Systemic manifestations of COPD such as exercise capacity limitation, muscle wasting, fatigue and depression have been shown to contribute substantially to COPD morbidity and mortality. The author examined this topic in his PhD clinical research programme at the University Hospital of South Manchester, University of Manchester under supervision of Prof Jorgen Vestbo. Dr Al-shair presented his work at British and American Thoracic Societies and in three consecutive years at the European Respiratory Society (2008-2010) where he received conference awards; and published 3 major manuscripts in peer reviewed journals, as Prof Ashley Woodcock described in the preface of this book. Muscle wasting was prevalent in COPD; and depression was associated with poor functional performance in COPD. The book describes the Manchester COPD Fatigue Scale; a robust scale that provides a simple, reliable and valid measure of total and dimensional fatigue in COPD. This work is first to indicate a possible association between TNF-? and two major co-morbidities in COPD; i.e., depression and fatigue. TNF-? was mildly associated with poor functional performance and impairment in alveolar gases exchange.