**5. Prevention and treatment for respiratory viruses**

The diversity of viral serotypes in causing infection has made vaccine preparation very difficult. Frequent mutations of viral proteins of RNA viruses (e.g. genetic drift and shift of *influenza*) have further hampered the prevention of the illness.

In the UK, it has been reported that 2,150 deaths during the 2011/12 season was attributable to influenza [84], though some of the deaths may be attributed to *RSV*. *Influenza* vaccines are the only commercially available vaccines against common respiratory viruses. They have been used since the mid-1940s and they now have an established role in the prevention of *influenza A and B* infections. Inactivated *influenza* vaccine is effective even in young children including those younger than 2 years [85]. The waning of vaccine-induced immunity over time requires annual re-immunisation even if the vaccine antigens are unchanged.

Recent vaccines contain antigens of two *influenza A* subtypes, strains of the currently circulat‐ ing *H3N2 and H1N1 (Swine flu)* subtypes, and one *influenza B* virus. The current recommen‐ dation for *influenza* vaccination in the UK is to offer it to those over the age of 65, those with chronic heart, respiratory (including CF) or renal diseases and those who are diabetic or immunosuppressed.

Our group [34] recently showed that *influenza* vaccination provides protection against *influenza* acquisition in patients with CF, with 1 of 41 patients vaccinated having a positive nasal swab for influenza compared to 4 of the 22 non-vaccinated patients (p=0.046). Although *influenza* vaccination does not appear to have any impact on respiratory exacerbation rates, it does have a role in preventing live infections. In our study, respiratory exacerbation rates in the preceding 10 months before the study between the vaccinated and non-vaccinated groups were similar, indicating that these were unlikely to be the reasons influencing the decision on immunisation. The decision may be secondary to a combination of patient/parent education, social back‐ ground, awareness of vaccination and accessibility of vaccination.

Due to the lack of randomised controlled studies looking at the efficacy of *influenza* vaccine in CF, the Cochrane review recommends clinicians to make their own judgements on the benefits and risks of this therapy in this cohort of patients [86]. In addition to vaccine, neuraminidase inhibitors have been shown to have a role in preventing *influenza A and B* infections [87].

been identified. CFTR mutations have been shown to affect the epithelial induction of type I IFN expression by airway cells in response to *P. aeruginosa* infection [83]. This is achieved by abolishing this signalling pathway, an important component of the innate immune system that protects mucosal surfaces. Based on available evidence, chronic colonisation of *P. aeruginosa* in CF airways can be hypothesised to increase the predisposition of viral infections; however,

Taken together, these findings suggest conflicting data regarding the inflammatory response of the CF airway epithelium on virus infection and to some extent the symbiotic relationship between viruses and bacteria. Nonetheless, respiratory viruses may lead to epithelial disrup‐ tion, increase neutrophil influx, inhibition of macrophage phagocytosis, destruction of mucociliary escalator, down-regulation of cilia beat, liberation of pro-inflammatory planktonic *P. aeruginosa* from biofilm and increased neutrophil-induced peroxide release, indirectly

The diversity of viral serotypes in causing infection has made vaccine preparation very difficult. Frequent mutations of viral proteins of RNA viruses (e.g. genetic drift and shift of

In the UK, it has been reported that 2,150 deaths during the 2011/12 season was attributable to influenza [84], though some of the deaths may be attributed to *RSV*. *Influenza* vaccines are the only commercially available vaccines against common respiratory viruses. They have been used since the mid-1940s and they now have an established role in the prevention of *influenza A and B* infections. Inactivated *influenza* vaccine is effective even in young children including those younger than 2 years [85]. The waning of vaccine-induced immunity over time requires

Recent vaccines contain antigens of two *influenza A* subtypes, strains of the currently circulat‐ ing *H3N2 and H1N1 (Swine flu)* subtypes, and one *influenza B* virus. The current recommen‐ dation for *influenza* vaccination in the UK is to offer it to those over the age of 65, those with chronic heart, respiratory (including CF) or renal diseases and those who are diabetic or

Our group [34] recently showed that *influenza* vaccination provides protection against *influenza* acquisition in patients with CF, with 1 of 41 patients vaccinated having a positive nasal swab for influenza compared to 4 of the 22 non-vaccinated patients (p=0.046). Although *influenza* vaccination does not appear to have any impact on respiratory exacerbation rates, it does have a role in preventing live infections. In our study, respiratory exacerbation rates in the preceding 10 months before the study between the vaccinated and non-vaccinated groups were similar, indicating that these were unlikely to be the reasons influencing the decision on immunisation. The decision may be secondary to a combination of patient/parent education, social back‐

more in-depth studies are required to elucidate this hypothesis.

**5. Prevention and treatment for respiratory viruses**

*influenza*) have further hampered the prevention of the illness.

annual re-immunisation even if the vaccine antigens are unchanged.

ground, awareness of vaccination and accessibility of vaccination.

facilitating bacterial infection of the airway.

156 Cystic Fibrosis in the Light of New Research

immunosuppressed.

*Rhinovirus* has more than 100 serotypes; therefore, it will be unlikely that a unifying vaccine can be developed. VP4, one of the non-enveloped capsids, is highly conserved among all of the rhinoviruses; anti-VP4 antibodies have recently been generated and been shown to have the potential for future vaccine development [88].

The development of an *RSV v*accine has been hampered by the experience with formalininactivated whole *RSV* vaccine in the 1960s, as it caused 80% of *RSV* vaccinees to become hospitalised compared with 5% of controls, as well as two fatalities [89]. Current major research work has focused on a prophylaxis using a humanised mouse monoclonal antibody, Palizi‐ vumab. In patients with CF, monthly Palizivumab injection significantly reduced the hospi‐ talisation rate for acute respiratory illness during the *RSV* season compared to those who were not immunised (p<0.05). The former group also had fewer hospital days for acute respiratory illness [90]. However, the Cochrane database systematic reviews were not able to draw any firm conclusions on the safety and tolerability of RSV prophylaxis with Palivizumab in infants with cystic fibrosis up to 2 years of age due to a lack of randomised controlled studies [91]. Further studies are required to evaluate the safety and effectiveness of this treatment in CF patients.

There is currently no licensed *PIV* vaccine. The formalin-inactivated vaccine generated in the 1960s was not able to prevent *PIV* infection and was soon abandoned. Recently, recombinant bovine *PIV type 3* and human *PIV type 3* attenuated vaccines are being evaluated in animal models as vectors for the delivery of other viral antigens such as *RSV*-G and *RSV*-F proteins. This bivalent vaccine combination provides high level of resistance to challenges with *PIV type 3* and *RSV* in animal models [92].

The conventional methods of vaccination are via the intramuscular and subcutaneous routes. Mucosal immunisation has recently been introduced as it represents an attractive manner of delivering vaccines. It is fast, simple, non-invasive and can be carried out by unskilled individuals. The use of mucosal vaccination seems logical in that most of respiratory viral infections initially start at the mucosal sites and therefore induce local immunity. In the autumn/winter of 2014/15 the annual nasal spray flu vaccine (Fluenz Tetra) became available for children aged 2, 3 and 4 year as part of the UK NHS childhood vaccination programme. The nasal spray flu vaccine is also for children aged 2-18 years who are "at risk" from flu, such as children with long-term health conditions.

Amantadine has been the conventional anti-viral against *influenza*. However, it is strainspecific as it is only effective against *influenza A* and has common side effects such as insomnia, poor concentration and irritability. It is now largely being replaced by neuraminidase inhibi‐ tors such as Zanamivir and Oseltamivir, which are licensed for the treatment of *influenza A and* *B*, including *avian flu H5N1* and *swine flu H1N1*. However, Amantadine still has a role in dealing with Oseltamivir-resistant H1N1 virus. In children and adults, early initiation of neuramini‐ dase inhibitors within 48 hours of the onset of symptoms can reduce the duration of flulike symptoms by 0.5 to 2.5 days [93]. Early use of these medications can also reduce development of complications such as pneumonia [94]. The 2009 pandemic *H1N1* virus remains susceptible to neuraminidase inhibitors, and Oseltamivir has been used extensively for treatment related to this viral infection. Resistance to Oseltamivir has been reported with *H1N1* viral infection but this is mainly restricted to immunocompromised individuals [95]. Zanamivir has a poor oral bioavailability, and intranasal application has been shown to be effective in treating experimental *influenz*a infection with the reduction in symptoms caused, virus shedding and development of otitis media [96]. Intravenous use of Peramivir or Zanamivir could be lifesaving in critically ill patients with *influenza* infection [97, 98]. However, currently the Cochrane database of systematic reviews does not recommend the routine use of neuraminidase inhibitors in influenza infection in CF because of the absence of high level evidence for the effectiveness of these interventions [99].

Ribavarin, a synthetic guanosine nucleoside that has a broad spectrum of anti-viral activity, has been used for treatment of infections related to *RSV*, *metapneumovirus, and parainfluen‐ za and influenza viruses* [100]. Potential benefits of ribavarin therapy include the inhibition of RSV-specific IgE production in nasal secretions, which has been associated with the development of hypoxaemia and wheezing [101] and it has improved pulmonary func‐ tions [102]. Controlled studies also show that the use of ribavarin is effective in reducing the clinical severity score, duration of mechanical ventilation, supplemental oxygen use and days of hospitalisation [103]. Aerosolised ribavarin has been used for the treatment of *RSV*-related bronchiolitis and pneumonia. Intravenous formulation could be used for treatment of severe pneumonia, caused by infection *RSV*, *metapneumovirus*, *or parainfluen‐ za virus*, on the basis of experience in immunocompromised patients [104]. Bonney et al. have shown that *metapneumovirus* can be successfully treated with a combination of intravenous ribavarin and immunoglobulin [105].

Although *rhinovirus* is the major cause of colds, its vast amount of serotypes has made development of anti-virals against it problematic. A 90% of *rhinovirus* serotypes gain entry into epithelial cells using ICAM-1 cellular receptors, and blockade of these receptors in experi‐ mental studies has shown reduced infection severity [106], but further study is required before this treatment option becomes widely available. Macrolide antibiotics, Bafilomycin A1 and Erythromycin have been shown to inhibit ICAM-1 epithelial expression and hypotheses about their potential as anti-inflammatory agents have yet to be definitive, as clinical proof is either negative or inconclusive [107].

Recently, an anti-rhinoviral agent known as Plecoranil, which acts by inhibiting the uncoating of Picornaviruses [108], the RV 3C protease inhibitor, Ruprintrivir[109] and soluble ICAM-1, Tremacamra[106] have shown promising results in early-stage clinical trials, but each of these medications was derailed by a combination of cost, pharmacokinetics, toxicity, drug interac‐ tions, and limited efficacy [110].

A previous study suggests that the increased morbidity in CF patients after virus infection is not due to an exaggerated inflammatory response of the airway epithelium but rather linked to increased cell death. Thus, they provide a rationale for implementing therapies aimed at controlling viruses and their replication rather than primarily targeting inflammation. In this respect, a promising candidate is the macrolide-antibiotic azithromycin, which is increasingly used in CF patients as a beneficial immunomodulatory agent [111] and has recently been shown to possess anti-viral properties [57].
