Chronic obstructive pulmonary disease (COPD) is characterized by periodic episodes of worsening symptom (e.g., shortness of breath, irregular breathing, and worse coughing with increased phlegm production), also called pulmonary exacerbations. Inflammation is an important cause of reduced lung function as inflammation contributes to airflow obstruction in the small airways and lung parenchyma. Even in individuals with mild COPD, inflammation reduces lung function, accelerates decline in lung function overtime, and increases the risk for respiratory exacerbations. Agents that reduce systemic inflammation are hypothesized to decrease the inflammation in the lungs, resulting in improvements in lung function and a decrease in exacerbation frequency. We hypothesize that antidepressants have a beneficial effect on lung function. In addition to having anti-inflammatory properties, antidepressants act upon serotonin, which is integral in central breathing control. The combination of the anti-inflammatory and serotonergic effects may provide users of selective serotonin reuptake inhibitors with a lung function benefit while avoiding the side effects of steroids. This dissertation assesses whether selective serotonin reuptake inhibitors increase concurrent lung function and reduce the risk for respiratory exacerbations. It consists of three parts: a systematic literature review and two analytic papers using large prospective databases. The systematic review of the literature identified limitations concerning the effect of selective serotonin reuptake inhibitors on lung function. Overall, the analytic papers found no support for a beneficial association between selective serotonin reuptake inhibitors and spirometry, dyspnea or pulmonary exacerbations; indeed the association was in the opposite direction as hypothesized. In addition, there was no support for meaningful mediation by inflammatory markers. Further research is needed to determine if selective serotonin reuptake inhibitors have a harmful effect on lung function and pulmonary exacerbations.

Among those subjects admitted with AECOPD and concomitant pneumonia, a total of 118 patients (91 males) with 150 episodes were identified. Haemophilus influenzae was the commonest organism found in sputum (26.0%), followed by Pseudomonas aeruginosa (5.5%), Streptococcus pneumoniae (3.4%), and Moraxella catarrhalis (3.4%). In contrast to most studies from other countries reporting Streptococcus pneumoniae as the most likely bacterial pathogen, Haemophilus influenzae was the commonest bacterium isolated in sputum in this cohort of patients with AECOPD and concomitant pneumonia. / Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. / Exhaled breath condensate (EBC) analysis is a novel tool which has been developed in recent years and the technique is believed to reflect the lower airway lining fluid. My previous work has demonstrated the repeatability of certain inflammatory markers in the EBC of stable asthma and COPD patients. / Hypothesis 1: Bacterial pathogens are the major cause of AECOPD with and without concomitant pneumonia in patients requiring hospitalization. In the one-year retrospective bacteriology study, there were 329 patients with 418 episodes of AECOPD without concomitant pneumonia. These result noted that H. influenzae was the commonest bacterium isolated in sputum in patients with AECOPD without concomitant pneumonia. In areas endemic of tuberculosis, it is advisable to use fluoroquinolones for AECOPD with caution in view of the positive sputum culture of mycobacterium tuberculosis in some patients. / Hypothesis 2: Viral pathogens are an important cause of AECOPD in patients hospitalized with AECOPD. For the prospective infectious aetiology study, there were 643 episodes of AECOPD among 373 patients (307 males). Severe airflow obstruction (stable state spirometry) was associated with a higher chance of positive sputum culture (28.2% for FEV1 ≥30% vs. 40.4% for FEV1 <30% predicted normal, p=0.006). In this study, Haemophilus influenzae and influenza A were the commonest aetiological agents in patients hospitalized with AECOPD. More severe airflow obstruction was associated with a higher chance of positive sputum culture. / Hypothesis 3: The rates of hospital admissions due to AECOPD are associated with indices of air pollution in Hong Kong. Concerning the effect of air pollutants on AECOPD, significant associations were found between hospital admissions for COPD with all 5 air pollutants. Adverse effects of ambient concentrations of air pollutants on hospitalization rates for COPD are evident, especially during the winter season in Hong Kong. / Hypothesis 4: During the course of AECOPD, it is possible to assess inflammation in the airway by measuring biomarkers non-invasively using the method of EBC collection. To explore the course of inflammation in the airway during AECOPD, 26 patients (22 male) with AECOPD (mean percentage predicted FEV1, 44.8 +/- 14.3), 11 stable COPD and 14 age and sex-matched healthy controls were studied. Repeatability measurements of TNFalpha and LTB4 in 6 stable COPD patients were satisfactory. EBC TNFalpha level was low in patients receiving systemic steroid and antibiotic therapy for AECOPD whereas EBC TNFalpha level was also lower in stable patients receiving ICS post AECOPD than those who were not. These findings suggest a potential role for serial EBC TNFalpha for non-invasive monitoring of disease activity. / Summary. The above studies have shown that bacterial pathogens are the major cause of AECOPD with and without concomitant pneumonia in patients requiring hospitalization and the commonest bacterium found in the sputum of the patients was Haemophilus influenzae. Viral pathogens are also an important cause of AECOPD in patients hospitalized with AECOPD in Hong Kong and the commonest virus identified in the NPA of the patients was influenza A. Concerning the effect of air pollutants on AECOPD, significant associations were found between hospital admissions for AECOPD with the air pollutants of SO2, NO3, O3, PM10 and PM2.5. Finally, TNFalpha could be measured in the EBC of patients during the course of AECOPD and its level was low in patients receiving systemic steroid and antibiotic therapy for AECOPD. The results suggest that it is possible to assess inflammation in the airway by measuring biomarkers non-invasively using the method of EBC collection. (Abstract shortened by UMI.) / Ko, Wai-san Fanny. / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0926. / Thesis (M.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 207-250). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

Introduction: COPD is a worldwide public health issue, while anxiety and depression are highly prevalent comorbidities in COPD, some reviews in overseas reported prevalence rates of up to 75% for anxiety and up to 80% for depression among COPD patients. The situation in Hong Kong is largely unclear and information is lacking. Objective: To assess the prevalence of anxiety and depression in a regional hospital in Hong Kong and to evaluate the odds ratio of different stages of severity in COPD. Method: COPD patients before hospital discharge from E3 ward in Princess Margaret Hospital (in-patient) and COPD patients who attend out-patient clinic in block K7 in PMH (out-patient) will be asked for consent to participate in the study. Baseline demographic and clinical information includes staging of COPD, questionnaires of HADS, MMRC, CAT score will be collected by research nurses after consent is obtained. Result: A total of 260 patients have been approached, with a response rate of 58.08%. 75 in-patients and 76 out-patients were eligible for the study. Our study showed the overall prevalence of depression and anxiety among COPD population are 61.6% and 23.2% respectively. Odds Ratio of depression and anxiety were increased when severity of COPD increased from stage I to IV. Compared with stage I COPD patients, the respective crude odds ratio of depression for stage II is 1.25 (95% CI: 0.15-10.23), stage III is 1.44 (95% CI: 0.19-10.89), while stage IV is 2.09 (95% CI: 0.26-16.86); But in anxiety, the value is insignificant as the odds ratio is less than 1. Conclusion: This is the first study in Hong Kong which is targeted on estimating the prevalence of depression and anxiety among COPD population and to correlate the finding with the COPD severity. Depression and anxiety are prevalent among the COPD patients as suggested in the study. The possibility of depression increased when severity of COPD stage increases, but the result in anxiety cannot be confirmed. No specific risk factors were found to have statistical significant association with the presence of depression and anxiety, but the current study still warrant attention. Further large scale study may be needed to reveal the situation. A more comprehensive and holistic approach to the COPD patients should be employed to tackle their special need during disease progress, in order to reduce the whole health care system burden. / published_or_final_version / Public Health / Master / Master of Public Health

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by persistent airway obstruction that is only partially reversible. It is the fourth leading cause of death and is predicted to be the third by 2030. The progression of the disease involves chronic inflammation, oxidative stress, excess protease activity, increased lung cell apoptosis and accelerated lung aging, but the exact pathogenesis is still unclear. The major cause of COPD is cigarette smoking(CS). Although COPD is associated with increasing social and economical burden, there have been few advances in pharmacological therapy of COPD. Mesenchymal stem cells (MSCs) are fibroblast-like multipotent stem cells which can be isolated from a broad range of sources including bone marrow (BM) and adipose tissue. Administration of BM-derivedMSCs (BM-MSC) or adipose tissue-derived MSCs was reported to attenuate CS-induced emphysema in murine models. Induced pluripotent stem cell-derived MSC (IPSC-MSC) are MSCs differentiated from induced pluripotent stem cells(IPSCs), which are pluripotent cells generated by somatic cell reprogramming in vitro. IPSC-MSCs have several advantages over BM-MSC, including more abundant sources and high capacity of doubling without loss of differentiation potency. A general exploration and comparison on the effects of human IPSC-MSC and BM-MSC treatments were carried out in a 56-day CS-exposed rat model. Compared to BM-MSC, IPSC-MSC showed a higher capacity to reside in lung tissue. The two treatments shared similar efficacy to attenuate CS-induced lung cell apoptosis, to restore CS-induced reduction of lungIL-10and to alleviate CS-induced elevation of systemic TGF-β1. In addition, IPSC-MSC was found to cause reduction in CS-induced elevation of systemic oxidative stress and reversal of CS-induced reduction of lung adiponectin. Furthermore, in order to understand the possible paracrine mechanism involved, human airway epithelial cells were treated with IPSC-MSC or BM-MSC-conditioned medium in a cell culture system in the presence of cigarette smoke medium (CSM). Potentiation rather than attenuation of CSM-induced release of pro-inflammatory cytokine IL-8, MCP-1 and IL-6 was observed with IPSC-MSC or BM-MSC conditioned medium. It is currently unknown whether cultured IPSC-MSCs or BM-MSCs will release pro-inflammatory mediators into the conditioned medium or not. In order to study CS-induced oxidative stress and inflammation in a short time frame, anacute (5-day) CS-exposed rat model was established in juvenile and adult groups. An age-dependent alteration of CS-induced oxidative and inflammatory responses was demonstrated in this model. In summary, our in vivo rat model provides a platform for elucidating the effects of stem cell treatment in CS-induced oxidative stress and inflammation, leading to lung damage. Our findings suggest that treatment of IPSC-MSC or BM-MSC might be able to slow down CS-induced disease progression, possibly through anti-oxidant, anti-inflammatory and anti-apoptotic properties. However, caution should be taken as our in vitro data revealed that conditioned medium from MSCs may provoke pro-inflammatory responses. Further studies on the regulation of the activity of MSCs in vivo will be needed before developing IPSC-MSC into cell therapies for COPD to halt the progression over time. / published_or_final_version / Medicine / Master / Master of Philosophy

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Gerontology / Master / Master of Social Sciences

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