Phenotypic characterisation of non-smoking COPD

Chronic obstructive pulmonary disease (COPD) is a severe, progressive, long-standing disorder of the lungs that affects over 300 million people worldwide. It is the 5th leading cause of death but by 2030 is predicted to rise to the 4th position. Death rates are increasing in Western countries, but to an even greater extent in developing countries. Although tobacco smoking is a well established risk factor for COPD, other causes, such as use of biomass fuel for cooking, outdoor air pollution, occupational exposures and poor socioeconomic status are also believed to be important causes, especially in the developing countries. Indeed, globally around 40% of COPD can be attributed to non-smoking causes. Despite this huge and growing burden, little is known about this non-smoking type of COPD. The first aim of our study is to compare the clinical features (symptoms, quality of life), lung function tests, lung scans and inflammatory profiles in sputum and lung lavage, systemic inflammation and comorbidities of non-smoking COPD patients compared to smoking-induced COPD in India and the UK. We will also document disease progression by measuring decline in lung function and health status over 3 years. The second aim to investigate whether the lower airways are colonised with bacteria and whether bacterial profiles measured by a new sensitive molecular technique differ from exposed and non-exposed controls and smoking COPD patients and whether this is linked to impaired uptake of bacteria by scavenger cells, as it is in smoking COPD patients. Thirdly, we will investigate underlying mechanisms in non-smoking compared to smoking COPD by measuring inflammatory regulators that are linked to increased inflammation and steroid resistance in smoking COPD. We will also study DNA methylation patterns in sputum samples of subjects with non-smoking and smoking COPD to understand the long-term mechanisms that may drive the underlying inflammatory process. We will measure the black carbon content in alveolar macrophages of healthy individuals, individuals with COPD due to exposure to biomass smoke and smoking COPD patients and to relate this to exposure to carbon particulates monitored in the air of homes using biomass fuels. Finally, we will determine the impact of replacing biomass fuel with a cleaner form of cooking (liquefied petroleum gas) on indoor air pollution levels, alveolar carbon content and on lung health using questionnaires, physiological measurements and sputum cellular and inflammatory mediator profiles. The proposed research study will help us better understand a common non-smoking phenotype of COPD, which is one of the leading causes of death in the world, especially in the developing countries, yet almost completely neglected by researchers and the pharmaceutical industry. We will also understand whether simple and relatively inexpensive environmental interventions, such as change in the fuel type, reduces levels of indoor air pollutants and has any impact on health outcomes. These pilot studies will inform future long-term controlled trials of cheap treatments, including low doses of oral and inhaled steroids and theophylline that may reverse steroid resistance, with measurement of important health outcomes, such as exacerbations, disease progression and mortality that are beyond the scope of the current proposal. The results of the study will help to generate new knowledge about non-smoking COPD in India and the UK, but will also have a direct impact on preventative and therapeutic strategies that will benefit policy makers and health care providers across the world. The study will help the exchange of knowledge between the British and Indian research teams and will build up research capacity. Our proposed study addresses a very important unmet clinical need and profits by the complementary strengths and approaches of the Indian and UK research teams.

COPD affects over 300 million people worldwide and is a leading cause of death in the western as well as developing countries. Most of the basic and clinical research is in tobacco smoke-induced COPD. Non-smoking COPD is emerging as an important phenotype of COPD but is very poorly understood. The overall aim of this proposed study is to better characterise the non-smoking phenotype of COPD and to investigate how it differs from smoking COPD. Our main objectives are to: (1) Study and compare the clinical, physiological, radiological and inflammatory profiles in induced sputum and bronchoalveolar lavage, systemic inflammation and co-morbidities of non-smoking COPD with smoking-induced COPD in India and UK. We will also study disease progression of non-smoking COPD in India over 3 years; (2) Study bacterial colonization of lower airways in non-smoking COPD and exposed controls using culture and 16s rRNA metagenomic profiling, and whether this is linked to impaired bacterial phagocytosis by macrophages and neutrophils; (3) Study histone deacetylase and phosphoinositide-3-kinase activity in the sputum and alveolar macrophages of non-smoking COPD to better understand the molecular mechanisms of lung inflammation; (4) Study DNA methylation patterns of non-smoking COPD to understand epigenetic dysregulation; (5) Quantify and compare the black carbon content in the cytoplasm of alveolar macrophages from biomass smoke-induced COPD and smoking COPD subjects; (6) Study the impact of replacing biomass fuel with liquefied petroleum gas on indoor air pollution, alveolar black carbon content and its effects on lung health using physiological and sputum cellular and inflammatory mediator profiles. The study will be conducted using well established and validated methods and will provide new knowledge in this field of respiratory medicine that will not only benefit clinicians, respiratory researchers, public health workers, pharmaceutical industry, but also the policy makers.

Who will benefit from this research?
We believe that our research on non-smoking COPD will benefit a wide range of stakeholders world-wide. The results of the study will not only help generate new knowledge about non-smoking COPD, but will also have a direct impact on preventative and therapeutic strategies that will benefit policy makers and health care providers across the world. Our research will highlight the enormous importance of non-smoking forms of COPD and emphasise the need for far more research in this neglected area. Many patients with non-smoking COPD are undiagnosed as the diagnosis is often ignored if the patient has no smoking history. The increased understanding of non-smoking causes of COPD will lead to a greater interest across the research community world-wide. It will not only have impact on respiratory researchers, but also public health specialists, epidemiologists and general practitioners. Better understanding of non-smoking phenotypes of COPD will also highlight the importance of understanding how to manage these patients more effectively and the need to undertake large therapeutic trials in these phenotypes of COPD, which may respond differently to therapeutic interventions than smoking COPD. There are no reported studies of treatment in non-smoking COPD patients as all large controlled trials have required a minimal smoking history for inclusion. This area of research would therefore be of great interest to the pharmaceutical industry, which has identified COPD as an area of major unmet need and opportunity. Finally, patients will benefit from the recognition that smoking is not the only cause of COPD and our research should emphasise the importance of early diagnosis in the community as we will develop information about disease progression and intervention. There has been considerable interest amongst patients groups in non-smoking forms of COPD and how this differs from the usual smoking COPD.

How will they benefit?
Better understanding about non-smoking COPD should ultimately help reduce the burden and suffering caused by this not uncommon form of disease. The results of this study will be presented in international and national conferences, and also to health authorities of respective countries, which will assist in the development of various national COPD control programmes in near future. This study will lay the foundation for conduct of larger scale therapeutic interventional studies in prevention, management and new drug development for non-smoking COPD phenotypes. This study will help the exchange of knowledge between the British and Indian research teams and apart from building up research capacity in this area, this collaborative study will help to promote a strong bond for future collaborative interdisciplinary research between the two countries in the field of COPD, and hopefully help address some of the key health issues that will have a significant impact on survival and quality of life of patients with COPD. Increasing publicity about non-smoking forms of COPD should increase interest in research, in conducting therapeutic trials and in preventive measures in the future.