Chronic pulmonary aspergillosis (CPA) is a serious disease that occurs secondary to tuberculosis and is estimated to affect 1.2 million persons globally. Pulmonary aspergillosis is found in 2-3% of all AIDS autopsies, but 90% of cases go undiagnosed ante-mortem. Here the sensitivity and specificity of optimal diagnostic thresholds for CPA have been defined in relation to six Aspergillus-specific IgG assays. The prevalence of CPA in an area of high tuberculosis prevalence has been measured. Receiver operating characteristic (ROC) curves were used to compare results of testing with six Aspergillus-specific IgG assays in 241 patients with CPA and 100 healthy controls. ThermoFisher Scientific ImmunoCAP and Siemens Immulite had ROC area under curve (AUC) results of 0.995 and 0.991 respectively. Both were statistically significantly superior to all other assays. Both had a sensitivity of 96% and specificity of 98% using diagnostic cut offs of 20 mg/L and 10 mg/L respectively. Eighty patients with allergic bronchopulmonary aspergillosis (ABPA) were also assessed. ROC AUC results were 0.959 for ImmunoCAP and 0.932 for Immulite. The new thresholds produced specificities of 98% for both assays and sensitivities of 78% and 81% respectively. Levels in ABPA patients were also compared to asthmatic controls.398 patients with treated tuberculosis in Gulu, Uganda were assessed in a cross-sectional survey. CCPA diagnostic criteria were; 1 – Cough or haemoptysis for one month, 2 – Progressive cavitation on serial chest X-ray or either paracavitary fibrosis or aspergilloma on CT scan and 3 – Raised Siemens Immulite Aspergillus-specific IgG. All three were required for diagnosis. CCPA was present in 5.7% of patients and simple aspergilloma in 0.7% of patients. There was a non-significant trend to less frequent CCPA in HIV positive patients (p=0.18). Aspergillus-specific IgG levels were measured in stored sera from two adult in patient groups at Mulago Hospital, Kampala, Uganda. 26% of 39 patients with HIV infection and subacute respiratory illness and no diagnosis after extensive investigation had raised levels. 47% of 57 patients with proven active pulmonary tuberculosis had raised levels. The Immulite and ImmunoCAP assays both have good sensitivity and specificity for the diagnosis of CPA. New diagnostic thresholds improve the performance of all assays. CCPA has been shown to complicate pulmonary tuberculosis in Gulu, Uganda. Subacute invasive pulmonary aspergillosis is likely to affect many patients with AIDS and subacute respiratory illness. CPA may begin during active pulmonary tuberculosis infection. CPA associated with tuberculosis constitutes a significant unrecognized public health problem, which is probably being incorrectly identified as ‘smear-negative tuberculosis’ clinically and in public health data. Prospective studies are now needed to confirm the prevalence of CPA secondary to tuberculosis and define the optimal strategy for routine CPA screening, followed by studies to define optimal treatment regimes for use in research poor-settings, where most cases of CPA are likely to occur.

Nonmalignant respiratory diseases (NMRD), such as Chronic Obstructive Pulmonary Disease (COPD), are a leading cause of morbidity worldwide. Research has shown that patients with NMRD in the UK, Canada and the US have less access to palliative care services than patients with other respiratory diseases such as lung cancer. Discussing preferences for end-of-life care in NMRD can be difficult for patients, carers and health professionals, however it is essential to ensure that the patient’s wishes are met, particularly when resources are scarce. Despite similar nationalised health care systems in the UK and Canada, a recent report by the Economist Intelligence Unit ranked overall quality of end-of- life care in the UK first out of forty, while Canada was ranked ninth out of forty. Therefore, it was deemed useful to investigate how end-of-life for people with NMRD is discussed between health professionals and patients in the UK and Canada and to develop an instrument allowing health professionals to determine constraints and opportunities for facilitating such discussions in each country as comparing care between countries is helpful to determine the best solutions for individuals and families with complex needs. This study was guided by the Medical Research Council guidelines for developing and implementing complex interventions, and the research process followed the requirements for the development phase of these guidelines. First, two systematic reviews were carried out to establish the evidence base regarding of end-of-life discussions. The first focused on how end-of-life is discussed in NMRD, while the second focused exclusively on end-of-life discussions in a single NMRD (COPD) in the UK and Canada only. The findings of the systematic reviews pointed toward the need for further training of health professionals to iii discuss end-of-life with this patient group, as well as the lack indicators that this patient group is ready or willing to discuss end-of-life. Then, a Delphi study was conducted with specialist respiratory nurses in the UK to determine expert opinion on how health professionals know a patient with NMRD is ready to discuss end-of-life, and to establish the key considerations and topics in such discussions. This study was replicated in Canada with health professionals working with patients with NMRD. Each Delphi study resulted in a country specific tool to assist less experienced health professionals discuss end-of-life with this patient group. Finally, the findings of these Delphi studies were compared to determine what health professionals in each country could learn from each other, as well as specific considerations in each country, and areas for future research. The findings from the comparison process demonstrated that the emotional intelligence of health professionals, the patient education context and the recognition of cultural issues were all important factors when approaching end-of-life discussions. Findings from each phase of the intervention development process resulted in a theoretical model of how end-of-life is discussed in the UK and Canada. This model identifies constraints and opportunities for such discussions from a systems level perspective including: end-of-life policies, prognosis in non-malignant respiratory disease, time, clinical indicators, initiation responsibility, the educational role of health professionals, emotional intelligence, cultural competence and readiness versus willingness to discuss end-of-life. Recommendations are made from the findings of this study for research, clinical practice, education and policy. A detailed plan for the next stage of the development of the intervention is included.

Evidence-based practice is an integral part of multi-disciplinary healthcare, but its routine clinical implementation remains a challenge internationally. Written asthma action plans are an example of sub-optimal evidence-based practice because, despite being recommended, these plans are under-issued by health professionals and under-used by patients/carers. This thesis is a critical analysis of the generation and implementation of evidence in this area and provides fresh insight into this specific theory/practice gap. This submission brings together, in five published papers, a body of work conducted by the candidate. Findings report that known barriers to action plan use (such as a lack of practitioner time) are symptomatic of deeper and more complex underlying factors. In particular, over-reliance on knowledge derived from randomised controlled trials and their systematic review, as the primary and sole source of evidence for healthcare practice, hindered the implementation of these plans. A lack of evidence reflecting the personal experience of using these plans in the real world, rather than in trial settings, contributed to a mismatch between what patients/carers want from asthma action plans and what they are currently being provided with by professionals. This submission illustrates the benefits of utilising a broader range of knowledge as a basis for clinical practice. The presented papers report how new and innovative research methodologies (including meta-ethnography and cross-study synthesis) can be used to synthesise individual studies reporting the personal experiences of patients and professionals and how such findings can then be used to better understand why interventions can be implemented in trial settings rather than everyday practice. Whilst these emerging approaches have great potential to contribute to evidence-based practice by, for example, strengthening the ‘weight’ of experiential knowledge, there are methodological challenges which, whilst acknowledged, have yet to be fully addressed.