Orientador: Suzana Erico Tanni / Resumo: Introdução: As manifestações sistêmicas da Doença Pulmonar Obstrutiva Crônica (DPOC) estão relacionadas ao aumento do processo inflamatório sistêmico, entretanto, não está totalmente esclarecido o quanto a inflamação sistêmica, em especial a interleucina-6 (IL-6), está associada com o risco de mortalidade. Dessa forma, o objetivo desse estudo consistiu em avaliar a evolução das concentrações séricas da IL-6 e sua associação com a mortalidade de pacientes com DPOC em nove anos. Pacientes e métodos: 133 pacientes foram avaliados no momento basal entre 2004 e 2006 e reavaliados depois de três e nove anos por meio de avaliação clínica, espirometria, oximetria de pulso e gases arteriais, composição corporal, distância percorrida em seis minutos (DP6), qualidade de vida, intensidade de dispneia, Índice BODE, comorbidades, IL-6 e número de exacerbações nos três primeiros anos de seguimento. Resultados: Durante acompanhamento, 19 pacientes perderam seguimento, quatro não tiveram a causa da morte identificada e 18 estavam com dados incompletos; assim, 92 pacientes foram incluídos na análise de mortalidade tendo a IL-6 como covariável tempo dependente. Na reavaliação dos sobreviventes, 64 pacientes morreram, 23 perderam seguimento, 12 recusaram continuar participando e um não pode ser reavaliado em decorrência de exacerbações frequentes; dessa forma, 33 foram incluídos na reavaliação após nove anos. Sobre o perfil inflamatório, nos pacientes que sobreviveram após nove anos, houve aumen... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Systemic manifestations of Chronic Obstructive Pulmonary Disease (COPD) are related to increased systemic inflammatory process; however, it is not entirely clear how the systemic inflammation, in particular interleukin-6 (IL-6), is associated with mortality risk. Therefore, this study aimed to evaluate the evolution of serum IL-6 concentrations and its association with mortality of COPD patients over nine years. Patients and methods: 133 COPD patients were assessed at baseline between 2004 and 2006 and reassessed after three and nine years through clinical evaluation, spirometry, pulse oximetry and arterial gases, body composition, 6-minute walk distance (6MWD), quality of life, dyspnea intensity, BODE Index, comorbidities, IL-6 and number of exacerbations in the first three years of follow-up. Results: After nine years, 19 patients lost the follow-up, was not possible to identify the date of death of 4 patients and 18 had incomplete data; thus, 92 patients were included in the Cox mortality analysis with IL-6 as a time dependent covariate. In the reassessment of survivors, 64 patients died, 23 lost the follow-up, 12 refused to participate and 1 could not be involved due to recurrent exacerbations; therefore, 33 patients were included in the reassessment after nine years of followup. Regarding the inflammatory profile, in patients who survived after nine years, there was a significant increase in IL-6 [0.4(0.2-0.8) vs 5.7(3.4-11)pg/mL; p<0.001] and reduction in ... (Complete abstract click electronic access below) / Doutor

Assessing the global impact of chronic obstructive pulmonary disease (COPD) on a patient’s life can be difficult to perform in the clinical setting due to time constraints and workflow challenges. The primary objective of this study was to compare disease impact ratings between patient selfadministered COPD Assessment Test (CAT) and physician standard office assessment. This prospective study was conducted at a family medicine residency clinic in northeast Tennessee. The study included two study groups: 1) adult patients seen at the clinic during the 3-month study period with an active diagnosis of COPD, and 2) their physicians. Physicians’ assessment of the impact of COPD on their patients’ daily lives was compared to patients’ self-administered CAT assessments. Physician assessment of COPD impact and patient ssessment of CAT categories significantly differed (χ2 =11.0, P=0.012). There was very poor agreement between patient and physician ratings (κ=0.003), with 42.9% of physician ratings underestimating the impact, 28.6% overestimating the impact, and 28.6% orrectly estimating the impact COPD had on their patients’ lives. These findings support the use of validated assessment tools to help providers understand the symptom burden for patients with COPD.

Chronic Obstructive Pulmonary Disease (COPD) is the 3rd leading cause of death in the US, and idiopathic pulmonary fibrosis (IPF), a type of Interstitial Lung Disease (ILD), is a fast acting, irreversible disease that leads to mortality within 3-5 years. RNA-sequencing provides the opportunity to quantitatively examine the sequences of millions mRNAs, and offers the potential to gain unprecedented insights into the structure of chronic non-malignant lung disease transcriptome. By identifying changes in splicing and novel loci expression associated with disease, we may be able to gain a better understanding of their pathogenesis, identify novel disease-specific biomarkers, and find better targets for therapy. Using RNA-seq data that our group generated on 281 human lung tissue samples (47=Control, 131=COPD, 103=ILD), I initially defined the transcriptomic landscape of lung tissue by identifying which genes were expressed in each tissue sample. I used a mixture model to separate genes into reliable and not reliable expression. Next, I employed reads that overlapped splice junctions in a linear model interaction term to identify disease-specific differential splicing. I identified alternatively spliced genes between control and disease tissues and validated three (PDGFA, NUMB, SCEL) of these genes with qPCR and nanostring (a hybridization-based barcoding technique used to quantify transcripts). Finally, I implemented and improved a pipeline to perform transcriptome assembly using Cufflinks that led to the identification of 1,855 novel loci that did not overlap with UCSC, Vega, and Ensembl annotations. The loci were classified into potential coding and non-coding loci (191 and 1,664, respectively). Expression analysis revealed that there were 120 IPF-associated and 10 emphysema-associated differentially expressed (q < 0.01) novel loci. RNA-seq provides a high-resolution transcript-level view of the pulmonary transcriptome and its modification in lung disease. It has enabled a new understanding of the lung transcriptome structure because it measures not only the transcripts we know but also the ones we do not know. The approaches and improvements I have employed have identified these novel targets and make possible further downstream functional analysis that could identify better targets for therapy and lead to an even better understanding of chronic lung disease pathogenesis. / 2031-01-01T00:00:00Z

Acute exacerbation of chronic obstructive pulmonary disease (COPD) is one of the leading causes of hospital readmissions within 30 days. Frequent readmissions negatively affect hospital reimbursements and patient outcomes. Creative strategies, such as COPD care bundles, have been shown to reduce readmission rates according to existing studies. A COPD discharge bundle was developed and implemented at 1 community hospital in response to an identified problem with COPD readmissions. Evaluation of this quality improvement initiative was the purpose of this project study. The practice-focused question was: Have 30-day readmission rates changed following the implementation of a COPD discharge bundle prior to transitioning from hospital to home? The framework selected for this project was the model for improvement. Sources of evidence included existing hospital data to evaluate the change in readmissions. The chi-square test of independence was used to assess the difference in frequency of 30-day readmissions. Pre and post-bundle implementation comparisons of readmission rates showed a decrease for 3 out of the 4 groups compared; these results were not statistically significant. Analysis of the post-bundle intervention groups revealed lower 30-day readmissions for individuals who were bundle compliant versus noncompliant and for those who spoke with a pharmacist within 48 hours of discharge opposed to those who did not; these results were statistically significant. Continued use of the bundle and maintaining the role of the pharmacist was recommended. Reduction of readmissions within 30-days has positive social implications for hospitals through financial gains and for the COPD population by improving overall health outcomes.

Chronic obstructive pulmonary disease is the fourth largest cause of death worldwide and the prevalence is predicted to increase even further to make it the third largest cause of death by 2020. The main cause of the disease is exposure to tobacco smoke. COPD is a complex disease and there is a strong need of better understanding of the pathogenetic mechanisms in order to come up with novel therapeutic interventions and preventive strategies. The golden standard to image the lungs today is to use computed tomography (CT) which is an imaging modality that involves ionizing radiation and could thus harm the patient, especially with repeated exposure. New techniques in the image acquisition of magnetic resonance imaging (MRI), an imaging modality that does not involve ionizing radiation, has emerged that allows for lung imaging. The work included segmentation of the lungs, image registration and partitioning of the lungs inorder to perform regional analysis. The results indicate that the mean value of the T1-parameter in the left and right lung is not affected to the same degree, where the left lung showed a greater decrease. The results also showed that the anterior parts of the lungs are not showing any statistically significant changes but the changes were instead seen in the center and posterior parts. Both lungs also showed results that indicate that the mean T1-value is recovered at the end of the longitudinal study, a phenomenon that couldn’t be explained and further studies have to be performed.

<p> The cellular, molecular, and genetic mechanisms underlying the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) are not well understood. The purpose of this thesis was to address the hypothesis that microbial infection is important for the development and/or progression of COPD through investigation of how cigarette smoke alters the response to a bacterial challenge in a mouse model of cigarette smoke-exposure. To this end, in chapter 2 of this thesis we tested the hypothesis that cigarette smoke-exposure attenuates the ability of alveolar macrophages to sense microbial antigens through innate pattern recognition receptors. The central point of this study was the observation that alveolar macrophages isolated from cigarette smoke-exposed mice had attenuated expression of typical inflammatory cytokines following microbial stimulation. Building on this main observation, in chapter 3 we questioned what the consequences of this would be to an in vivo bacterial challenge with nontypeable Haemophilus influenzae. We demonstrated that cigarette smoke-exposure resulted in chronic inflammation, this inflammation was exacerbated following bacterial challenge, and perhaps most importantly, the nature of the inflammatory response was altered. Interestingly, an observation from the study in chapter 3 indicated that exacerbated inflammation in cigarette smoke-exposed mice may be beneficial for clearance of the bacteria, but may come at the expense of damage to the lungs. Consequently, in chapter 4 we questioned the strain and dose/ frequency stringencies of cigarette smoke-exposure on the observation of accelerated bacterial clearance. We demonstrated a role for antibodies in bacterial clearance. Collectively, this thesis provides insight into our understanding of COPD by demonstrating that cigarette smoke-exposure alters the pulmonary immune/ inflammatory response to a microbial challenge, which has a detrimental impact on the lungs. </p> / Thesis / Doctor of Philosophy (PhD)

Bakgrund: KOL är den tredje vanligaste dödsorsaken världen över. Pulmonary rehabilitation är en vanlig del av behandlingen som fysioterapeuter ofta utgår ifrån vid rehabilitering för patienter som lider av KOL. Telerehabilitering är ett alternativ till pulmonary rehabilitation. Forskning som jämför effektiviteten av telerehabilitering hos patienter som lider av KOL är dock begränsad. På senare tid har det på grund av bland annat coronapandemin uppkommit ett ökat behov av att utvärdera hur effektiv telerehabilitering är jämfört med pulmonary rehabilitation eller obehandlad kontrollgrupp.  Syfte: Syftet med denna litteraturstudie var att systematiskt granska vetenskapliga artiklar vad gäller effekten av telerehabiltering på livskvalité samt, kondition och muskelstyrka hos patienter med KOL och att bedöma tillförlitligheten av artiklarnas sammanvägda resultat. Metod: Metoden som valdes var en litteraturstudie. Sökningen genomfördes i Pubmed och CINAHL. Kvalitén av åtta studier från sökningen granskades med PEDro och resultatets tillförlitlighet bedömdes med GRADEstud. Resultat: Kvalitén i de åtta studierna som inkluderades varierade mellan medelgod och hög. För utfallsmåttet livskvalité påvisades att telerehabilitering är lika effektivt som pulmonary rehabilitation och tillförlitligheten bedömdes som måttligt hög (+++). För utfallsmåttet fysisk kapacitet kunde man inte påvisa att telerehabilitering är lika effektivt som pulmonary rehabilitation där tillförlitligheten bedömdes som låg (++). Endast två studier hade med utfallsmåttet muskelstyrka vilket gjorde resultatet svårbedömt.  Konklusion: Telerehabilitering bedömdes vara lika effektivt som pulmonary rehabilitation avseende livskvalité men detsamma kunde inte påvisas för fysisk kapacitet. Mer forskning inom området behövs och framtida forskning bör försöka eftersträva mer likhet i interventionerna. / Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Pulmonary rehabilitation is a common part of the treatment that is often used by physical therapists. Telerehabilitation is an alternative to traditional pulmonary rehabilitation, but it has a limited amount of research. Lately, partially because of the Covid-19 pandemic there has been an increased need to evaluate the effects of telerehabilitation.  Objective: The objective of this systematic review was to systematically review scientific studies regarding the effects of telerehabilitation on health-related quality of life, physical capacity and muscle strength among patients suffering from COPD. The aim of this study was also to assess the reliability of the combined results of the studies. Method: A systematic search was conducted in Pubmed and CINAHL. Eight studies were reviewed using PEDro and the reliability of the result was assessed using GRADEstud. Results: The quality of the studies varied between good and excellent. Telerehabilitation was deemed to be equally effective as pulmonary rehabilitation regarding the outcome health related quality of life and the reliability for the result was rated as moderately high (+++). The effectiveness of telerehabilitation for the outcome physical capacity proved not to be certain with a low (++) reliability. Only two studies included the outcome muscle strength which meant it could not be assessed.  Conclusion: Telerehabilitation was deemed to be equally effective as pulmonary rehabilitation for the outcome health related quality of life but not for the outcome physical capacity. More research on the subject is needed and future studies should aim to have the interventions be more similar.

Fibrosis is a disease where the normally transitory wound healing response enters a chronic state. Bleomycin and Adenovector models of pulmonary fibrosis have implicated TGF-β1 in this disease. Concern regarding a synergistic combination of TGF-β1 with an adaptive immune response within the Adenovector model prompted its use within mice devoid of T Lymphocytes, Balb/c SCIDs. The lack of an adaptive immune response within these mice did not affect the severity of fibrogenesis, as compared to Balb/c data in a hydroxyproline assay. TGF-β1 is a pluripotent cytokine with key roles in wound healing, immune regulation, and development, making it a dangerous molecule to therapeutically modulate directly. Future strategies will likely focus on downstream fibrotic molecules uninvolved in immune regulation, such as CTGF. While CTGF has been associated with fibrosis and is likely activated by TGF-β1, no conclusive evidence is available within an animal model. TGF-β1 stimulates cells by binding its receptor and signaling through the Smad signal transduction pathway. Smad3 knockout mice were used to examine the regulation of CTGF by TGF-β1, and study its role in pulmonary fibrosis. We show that these mice produce dramatically less CTGF in response to TGF-β1 than littermates expressing Smad3, and they show protection against TGF-β1 induced pulmonary fibrosis, using the Adenovector system. TGF-β1 can alter lung development, and is thought to be a causative agent in Bronchopulmonary Dysplasia, a disease affecting immature lungs. Utilizing the Adenovector system, we developed a neonatal rat model of BPD that closely resembles the human disease, providing researchers with a system to study the disease course. TGF-β1 is part of a family of growth factors, of which TGF-β3 is also a member. What role TGF-β3 plays in pulmonary fibrosis has not been evaluated. To allow future in vivo studies on the effect of TGF-β3 on lung morphology, we constructed a replication deficient Adenovector expressing constitutively active TGF-β3. / Thesis / Master of Science (MSc)

No / Context. The End of Life Care Strategy for England highlights effective communication between patients and professionals as key to facilitating patient involvement in advance care planning. The strategy emphasizes that, currently, communication in patients with noncancer life-limiting conditions is likely to be inadequate, and research has identified that patients with chronic obstructive pulmonary disease and heart failure have a poor understanding of their condition. Objectives. To identify existing interventions of patient-professional communication developed for life-limiting conditions and explore the applicability of interventions developed within a cancer framework to other diagnostic groups. Methods. A comprehensive literature review of studies describing communication interventions for patients receiving end-of-life care was undertaken. Ten electronic databases were searched. Inclusion criteria were all English language studies relating to patient-professional communication interventions for patients with life-limiting conditions receiving end-of-life care. Results. Of the 755 articles initially identified, 16 met the inclusion criteria. Three core themes emerged from the synthesis of the literature: using education to enhance professional communication skills, using communication to improve patient understanding, and using communication skills to facilitate advance care planning. Conclusion. Although limited, evidence relating to the development and evaluation of communication interventions for patients with life-limiting illnesses would suggest that a successful intervention should include combined components of training, patient discussion, and education. In a context of limited resources and an increasing number of patients living and dying with chronic life-limiting conditions, the need for appropriate and effective communication strategies should be seen as a priority for both research and policy.

From a BPS perspective, COPD and other chronic diseases may have a significant negative impact on those living with them and may be associated with higher rates of depression and anxiety and lower levels of health-related quality of life (HRQOL). Certain factors, such as spirituality, may influence the negative impact of chronic disease on the relationship between mood and functional independence and HRQOL. Also, gender may influence the relationship between mood, spirituality, and HRQOL for men and women living with chronic diseases. The current study included 136 patients undergoing physical rehabilitation at an IRF. Anxiety, depression, spirituality, HRQOL, and functional independence were evaluated for all. Mediation models were tested to determine the impact of spirituality on the relationships between mood and HRQOL and functional independence, and moderation models were tested to evaluate the impact of gender on the relationships between mood, spirituality, functional independence, and HRQOL. The current study yielded some inconclusive results but did evidence that COPD patients in acute inpatient physical rehabilitation facilities (IRF) have higher levels of anxiety than patients without COPD and also revealed that men with COPD have better HRQOL than do women with COPD. Spirituality was found to partially mediate the relationship between depression and HRQOL in IRF patients with COPD, but gender did not appear to moderate the relationships between mood, spirituality, functional independence, or HRQOL in IRF patients. As few studies on IRF patients with chronic diseases exist, continuing to evaluate patients in IRFs is important to enhance our BPS understanding of chronic disease.