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Human respiratory syncytial virus is a leading cause of lower respiratory tract infection in infants. Current prophylaxis with Palivizumab, a humanised anti-fusion glycoprotein monoclonal antibody, has only achieved moderate success. In animal models, immunization with G glycoprotein has led to largely genotype specific immunity. This suggests the hypothesis that anti-G antibodies to the infecting virus genotype, either acquired transplacentally or induced by immunisation, may contribute to protection of the infant in the early months of life. The aim of this study has been to test this hypothesis by measuring levels of maternally acquired antibody to the G glycoprotein of the infecting virus genotype in an index group of infants with severe HRSV infection and, to the same genotype, in a comparison group of infants with no history of HRSV infection. As only 2% of infants suffer severe disease on primary HRSV infection, the comparison group are assumed to be destined to be resistant to severe infection. A deficiency of anti-G antibodies in the index group will thus indicate a protective role for these antibodies. A phylogenetic study was carried out in Newcastle upon Tyne from autumn 2007 to spring 2010 revealing three circulating genotypes of HRSV, namely GA2, GA5 and BA4 although GA5 was not detected in the third epidemic. The G genes of GA2 and BA4 and the F gene of GA2 were cloned and expressed individually in modified vaccinia Ankara virus. The recombinant proteins were used in the development of a concanavalinA capture ELISA sufficiently sensitive to detect maternal antibodies in the acute sera of infants under 6 months of age. An attempt was made to refine the assay in order to separately detect antibodies to the conserved and variable epitopes of the G glycoprotein. However, mapping of conserved and variable epitopes revealed overlap epitopes precluding the development of a differentiation in a simple ELISA assay. An index group of infants with severe HRSV infection and a comparison group of infants of similar age with no history of HRSV infection were recruited with consent by their legal carer during the epidemic of 2009/2010. The infecting virus lineage of each infant in the index group, either GA2 or BA4, was identified by reverse transciptasepolymerase chain reaction of virus recovered from nasal secretions. Sera were collected from both groups, at the acute stage of infection for the index group, and screened for ii HRSV specific IgA by ELISA. Only those without detectable IgA were included in the study. IgG maternal antibodies to the recombinant G glycoprotein of the infecting virus genotype and the F glycoprotein of the GA2 genotype were measured in the sera of index and comparison group infants whilst maternal antibody levels to both F and G glycoproteins in the sera of both index and control sera decayed at similar rates with age, the index group possessed significantly more anti-G and anti-F antibody at all ages suggesting that infants hospitalized with severe HRSV infection were not deficient in antibodies to either glycoprotein contrary to the hypothesis under test. However, mean maternal antibody levels at birth have been shown to fall across the winter epidemic and the above analysis may be susceptible to bias introduced by uneven sampling of infants across the epidemic. To avoid this potential error, anti-F/anti-G antibody ratios, which give a measure of anti-G immunity independent of age and time of collection, were also compared in the sera of index and comparison group infants. Mean ratios were not significantly different between the two groups also rejecting the hypothesis that severely affected infants have a deficiency in maternal anti-G antibodies. These studies, therefore, fail to establish a role for anti-G glycoprotein antibodies in the protection of infants against severe lower respiratory tract disease.

Neonatal bronchial responsiveness (BR) predicts childhood asthma and decreased lung function. Examination of neonatal BR, on a larger scale than has previously been possible, would enable investigation of prenatal lung development to BR, in order to examine the relationship between foetal environment and airway function, the genetic epidemiology of BR, the role of BR in airway disease and postnatal lung development, and the classification of airway disease into phenotypes in infancy.;The aim of this project was to develop a test of bronchial responsiveness suitable for use in unsedated infants in a domiciliary setting, as a prelude to population studies. Current techniques involve prolonged procedures, carried out under sedation in a laboratory setting.;Resistance by interruption (Rint) has been comprehensively evaluated in infants in the course of this work. Feasibility has been demonstrated in unsedated infants and the entire process of obtaining data from initial approach to parents to laboratory success rates examined. For the first time, Rint measurements have been obtained in unsedated infants in the community. Preliminary reference values have been generated.;Rint and another technique applicable in unsedated infants, the high speed interrupter technique (HIT) were compared with the rapid thoracoabdominal compression (RTC) method in the context of a bronchial challenge test with doses of 0.9%, 2% and 4% saline. Following saline challenge, complex changes in HIT were found, which discount it as a suitable test for bronchial challenge, but have added to theories of the physiology of infant wheezing.;Large decreases in Rint were demonstrated after saline challenge, which may be explained by the dynamic nature of infant breathing patterns, which were also examined.;In summary, both techniques (HIT and Rint), originally proposed for use in assessment of BR in unsedated infants have been excluded from use in this context, and their use lies elsewhere.

Bronchopulmonary dysplasia (BPD) is the most common form of chronic lung disease in infancy and a major complication in mechanically ventilated premature babies. It has a mortality of up to 40% and develops in 20% of premature infants born weighing under 1500g. With increased survival of extremely premature infants, the incidence of BPD will remain high. Although those who survive are considered 'miracles' of medical technology, current evidence suggests they suffer significant health problems throughout childhood and adolescence. However, almost nothing is known about those reaching adulthood. This was a cross-sectional study of adult survivors of BPD (n=72) cared for in the Neonatal Intensive Care Unit, Royal Maternity Hospital, Belfast (January 1979 to April 1993). Two reference groups cared for in the same hospital were also included; adults born preterm who did not develop BPD (n=58) and adults born at term with normal birth weights (n=78). Results show that BPD adults were significantly more likely to report respiratory symptoms (wheeze and shortness of breath), use asthma medication and have pulmonary impairment, particularly, reduced FEV1 and mid-expiratory flow rates (FEF2S•7S ) compared with both the non-BPD and term controls. Significantly more BPD adults had deficits in executive functioning related to problem solving and organisation of their environment. Adult survivors of BPD utilise more health and ~ .... social care services, report significantly reduced HRQol and greater social dysfunction compared with controls. The studies described in this thesis suggest significant health impairment associated with BPD exists beyond the neonatal period and into adulthood and is not confined to the respiratory system. The longitudinal follow up of larger cohorts of these infants throughout adulthood is required in order to improve understanding and raise awareness of long term health sequelae and identify more effective treatment strategies.

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