Chronic respiratory disease (CRD) is a silent, ongoing pandemic. It disproportionally affects low-resource settings. Tobacco smoke and kitchen smoke (caused by the use of solid fuels and... Show moreChronic respiratory disease (CRD) is a silent, ongoing pandemic. It disproportionally affects low-resource settings. Tobacco smoke and kitchen smoke (caused by the use of solid fuels and inefficient stoves) are major risk factors. Evidence-based solutions to CRD often fail to be effective, as they misalign with local needs and then fail to be implemented. This thesis focused on how lung health solutions can be implemented successfully by capitalising on the local needs.Within the Horizon2020 FRESH AIR implementation research project, we first studied local settings in Kyrgyzstan, Uganda, Greece, and Vietnam. For example, we found that COPD in the highlands of Kyrgyzstan occurred three times more frequently than in the lowlands, partly due to higher levels of kitchen smoke. We discovered the high indirect burden of asthma and COPD, by their impact on work- and daily activities. We also found that many communities and their health workers mistook CRD for infectious disease like tuberculosis. Based on these findings and on implementation literature, we then designed several practical tools addressing critical factors for implementation success of lung health interventions. These evidence-based tools can facilitate implementation success, thereby optimising the use of already scarce resources and benefitting health outcomes. Show less
Primary endpoints in pediatric clinical trials are currently very similar to those in adult trials1, and focus on quantifying or counting hard endpoints like mortality, hospital admissions and... Show morePrimary endpoints in pediatric clinical trials are currently very similar to those in adult trials1, and focus on quantifying or counting hard endpoints like mortality, hospital admissions and length of stay. Additionally, biochemical biomarkers in serum are often measured to assess drug effects on a biochemical level. The occurrence of mortality and hospital admissions is rare thanks to the improvements in clinical care that have occurred in the last century, and adopting these as primary endpoints in clinical trials gives disproportional weight to rare events which most patients will not experience. Conversely, length of stay for many clinical conditions is short, and this duration only captures a small part of the clinical recovery trajectory that patients must undergo. This dissertation described the development, technical validation and clinical validation of a new type of clinical endpoints ('value based endpoints') and a new clinical trial paradigm (The remote clinical trial), consisting of digital endpoints and non-invasive pharmacokinetic sampling. Both have the potential to transform pediatric clinical trials and pediatric clinical care. The process towards implementation is challenging and can only proceed after a rigorous validation process. The current work provides a roadmap towards selection, validation, and implementation of digital endpoints, and describes preliminary steps taken for several candidates. The digital endpoints investigated in this work fulfill several validation criteria in a range of clinical conditions and, combined with non-invasive pharmacokinetics, may move the pediatric clinical trial completely towards the home. Show less
The fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved... Show moreThe fact that most healthcare resources are spend on a small subgroup of patients with an unfavourable prognosis has long been recognized. Therefore change is needed in terms of an improved identification of patients with an unfavourable prognosis, early in their treatment course, which may facilitate proactive approaches to improve outcomes. We discussed two conceptually distinct constructs of predictors of prognosis in order to improve the identification of patients with an unfavourable prognosis. First, the level of control of the chronic condition as a predictor could reflect to some extent the presence of a multitude of other risk factors. Second, information on early treatment response had better predictive ability for long-term outcomes and so acts as a proxy for treatment effectiveness. Treatment effectiveness depends on different aspects e.g. adequateness of initial treatment and/or drugs, the mutual trust between clinician and patient and behavioral aspects such as treatment adherence. Treatment response adds an insight that can be acted upon; guiding personalized decisions in the treatment plan. In conclusion, this thesis leads to improvement of personalized medicine and thereby could increase the efficient use of healthcare resources, with the early identification of patients at risk of an unfavourable prognosis. Show less
In this thesis, we focussed on the management of obese patients with asthma. Based on the available knowledge about the obesity and asthma relationship, and the effects of different weight loss... Show moreIn this thesis, we focussed on the management of obese patients with asthma. Based on the available knowledge about the obesity and asthma relationship, and the effects of different weight loss interventions in obese asthmatics, we defined the following aimsfor this thesis:1. To gain insight in the effects of exercise training in obese asthmatics and to determine the feasibility and effects of high intensity training in obese subjects2. To design a pulmonary rehabilitation program for obese patients with suboptimalcontrolled asthma and to determine the effectiveness of this program in a randomized controlled trial3. To improve our knowledge on the pathophysiology of obesity related asthma4. To gain insight in the risks and long-term effects of bariatric surgery in morbidlyobese subjects with asthma. Show less
The studies presented in this thesis were aimed at developing and using in vitro models that could benefit research towards understanding asthma and COPD. We used an in vitro model... Show moreThe studies presented in this thesis were aimed at developing and using in vitro models that could benefit research towards understanding asthma and COPD. We used an in vitro model representing a Th2-high gene signature and studied how this gene signature may be affected by external factors such as cigarette smoke or drugs. Using these in vitro models may help to predict clinical outcomes, although they will require extensive validation. We also investigated the possibility of using primary human airway epithelial cells to model bacterial and viral exacerbations. Whereas this model is currently still under investigation, it could be particularly useful to study possible biomarkers of exacerbations and how these may be affected by external factors. Additionally, we also developed a new method to expand and differentiate mouse tracheal epithelial cells in vitro. Overall, studying airway epithelial cells may provide important clues for understanding disease pathogenesis, lead to identification of new treatment targets, and may provide important biomarkers. Using airway epithelial cells and their derived biomarkers could significantly improve our understanding in disease phenotypes of asthma and COPD. Additionally, with increasing knowledge of the disease phenotypes, we could better address the unmet need in treatment of asthma and COPD. Show less
