Análisis estadístico

Chronic respiratory tract diseases are of major global importance; they are increasing in incidence worldwide and are now classified by the World Health Organisation (WHO) as non-communicable diseases (NCDs) in addition to cardiovascular disease, cancer, and diabetes, collectively they account for the highest rates of mortality on a global scale than all other causes combined (Reardon, 2011). Chronic respiratory diseases encompass conditions such as CF, COPD, non-cystic fibrosis bronchiectasis, and asthma amongst others. Asthma and COPD present problems worldwide, both in terms of morbidity and mortality, but also in economic costs on healthcare resources. Asthma is a chronic inflammatory airway disease in which individuals suffer from exacerbations which result in chest tightness, wheezing, cough and dyspnoea, all symptoms associated with airway obstruction (Jarjour and Kelly, 2002). In the Western world, asthma is the most common chronic respiratory disease affecting 10 % of adults and 30 % of children, in the U.S. alone, 1.75 million asthma-related emergency department visits and 456 000 asthma-related hospitalisations were recorded contributing towards one-third of the total $14.7 billion annual U.S. asthma-related health care expenditure (Akinbami et al., 2011, American Lung Association). Chronic obstructive pulmonary disease is primarily induced by cigarette smoking and is characterised by irreversible airflow limitation and chronic inflammation in the LRT (Pauwels et al., 2001). COPD is an increasingly leading cause of morbidity and mortality globally, but woefully under-recognised (Pauwels and Rabe, 2004); from 1990 to 2020, the 30 year projection of COPD ranking will be a rise from sixth to third most common cause of mortality and fifth in the cause of disability worldwide (Lopez and Murray, 1998). Economically, in the U.K., £500 million is spent annually through direct healthcare costs relating to COPD in addition to 24 million working days also wasted (British Lung Foundation, 2006).

Cystic fibrosis is the most common recessive autosomal genetic disorder affecting individuals of Caucasian descent, ~ 1:2,500 children are afflicted with the condition from birth and ~ 70,000 adults and children are thought to be affected with CF worldwide (Cystic Fibrosis Foundation, World Health Organization, 2002) Genetically, CF is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on the long arm of chromosome 7, encoding for a membrane-bound cyclic-adenosine monophosphate (cAMP)-regulated chloride channel (Kerem et al., 1989, Riordan et al., 1989, Rommens et al., 1989). Mutations of the CFTR gene vary tremendously, and > 1,500

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mutations and sequence variants have been identified presently and deposited into the Cystic Fibrosis Genetic Analysis Consortium. Although many of these mutations are rare, only four occur at > 1 % frequency, in particular, the most frequent mutation F508del exists in the region of DNA within the CFTR gene that encodes for one of two nucleotide-binding domains (NBDs), i.e., NBD1 (Döring and Ratjen, 2005). The mutation in NBD1 results in abnormal transport of chloride and sodium ions affecting water transport across mucus-rich epithelial tissues inducing systemic pathophysiological effects in CF individuals where the

CFTR gene is expressed in various organs such as the respiratory, gastrointestinal, and

reproductive tracts, the pancreas, and liver (Tizzano and Buchwald, 1995). Physiological dysfunction in the respiratory tract is the leading cause of morbidity in CF individuals as ~ 90 % die of respiratory failure due to this CFTR defect consequently leading to several cascading factors; dehydration of the airway mucous, reduced mucocilliary clearance, mucous retention, and predisposition of the CF patient to recurrent chronic lung infections (Boucher, 2002, George et al., 2009).

One of the main defining clinical features in CF and COPD is bronchiectasis; an abnormal dilatation of the bronchi and bronchioles due to repeated cycles of respiratory tract infection and subsequent inflammation (Barker, 2002, O'Donnell, 2008). Bronchiectasis is a highly debilitating disease which can cause premature mortality and chronic morbidity in some instances due to severe pulmonary infections and lung function impairment (Alzeer et al., 2007, King et al., 2005). The paradigm relating to chronic infection in bronchiectasis is a vicious circle of continual transmural infection and inflammation followed by mediator release, the retention of inflammatory secretions and micro-organisms in the LRT cause further lung tissue damage thus accelerating pulmonary obstruction and recurrent chest infection (Cole, 1986). Patients with CF present with a very severe form of bronchiectasis, but increasingly, other individuals are now being diagnosed with an idiopathic variant of this disease, termed non-CF bronchiectasis (nCFBR). The term idiopathic arises from the initial diagnosis of nCFBR in many patients in which the aetiology of the disease is unknown. The increasing frequency in the diagnosis of nCFBR is due to the widespread use of high- resolution chest computed tomography (HRCT) scanning (Cohen and Sahn, 1999), although the prevalence of nCFBR globally is unknown (O'Donnell, 2008). However, a recent study conducted in the U.S. alone revealed that 110,000 individuals may be receiving treatment for

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nCFBR with an annual cost to the U.S. healthcare system of $630 million respectively (Weycker et al., 2005).

Most, if not all, individuals who are afflicted with asthma, COPD, CF, and nCFBR suffer from punctuated episodes of exacerbations, i.e., a worsening of symptoms which induce airway obstruction in these patients clinically presented as dyspnoea, cough, chest pain, and wheeze. Exacerbations can be triggered by several factors, including a secondary infection of both the URT and LRT of several aetiologies, but they also vary in their severity and frequency in the chronic respiratory disease briefly described above. In summary, chronic respiratory tract diseases play a significant role in the morbidity, mortality, and economies not only in the Western world, but increasingly in the developing world.

Cough, breathlessness, wheeze, chest pain, and sputum production, all major symptoms of respiratory disease may be indicative of acute or chronic respiratory tract infection (Leach, 2007). As the respiratory tract is a continuous entity, via the nose to the alveoli, respiratory tract infections (RTI) are distinguished by diagnoses of the ‘preferred focus’ of the infectious agent, either in the URT or LRT, although there can be at times ambiguity concerning this issue; for instance, the parainfluenza virus can infect the nasopharynx, larynx, trachea, and occasionally the bronchi and bronchioles resulting in the common cold, laryngotracheitis (croup), bronchitis, bronchiolitis, or pneumonia respectively (Goering et al., 2008). The aetiology of respiratory tract infection may be bacterial, viral or fungal in origin. Some patients may already present with an underlying lung disease such as nCFBR, CF, and COPD, of which infection in the upper and lower respiratory tract is a secondary disease, but nevertheless a critical contributing factor to the morbidity and mortality of the individual in question. For the purposes of the investigative work contained herein, the author will focus primarily on lower respiratory tract infections in non-CF bronchiectasis and COPD.