR = 8.7, 95% CI 3.2-23.4) and older patients over 70 years (OR = 2.3, 95% CI 1.0-5.2). COPD severity was also found to be a significant factor (p = 0.007), with very severe patients at slightly higher risk of urinary incontinence (OR = 1.1, 95% CI 0.3-3.5) than mild COPD patients, though the relationship appeared not to be linear across the severity classifications. It is alarming to find mild and moderate COPD patients continue to smoke. The implementation of a co-ordinated tobacco control program immediately post diagnosis is needed for the effective pulmonary rehabilitation of COPD patients. The high alcohol consumption by COPD patients is also alarming. Alcohol control programs targeting male patients should be promoted during pulmonary rehabilitation in order to minimise the harm due to excessive drinking. Dietary supplements are popular for patients with COPD especially among older patients.
The findings are important to clinical trials and experimental interventions advocating nutritional supplementation therapy for pulmonary rehabilitation. Patients with COPD had lower physical activity levels than the general elderly population. Older patients with very severe COPD and those who currently smoke should be targeted for intervention and encouraged to increase their participation in physical activity so as to maintain their health and well being. The high prevalence yet underreporting of urinary incontinence suggested that education and regular assessment are needed after COPD diagnosis. Appropriate exercise and treatment tailored for the specific type of incontinence incurred should be incorporated within the rehabilitation program of COPD patients. To maintain a healthy lifestyle and to achieve optimal outcomes during the pulmonary rehabilitation of COPD patients, the identified factors should be taken into consideration and health awareness programs should be promoted in conjunction with respiratory physicians and allied health professionals.

The aims of this study were to explore the lived experience of people with COPD and the views of healthcare professionals involved in the care of patients with COPD. The research question asked how health providers are meeting the psychosocial needs of people with COPD. Recent literature suggests that some patients with COPD are leaving primary care consultations with unmet psychosocial needs and that healthcare providers report being unwilling to promote behaviour change as they perceive it could damage their ongoing relationships with their patients. Data were collected from semi-structured interviews carried out with nine people with COPD and ten healthcare professionals (HCPs). The interviews were transcribed verbatim and the data analysed using Attride-Stirling’s (2001) model of thematic network analysis. Examples of themes deduced from the findings of the COPD group were loss and lifespan health. Those from the HCP group included attitudes and patient care. Both groups yielded a global theme of individuality. Findings from the study suggest that COPD patients are happy with their experience of healthcare although they valued prompt, accessible care in an emergency more highly than routine review appointments. They did not indicate that their psychosocial needs were met in routine consultations although they reported that some of these needs were met during pulmonary rehabilitation. HCPs perceived that they provided good care but that there were barriers to introducing psychosocial issues into routine appointments. In a time of change in patient demographics resulting in an increased number of older people with long-term conditions, this study adds to the body of knowledge in this field by exploring the lived experience of both people with COPD and of HCPs. The global theme of individuality for each group supports the need for person-centred care in the healthcare system in order to meet individuals’ psychosocial needs. Recommendations include; increased provision of pulmonary rehabilitation courses and training for HCPs in order for them to be more aware of the psychosocial needs of patients attending routine appointments.

BACKGROUND: Multimorbidity (i.e. the presence of more than one chronic disease in the same patient) and comorbidity (i.e. the presence of more than one chronic disease in the presence of an index disease) are main sources of dysfunction in chronic patients and avoidable costs in conventional health systems worldwide. By affecting a majority of elderly population worldwide, multimorbidity prompts the need for revisiting the single disease approach followed by contemporary clinical practice and elaborate strategies that target shared mechanisms of associated diseases with the potential of preventing, decelerating or even halting multimorbid disease progression. However, our current understanding on disease interactions is rather limited, and although many disorders have been associated based on their shared molecular traits and their observed co-occurrence in different populations, no comprehensive approach has been outlined to translate this knowledge into clinical practice. The advent of novel measurement technologies (e.g. omics) and recent initiatives on digital health (e.g. registries, electronic health records) are facilitating access to an enormous amount of patient-related information from whole populations to molecular levels. State-of-the art computational models and machine learning tools demonstrate high potential for health prediction and together with systems biology are shaping the practicalities of systems medicine. Given the extremely long and expensive bench to clinics cycles of the biomedical sector, systems medicine promises a fast track approach where scientific evidence support clinical care, while simultaneously collected insights from daily clinical practice promote new scientific discoveries and optimize healthcare. The PhD thesis aims to explore multimorbidity from a systems medicine perspective on the concrete and practical use case of chronic obstructive pulmonary disease (COPD). COPD constitutes an ideal use case due to several factors, including: i) its high impact on healthcare and its ever-increasing burden; ii) its heterogeneous disease manifestations, and progress, often involving extra-pulmonary effects, including highly prevalent comorbidities (e.g. type 2 diabetes mellitus, cardiovascular disorders, anxiety-depression and lung cancer); and, iii) its well described systemic effects that are suggested associations with comorbidities in terms of underlying mechanisms. HYPOTHESIS: The central hypothesis of the PhD thesis builds on the emerging biological evidence that clustering of comorbid conditions, a phenomenon seen in complex chronic patients, could be due to shared abnormalities in relevant biological pathways (i.e. bioenergetics, inflammation and tissue remodelling). It is assumed that a systems understanding of the patient conditions may help to uncover the molecular mechanisms and lead to the design of preventive and targeted therapeutic strategies aiming at modulating patient prognosis. The PhD thesis focuses on non-pulmonary phenomena of COPD; that is, systemic effects and comorbidities, often observed in patients with COPD as a paradigm of complex chronic disease. OBJECTIVES: The general objective of the PhD thesis is threefold: i) to investigate molecular disturbances at body systems level that may lead to a better understanding of characteristic systemic effects and comorbidities of patients with COPD; ii) to analyse population level patterns of COPD comorbidities and investigate their role in the health risk of patients with COPD; and, iii) to explore technological strategies and tools that facilitate the transfer of the collected knowledge on comorbidity into clinical practice. MAIN FINDINGS: Firstly, the PhD thesis introduced a novel knowledge management tool for targeted molecular analysis of underlying disease mechanisms of skeletal muscle dysfunction in patients with COPD. Second, a network analysis approach was outlined to further study this systemic effect, as well as the causes of abnormal adaptation of COPD muscle to exercise training. Furthermore, this work together with three other studies also aimed to reveal the general underlying causes of comorbidity clustering in COPD, using different modelling approaches. Overarching outcome of these studies indicates abnormalities in the complex co-regulation of core biological pathways (i.e. bioenergetics, inflammation, oxidative stress and tissue remodelling) both on muscle and body systems level (blood, lung), which paves the way for the development of novel pharmacological and non-pharmacological preventive interventions on non- pulmonary phenomena in patients with COPD. Furthermore, results indicated strong relation of muscle related dysregulations to aerobic capacity, in opposed to pulmonary severity of COPD. These findings have far reaching potential in COPD care, starting from defining the need for better characterization of exercise performance in the clinic practice and the promotion of physical activity from early stages of the disease. This PhD thesis also generated outcomes with respect to the risk of multimorbidity in patients with COPD using a population health approach. The thesis validated that patients with COPD are in increased risk to co-occur with other diseases compared to non-COPD patients, regardless of the population and healthcare system specificities of different regions (i.e. Catalonia, US). These findings indicated the potential role of multimorbidity as a risk factor for COPD, that was evaluated in the PhD thesis by constructing health risk assessment models to predict unexpected medical events in patients with COPD. The promising performance of the models and the prominent role of multimorbidity in these models presented a powerful argument for its role in clinical staging of the disease and their potential in clinical decision support. CONCLUSIONS: The PhD thesis achieved main points of the general objectives, namely: i) to perform a systems analysis of patients with COPD by investigating molecular disturbances at body systems level leading to a better understanding of characteristic systemic effects and comorbidities of patient with COPD; ii) to analyse population level patterns of COPD comorbidities and investigate their role in the health risk of patients with COPD; and iii) to explore technological strategies and tools that facilitate the transfer of the collected knowledge on comorbidity into clinical practice. Accordingly, the following conclusions arise: 1. Non-pulmonary manifestations in patients with Chronic Obstructive Pulmonary Disease (COPD) have a major negative impact on: highly relevant clinical events, use of healthcare resources and prognosis. Accordingly, the following indications were made: a. Actionable insights on non-pulmonary phenomena should be included in the clinical staging of these patients in an operational manner. b. Management of patients with COPD should be revisited to incorporate an integrative approach to non-pulmonary phenomena. c. Innovative cost-effective interventions, and pharmacological and non- pharmacological treatments targeting prevention of non-pulmonary manifestations in patients with COPD should be developed, and properly assessed. 2. Abnormal co-regulation of core biological pathways (i.e. bioenergetics, inflammation, tissue remodelling and oxidative stress), both in skeletal muscle and at body systems level, are common characteristics of patients with COPD, which potentially play a major role in comorbidity clustering. 3. Consistent relationships between cardiovascular health, skeletal muscle dysfunction and clinical outcomes in patients with COPD was identified, which makes it a priority to characterize patient exercise performance and physical activity in the clinic, and to adopt early cardiopulmonary rehabilitation strategies to modulate prognosis and prevent comorbidity clustering in these patients. 4. Multimorbidity is a strong predictor of unplanned medical events in patients with COPD and shows high potential to be used for personalized health risk prediction and service workflow selection. 5. Personalized health risk prediction was identified as a high potential tool for the integration and transfer of scientific evidence on multimorbidity to daily clinical practice. Limiting factors of its present applicability were explored and implementation strategies based on cloud computing solutions were proposed.
INTRODUCCIÓ: Tant la multimorbiditat (la presència de més d'una malaltia crònica en el mateix pacient), com la comorbiditat (la presència de més d'una malaltia crònica quan hi ha una malaltia de referència) són una font important de disfuncions en l’atenció sanitària dels pacients crònics i generen importants despeses evitables en sistemes de salut arreu del món. La multimorbiditat/comorbiditat afecta la majoria de població de més de 65 anys. El seu gran impacte sanitari i social fa necessària la revisió d’aspectes essencials de la pràctica mèdica convencional, molt enfocada al tractament de cada malaltia de forma aïllada. En aquest sentit, cal elaborar estratègies que considerin els mecanismes biològics comuns entre patologies, per tal de prevenir, retardar o fins i tot aturar la progressió del fenomen. Malauradament, el poc coneixement dels mecanismes biològics que modulen les interaccions entre malalties és un factor limitant important. Hi ha estudis sobre els mecanismes moleculars comuns entre malalties i s’han realitzat anàlisis poblacionals de la multimorbiditat, però no existeix encara una aproximació holística per tal de traduir aquest coneixement a la pràctica clínica. L’aparició de noves tecnologies òmiques, així com iniciatives recents en l’àmbit de la salut digital, han facilitat l'accés a una quantitat enorme d'informació dels pacients, tant a nivell poblacional com a nivell molecular. A més, les eines computacionals i d'aprenentatge automàtic existents estan demostrant un gran potencial predictiu que, conjuntament amb les metodologies de la biologia de sistemes, estan conformant els aspectes pràctics del desplegament de la medicina de sistemes. De forma progressiva, aquesta última esdevé una via efectiva per accelerar el rol de l’evidència científica com a suport a la atenció clínica. De forma recíproca, la digitalització sistemàtica de la pràctica clínica diària, permet la generació de noves descobertes científiques i la optimització de l’assistència sanitària. Aquesta tesis doctoral pretén explorar la multimorbiditat des d’una perspectiva de medicina de sistemes, considerant com a cas d'ús concret i pràctic la malaltia pulmonar obstructiva crònica (MPOC). La MPOC constitueix un cas d'ús ideal a causa de diversos factors: i) el seu alt impacte a nivell sanitari; ii) la heterogeneïtat en quant a manifestacions i progrés, sovint amb efectes extra-pulmonars, incloent de forma freqüent comorbiditats com la diabetis mellitus tipus 2, trastorns cardiovasculars, l'ansietat-depressió i el càncer de pulmó; i, iii) els efectes sistèmics de la malaltia pulmonar, que podrien presentar mecanismes biològics comuns a algunes comorbiditats. HIPÒTESIS: La hipòtesi central d’aquesta tesis doctoral considera que la multimorbiditat podria explicar-se per alteracions en les xarxes de regulació de mecanismes biològics rellevants com la bioenergètica, inflamació i remodelació de teixits. En aquest sentit, l’anàlisi holística del problema podria millorar la comprensió dels mecanismes moleculars que modulen les associacions entre malalties i, per tant, facilitar el disseny d'estratègies terapèutiques preventives i dirigides a modular el pronòstic dels pacients. Aquesta tesis doctoral estudia els fenòmens extra-pulmonars de la MPOC; és a dir, efectes sistèmics (disfunció del múscul esquelètic) i comorbiditats, com a paradigma de malalties cròniques complexes. OBJECTIUS: L'objectiu general d’aquesta tesis doctoral és triple: i) l’anàlisi holístic de pacients amb MPOC amb focus en la disfunció muscular i les comorbiditats; ii) avaluar el paper de les comorbiditats en el risc de salut dels pacients amb MPOC, tant a nivell poblacional com individual; i, iii) explorar estratègies tecnològiques i eines de salut digital que facilitin la transferència de coneixement a la pràctica clínica diària. RESULTATS: El primer manuscrit de la tesi descriu una nova eina de gestió del coneixement per l’anàlisi molecular dels mecanismes de disfunció del múscul esquelètic en pacients amb MPOC. També dins el primer objectiu de la tesi, s’efectua un anàlisi de xarxes orientat a la identificació de mòduls biològics explicatius de la disfunció muscular i de l’adaptació anòmala d’aquests malalts a l’entrenament físic, tal com es descriu en el segon manuscrit. Els tres articles següents exploren, des de diferents perspectives, l’impacte i mecanismes de les comorbiditats en els pacients amb MPOC. Els principals resultats d'aquests estudis indiquen una complexa i anormal regulació de vies biològiques principals, com es el cas de la bioenergètica, inflamació, estrès oxidatiu i remodelació de teixits, tant a nivell del múscul com a nivell sistèmic (sang, pulmó). Aquests resultats obren noves vies per a intervencions preventives, tant farmacològiques com no farmacològiques, sobre els fenòmens no pulmonars que presenten els pacients amb MPOC. Els resultats indiquen una associació de les alteracions musculars amb la capacitat aeròbica, i no pas amb la gravetat de la malaltia pulmonar. Aquestes troballes tenen un gran potencial en la millora de la gestió dels pacients amb MPOC, començant per la necessitat d’una millor caracterització de la capacitat aeròbica en la pràctica clínica i la promoció d'activitat física des de les primeres etapes de la malaltia. La tesi també ha generat resultats d’interès en relació amb el risc de multimorbiditat en pacients amb MPOC, mitjançant un enfocament de salut poblacional. Els resultats evidencien que els pacients amb MPOC presenten un risc mes elevat de comorbiditat que els pacients sense MPOC, independentment de les especificitats de la població i del sistema sanitari de les àrees analitzades (Catalunya, EUA). La tesi també demostra el paper de la multimorbiditat com a factor modulador del risc clínic dels pacients amb MPOC. Aquests resultats indiquen l’interès de l’ús de la multimobiditat en l’estadiatge dels pacients amb MPOC i en l’elaboració d’eines de suport al procés de decisió clínica. CONCLUSIONS: Aquesta tesi doctoral ha assolit els objectius generals plantejats i proposa les següents conclusions: 1. Les manifestacions no pulmonars en els pacients amb malaltia pulmonar obstructiva crònica (MPOC) tenen un impacte negatiu respecte a esdeveniments de gran rellevància clínica, ús de recursos sanitaris i pronòstic. En conseqüència, es fan les següents recomanacions: a. Els fenòmens no pulmonars de la MPOC s’haurien d’incloure de manera operativa en l’estadiatge d'aquests pacients. b. S’hauria de redefinir la gestió clínica dels pacients amb MPOC tot incorporant un enfocament holístic dels fenòmens no pulmonars. c. S’haurien de desenvolupar i avaluar correctament noves intervencions, farmacològiques i no farmacològiques, per a la prevenció de les manifestacions no pulmonars en pacients amb MPOC. 2. Les alteracions de la regulació de vies biològiques rellevants com la bioenergètica, inflamació, estrès oxidatiu i la remodelació de teixits a nivell del múscul esquelètic, i també a nivell sistèmic, s’observa en els pacients amb MPOC i pot tenir un paper important en les co-morbiditats. 3. Les relacions entre alteracions cardiovasculars, disfunció del múscul esquelètic i altres aspectes clínics dels pacients amb MPOC, indiquen la necessitat de caracteritzar la capacitat aeròbica i els nivells d'activitat física en la pràctica clínica, així com la implementació d’estratègies de rehabilitació cardiopulmonar en les primeres etapes de la malaltia, per tal de modular la prognosis dels malalts i prevenir l’aparició de comorbiditats. 4. La multimorbiditat és un bon predictor d’esdeveniments clínics rellevants en pacients amb MPOC i mostra un gran potencial per a personalitzar l’estimació de risc i la selecció de serveis. 5. La predicció de risc de forma personalitzada s’ha identificat com una eina amb molt potencial per a la gestió de la multimorbiditat en la pràctica clínica diària. S’han explorat els factors limitants de la seva aplicabilitat i s’han proposat estratègies d'implementació d’eines predictives adients, basades en solucions de computació en el núvol.
INTRODUCCIÓN: Tanto la multimorbilidad (la presencia de más de una enfermedad crónica en un mismo paciente) como la comorbilidad (la presencia de más de una enfermedad crónica en presencia de una enfermedad de referencia) son una fuente importante de disfunciones en la atención sanitaria de los pacientes crónicos y generan importantes costes evitables en los sistemas de salud de todo el mundo. La multimorbilidad/comorbilidad afecta a la mayoría de la población de más de 65 años. Debido a su gran impacto sanitario y social, resulta necesaria la revisión de aspectos esenciales de la práctica médica convencional, muy enfocada en el tratamiento de cada enfermedad de forma aislada. En este sentido, es necesario elaborar estrategias que consideren mecanismos biológicos comunes entre patologías, con el fin de prevenir, retrasar o incluso detener la progresión del fenómeno. Desgraciadamente, el escaso conocimiento de los mecanismos biológicos que modulan las interacciones entre enfermedades es un factor limitante importante. Existen estudios sobre los mecanismos moleculares comunes entre enfermedades y se han realizados análisis poblaciones de la multimorbilidad, pero no existe aún una aproximación holística que permita traducir este conocimiento a la práctica clínica. La aparición de nuevas tecnologías ómicas, así como recientes iniciativas en el ámbito de la salud digital, han facilitado el acceso a una cantidad enorme de información sobre los pacientes, tanto a nivel poblacional como a nivel molecular. Además, las herramientas computacionales y de aprendizaje automático existentes demuestran un gran potencial predictivo que, conjuntamente con las metodologías de biología de sistemas, están conformando los aspectos prácticos de la medicina de sistemas. De manera progresiva esta última se está convirtiendo en una vía efectiva para acelerar el papel de la evidencia científica como soporte a la atención clínica. De forma recíproca, la digitalización sistemática de la práctica clínica diaria permite la generación de nuevos descubrimientos científicos y la optimización de la asistencia sanitaria. Esta tesis doctoral pretende explorar la multimorbilidad desde una perspectiva de medicina de sistemas, considerando como caso de uso concreto y práctico la enfermedad pulmonar obstructiva crónica (EPOC). La EPOC constituye un caso de uso ideal debido a diversos factores: i) su alto impacto a nivel sanitario; ii) la heterogeneidad en cuanto a manifestaciones y progreso, a menudo con efectos extra pulmonares, incluyendo de forma frecuente comorbilidades como la diabetes mellitus tipo 2, trastornos cardiovasculares, la ansiedad-depresión y el cáncer de pulmón; y, iii) los efectos sistémicos de la enfermedad pulmonar, que podrían presentar mecanismos biológicos comunes a algunas comorbilidades. HIPÓTESIS: La hipótesis central de esta tesis doctoral considera que la multimorbilidad podría explicarse por alteraciones en las redes de regulación de mecanismos biológicos relevantes como la bioenergética, inflamación y remodelación de tejidos. En este sentido, el análisis holístico del problema podría mejorar la comprensión de los mecanismos moleculares que modulan las asociaciones entre enfermedades y, por tanto, facilitar el diseño de estrategias terapéuticas preventivas y dirigidas a modular el pronóstico de los pacientes. Esta tesis doctoral estudia los fenómenos extra pulmonares de la EPOC; es decir, efectos sistémicos (disfunción del músculo esquelético) y comorbilidades, como paradigma de enfermedades crónicas complejas. OBJETIVOS: El objetivo general de esta tesis doctoral es triple: i) el análisis holístico de pacientes con EPOC focalizando en la disfunción muscular y la comorbilidades; ii) evaluar el papel de las comorbilidades en el riesgo de salud de los pacientes con EPOC, tanto a nivel poblacional como individual; y, iii) explorar estrategias tecnológicas y herramientas de salud digital que faciliten la transferencia de conocimiento a la práctica clínica diaria. RESULTADOS: El primer manuscrito de la tesis describe una nueva herramienta de gestión del conocimiento para el análisis molecular de los mecanismos de disfunción del músculo esquelético en pacientes con EPOC. Incluido en el primer objetivo de la tesis, se efectúa un análisis de redes orientado a la identificación de módulos biológicos que explican la disfunción muscular y la adaptación anómala de estos pacientes al entrenamiento físico, tal y cómo se describe en el segundo manuscrito. Los tres artículos siguientes exploran, desde perspectivas diferentes, el impacto y mecanismos de las comorbilidades en los pacientes con EPOC. Los principales resultados de estos estudios indican una compleja y anormal regulación de vías biológicas principales, como es el caso de la bioenergética, inflamación, estrés oxidativo y remodelación de tejidos, tanto a nivel del músculo como a nivel sistémico (sangre, pulmón). Estos resultados abren nuevas vías para intervenciones preventivas, tanto farmacológicas como no farmacológicas, sobre los fenómenos no pulmonares que presentan los pacientes con EPOC. Los resultados indican una asociación de las alteraciones musculares con la capacidad aeróbica, y no con la gravedad de la enfermedad pulmonar. Estos hallazgos tienen un gran potencial en la mejora de la gestión de los pacientes con EPOC, empezando por la necesidad de una mejor caracterización de la capacidad aeróbica en la práctica clínica y la promoción de actividad física desde etapas tempranas de la enfermedad. La tesis también ha generado resultados de interés en relación con el riesgo de multimorbilidad en pacientes con EPOC, mediante un enfoque de salud poblacional. Los resultados evidencian que los pacientes con EPOC presentan un mayor riesgo de comorbilidad que los pacientes sin EPOC, independientemente de las especificidades de la población y del sistema sanitario de las áreas analizadas (Cataluña, EUA). La tesis demuestra también el papel de la multimorbilidad como factor modulador del riesgo clínico de los pacientes con EPOC. Estos resultados indican la conveniencia del uso de la multimorbilidad en el estadiaje de los pacientes con EPOC y en la elaboración de herramientas de soporte al proceso de decisión clínica. CONCLUSIONES: Esta tesis doctoral ha conseguido los objetivos generales planteados y propone las siguientes conclusiones: 1. Las manifestaciones no pulmonares en los pacientes con enfermedad pulmonar obstructiva crónica (EPOC) tienen un impacto negativo respecto a eventos de gran relevancia clínica, uso de recursos sanitarios y pronóstico. En consecuencia, se formulan las siguientes recomendaciones: a) Los fenómenos no pulmonares de la EPOC deberían incluirse de manera operativa en el estadiaje de estos pacientes. b) Se debería redefinir la gestión clínica de los pacientes con EPOC incorporando un enfoque holístico de los fenómenos no pulmonares. c) Se deberían desarrollar y evaluar correctamente nuevas intervenciones, farmacológicas y no farmacológicas, para la prevención de las manifestaciones no pulmonares en pacientes con EPOC. 2. Las alteraciones de la regulación de vías biológicas relevantes como la bioenergética, inflamación, estrés oxidativo y la remodelación de tejidos a nivel del músculo esquelético y también a nivel sistémico, se observa en pacientes con EPOC y puede tener un papel importante en las comorbilidades. 3. Las relaciones entre alteraciones cardiovasculares, disfunción del músculo esquelético y otros aspectos clínicos de los pacientes con EPOC, indican la necesidad de caracterizar la capacidad aeróbica y los niveles de actividad física en la práctica clínica, así como la implementación de estrategias de rehabilitación cardiopulmonar en las primeras etapas de la enfermedad, con el fin de modular el pronóstico de los pacientes y prevenir la aparición de comorbilidades. 4. La multimorbilidad es un buen predictor de eventos clínicos relevantes en pacientes con EPOC y muestra un gran potencial para personalizar la estimación de riesgo y la selección de servicios. 5. La predicción del riesgo de forma personalizada se ha identificado como una herramienta con alto potencial para la gestión de la multimorbilidad en la práctica clínica diaria. Se han explorado los factores limitantes de su aplicabilidad y se han propuesto estrategias de implementación de herramientas predictivas adecuadas, basadas en soluciones de computación en la nube.

BACKGROUND The epidemics of non-communicable diseases and the need for cost-containment are triggering a profound reshaping of healthcare delivery toward adoption of the Chronic Care model, involving deployment of integrated care services (ICS) with the support of information and communication technologies (ICS-ICT). In this scenario, emerging systems medicine, with a holistic mechanism-based approach to diseases, may play a relevant role in health risk assessment and patient stratification. The general aim of Synergy-COPD was to explore the potential of a systems medicine approach to improve knowledge on underlying mechanisms of chronic obstructive pulmonary disease (COPD) heterogeneity, focusing on systemic effects of the disease and co-morbidity clustering. The transfer of acquired knowledge to healthcare was also a core aim of the project. Moreover, Synergy-COPD explored novel cross talk between biomedical research and healthcare to foster deployment of 4P (Predictive, Preventive, Personalized and Participatory) Medicine for patients with chronic disorders. The current PhD thesis contributed to Synergy-COPD focusing on two specific areas: i) a quantitative analysis of the relationships between cellular oxygenation and mitochondrial reactive oxygen species (ROS) generation; and, ii) different ICT developments addressing transfer of knowledge to healthcare and the interplay with biomedical research. HYPOTHESIS The overarching hypothesis of this PhD thesis is that subject-specific health risk assessment and stratification may lead to novel and a more efficient patient-oriented healthcare delivery. Specifically, the current PhD studies hypothesize that predictive mechanistic modeling integrating oxygen pathway and mitochondrial function can contribute to assess the biological effects of cellular hypoxia and its role on skeletal muscle dysfunction in COPD. Moreover, it is hypothesized that a holistic design of the ICT support may contribute to a successful deployment of ICS-ICT for chronic patients fostering the transfer of the achievements of systems-oriented research into healthcare. OBJECTIVES To integrate physiological modeling of the O2 pathway and biochemical modeling of mitochondrial ROS generation to quantitatively analyze the relationships between skeletal muscle oxygenation and mitochondrial ROS generation. To develop ICT tools supporting Integrated Care Services (ICS-ICT) for chronic patients, as well as innovative cross talk between systems-oriented biomedical research and healthcare. MAIN FINDINGS Quantitative analysis between cellular oxygenation and mitochondrial ROS generation The model analyzed the role of all the physiological determinants of the O2 pathway. It was shown that a given degree of heterogeneity in the skeletal muscle reduces overall O2 transfer more than does lung heterogeneity, but actually observed heterogeneity in lung is greater than in muscle, so that lung heterogeneity has a greater impact on overall O2 transport. In addition, muscle heterogeneity showed to increase the range of skeletal muscle PmO2 values, and in regions with a low ratio of metabolic capacity to blood flow, mitochondrial PO2 (PmO2) could exceed that of mixed tissue venous blood. Unfortunately, assessment of skeletal muscle functional heterogeneities is highly limited due to technological constraints. The model indicates that the ratio between O2 transport capacity and mitochondrial O2 utilization potential determines PmO2. The phenomenon might be highly relevant after high intensity resistance training in COPD patients with limitation of O2 transport due to the pulmonary disease. Simulations using data from healthy subjects during maximal exercise revealed that altitude triggers high mitochondrial ROS production in skeletal muscle regions with high metabolic capacity, but limited O2 delivery, already evident at approx. 17,000 ft. above sea level. This is the altitude above which permanent human habitation does not occur, and the altitude above which humans experience inexorable loss of body mass. However, it is concluded that the use of the integrated model in disease conditions requires further refinement of mitochondrial parameter estimation. ICT-support to the deployment of integrated care services (ICS-ICT) and to the cross talk between healthcare and systems-oriented biomedical research An open and modular platform was developed to provide the common basic set of tools and technologies to support the implementation of ICS-ICT for chronic patients. The platform has effectively covered the four ICS developed and assessed within the NEXES European project (2008-2013, www.nexeshealth.eu) in one of Barcelona’s Health Care Districts accounting for 540.000 inhabitants, and has shown potential for further deployment at regional level. The concept of the Digital Health Framework (DHF) was articulated to provide linkage between healthcare and innovative systems-oriented biomedical research. The Synergy-COPD knowledge base was developed as a component of the DHF-research to enforce the transition toward 4P medicine. CONCLUSIONS 1. The model integrating physiological determinants of the O2 pathway and biochemical modulators of mitochondrial ROS formation provides, for the first time, a quantitative assessment of the relationships between cellular oxygenation and mitochondrial ROS production. The model generates consistent results in health, but parameter estimations when applied to COPD needs refinement. 2. The ICT-platform supporting integrated care services (ICS) for chronic patients effectively covered the functional requirements for deployment within a single-provider environment. The challenges to be faced for regional deployment of the ICS were identified and strategies for adoption have been proposed. 3. The Digital Health Framework (DHF) conceptualizes a scenario for an effective cross talk between integrated care and systems-oriented biomedical research that should foster deployment of 4P medicine. Future steps for adoption of the DHF have been proposed. 4. The COPD-specific knowledge base (COPDkb), developed and assessed in the current PhD thesis, constitutes a pivotal component of systems-oriented biomedical research.
INTRODUCCIÓ La proliferació de les malalties no contagioses i la creixent necessitat de reduir costos està desencadenant una remodelació estructural de l’atenció sanitària envers el model d’atenció a crònics, involucrant la implementació de serveis d’atenció integrada (SAI) amb el suport de les tecnologies de la informació i la comunicació (SAI-TIC). En aquest escenari, la emergent medicina de sistemes, amb un aproximació holística basada en els mecanismes de les malalties, juga un rol rellevant a l’avaluació del risc per la salut i la estratificació de pacients. L’objectiu principal de Synergy-COPD ha estat la exploració del potencial de una aproximació de la medicina de sistemes per tal de millorar el coneixement dels mecanismes subjacents a la heterogeneïtat de la malaltia pulmonar obstructiva crònica (MPOC). Fent èmfasi als efectes sistèmics de la malaltia, així com en la comorbiditat. La transferència de nous coneixements a l’atenció sanitària ha estat també un dels objectius principals d’aquest projecte. A més, Synergy-COPD ha explorat noves interaccions envers la investigació biomèdica i l’atenció sanitària, amb la darrera finalitat de promoure la medicina 4P (predictiva, preventiva, personalitzada i participatòria) per a pacients amb malalties cròniques. Aquesta tesi doctoral contribueix amb Synergy-COPD en dos aspectes específics: 1. Un anàlisi quantitatiu de la relació entre la oxigenació cel•lular i la producció de radicals lliures d’oxigen (ROS) a nivell mitocondrial. 2. Diversos desenvolupament tecnològics adreçats a la transferència de coneixement biomèdic envers a l’atenció sanitària i la investigació biomèdica. HIPÒTESIS La hipòtesi general d’aquesta tesi doctoral és que una personalització de l’avaluació del risc per a la salut i la estratificació de pacients ha de desencadenar en una atenció sanitària més eficient i orientada envers pacient. Específicament aquesta tesi doctoral planteja la hipòtesi de que el modelatge mecanicista del sistema de transport i utilització d’oxigen, tenint en compte la funció mitocondrial, pot contribuir a avaluar els efectes biològics d ela hipòxia cel•lular i el seu paper a la disfunció del múscul esquelètic a la MPOC. D’altra banda, aquesta tesi doctoral planteja també la hipòtesi referent a que un disseny holístic basat en les TIC pot contribuir a un desplegament efectiu de SAI-TIC per a pacients crònics, fomentant l’aplicació dels assoliments de la investigació orientada a sistemes a l’assistència sanitària. OBJECTIUS La integració de un modelatge fisiològic del sistema de transport i utilització d’oxigen amb el modelatge bioquímic de la generació mitocondrial de ROS, amb la finalitat d’analitzar les relacions entre la oxigenació del múscul esquelètic i la producció mitocondrial de ROS. El desenvolupament d’eines TIC que donin suport a Serveis d’Atenció Integrada (SAI-TIC) per a pacients crònics, i per tal de fomentar la interacció entre la investigació biomèdica basada en la medicina de sistemes i l’atenció sanitària. RESULTATS PRINCIPALS Anàlisi quantitatiu de la relació entre oxigenació cel•lular i la generació mitocondrial de ROS El modelatge realitzat en aquesta tesi doctoral analitza tots els factor determinants del sistema de la cadena de transport d’oxigen. S’ha demostrat que donat un cert grau d’heterogeneïtat al múscul esquelètic es disminueix la transferència global d’oxigen més de lo que la redueix la heterogeneïtat pulmonar. D’altra banda, la heterogeneïtat observada actualment a nivell pulmonar es major que la observada al múscul, per tant la heterogeneïtat pulmonar en general té un impacte més gran sobre la transferència total d’oxigen. A més, es demostra que la heterogeneïtat muscular incrementa el rang de nivells d’oxigenació cel•lular (PmO2), i a regions del múscul esquelètic amb una major aportació sanguínia en comparació a la capacitat metabòlica, els valors de PmO2 poden excedir els valors d’oxigenació venosa mixta. Malauradament, la mesura del nivell d’heterogeneïtat funcional al múscul esquelètic és molt insuficient degut a les limitacions tecnològiques. El model indica que la relació entre la capacitat de transport d’oxigen i utilització d’oxigen determina principalment els valors d’oxigenació cel•lular PmO2. Aquest fenomen, pot ser molt rellevant després d’un procés d’entrenament d’alta intensitat a pacients MPOC amb limitacions de transport d’oxigen degut a la malaltia pulmonar. Les simulacions utilitzant dades mesurades en subjectes sans realitzant exercici màxim han desvelat que l’altitud desencadena una alta producció de ROS mitocondrial a les regions del múscul esquelètic amb una altra capacitat mitocondrial però amb una limitada capacitat d’aportació d’oxigen. Aquesta observació és evident a partir d’una altitud corresponent a uns 5000 metres sobre el nivell del mar. Per sobre d’aquesta altitud no existeix cap assentament humà permanentment habitat i els humans experimenten una pèrdua inexorable de massa corporal. Però, es conclou que l’ús del model integrat en condicions de malaltia requereix una millor estimació dels paràmetres mitocondrials. Suport TIC per al desplegament de serveis d’atenció integrada (SAI-TIC) i la interacció entre l’atenció sanitària i la investigació biomèdica basada en la medicina de sistemes S’ha desenvolupat una plataforma tecnològica modular que proporciona un conjunt bàsic d’eines i tecnologies per donar suport a la implementació de SAI-TIC per a pacients crònics. Aquesta plataforma tecnològica ha suportat de manera eficient els quatre SAI dissenyats i avaluats en el context del projecte europeu NEXES (2008-2013, www.nexeshealth.eu) a un dels districtes sanitaris de Barcelona, amb un total de 540.000 habitants, i ha mostrat potencial d’escalabilitat a nivell regional. El concepte de “Digital Health Framework (DHF)” ha estat articulat amb la finalitat d’enllaçar l’atenció sanitària i a la investigació biomèdica basada en la medicina de sistemes. La base de coneixement de Synergy-COPD ha estat desenvolupada com a un component d’investigació del DHF per tal de fomentar la transició envers una medicina 4P. CONCLUSIONS 1. El model que integra els determinants fisiològics de la cadena de transport d’oxigen i els elements bioquímics moduladors de la formació a nivell mitocondrial de ROS, ha proporcionat, per primera vegada, un anàlisi quantitatiu de la relació entre la oxigenació cel•lular i la producció mitocondrial de ROS. El model genera resultats consistents en salut, però una millor estimació dels paràmetres mitocondrials és necessària quan s’aplica a MPOC. 2. La plataforma tecnològica per al suport de serveis d’atenció integrada (SAI) per a pacients crònics ha cobert de forma efectiva els requisits funcionals per al desplegament d’un entorn amb un únic proveïdor. Els reptes que cal afrontar per a un desplegament a nivell regional de SAI han estat identificats i s’han proposat estratègies per a la seva adopció. 3. El concepte de “Digital Health Framework (DHF)” representa un escenari on l’enllaç entre l’atenció integrada i la investigació biomèdica de medicina de sistemes han de promoure el desplegament de la medicina 4P. S’ha proposat les línies estratègiques per a una correcta adopció del DHF. 4. La base del coneixement específica per a MPOC (COPDkb) ha estat desenvolupada i analitzada en aquesta tesi doctoral, constitueix un component principal de la investigació biomèdica basada en la medicina de sistemes.
INTRODUCCIÓN La proliferación de enfermedades no transmisibles y la creciente necesidad de contención de costes están desencadenando un profundo rediseño de la atención sanitaria hacia la adopción de un modelo de atención a crónicos, involucrando la implementación de servicios de atención integrada (SAI) con el soporte de las tecnologías de la información y de la comunicación (SAI-TIC). En este escenario, la emergente medicina de sistemas, con una aproximación holística basada en los mecanismos de las enfermedades, juega un papel muy relevante en la evaluación del riesgo para la salud y la estratificación de pacientes. El objetivo principal de Synergy-COPD ha sido la exploración del potencial de una aproximación de medicina de sistemas para mejorar el conocimiento de los mecanismos subyacentes a la heterogeneidad de la enfermedad pulmonar obstructiva crónica (EPOC). Haciendo énfasis en los efectos sistémicos de la enfermedad, así como en la comorbilidad. La transferencia de nuevos conocimiento a la atención sanitaria ha sido también un objetivo principal del proyecto. Por otro lado, Synergy-COPD ha explorado nuevas interacciones entre investigación biomédica y atención sanitaria, con la finalidad última de promover la medicina 4P (Predictiva, Preventiva, Personalidad y Participativa) para pacientes con enfermedades crónicas. Esta tesis doctoral contribuye con Synergy-COPD en dos aspectos específicos: 1. Un análisis cuantitativo de la relación entre la oxigenación celular y la producción de radicales libres de oxígeno (ROS) a nivel mitocondrial. 2. Diversos desarrollos tecnológicos dirigidos a la trasferencia de conocimiento biomédico a la atención sanitaria y la investigación biomédica. HIPÓTESIS La hipótesis general de esta tesis doctoral es que una personalización de la evaluación del riesgo para la salud y la estratificación, tiene que desencadenar una atención sanitaria más eficiente y orientada al paciente. Específicamente, esta tesis doctoral plantea la hipótesis de que un modelado mecanicista del sistema de transporte y utilización de oxígeno, teniendo en cuenta la función mitocondrial, puede contribuir a evaluar los efectos biológicos de la hipoxia celular y su papel en la disfunción del músculo esquelético en la EPOC. Por otra parte, se plantea la hipótesis de que un diseño holístico basado en las TIC puede contribuir a una implementación exitosa de SAI-TIC para los pacientes crónicos, fomentando la transferencia de los logros de la investigación orientada a sistemas en la asistencia sanitaria. OBJETIVOS La integración del modelado fisiológico del sistema de transporte y utilización de oxígeno con el modelado bioquímico de la generación mitocondrial de ROS, con la finalidad de analizar las relaciones entre la oxigenación del músculo esquelético y la producción mitocondrial de ROS. El desarrollo de herramientas TIC que den soporte a servicios de atención integrada (SAI-TIC) para pacientes crónicos, y que fomenten la interacción entre la investigación biomédica basada en la medicina de sistemas y la atención sanitaria. RESULTADOS PRINCIPALES Análisis cuantitativo de la relación entre oxigenación celular y la generación mitocondrial de ROS El modelaje realizado en esta tesis doctoral analiza todos los factores determinantes de la cadena de transporte de oxígeno. Se ha mostrado que un determinado grado de heterogeneidad en el músculo esquelético reduce la transferencia global de oxígeno más de lo que la reduce la heterogeneidad pulmonar. Sin embargo, la heterogeneidad observada actualmente a nivel pulmonar es mayor que la observada en músculo, por lo tanto, la heterogeneidad pulmonar en general tiene un impacto mayor sobre la transferencia total de oxígeno. Por otra parte, hemos mostrado que la heterogeneidad muscular incrementa el rango de niveles de oxigenación celular (PmO2), y en regiones del músculo esquelético con un mayor aporte sanguíneo en comparación con la capacidad metabólica, los valores de PmO2 pueden exceder los correspondientes valores de oxigenación venosa mixta. Desafortunadamente, la medición del nivel de heterogeneidad funcional en músculo esquelético es muy insuficiente debido a las limitaciones tecnológicas. El modelo indica que la relación entre la capacidad de transporte y utilización de oxígeno determina principalmente los valores de oxigenación celular (PmO2). Este fenómeno, puede que sea muy relevante después de un proceso de entrenamiento de alta intensidad en pacientes EPOC con limitaciones de transporte de oxígeno debido a la enfermedad pulmonar. Simulaciones utilizando datos medidos en sujetos sanos realizando ejercicio máximo han desvelado que la altitud desencadena una alta producción de ROS mitocondrial en las regiones del músculo esquelético con una alta capacidad metabólica pero con una limitada capacidad de aporte de oxígeno. Esta observación, es evidente a partir de una altitud correspondiente a 5000 metros sobre el nivel del mar. Por encima de esta altitud no existe ningún asentamiento humano permanentemente habitado y los humanos experimentan una perdida inexorable de masa corporal. Sin embargo, se concluye que el uso del modelo integrado en condiciones de enfermedad requiere una mejor estimación de los parámetros mitocondriales. Soporte TIC para el despliegue de servicios de atención integrada (SAI-TIC) y la interacción entre la atención sanitaria y la investigación biomédica basada en la medicina de sistemas Se ha desarrollado una plataforma tecnológica modular que proporciona un conjunto básico de herramientas y tecnologías para dar soporte a la implantación de SAI-TIC para pacientes crónicos. Esta plataforma tecnológica ha soportado de manera eficiente los cuatro SAI diseñados y evaluados en el contexto del proyecto europeo NEXES (2008-2013, www.nexeshealth.eu) en uno de los distritos sanitarios de Barcelona, con un total de 540.000 habitantes, y ha mostrado potencial de escalabilidad a nivel regional. El concepto de “Digital Health Framework (DHF)” ha sido articulado con el fin de enlazar la atención sanitaria y la investigación biomédica basada en la medicina de sistemas. La basa de conocimiento de Synergy-COPD ha sido desarrollada como un componente de investigación del DHF para fomentar la transición hacia una medicina 4P. CONCLUSIONES 1. El modelo que integra los determinantes fisiológicos de la cadena de transporte de oxígeno y los elementos bioquímicos moduladores de la formación a nivel mitocondrial de ROS, ha proporcionado, por primera vez, un análisis cuantitativo de la relación entre la oxigenación celular y la producción mitocondrial de ROS. El modelo genera resultados consistentes en salud, pero una mejor estimación de los parámetros mitocondriales es necesaria cuando se aplica en EPOC. 2. La plataforma tecnológica para el soporte de servicios de atención integrada (SAI) pra pacientes crónicos ha cubierto de forma efectiva los requisitos funcionales para el despliegue en un entorno con un único proveedor. Los retos que se han afrontar un despliegue regional de SAI, han sido identificados y se han propuesto estrategias para su adopción. 3. El concepto de “Digital Health Framework (DHF)” representa un escenario en el que el enlace entre atención integrada e investigación biomédica de medicina de sistemas debe promover el despliegue de la medicina 4P. Se han propuesto líneas estratégicas para una correcta adopción del DHF. 4. La base de conocimiento específica para EPOC (COPDkb) que ha sido desarrollada y analizada en esta tesis doctoral, constituye un componente principal de la investigación biomédica basada en la medicina de sistemas.