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Objective: To determine the quality of life in individuals with corrected tetralogy of Fallot. Methods and subjects: Questionnaires concerning quality of life were sent to all 87 surviving patients aged between 16 and 40 years who had undergone intracardiac repair of tetralogy of Fallot and follow-up in the Wessex Cardiothoracic Unit, and to 87 age and sex matched controls, with medically treated haemodynamically insignificant ventricular septal defects. Results: The only significant difference found between the cases and controls was in requirements for schooling, where those with tetralogy of Fallot were more likely to require additional educational help at school (p = 0.044). For all other aspects of quality of life examined by the questionnaire, including social and genetic history, exercise ability, and health related quality of life, no significant differences were found. Different operative techniques, such as transjunctional patching, right ventriculotomy, and previous palliative shunting, did not affect the quality of life of our population with Tetralogy of Fallot, on average twenty years after their surgery, although the range of operative techniques was limited. Neither age at surgery, nor time since surgery, was correlated with measurements of quality of life. Conclusions: Those who have undergone surgical correction of tetralogy of Fallot have a normal quality of life, with few differences compared to controls.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Non-typeable Haemophilus influenzae (NTHi) is the most common pathogen in primary ciliary dyskinesia (PCD) patients. We hypothesised that abnormal ciliary motility and low airway nitric oxide (NO) levels on airway epithelial cells from PCD patients might be permissive for NTHi colonisation and biofilm development. We used a primary epithelial cell co-culture model to investigate NTHi infection. Primary airway epithelial cells from PCD and non-PCD patients were differentiated to ciliation using an air–liquid interface culture and then co-cultured with NTHi. NTHi adherence was greater on PCD epithelial cells compared to non-PCD cells ( p

1article. The study was approved by the Southampton and South West Hampshire Research Ethics Committee (06/Q1702/109). Airway epithelium from patients with PCD and control patients without PCD was obtained by nasal brushing and was cultured at the air-liquid interface until differentiated and ciliated. We quantifi ed the presence of NO using a total NO detection assay (Enzo Life Sciences, Inc) within phosphate-buffered saline washes applied to the apical surface of air-liquid interface cultures. NO levels were measured before and after epithelial cells were apically cocultured for 72 h with NTHi at a multiplicity of infection of 100 to evaluate biofi lm infection. Cell viability was demonstrated by daily stable transepithelial electrical resistance (PCD and non-PCD) and ciliary beat frequency measurements (control subjects without PCD). We also measured levels following an 18-h incubation with a cocktail of proinflammatory cytokines (10 ng/mL each of IL-1 b /interferon- g /tumor necrosis factor- a ) applied basolaterally to the cells (n 5 14 for each experiment). Our baseline data were consistent with that of Smith et al, 1

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary function, leading to compromised airway clearance and chronic bacterial infection of the upper and lower airways. The compositions of these infections and the relationships between their characteristics and disease presentation are poorly defined. We describe here the first systematic culture-independent evaluation of lower airway bacteriology in PCD. Thirty-three airway samples (26 from sputum, 7 from bronchoalveolar lavage [BAL] fluid) were collected from 24 PCD patients aged 4 to 73 years. 16S rRNA quantitative PCR and pyrosequencing were used to determine the bacterial loads and community compositions of the samples. Bacterial loads, which ranged from 1.3 × 10 4 to 5.2 × 10 9 CFU/ml, were positively correlated with age ( P = 0.002) but not lung function. An analysis of ∼7,000 16S rRNA sequences per sample identified bacterial species belonging to 128 genera. The concurrently collected paired samples showed high bacterial community similarity. The mean relative abundance of the dominant genera was 64.5% (standard deviation [SD], 24.5), including taxa reported through standard diagnostic microbiology (members of the genera Pseudomonas , Haemophilus , and Streptococcus ) and those requiring specific ex vivo growth conditions (members of the genera Prevotella and Porphyromonas ). The significant correlations observed included a positive relationship between Pseudomonas aeruginosa relative abundance and age and a negative relationship between P. aeruginosa relative abundance and lung function. Members of the genus Ralstonia were also found to contribute substantially to the bacterial communities in a number of patients. Follow-up samples from a subset of patients revealed high levels of bacterial community temporal stability. The detailed microbiological characterization presented here provides a basis for the reassessment of the clinical management of PCD airway infections.

Background Nasal nitric oxide (nNO) levels are very low in primary ciliary dyskinesia (PCD) and it is used as a screening test. Methods We assessed the reliability and usability of a hand-held analyser in comparison to a stationary nitric oxide (NO) analyser in 50 participants (15 healthy, 13 PCD, 22 other respiratory diseases; age 6–79 years). Nasal NO was measured using a stationary NO analyser during a breath-holding maneuver, and using a hand-held analyser during tidal breathing, sampling at 2 ml/sec or 5 ml/sec. The three methods were compared for their specificity and sensitivity as a screen for PCD, their success rate in different age groups, within subject repeatability and acceptability. Correlation between methods was assessed. Results Valid nNO measurements were obtained in 94% of participants using the stationary analyser, 96% using the hand-held analyser at 5 ml/sec and 76% at 2 ml/sec. The hand-held device at 5 ml/sec had excellent sensitivity and specificity as a screening test for PCD during tidal breathing (cut-off of 30 nL/min,100% sensitivity, >95% specificity). The cut-off using the stationary analyser during breath-hold was 38 nL/min (100% sensitivity, 95% specificity). The stationary and hand-held analyser (5 ml/sec) showed reasonable within-subject repeatability(% coefficient of variation = 15). Conclusion The hand-held NO analyser provides a promising screening tool for PCD.

Nitric oxide is continually synthesized in the respiratory epithelium and is upregulated in response to infection or inflammation. Primary ciliary dyskinesia is characterized by recurrent sinopulmonary infections due to impaired mucociliary clearance. Despite chronic infections, nasal nitric oxide in such patients is markedly reduced and is used as a screening test for this condition. These low levels were first described over 15 years ago but the underlying mechanisms have yet to be fully elucidated. We review epithelial nitric oxide synthesis, release and measurement in the upper airways with particular reference to primary ciliary dyskinesia. The key hypotheses that have been proposed to explain the low levels in this condition are explored and the potential benefits of augmenting airway nitric oxide levels are considered. Further work in these patients clarifying both whether the respiratory epithelium is able to biosynthesise normal levels of nitric oxide and the role played by abnormalities in the anatomy of the paranasal sinuses is essential. While nitric oxide augmentation is unlikely to be beneficial in common primary ciliary dyskinesia phenotypes, it has potential in the treatment of secondary dyskinesias and may also improve treatment of bacterial infections, particularly where biofilms are implicated.

Introduction: Pandemic influenza A H1N1 infections occurred worldwide from 2009. Children were particularly vulnerable. Novel vaccines were used during the pandemic. Objective: To assess the persistence of antibody to H1N1 influenza 1 year after children aged 6 months to 12 years had been immunised with two doses of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03 B-adjuvanted split-virion H1N1 influenza vaccine; and also to assess the immunogenicity and reactogenicity in this population of a single dose of 2010-11 trivalent seasonal influenza vaccine. Design: Multicentre, open-label, follow-on from randomised, head-to-head trial. Setting: Five UK sites (Southampton, Oxford, Bristol, London and Exeter). Participants: Children who completed last year's head-to-head randomised study were invited to participate. Children who had subsequently received a further dose of H1N1 vaccine, or who had already received a dose of 2010-11 trivalent seasonal influenza vaccine, were excluded. Interventions: In the previous study, children were randomised (in a 1: 1 ratio) to receive two doses, 21 days apart, of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03 B-adjuvanted split-virion H1N1 influenza vaccine. In this follow-on study, a blood sample was taken to assess the persistence of antibody 1 year later, followed by administration of one 0.5 ml-dose of trivalent seasonal influenza vaccine. A second blood sample was taken 3 weeks later. Main outcome measures: Comparison between vaccines of the percentage of participants with a microneutralisation (MN) titre ≥ 1: 40 and a haemagglutination titre ≥ 1: 32, 1 year after vaccination. Immunogenicity of the trivalent seasonal influenza vaccine was assessed 3 weeks after vaccination by both the MN and the haemagglutination inhibition (HI) titres. Reactogenicity data were recorded for 7 days after vaccination. Results: A total of 323 children were enrolled and 318 were included in the analysis of the persistence of antibody. One year after receipt of whole-virion vaccine, the MN titre was ≥ 1: 40 in 32.4% of those vaccinated when < 3 years old and in 65.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1: 32 in 63.2% and 79.1% of children in the respective age groups. One year after receipt of the adjuvanted vaccine, the MN titre was ≥ 1: 40 in 100% of those vaccinated when < 3 years old and in 96.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1: 32 in 98.4% and 96.9% of children in the respective age groups. Three hundred and two children were given trivalent seasonal influenza vaccination. Three weeks later, sera were obtained from 282 children; 100% had an MN titre ≥ 1: 40 and HI titre ≥ 1: 32. Trivalent seasonal influenza vaccine was well tolerated, although in children < 5 years old, fever ≥ 38 °C was reported in 13.6% of those who had previously received whole-virion vaccine, and in 18.3% of those who had received adjuvanted vaccine. Conclusions: Nearly all children who received two doses of AS03 B-adjuvanted split-virion pandemic H1N1 influenza vaccine had titres of antibody deemed protective (HI titre ≥ 1: 32, MN titre ≥ 1: 40) 1 year later. Children who received two doses of whole-virion vaccine had lower titres, although many were above the putative protective thresholds. One year after either pandemic vaccine, the 2010-11 trivalent seasonal influenza vaccine produced a marked serological response to the H1N1 component of the vaccine and was well tolerated. We propose to investigate whether or not previous receipt of monovalent influenza vaccines affected serological response to the H3N2 and B components of the 2010-11 seasonal influenza vaccine, using stored sera. Trial registration: ClinicalTrials.gov NCT01239537. Funding: The National Institute for Health Research Health Technology Assessment programme. © Queen's Printer and Controller of HMSO 2011.

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease with an incidence estimated between 1:2,000 and 1:40,000. Ciliated epithelia line the airways, nasal and sinus cavities, Eustachian tube and fallopian tubes. Congenital abnormalities of ciliary structure and function impair mucociliary clearance. As a consequence, patients present with chronic sinopulmonary infections, recurrent glue ear and female subfertility. Similarities in the ultrastructure of respiratory cilia, nodal cilia and sperm result in patients with PCD also presenting with male infertility, abnormalities of left-right asymmetry (most commonly situs inversus totalis) and congenital heart disease. Early diagnosis is essential to ensure specialist management of the respiratory and otological complications of PCD. Diagnostic tests focus on analysis of ciliary function and electron microscopy structure. Analysis is technically difficult and labour intensive. It requires expertise for interpretation, restricting diagnosis to specialist centres. Management is currently based on the consensus of experts, and there is a pressing need for randomised clinical trials to inform treatment.

In 2009, 943 children aged 6 months to 10 years were randomised to receive two doses of an oil-in water AS03B-adjuvanted split virion or a non-adjuvanted whole virion H1N1 (2009) vaccine. The large numbers allowed investigation of possible predictors of immune response and reactogenicity. We used regression analysis to examine the effect of variables including past receipt of seasonal vaccine, antipyretics post-vaccination, interval between doses and pre-existing antibodies to H1N1 (2009) on immunogenicity. We also examined the relationship between immunogenicity and reactogenicity and whether prior infection or underlying conditions affected reactogenicity. For both vaccines, haemagglutination-inhibition titres were 60% higher in children with fever ≥38. °C after vaccination and 29% lower in those previously given seasonal vaccine. Early use of antipyretics did not affect immunogenicity. Post-vaccination titres were higher with longer intervals between doses and in those with evidence of prior infection, but reactogenicity in the latter was unaffected. In the adjuvanted vaccine group, reactions were more common in children with atopy. Both vaccines were safe and immunogenic in those with prior infection. Reduction in the interval between doses for earlier protection would be at the cost of reduced immunogenicity. The effect of seasonal vaccine on immunogenicity merits further investigation. © 2011 Elsevier Ltd.

The first cases of pandemic influenza A (H1N1) 2009 infection were seen in Mexico in March 2009. Since then, it is thought to have been responsible for at least 18,337 deaths globally. Owing to the young age of fatalities, there have been an estimated 2 million years of life lost, which is comparable to the previous pandemics of 1957 and 1968. In this article, we consider the available data on a monovalent inactivated split-virion AS03-adjuvanted pandemic influenza A (H1N1) vaccine, Pandemrix™ (GlaxoSmithKline, Rixensart, Belgium). At present, Pandemrix appears to be highly immunogenic in all age groups, including children and infants under 3 years of age, with an acceptable safety profile in the context of an influenza pandemic. However, owing to the novel adjuvant, further studies on the safety, immunogenicity and vaccine effectiveness of Pandemrix together with robust post-marketing surveillance are required.

Background: Children are a priority for vaccination in an influenza pandemic, but safety and immunogenicity data for new-generation adjuvanted and whole-virion vaccines are limited. Objectives: Immunogenicity •How does the percentage of children aged 6 months to 12 years of age with a fourfold rise in microneutralisation titres between the prevaccination sample and the sample taken 3 weeks after completion of a two-dose course of the non-adjuvanted, whole-virion vaccine and the AS03B-adjuvanted split-virion vaccine compare? •How does the percentage of children aged 6 months to 12 years of age with haemagglutination inhibition titres of ? 1 : 32 3 weeks after completion of a two-dose course of the non-adjuvanted, whole-virion vaccine and the AS03B-adjuvanted split-virion vaccine compare? •How does the percentage of children aged 6 months to 12 years of age with a fourfold rise in haemagglutination inhibition titres between the prevaccination sample and the sample taken 3 weeks after completion of a two-dose course of the non-adjuvanted, whole-virion vaccine and the AS03B-adjuvanted split-virion vaccine compare? •What is the geometric mean fold rise in haemagglutination inhibition titres from baseline to 3 weeks after two doses of the non-adjuvanted, whole-virion vaccine and the AS03B-adjuvanted split-virion vaccine? •What is the geometric mean haemagglutination inhibition titre 3 weeks after two doses of the non-adjuvanted, whole-virion vaccine and the AS03B-adjuvanted split-virion vaccine? Reactogenicity •How does the percentage of children aged 6 months to 12 years of age experiencing fever and local reactions within the 7 days following each dose of the non-adjuvanted, whole-virion and the AS03B-adjuvanted split-virion vaccines compare? •What percentage of children aged 6 months to 12 years of age experience non-febrile systemic reactions within the 7 days following each dose of the non-adjuvanted, whole-virion and the AS03B-adjuvanted split-virion vaccine? Methods: The safety, reactogenicity and immunogenicity of a tocopherol/oil-in-water emulsion-adjuvanted (AS03B) egg culture-derived split-virion H1N1 vaccine and a non-adjuvanted cell culture-derived whole-virion vaccine, given as a two-dose schedule, 21 days apart, were compared in a randomised, open-label trial of children aged 6 months to 12 years of age. Local reactions and systemic symptoms were collected for 1 week post immunisation, and serum was collected at baseline and after the second dose. Results: Among 937 children receiving vaccine, per-protocol seroconversion rates were higher after the AS03B-adjuvanted vaccine than after the whole-virion vaccine (98.2% vs 80.1% in children 38.0°C in those under 5 years of age (8.9% vs 22.4%). Conclusion: In this first direct comparison of an AS03B-adjuvanted split-virion vaccine versus whole-virion non-adjuvanted H1N1 vaccine, the adjuvanted vaccine – while reactogenic – was more immunogenic, especially in younger children, indicating the potential for improved immunogenicity of influenza vaccines in this age group.

OBJECTIVES: To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom. DESIGN: Open label, randomised, parallel group, phase II study. SETTING: Five UK centres (Oxford, Southampton, Bristol, Exeter, and London). PARTICIPANTS: Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible. Those with laboratory confirmed pandemic H1N1 influenza or clinically diagnosed disease meriting antiviral treatment, allergy to egg or any other vaccine components, or coagulation defects, or who were severely immunocompromised or had recently received blood products were excluded. Children were grouped by age: 6 months-or=1:40 from before vaccination to three weeks after the second dose). RESULTS: Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine, most notably in the youngest children (163 of 166 participants with paired serum samples (98.2%, 95% confidence interval 94.8% to 99.6%) v 157 of 196 (80.1%, 73.8% to 85.5%), Por=38 masculineC in those aged under 5 (24 (8.9%, 5.8% to 12.9%) v 57 (22.4%, 17.5% to 28.1%), P

Summary Background Patients with primary ciliary dyskinesia (PCD) have abnormal ciliary function and low nitric oxide levels. Nitric oxide (NO) biosynthesis is dependent on nitric oxide synthases (NOS). Cilia line the bronchial but not the alveolar epithelium. It has been hypothesised that NOS function relies on normal ciliary function and that in PCD bronchial but not alveolar NO might therefore be reduced. The aim of this study was to assess bronchial and alveolar NO levels primarily comparing healthy children to PCD and secondarily to cystic fibrosis (CF) and asthmatic children. Methods Multiple flow-rate fractional exhaled and nasal NO measurements were performed using a NIOX ® Flex NO analyser (Aerocrine, Sweden) in children with PCD ( n = 14), asthma ( n = 18), CF ( n = 12) and healthy controls ( n = 18). Alveolar and bronchial NO levels were derived using a model of pulmonary NO exchange-dynamics. Results Both the bronchial and alveolar NO were significantly lower in PCD than healthy controls (mean (SD) 264 (209) picolitres/second (pl/s) vs. 720 (514) pl/s, p = 0.024 and 1.7 (0.8) parts per billion (ppb) vs. 3.5 (1.3) ppb, p = 0.001 respectively.) In asthmatics bronchial NO was found to be significantly higher than in healthy controls and in children with CF alveolar NO was significantly lower (2100 (1935) pl/s, p = 0.045 and 2.5 (1.2) ppb, p = 0.034 respectively.) Conclusion Our findings do not support the hypothesis that NOS and ciliary function are coupled instead suggesting a more generalised mechanism for the low levels of NO seen in PCD. Our findings in CF and asthma corroborate evidence that these are diseases of the lung peripheries and bronchi respectively.

Background Patients with primary ciliary dyskinesia (PCD) have abnormal ciliary function and low nasal nitric oxide (nNO) and fractional exhaled NO (FeNO). Nitric oxide (NO) biosynthesis is dependent on nitric oxide synthases (NOS). Cilia line the bronchial but not the alveolar epithelium. It has been hypothesised that NOS function relies on normal ciliary function and that in PCD bronchial (JNO) but not alveolar (CalvNO) NO might therefore be reduced. The aim of this study was to compare JNO and CalvNO in children with PCD, cystic fibrosis (CF), asthma and healthy subjects.