Objective: To estimate national prevalence and direct incremental expenditures in Chronic Obstructive Pulmonary Disease (COPD) and asthma using 2007 Medical Expenditure Panel Survey (MEPS) data. <br>Methods: COPD and asthma were identified using ICD-9 codes and were the main independent variables. Covariates included age, gender, race, income, region, insurance and marital status. Dependent variables were total health care, office-based, outpatient, inpatient, emergency room and prescription expenditures. Descriptive statistics and regression analysis were used to fulfill the study objectives. <br>Results: Prevalence of COPD and asthma was 1.3 million and 28.3 million, respectively. Total direct incremental health care expenditures per person for COPD and asthma were $1,739.27 and $2,133.83, respectively. High cost categories among COPD and asthma included office-based, inpatient and prescription expenditures. Age, gender, region, insurance and marital status were significant predictors for health care expenditures. <br>Conclusion: Results highlight socio-demographic disparities and high health care expenditures due to COPD and asthma in the United States. <br>Keywords: Asthma, COPD, Medical Expenditures Panel Survey (MEPS), incremental health care expenditures, retrospective analysis / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Pharmacy Administration / MS / Thesis

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Background: Airways diseases comprise mainly of COPD and asthma. There is a need to develop both new models and improve methodologies of existing models these diseases. LPS challenges in smokers would be an excellent model to study the drugs directed against TLR4 mediated inflammation in COPD. In asthma allergen challenges are established models of disease and extensively used in clinical trials. Back to back reproducibility of two bolus dose allergen challenges has not been studied; this would provide intra subject standard deviations which are useful for accurate power calculations for bolus allergen challenge studies. Aims: 1. To investigate Inhaled LPS Challenges in healthy smokers as a model of inflammation in COPD; study systemic and sputum biomarkers for use in such studies and use LPS challenge as a model to study corticosteroid insensitivity 2. Investigate LPS Challenges in HNS as a model to study neutrophil chemotaxis mechanisms 3. Study Reproducibility of bolus dose allergen challengeMethods 1. HNS and HS were recruited and underwent inhaled LPS challenges. Safety, airway and systemic inflammation was studied. 2. Mild atopic asthmatics underwent two bolus allergen challenges, reproducibility of EAR and LAR was studied and intrasubject SD was used for power calculationsResult LPS Challenges were safe in both HNS and HS and led to increase in sputum neutrophil% in both these populations with maximum effect at 6hours post 30µg LPS inhalation. The resulting airway neutrophilic inflammation was reproducible in HS. LPS challenge in HS also leads to increase in systemic biomarkers and upregulation of NFĸB pathways in induced sputum. There was moderate corticosteroid insensitivity in airway inflammation in HS which didnot increase post LPS challenge. In HNS sputum supernatants post LPS challenge increase chemotaxis of blood neutrophils which is related to CXCL8 levels and mediated by both CXCR1 and 2 receptors. Bolus allergen challenges in mild asthmatics show good reproducibility for both EAR and LAR; I have also presented intrasubject SD which maybe used for accurate power calculations for future studies.Conclusions LPS Challenges lead to neutrophilic airway inflammation in HS which is reproducible and mediated by upregulation of TLR4 signalling making this a good model to study anti-inflammatory drugs for COPD in clinical trials. Additionally, LPS challenges in HNS provide a model to study neutrophil chemotaxis mechanisms. Bolus allergen challenges show good reproducibility and accurate power calculations are presented in this thesis.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24193号 / 医博第4887号 / 新制||医||1060(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 山本 洋介, 教授 永井 純正 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No / Introduction: Harold Shipman, a general practitioner (GP) working near Manchester in England, is thought to have killed 250 of his patients by diamorphine overdose between 1975 and 1998. Opiates are recommended for relieving dyspnoea in end stage chronic obstructive pulmonary disease (COPD). Little is known about the effect of the Shipman case on clinician attitudes to prescribing of opiates in advanced COPD. Subjects and methods: Focus groups were held with a total of 39 health professionals in primary (n = 3) and secondary care settings (n = 2) in two sociodemographically contrasting areas of England. Results: Participants identified that the experience of dyspnoea in end-stage COPD was often distressing for patients, their families and their professional carers. Whilst opiates were recognised to be effective in relieving dyspnoea, the Shipman case, and associated fears of litigation, was identified as the key barrier to prescribing. Whilst this was seen as a particular problem within primary care settings leading, for example, GPs to admit patients to hospital rather than prescribe opiates, it was also considered an issue within acute hospital settings. Of particular concern to participants was recognising when an exacerbation was 'terminal' and hence opiate prescribing appropriate. Conclusions: There is evidence to show that opiates are effective in managing end-stage dyspnoea in COPD without hastening death. However, participants did not perceive this to be the case and expressed considerable anxiety about appropriate prescribing in this situation. Given the significant burden of dyspnoea on patients with advanced COPD, there is an urgent need for appropriate training to increase clinician confidence regarding opiate use in this patient group which is sensitive to the concerns raised by the Shipman murders.

Chronic obstructive pulmonary disease (COPD) is an illness characterized by progressive respiratory symptoms and frequent exacerbations. Acute exacerbations of COPD (AECOPD) are mostly treated in the outpatient setting and the use of antibiotics for this patient population remains controversial. This thesis aimed to explore the role of antibiotics in the outpatient management of AECOPD through two studies. The first study was a systematic review of randomized controlled trials examining the impact of antibiotics on the outcome of treatment failure in outpatients with AECOPD. Meta-analysis was conducted using both frequentist random effects and Bayesian analyses. The second study was a secondary analysis of a prospective cohort of patients with AECOPD discharged from the emergency department. The association between antibiotic treatment and the outcome of rehospitalization within 14 days of discharge was examined using logistic regression and propensity score matched analyses. In the systematic review and meta-analysis, both frequentist random effects and Bayesian analyses revealed a high likelihood of benefit for antibiotics. In the secondary analysis, there was no association between treatment with antibiotics and rehospitalization however due to a small sample size and a low event rate, there was considerable risk of Type II error. Overall, when considering the results of these two studies in the context of previous literature, treatment with antibiotics likely provides a modest benefit in the outpatient management of AECOPD.

Background: Many COPD patients have recurrent exacerbations due to infection, but there are no valid predictors of this phenotype. Previously an observational study showed that higher iron content in sputum macrophages was associated with infectious exacerbations. Objectives: The thesis aimed to assess the mechanisms of pulmonary macrophage iron sequestration, test the effect of macrophage iron-loading on bacterial uptake and killing, and prospectively determine if sputum hemosiderin index can predict infectious exacerbations of COPD. Methods: Intracellular iron was measured directly and indirectly in cell-line-derived and isolated sputum macrophages after treatment with exogenous IL-6, hepcidin or heat-inactivated H.influenzae. Bacterial uptake and killing were compared in both types of macrophages, in the presence or absence of iron-loading. A prospective cohort of COPD patients had their sputum hemosiderin index measured at baseline and were monitored for 1-year for infectious exacerbations requiring admission to hospital. Results: For pulmonary iron sequestration, IL-6 appears important, but the role of hepcidin is not clear. Iron-loading reduced the uptake of COPD-relevant organisms by almost one-third in cell-line-derived macrophage, and there was a near-significant linear relationship between sputum hemosiderin index and killing of H.influenzae (p=0.075). In terms of infective exacerbations, FEV1 had predictive utility (beta=-0.051, p=0.017) while a positive trend for sputum hemosiderin index (beta=0.035, p=0.051) suggests that this biomarker has clinical promise. Conclusion: Through in vitro experiments and cohort data, we have established a framework suggesting that excess iron in pulmonary macrophage may contribute to recurrent bacterial airway infection in COPD. IL-6 appears to contribute to sputum macrophage iron sequestration, which subsequently may lead to immune cell dysfunction and ultimately result in an increased frequency of infective exacerbation. / Thesis / Master of Science (MSc) / COPD patients often require hospitalization due to respiratory infections (bacterial or viral) that result in worsening of their breathing. It is difficult to predict who is at high risk for this to occur, which makes it harder to prevent. Many species of bacteria depend on iron as a nutrient. We wanted to see if iron being present in certain immune cells (macrophages) in the sputum could predict these flares by: testing how iron enters these cells, seeing if bacterial growth is altered by putting iron into these cells, and following a group of COPD patients and seeing if those with higher iron in their sputum had higher risk of infectious flares. Though more testing is needed, we found that a protein often present with chronic inflammation may be associated with higher sputum macrophage iron, and that there is evidence that killing of bacteria in COPD sputum macrophages is lower with high iron, and that patients with higher sputum iron are at greater risk of having infectious flares.

Background: People with COPD have significant balance impairments and an increased risk of falls. The psychometric properties of short balance screening tests to inform fall risk assessment in COPD have not been studied. The objective of this study was to compare the validity of four short balance tests suitable for fall risk screening to identify the most optimal screening tool(s). Methods: Participants at least 60 years old with COPD attended a single physical assessment with completion of questionnaires. Correlation coefficients were used to describe relationships between the Brief Balance Evaluation Systems Test (Brief BESTest), Single-Leg Stance (SLS), Timed Up and Go (TUG) and Timed Up and Go Dual-Task (TUG-DT) tests, and other measures of balance, measures of muscle strength, exercise tolerance, functional limitation, disability and prognosis. Independent t-tests or Mann-Whitney U tests were used to examine differences between groups with respect to fall risk. Receiver operating characteristic curves were plotted to examine the ability to of the screening tests to identify individuals with previous falls. Results: Seventy-three participants with COPD completed the study (age 73.0 ± 6.9 years; FEV1 47.0 ± 19.8% predicted). All balance screening tests demonstrated moderate to strong correlations with the Berg Balance Scale (r= 0.47 to 0.80, p<0.05) and Activities-specific Balance Confidence scale (r= 0.44 to 0.61, p<0.05). The Brief BESTest and SLS showed the strongest correlations with other balance measures and demonstrated the most consistent ability to discriminate between fall risk groups. The Brief BESTest was the only screening test that identified individuals who reported a previous fall with acceptable accuracy (AUC= 0.7). Conclusions: The Brief BESTest and SLS show the most promise as balance screening tools for fall risk assessment in older adults with COPD. These results will need to be prospectively confirmed with a larger sample size. / Thesis / Master of Science Rehabilitation Science (MSc)

Die chronisch obstruktive Lungenerkrankung geht mit einer nachweislich erhöhten sympathischen Aktivität einher. Von Erkrankungen, wie der Herzinsuffizienz, die ebenfalls mit einer erhöhten sympathischen Aktivierung einhergehen, lässt sich ein die Prognose verschlechternder Effekt der erhöhten sympathischen Aktivierung annehmen. Auf dieser Annahme beruhend war das Ziel dieser Studie einen möglichen Zusammenhang zwischen sympathischer Aktivierung und Morbidität sowie Mortalität bei COPD zu untersuchen. In dieser Studie wurde in einem Follow-Up 20 Herzinsuffizienz-Patienten, 20 COPD-Patienten und 23 Kontrollpersonen, die mikroneurographisch untersucht wurden, telefonisch nach Krankenhausaufenthalten aufgrund ihrer Grunderkrankung befragt, beziehungsweise der Todeszeitpunkt ermittelt. Nach erfolgter statistischer Auswertung wurden die entsprechenden Kollektive nach klinischen Endpunkten in Subgruppen unterteilt und der Grad der initial mikroneurographisch gemessenen sympathischen Aktivierung verglichen. Sowohl Herzinsuffizienz- als auch COPD-Patienten, die aufgrund ihrer Erkrankung einen Krankenhausaufenthalt hatten oder verstarben, wiesen gegenüber Patienten, die keinen Krankenhausaufenthalt hatten, eine signifikant erhöhte sympathische Aktivierung auf. Durch diese Studie konnte bei COPD-Patienten erstmalig eine signifikante Assoziation einer erhöhten sympathischen Aktivierung mit einer gesteigerten Morbidität und Mortalität nachgewiesen werden. Nach ausführlicheren Untersuchungen bietet dieses noch junge Forschungsfeld perspektivisch eventuell die Möglichkeit, die bisherigen COPD-Therapien um eine kausalere, die Prognose potentiell verbessernde Therapie zu ergänzen.

Background: COPD is characterised by increased neutrophilic inflammation which further increases during exacerbations. Corticosteroids are currently one of the mainstays of treatment but they have limited effectiveness; there is a great need to develop new anti-inflammatory pharmacotherapies for use in COPD. Inhaled LPS has been used as a model of increased neutrophilic inflammation in healthy patients, smokers and asthmatics. Its use in patients with COPD as a model of exacerbations has not yet been evaluated. PI3 kinase is a vital intracellular enzyme, which upon activation leads to a number of cellular processes; the γ and δ isoforms of the enzyme are of particular importance in leucocyte migration, development and activation. There is increasing evidence for upregulation of this pathway in COPD.Aims: (1) To test the safety of the use of inhaled LPS in patients with COPD for use as a model of exacerbation and to investigate the systemic and airway inflammatory response in vivo. (2) To investigate the action of PI3 kinase enzyme inhibitors and dexamethasone in vitro on neutrophilic inflammation in COPD patients during the stable state and exacerbations. Methods: (1) 12 patients with mild to moderate COPD inhaled 5µg LPS; safety measurements and airway and systemic biomarkers were collected up to 24 hours post inhalation. (2) The effect of PI3 kinase enzyme inhibitors and dexamethasone on MMP-9 and ROS release from peripheral and airway neutrophils from stable COPD and exacerbations was examined in vitro. The effect of PI3 kinase enzyme inhibitors and dexamethasone on cytokine release from peripheral neutrophils from stable COPD patients was also investigated. Results: (1) Inhaled LPS (5µg) caused a significant fall in FEV1 and increase in sputum neutrophil numbers. There was an associated increase in systemic IL-6, CRP and CC-16, all with differing temporal patterns. No patients reported any significant symptoms. (2) PI3 kinase enzyme inhibitors significantly reduced MMP-9 and ROS release from airway and peripheral neutrophils from COPD patients in the stable state and during exacerbations; dexamethasone had minimal effect. Cytokine release from peripheral neutrophils from COPD patients in the stable state was also significantly inhibited by PI3 kinase enzyme inhibitors and dexamethasone. Conclusions: (1) Inhaled LPS in patients with COPD is a safe model to induce acute on chronic neutrophilic inflammation and therefore could be used as a model to study COPD exacerbations. (2) PI3 kinase enzyme inhibitors reduce COPD neutrophil MMP-9, ROS and cytokine release in vitro and are therefore are a promising new anti-inflammatory pharmacotherapy.