**1. Introduction**

Cystic Fibrosis (CF) is the most commonly inherited potentially lethal disease amongst the Caucasian ancestry. The prevalence of CF is reported as 0.737 per 10,000 in 27 European Union countries [1]. The United States (US) Cystic Fibrosis Patient Registry reports a similar preva‐ lence of 0.797 CF patients per 10,000 people [2]. It is an autosomal recessive disease and is

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caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) [3]. The most common mutation is caused by deletion of phenylalanine at position 508 (Delta F508) of the CFTR on chromosome 7, which accounts for approximately 70% of CF cases. The primary function of CFTR in many tissues is to regulate and participate in the transport of chloride ions across epithelial cell membranes. To date, more than 1,900 mutations have been described in this gene.

CF is a multisystem disease as CFTR is expressed in different organs [4]; however, the lungs are the predominant organs that bear the brunt of the disease [5]. Recurrent pulmonary infections may start at very early stages in the lives of patients with CF. It has been hypothesised that low airway surface liquid volume and impaired mucociliary clearance are responsible for the pathogenesis of lung infections. These in turn lead to impaired bacterial clearance from respiratory epithelial cells [6]. Pulmonary infections remain the greatest cause of poor life quality, morbidity and mortality in CF that eventually lead to premature death in this condition [7].

Apart from chronic lung disease with recurrent exacerbations, exocrine pancreatic insuffi‐ ciency is also a feature that leads to malabsorption and subsequently growth retardation and maturation. Endocrine pancreatic insufficiency is another feature of CF with the manifestation of diabetes. Obstructive azoospermia in male CF patients leads to male infertility.

The median survival from CF has taken great strides over the past 40 years as a consequence of the introduction of specialist centre care, nutritional optimisation, prevention and aggres‐ sive management of pulmonary exacerbations [8]. In the United Kingdom (UK) CF population in 2012, the median survival was reported as 43.5 years, compared to 38.8 years for the population in 2008 as per the UK CF Registry [9]. It has been postulated that the continuing improvement in survival of CF patients in successive cohorts means that the previous prediction of patients with CF living beyond a median age of 50 years is not impossible. The recent introduction of Ivacaftor to the management of CF patients with G551D CFTR mutations may further enhance the overall survival [10].

Historically, bacteria have been the predominant cause for respiratory exacerbations. The presences of some organisms including *Staphylococcus aureus*, *Pseudomonas aeruginosa* and *Burkhoderia cepacia* in the airways have been shown to lead to clinical deterioration [11-13] and may subsequently lead to morbidity and mortality. Pulmonary exacerbations are associated with acquisition of new organisms and increased concentration of airway flora [14]. The new acquisitions of *P. aeruginosa* in CF have been demonstrated to occur in the winter months coinciding with the peak of respiratory viral infections [15, 16]. In the event of a pulmonary exacerbation the absence of pyrexia, raised inflammatory markers and systemic response, pathogens other than bacteria can be the potential cause. Respiratory viruses have been implicated by a number of studies in the last 30 years as potentiators for CF exacerbations [17-29]. *Influenza* is a substantial health threat; it is associated with approximately 36,000 deaths and 220,000 hospitalisations in the USA on an annual basis [30]. The recent emergence of novel *influenza virus (H1N1)* further heightened the awareness of influenza-like illness. CF Pulmo‐ nary exacerbation rates have also been shown to be significantly increased during the winter months and are highly associated with the influenza season [31]. Respiratory viruses that are associated with the exacerbations of CF include *influenza A and B, respiratory syncytial virus (RSV), parainfluenza virus (PIV) types 1 to 4, rhinovirus, metapneumovirus, coronavirus* and *adenovirus*.

In the last 30 years, there have been a number of published studies depicting the impact of respiratory viruses in CF. A number of studies have also demonstrated the relationship between respiratory viruses and bacteria in the pathogenesis of CF exacerbations [15, 32]. The introduction of molecular diagnostic technologies has further enhanced the awareness of respiratory viral aetiology in CF exacerbations as they have much higher detection rates than traditional methods. However, further understanding is required to appreciate their relation‐ ship in order to allow the development of potential novel treatment. If indeed respiratory virus does lead to secondary bacterial infection in CF, viral vaccinations and anti-viral therapies would be important therapeutic options for CF. On the other hand, the currently commercially available vaccines and anti-virals for the prevention and treatment of respiratory viral infections are limited; they are primarily for influenza infection. The potential development of new vaccines and anti-virals is an exciting field which may offer alternate therapeutic opportunities for CF exacerbations.

This chapter will focus on the literature regarding respiratory viruses in CF and their clinical implications, the detection techniques for viruses and their differences in sensitivities, the interaction between viruses and bacteria, and the management of viral infections.
