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Households represent a setting of frequent and intense contacts and hence are conducive to the spread of respiratory viruses, such as respiratory syncytial virus (RSV). Infants are most vulnerable to severe RSV disease but a vaccine is oat yet available hence the need to explore alternate strategies of protecting them, Such strategies would require better understanding of who infects the infants. During the RSV season of200912010, we undertook a prospective study in rural Kenya involving 493 members of 47 households each with a child born after the preceding RSV epidemic and at least one elder sibling. Throughout the epidemic a nasopharyngeal swab (NPS) was collected every 3-4 days irrespective of symptoms, from all household members, and tested for a range of respiratory viruses including RSV using a molecular diagnostic assay. Partial sequencing of the attachment protein (G) gene from positive swabs was used to compare RSV strains within the household. In addition, once-a-week a specimen of oral fluid (OF) from around the gums was co11ected for RSV -specific antibodies screening and for assessment of sensitivity of the OF in detection of RSV using molecular diagnostics. This is the first prospective study to investigate introduction and transmission of RSV in families using molecular techniques over a complete RSV season. Analysis of RSV infection data is reported in this thesis with particular interest to identifying from where infants derive !.heir infection, estimating the duration of RSV shedding and identify factors influencing the recovery rates, and estimating parameters of RSV susceptibility and transmission probability. In addition, data on diagnostic performance of OF in detection of RSV by molecular methods is presented. A total of 16,924 NPS were collected, representing 86% of planned. RSV was detected in 40 (85%) households and 179 (36%) of the participants. In 28 of the 44 households with complete data, there was transmission of RSV to the infants experiencing their first epidemic. The probable source of RSV infection of the naive infants was a household member in at least 54% of the cases. Co-primary infection between a household member and the RSV -naive infant was ascribed in 4 of the cases. Older children were assigned the primary case for 11 (39%) of the infant cases and 10 (91 %) of these were attending school. The infants appeared to play a role transmitting the introduced infections to the other members of the household including to the mothers. These findings support vaccination strategies that target school age children and pregnant women. Both of these vaccination strategies can have profound benefits to RSV naive infants directly by augmenting neutralizing antibodies against RSV (immunization of the pregnant women) and indirectly by reducing transmission from siblings to RSV-naive infants. Results from this study provide increased confidence in the rationale for RSV vaccination of individuals who are not the key targets for protection

Introduction: The emphasis on self-management of long-term conditions, including respiratory conditions, is growing. Patients with respiratory conditions often have to adhere to medical treatments to prevent ill health and promote good health. They have to deal with psychological and social needs and maintain effective communication with health ;are practitioners. The role of a self-management intervention is not known in the management of patients with bronchiectasis thus this thesis includes a series of studies investigating self-management in bronchiectasis. The programme of research follows the Medical Research Council framework for the design of complex interventions to improve health from the preclinical phase to phase II (Campbell, Fitzpatrick et al 2000).

Introduction: Patients with bronchiectasis infected with Pseudomonas aeruginosa are prescribed a complex treatment regimen. Current bronchiectasis guidelines recognise that adherence to treatment is important in this patient group but no published studies have determined the level of adherence to treatment in this population. Therefore, the overall aims of this thesis were to determine rates of adherence to treatment, explore factors influencing adherence to treatment and to determine associations between adherence to treatment and healthcare outcomes amongst patients with bronchiectasis infected with P. aeruginosa. Methods: Two studies were undertaken to meet these aims: a one year prospective study to determine the level of adherence to treatment in patients with bronchiectasis infected with P. aeruginosa and those factors' associated with adherence, and a qualitative study using semi-structured interviews to gain an in-depth understanding of patients' views on adherence to treatment in bronchiectasis. Results: Adherence was measured using self-report and prescription refill history for 75 patients with bronchiectasis infected with P. aeruginosa, recruited from four Trusts, and findings illustrated that between 41 % and 53% of participants were adherent (completed 2::80% of prescribed treatment) to airway clearance and medicines for bronchiectasis, respectively. Age, number of prescribed medicines, Beliefs about Medicines Questionnaire (BMQ) scores and Quality of Life-Bronchiectasis (QOL-B) scores were associated with adherence to treatment, although, the individual factors varied by treatment type. Being categorised as adherent to inhaled antibiotics was associated with a lower pulmonary exacerbation frequency and higher overall total healthcare costs. Four key themes (beliefs about treatment, practicalities of treatment, trust in healthcare professionals and acceptance of disease and treatment) emerged from the qualitative interviews with patients and were used to develop a conceptual model of factors influencing decision-making about adherence to treatment in patients with bronchiectasis. This model described how patients made conscious decisions about adherence to treatment by weighing up a combination of barriers and motivators to adherence for each treatment. Conclusion: Findings indicated that adherence to treatment is a problem in bronchiectasis and that patients made conscious decisions about adherence to treatment. These findings provide the theoretical basis from which to develop an intervention to improve adherence to treatment in patients with bronchiectasis.

Bronchiectasis is a disease characterised by chronic bronchial sepsis and exerts considerable morbidity in those affected. In approximately 50% of cases the aetiology is unknown (idiopathic), raising the possibility of genetic predisposition. Cytokines such as IL-1, IL-6, IL-8 and TNFα are potent neutrophil recruiting molecules and are abundant in bronchiectatic secretions. Cytokine polymorph isms can lead to constitutively high production, and have been associated with a number of chronic inflammatory states. Hypothesis: Gene polymorph isms associated with high cytokine production predispose to idiopathic bronchiectasis (IB). Aims and objectives: To determine if high production alleles of cytokines IL-1β, IL6, IL8, TNF and IFNG are associated with idiopathic bronchiectasis (I B). Frequencies of these alleles were compared in patients with IB, bronchiectasis of known cause and normal controls. Allele frequencies in IB were also correlated with clinical markers of disease severity. Methods Following ethical approval, prospectively recruited patients underwent extensive clinical. phenotyping. IB was established as a diagnosis of exclusion. Allele frequencies for candidate genes were determined by PCR, with control allele frequencies available from local blood donors. Comparisons were made by Chi Square tests. Results: 189 patients (95f, 94m), mean (SO) age 66.11 (11.52) years were recruited including 82 (43%) idiopathies, No differences in the candidate allele frequencies were found between IB with 200+ controls and bronchiectasis of known cause group (n=1 06). Within idiopathic group, IL8+781T, IL6-174C, and IL1B-511T alleles were significantly associated with daily sputum production. In addition, IL8+781T and IL6-174C were associated with high exacerbation frequency and positive Pseudomonas aeruginosa culture. IL-1 B+3953T was significantly under- represented in those with daily sputum production and positive Pseudomonas status. Conclusions: Gene polymorphisms predisposing to high cytokine production were not found to be associated with lB. Several alleles were found to significantly associated with more severe disease. Independent confirmation is required in an adequately powered study.

<b>Introduction:</b> Respiratory Syncytial Virus is the major viral cause of lower respiratory tract disease in young children worldwide, with the greatest burden of disease in infants aged 1-3 months. Consequently, vaccine development has centered on a vaccine to directly protect the infants in this age group. The fundamental problem is that these young infants are poor responders to candidate RSV vaccines. This thesis focuses on the use of mathematical models to explore the merits of vaccination. <b>Methods:</b> Following development and analysis of a simple non-age-structured ODE model, we elaborate this to a Realistic Age Structured model (RAS) capturing the key epidemiological characteristics of RSV and incorporating age-specific vaccination options. The compartmental ODE model was calibrated using agespecific and time series hospitalization data from a rural coastal Kenyan population. The determination of Who Acquires Infection From Whom (WAIFW) matrix was done using social contact data from 1) a synthetic mixing matrix generated from primarily household occupancy data and 2) a diary study that we conducted in the Kilifi Health and Demographic Surveillance System (KHDSS). The vaccine was assumed to elicit partial immunity equivalent to wild type infection and its impact was measured by the ratio of hospitalized RSV cases after to before introduction. of vaccination. Uncertainty and sensitivity analysis were undertaken using Latin Hypercube Sampling (LHS) and partial rank correlation respectively. Given the importance of households in the transmission of respiratory infections, an exploratory household model was developed to capture the transmission dynamics of RSV A and B in a population of households. <b>Results:</b> From the analytical work of the simple ODE model, we have demonstrated that the model has the potential to exhibit a backward bifurcation curve within realistic parameter ranges. Both the diary and the synthetic mixing matrices had similar characteristics i.e. strong assortative mixing in individuals less than 30 years old and strong mixing between children less than 5 years and adults between 20 and 50 years old. When the two matrices were jointly linearly regressed, their elements were well correlated with an R2 ~ 0.6. The RAS model was capable of capturing the age-specific disease and the temporal epidemic nature of RSV in the specified location. Introduction of routine universal vaccination at ages varying from the first month of life to the 10th year of life resulted in optimal long-term benefit at 7 months (for the diary contact model) and 5 months (for the synthetic contact model). The greatest benefit arose under the assumption of age-related mixing with the contact diary data with no great deal of effectiveness lost when the vaccine is delayed between 5 and 12 months of age from birth. Vaccination was also shown to change the temporal dynamics of RSV hospitalizations and also to increase the average age at primary infection. From the sensitivity analysis, we identified the duration of RSV specific maternal antibodies, duration of primary and tertiary infections as the most important parameters in explaining the imprecision observed in predicting both the age specific hospitalizations and the optimal month at vaccination. Results from the household model have demonstrated that the household epidemic profile may be different from the general population with strong interaction of the viruses in the household that do not necessarily reflect at the population level. <b>Conclusion:</b> The synthetic matrix method would be a preferable alternative route in estimating mixing patterns in populations with the required socio-demographic data. Retrospectively, the synthetic mixing data can be used to reconstruct contact patterns in the past and therefore beneficial in assessing the effect of demographic transition in disease transmission. Universal infant vaccination has the potential to significantly reduce the burden of RSV associated disease, even with delayed vaccination between 5 and 12 months. This age class represents the group that is being targeted by vaccines that are currently under development. More accurate data measuring the duration of RSV specific maternal antibodies and the duration of infections are required to reduce the uncertainty in the model predictions.