BACKGROUND:As a part of the Irish Comparative Outcome national cohort study of childhood CF, this cross-sectional study investigated challenges faced by parents of children with CF (CWCF) in the Republic of Ireland using a newly validated modified tool. METHODS:Parents completed the modified "Challenge of Living with Cystic Fibrosis-Short Form" (CLCF-SF), developed to determine caregiver burden for parents of CWCF, with limited items (N = 15) to complete. Linear regression examined associations between CLCF-SF scores and demographic and clinical factors. RESULTS:263 of 357 (73.6%) responded. Parents reported marginal to great difficulty in balancing daily lives and CF care (31%), managing extra expenses (46.8%), and establishing care routines (76.5%). Parents felt supported by medical teams. Parents of younger children reported more difficulties juggling CF demands with family needs (39.3% vs 25.0%), a more stressful family lifestyle (51.4% vs 39.1%). A greater proportion of parents of older CWCF (48.1% vs 28%) and of CWCF on CFTR modulator therapy (45% vs 27%) reported moodiness. Cronbach's α was 0.87, indicating very good internal consistency. CONCLUSION:This was the first use of the modified CLCF-SF in a population setting. High response rates indicate ease of completion. This study provides an assessment of internal consistency, usability, and performance of the modified version of the new tool; the need for age-adequate financial and psychological support is highlighted.

Chest computed tomography (CT) surpasses chest radiography (CR) in accurately assessing disease severity and detecting early structural pulmonary changes in patients with cystic fibrosis (CF). Chest CT provides detailed visualisation and quantification of CF-specific lung pathologies and can reveal these changes before they manifest clinically or become detectable on CR. The past decade has witnessed the advent and refinement of radiation-reducing techniques in CT which have enabled substantial dose reductions. Our study prospectively evaluates the efficacy of ultra-low dose CT (ULDCT) chest in identifying pulmonary changes within a paediatric patient cohort. Paediatric patients with CF, who presented for routine clinical outpatient follow-up between 01/07/2022, and 01/07/2023 underwent ULDCT and CR (if not recently performed) and image analysis was performed. Radiation dose, subjective and objective image quality and disease severity were recorded. 45 patients (mean age 10.5 years) underwent clinically indicated ULDCT chest ± CR. The mean effective dose was of ULDCT was 0.07 ± 0.01 mSv, a dose that approximates that of a frontal and lateral chest radiograph. The average ULDCT Brody II severity score across the entire cohort was 5.62, with excellent inter-rater reliability and intra-class correlation coefficient (ICC) of 0.98 (95% CI = 0.96, 0.99). The average Chrispin-Norman score on chest radiograph was 0.93 with moderate inter-rater reliability and ICC of 0.64 (95% CI = 0.19, 0.83). In light of its superior diagnostic capabilities, minimal radiation dose penalty, we advocate for ULDCT to be the preferred modality for surveillance imaging in paediatric patients with CF.

Background: Treatment with Ivacaftor provides a significant clinical benefit in people with cystic fibrosis (PWCF) with the class III G551D-CFTR mutation. This study determined the effect of CFTR modulation with ivacaftor on the lung microbiota in PWCF. Methods: Using both extended-culture and culture-independent molecular methods, we analysed the lower airway microbiota of 14 PWCF, prior to commencing ivacaftor treatment and at the last available visit within the following year. We determined total bacterial and Pseudomonas aeruginosa densities by both culture and qPCR, assessed ecological parameters and community structure and compared these with biomarkers of inflammation and clinical outcomes. Results: Significant improvement in FEV1, BMI, sweat chloride and levels of circulating inflammatory biomarkers were observed POST-ivacaftor treatment. Extended-culture demonstrated a higher density of strict anaerobic bacteria (p = 0.024), richness (p = 1.59* 10(-4)) and diversity (p = 0.003) POST-treatment. No significant difference in fold change was observed by qPCR for either total bacterial 16S rRNA copy number or P. aeruginosa density for oprL copy number with treatment. Culture-independent (MiSeq) analysis revealed a significant increase in richness (p = 0.03) and a trend towards increased diversity (p = 0.07). Moreover, improvement in lung function, richness and diversity displayed an inverse correlation with the main markers of inflammation (p < 0.05). Conclusions: Following treatment with ivacaftor, significant improvements in clinical parameters were seen. Despite modest changes in overall microbial community composition, there was a shift towards a bacterial ecology associated with less severe CF lung disease. Furthermore, a significant correlation was observed between richness and diversity and levels of circulating inflammatory markers. (C) 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

The introduction of NBS in Ireland in July 2011, provided a unique opportunity to investigate clinical outcomes using a comparative historical cohort study. Clinical cohort: children clinically diagnosed with CF born 7 January 2008 to 30 June 2011, and NBS cohort: children diagnosed with CF through NBS born 7 January 2008 to 30 June 2011. Clinical data were collected from the CF Registry of Ireland, medical charts, and data on weight/height before diagnosis from public health nurses and family doctors. SPSS was used for analysis. A total of 232 patients were recruited (response 93%) (93 clinically diagnosed, 139 NBS-detected). Following exclusions of meconium ileus (MI) (40), diagnosis outside Ireland (4), and being designated as CFSPID (2), a total of 77 clinically diagnosed patients and 109 NBS detected children were included in analysis. Over half were homozygous for F508del mutation. Being clinically diagnosed was independently associated with hospitalization for infective exacerbation of CF < 36 months (OR, 2.80; 95%CI 1.24-6.29). Diagnosis to first acquisition ofPseudomonas aeruginosawas significantly longer in NBS than clinically detected; from birth there was no significant difference. Weight and length/height were significantly greater in NBS cohort at 6 and 12 months. We provide evidence of improved growth, reduced hospitalization for acute exacerbations, and delayedP. aeruginosaacquisition (from diagnosis) to age 3 for the NBS cohort. Screening practices likely account for the non-significant difference inP. aeruginosaacquisition from birth.

Background A previous national audit looking at sweat testing in all age groups in 2011 found Cork University Hospital (CUH) had a high number of tests with quantity not sufficient (QNS) result. Since then there has been new equipment and staff training. International laboratory audit criteria examine failure rates for under 6 months which has recently been <1% in CUH (acceptable<5%). However higher failure rates (0–40%) for sweat testing have been noted internationally in newborn screening programmes, a more difficult cohort to successfully sweat test. Aims Sweat tests performed in CUH from 2011–2018 as part of newborn screening in relation to number of patients with positive (>60), negative (<30), equivocal and QNS results were reviewed. The gestational age at birth and at time of testing and birth weight were examined as potential variables. Methods Ethical approval obtained Newborn screening records for all patients from July 2011 to December 2018 reviewed. Sweat testing data obtained from laboratory. Data analysed using SPSS and Chi-Square test. Results 102 infants referred to Cork for sweat testing as part of newborn screening. Patients diagnosed by meconium ileus (n=7), had sweat testing elsewhere (n=1) or had antenatal diagnosis (n=2) were not included (N= 10). On initial testing 30 patients had a QNS result (32.6%). 7 had same day repeat testing which was sufficient, the remaining having sweat testing at a later date. Ultimately there were 23 with positive tests, 67 with negative tests, 2 equivocal tests. Gestational age and birth weight of the 30 patients with initial QNS result were compared to the 62 with successful testing. Infants were divided into two groups based on gestation, 38 weeks and below and 39 weeks and above. Results were dichotomised into sufficient and insufficient (QNS) results. The Chi square test indicated that there is a statistically significant association between gestational age and sufficient or insufficient result. (p=0.004) Discussion It would be helpful to compare our data to the same cohort in other centres and national rate to see if this is an acceptable QNS rate and obtain further data regarding gestational age. Collection techniques and laboratory analysis have already been optimised with current equipment and staff. Consideration could be given to delay offering sweat test by one to two weeks to those born at 37 and 38 weeks gestation in infants who only have 1 mutation. This may reduce need for time consuming and stressful repeat testing.

Introduction Orkambi (Lumacaftor/Ivacaftor) was first introduced for use in the Cystic Fibrosis population in Ireland in 2017. It is only licensed for those patients who are homozygous for the F508del gene mutation.Orkambi was originally approved for children aged 12 years and older in 2017 and then this was extended for those aged 6–11 years old in 2018. Recently, the EMA(European Medicines Agency) has approved use for children 2–5 years. CUH(Cork University Hospital) looks after 98 paediatric patients with CF of whom 37 have been commenced on Orkambi since July 2017. Objectives The primary objective was to assess the outcomes of Orkambi at 6 and 12 months on FEV1, BMI and BMI Centile and to compare the days on Intravenous antibiotics and weeks of oral antibiotics for pulmonary exacerbations in the year before and after commencing Orkambi. Results Thirty seven patients were included in the study population with a split of 21 females and 16 males. The average profile of our patient cohort before commencing Orkambi was 11.0 years, BMI 16.8 kg/m2, BMI Centile 43.2 and Average FEV1 96.7%. To date, 11 patients have completed over a year of treatment and the remainder will have completed 12 months by June 2019. Six month followup has shown that 30/37(81%) of patients have had an increase in their BMI with an average BMI at 6 months of 17.5 and BMI difference of +0.7 kg/m2. BMI centile was increased in 24/37(65%) with centile difference of +5.7 to an average of 48.9. Lung function did not show any improvement from Pre-Orkambi values with average FEV1 of 95.9% at 6 months. This was also shown in followup of patients who completed 12 months of treatment with average FEV1 difference of -2%. For those who had completed 12 months on Orkambi, the no of weeks on oral antibiotics and IV antibiotics both showed a reduction in the year following commencement. There was a 26% decrease in oral antibiotics prescribed with average reduction of 1.5 weeks. Three patients had required IV antibiotics in the year prior. Two of these had no IVs over the following year and one patient with severe CF disease had a 55% reduction in days on IVs from 121 to 66 days. Conclusion Orkambi has improved BMI/BMI centiles but has not shown any improvement in FEV1. Preliminary data has shown a reduction in pulmonary exacerbations although further analysis of the remaining patients will allow more accurate conclusions.

Objectives To examine the effects of Ivacaftor on growth and pancreatic function in patients attending the Paediatric Cystic fibrosis (CF) Centre at Cork University Hospital. Methods A retrospective, convenience sampled cohort analysis was conducted in patients aged 2 to 17 with genetically confirmed CF (N=28, 15 male, 13 female). Subjects who received Ivacaftor over a 1 year period had an oral dose of either 75 or 150 mg twice daily depending on weight. Patients were excluded if concurrently taking Lumacaftor. The primary end points were estimated mean change from baseline through one year in pancrealipase (Creon) consumption per day and body mass index (BMI). Secondary end points included the changes in mean percent of predicted forced expiratory volume in 1 second (FEV1) as well as exocrine pancreatic marker faecal elastase-1 (FE-1) and random blood glucose within the Ivacaftor group. Results The change in pancrealipase use was significantly decreased in the Ivacaftor group in comparison to controls (1202± 587 IU/kg, p=0.039). In addition, Ivacaftor users had a significant increase in gross BMI (0.98± 0.51 kg/m2, p=0.010) and a non-significant increase in FEV1% predicted (10.9± 5.06%, p=0.123) in comparison to controls. On subgroup analysis, there was significant improvement in FE-1 after one year of Ivacaftor use (107± 80.8μg/g, p= 0.013, N=7). As well, there was mild decrease seen in random blood glucose, however this result was not significant (-0.43± 0.87 mmol/L, p=0.153, N=10). Conclusions Ivacaftor improves paediatric CF patients' BMI, blood glucose, and FE-1 values while reducing their reliance on pancrealipase. This data supports previous research showing increasing lung function in Ivacaftor users. Subgroup analysis of those with serial FE-1 results revealed that 43% of those taking Ivacaftor reached pancreatic exocrine sufficiency (FE-1> 200μg/g). This implies that further study of Ivacaftor's pancreatic implications is warranted. Similarly, prospective studies of new and emerging drugs of this class in a similar manner could yield positive results for patients.

BACKGROUND: Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact of cystic fibrosis transmembrane conductance regulator modulation on multiple modalities of patient assessment. METHODS: Thirty-three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra-low-dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed. RESULTS: Significant improvements in FEV1, BMI, and sweat chloride levels were observed post-ivacaftor treatment. Improvement in ultra-low-dose CT imaging scores were observed after treatment, with significant mean reductions in total Bhalla score (P < .01), peribronchial thickening (P = .035), and extent of mucous plugging (P < .001). Reductions in circulating inflammatory markers, including interleukin (IL)-I beta, IL-6, and IL-8 were demonstrated. There was a 30% reduction in the relative abundance of Pseudomonas species and an increase in the relative abundance of bacteria associated with more stable community structures. Post-treatment community richness increased significantly (P = .03). CONCLUSIONS: Early and sustained improvements on ultra-low-dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota.

Rationale: Patient registries have the potential to collect and analyze high-quality postauthorization data on new medicines. Objectives: We used cystic fibrosis (CF) registry data to assess outcomes after the initiation of ivacaftor, a CF transmembrane conductance regulator (CFTR) potentiator approved for the treatment of CF with a defective gating CFTR mutation. Methods: Longitudinal trends were examined using mixed-effects regression analysis in 80 ivacaftor-treated patients with CF aged 6 to 56 years registered with the CF Registry of Ireland with at least 36 months of before and after commencement data. The effects of ivacaftor treatment on forced expiratory volume in 1 second (FEV I ) % predicted, body mass index (BMI), hospitalization for pulmonary exacerbation, and oral and intravenous antibiotic use were assessed. Results: In the 36 months after ivacaftor initiation, FEV1 % predicted improved by 2.26% per annum (95% confidence interval [CI], 0.2 to 4.3) for patients aged younger than 12 years, remained unchanged for 12- to younger than 18-year-olds (95% CI, -1.9 to 2.9), and declined in adults by 1.74% per annum (95% CI, -3.1 to -0.4). BMI in adults increased 0.28 kg/m(2) per annum (95% CI, 0.03 to 0.5), and there was no significant change in BMI z-score in children (95% CI, -0.01 to 0.1). In the year after ivacaftor initiation, intravenous antibiotic treatment reduced by 46% (95% CI, -62.5% to -23.3%, oral antibiotic treatment reduced by 49% (95% CI, -61.1% to -32.1%), and there was no significant reduction in hospitalization (95% CI, -59.2% to 9.7%). Conclusions: In this study of real-world CF registry data, clinical outcomes improved and healthcare resource utilization decreased after commencing ivacaftor.

Background Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact of cystic fibrosis transmembrane conductance regulator modulation on multiple modalities of patient assessment. Methods Thirty-three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra-low-dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed. Results Significant improvements in FEV1, BMI, and sweat chloride levels were observed post-ivacaftor treatment. Improvement in ultra-low-dose CT imaging scores were observed after treatment, with significant mean reductions in total Bhalla score (P < .01), peribronchial thickening (P = .035), and extent of mucous plugging (P < .001). Reductions in circulating inflammatory markers, including interleukin (IL)-1β, IL-6, and IL-8 were demonstrated. There was a 30% reduction in the relative abundance of Pseudomonas species and an increase in the relative abundance of bacteria associated with more stable community structures. Posttreatment community richness increased significantly (P = .03). Conclusions Early and sustained improvements on ultra-low-dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota.

The long-term use and respiratory benefits (as shown by an increase in FEV1 and reduction in pulmonary exacerbations) of ivacaftor in patients aged 6 years and older with cystic fibrosis with the G551D mutation are well established.1McKone EF Borowitz D Drevinek P et al.Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: a phase 3, open-label extension study (PERSIST).Lancet Respir Med. 2014; 2: 902-910Summary Full Text Full Text PDF Scopus (181) Google Scholar Of the comorbidities observed over time in cystic fibrosis, gastrointestinal symptoms and exocrine pancreatic dysfunction are prominent features; exocrine pancreatic insufficiency is traditionally regarded as irreversible on serial testing.2Plant BJ Goss CH Plant WD Bell SC Management of comorbidities in older patients with cystic fibrosis.Lancet Respir Med. 2013; 1: 164-174Summary Full Text Full Text PDF Scopus (78) Google Scholar, 3Meyts I Wuyts W Proesmans M De Boeck K Variability of fecal pancreatic elastase measurements in cystic fibrosis patients.J Cyst Fibros. 2002; 1: 265-268Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar Faecal elastase 1 (FE-1) is a glycoprotein that is synthesised in the pancreas and excreted in the stool. It is not degraded on passage through the gastrointestinal tract and is, therefore, regarded as a sensitive marker of exocrine pancreatic function (concentrations of <200 μg/g stool are considered indicative of pancreatic insufficiency). We read with interest the KIWI study,4Davies JC Cunningham S Harris WT et al.Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.Lancet Respir Med. 2016; 4: 107-115Summary Full Text Full Text PDF Scopus (230) Google Scholar which highlighted the safety and efficacy of ivacaftor in children aged 2–5 years with cystic fibrosis with gating mutations. At baseline, 93% of children had a FE-1 less than 50 μg/g, which is consistent with severe pancreatic insufficiency. Notably a 99·8 μg/g significant mean increase in FE-1 was observed after 24 weeks of treatment. Equally of interest was the observation that 26% of children had an FE-1 above the threshold of 200 μg/g at least once over the course of the study. This raises the biologically plausible possibility that commencement of cystic fibrosis transmembrane conductance regulator (CFTR) modulators in very young children (aged 2–5 years) might augment exocrine pancreatic function. However, no published studies exploring this possibility in older children or young adults exist. We have observed dynamic changes in FE-1 in an older child (aged 6·5 years) after commencing ivacaftor treatment. We present the case of a female (genotype F508del/G551D) diagnosed at 4 years and 9 months old, after hospital admission with increased respiratory effort and cough. FE-1 was measured at diagnosis and was consistent with severe pancreatic insufficiency at less than 15 μg/g. At this time, the patient was started on four 150 mg pancreatin capsules per day. The patient started ivacaftor therapy on her sixth birthday in accordance with local regulatory guidelines. The figure shows the change in % predicted FEV1 and BMI after ivacaftor. After 6 months of ivacaftor treatment, the patient reported abdominal pain and constipation. As a result, her treatment regimen was reduced by 50% to two 150 mg pancreatin capsules per day. FE-1 was measured and was in the normal range at 259 μg/g. Two subsequent FE-1 measurements were made after 7 months of treatment (118 μg/g and 121 μg/g) and were consistent with moderate pancreatic insufficiency (figure). The authors of the KIWI study have highlighted the potential for a partial restoration of pancreatic function in early life in some patients given ivacaftor.4Davies JC Cunningham S Harris WT et al.Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.Lancet Respir Med. 2016; 4: 107-115Summary Full Text Full Text PDF Scopus (230) Google Scholar We concur with this statement. However, until the potential effect of these therapies has been established in all patients starting CFTR modulatory therapy, we suggest serial monitoring of exocrine pancreatic function with FE-1 measurements in all age groups, because of the scarcity of data in relation to FE-1 change in adult patients given ivacaftor that exists despite case reports of a reduction in pancreatic enzyme replacement requirements in adults after ivacaftor.5Harrison MJ Murphy DM Plant BJ Ivacaftor in a G551D homozygote with cystic fibrosis.N Engl J Med. 2013; 369: 1280-1282Crossref PubMed Scopus (43) Google Scholar BJP reports personal fees from Vertex Pharmaceuticals, Gilead Sciences, and Novartis, during the conduct of the study. CH, NJR, MN, and DM declare no competing interests.

Despite aggressive antimicrobial therapy, many respiratory pathogens persist in the lung, underpinning the chronic inflammation and eventual lung decline that are characteristic of respiratory disease. Recently, bile acid aspiration has emerged as a major comorbidity associated with a range of lung diseases, shaping the lung microbiome and promoting colonisation by Pseudomonas aeruginosa in Cystic Fibrosis (CF) patients. In order to uncover the molecular mechanism through which bile modulates the respiratory microbiome, a combination of global transcriptomic and phenotypic analyses of the P. aeruginosa response to bile was undertaken. Bile responsive pathways responsible for virulence, adaptive metabolism, and redox control were identified, with macrolide and polymyxin antibiotic tolerance increased significantly in the presence of bile. Bile acids, and chenodeoxycholic acid (CDCA) in particular, elicited chronic biofilm behaviour in P. aeruginosa, while induction of the pro-inflammatory cytokine Interleukin-6 (IL-6) in lung epithelial cells by CDCA was Farnesoid X Receptor (FXR) dependent. Microbiome analysis of paediatric CF sputum samples demonstrated increased colonisation by P. aeruginosa and other Proteobacterial pathogens in bile aspirating compared to non-aspirating patients. Together, these data suggest that bile acid signalling is a leading trigger for the development of chronic phenotypes underlying the pathophysiology of chronic respiratory disease.

Introduction: COPD is believed to have origins in childhood, however it has not yet been traced back to infancy. Lung function tracks from infancy into adulthood and reduced FEV1/FVC is a cornerstone of COPD diagnosis. Aim: Our aim was to assess whether physiological, genetic and environmental factors in infancy affect the FEV1/FVC ratio in young adults and thus the risk for COPD in later adult life. Methods: We analysed data from the Perth Infant Asthma follow up study, a longitudinal birth cohort of 253 subjects recruited antenatally, who have had regular and comprehensive respiratory assessments from infancy up to 24 years, including genotyping of several genes known to be associated with respiratory function. Results: Neither in utero tobacco smoke exposure nor early bronchiolitis correlated with FEV1/FVC at 24 years (r=0.06, p=0.5; r=-0.12, p=0.2 respectively). There were small but significant correlations between infant lung function (VmaxFRC) at 1, 6 and 12 months and FEV1/FVC at 24 years (r=0.19 p=0.048; r=0.223 p= 0.024, r=0.22 p=0.042 respectively), with 4% of the variability at 24 years explained by lung function at 1 month. Only 12% of subjects who were exclusively breastfed for the first 3 months had an FEV1/FVC in the lowest quartile at 24 years, compared to 34% who were not (OR 0.26, p=0.014). The B2-adrenoceptor polymorphism (arg16gly) was not associated with FEV1/FVC ratio (r=-0.014 p=0.83). Conclusions: Lung function from soon after birth was predictive of FEV1/FVC ratio in young adults, suggesting that COPD may have origins in the antenatal developing lung. Breastfeeding was protective against reduced FEV1/FVC and should continue to be promoted for long term healthy lungs.

Background: Asthma is often associated with atopy. Cluster analysis shows the prevalence of atopy varies in different phenotypic groups of asthma from 50-90% but no longitudinal studies have assessed how this changes throughout childhood [1]. Our aim was to assess whether atopy precedes an asthma diagnosis, what proportion of asthmatics is atopic at different ages and how these change during childhood, to help decipher the link between the two. Methods: We collected data from a longitudinal birth cohort of 253 subjects, the Perth Infant Asthma Follow up study. A detailed respiratory questionnaire, lung function and skin prick testing were performed at 1, 6 and 12 months, 6, 11, 18 and 24 years. Asthma was physician diagnosed only and atopy was defined by a positive skin prick test. Results: The percentage of asthmatics with atopy rose from 50% at 6 years to 100% at 24 years. Of those with atopic asthma and full sequential data, an atopy diagnosis preceded that of asthma in 45% of cases (n=21) and both were diagnosed in the same time period in 55% (n=26). This was not significantly different. Of those with a history of asthma at 24 years, 90% (n=60) had been diagnosed by 11 years. All subjects with onset of asthma after 11 years of age were atopic. Atopy was less frequent in those with early transient asthma than persistant asthma after 6 years of age (65% vs 80%, p=0.045). Conclusion: The prevalence of atopy is higher in young adult asthmatics than as young children. Both diseases were diagnosed at a similar age in more than 50% of cases, suggesting a common predecessor, rather than a causal relationship. Haldar, P., et al., Cluster analysis and clinical asthma phenotypes. AMJRCCM 2008. 178(3):218-24.

Background Recent work has demonstrated tracking of lung function from early infancy to ages 18 and 22 years. We hypothesised that factors associated with wheeze would be associated with a changing trajectory of lung function tracking during infancy and childhood. Methods Lung function was measured longitudinally at one, six and twelve months (V’maxFRC) of age and at ages six, twelve and eighteen years (FEF 25-75 ). Repeated measures analysis of variance was used to explore chronological changes in % lung function. Results were analysed using the 91 individuals with data at all ages apart from 6 years (“restricted analysis”) and then for all individuals after replacing missing values with average values for that age (“whole cohort analysis”). Results The % lung function was determined in 241 individuals aged one month, 192 six months, 164 twelve months, 106 six years, 183 twelve years and 141 eighteen years. In the restricted analysis, maternal asthma was associated with reduced lung function from twelve months to 18 years (p=0.006). In the whole cohort analysis, associations were observed between: infant onset atopy and reduced lung function from six to 18 years (p=0.005); flow limitation at one month and reduced lung function only up to age six years (p<0.001); and maternal asthma and reduced lung function only at age 18 years (p=0.016). Conclusions The repeated measurements of lung function in our cohort have allowed identification of factors associated with changes in lung function growth. These include early lung function, early onset atopy and maternal asthma and one or other may be associated with acceleration in infants with low initial lung function or deceleration in those with normal initial lung function.

Importance: This is the first study to link reduced lung function in early life, before the development of symptoms, to wheeze in 18-year-olds. Additionally, the study gives insight into factors other than reduced lung function that are also associated with persistent wheeze in young adults. Objective: To test the hypothesis that reduced lung function in early life is associated with increased risk for persistent wheeze at age 18 years. Design: Birth cohort study. Setting: Perth, Western Australia. Participants: Individuals followed up from age 1 month to 18 years. Main Outcome Measures: Maximal flow at functional residual capacity (V'maxFRC) was measured in 1-month-old infants who were followed up at ages 6, 12, and 18 years. Based on reported symptoms, individuals were categorized as having remittent wheeze, later-onset wheeze, persistent wheeze, and no wheeze. Smoking status was noted at age 18 years. Results: Of the 253 individuals originally recruited, 150 were followed up at age 18 years; 37 of the 150 had recent wheeze. Compared with the no-wheeze group (n = 96), persistent wheeze (n = 13) was independently associated with reduced percentage of predicted V'maxFRC (mean reduction, 43%; 95% CI, 13-74). Compared with the no-wheeze group, persistent wheeze was also associated with atopy in infancy (odds ratio = 7.1; 95% CI, 1.5-34.5), maternal asthma (odds ratio = 6.8; 95% CI, 1.4-32.3), and active smoking (odds ratio = 4.8; 95% CI, 1.0-21.3). When only wheeze at age 18 years was considered, reduced percentage of predicted V'maxFRC was associated with wheeze at age 18 years only among current smokers (P =. 04). Conclusions and Relevance: Wheeze persisting from ages 6 to 18 years is associated with multiple factors, including reduced infant lung function, infant-onset atopy, maternal asthma, and active smoking. Wheeze at age 18 years (regardless of previous wheeze status) is associated with active smoking, but only among those with reduced lung function in infancy. These findings give unique insight into the cause of obstructive airways disease in 18-year-olds, and follow-up of this cohort might be expected to further extend our understanding.

OBJECTIVE:With the increasing life expectancy for patients with cystic fibrosis (CF), and a known predisposition to certain cancers, cumulative radiation exposure from radiologic imaging is of increasing significance. This study explores the estimated cumulative effective radiation dose over a 17-year period from radiologic procedures and changing trends of imaging modalities over this period.METHODS:Estimated cumulative effective dose (CED) from all thoracic and extrathoracic imaging modalities and interventional radiology procedures for both adult and pediatric patients with CF, exclusively attending a nationally designated CF center between 1992-2009 for > 1 year, was determined. The study period was divided into three equal tertiles, and estimated CED attributable to all radiologic procedures was estimated for each tertile.RESULTS:Two hundred thirty patients met inclusion criteria (2,240 person-years of follow-up; 5,596 radiologic procedures). CED was > 75 mSv for one patient (0.43%), 36 patients (15.6%) had a CED between 20 and 75 mSv, 56 patients (24.3%) had a CED between 5 and 20 mSv, and in 138 patients (60%) the CED was estimated to be between 0 and 5 mSv over the study period. The mean annual CED per patient increased consecutively from 0.39 mSv/y to 0.47 mSv/y to 1.67 mSv/y over the tertiles one to three of the study period, respectively (P < .001). Thoracic imaging accounted for 46.9% of the total CED and abdominopelvic imaging accounted for 42.9% of the CED, respectively. There was an associated 5.9-fold increase in the use of all CT scanning per patient (P < .001).CONCLUSIONS:This study highlights the increasing exposure to ionizing radiation to patients with CF as a result of diagnostic imaging, primarily attributable to CT scanning. Increased awareness of CED and strategies to reduce this exposure are needed.

There is controversy regarding whether cystic fibrosis (CF) airway epithelial cells (AECs) are intrinsically proinflammatory. The objective of the current study was to characterize the inflammatory profiles of AECs from children with CF compared with cells from healthy control subjects. We obtained AECs from healthy children (12) and children with CF (27). Biochemical and functional characteristics were assessed by stimulating cells with IFNγ, LPS, a cocktail referred to as cytomix, which consists of IFNγ, IL-1β, TNF-α, and LPS, or with human rhinovirus (HRV). Cytokine production was assessed using ELISA. Apoptotic responses to HRV infection were measured via production of single-stranded DNA. Our results indicated that CF and healthy cells exhibited similar morphology in monolayer culture. CF cells constitutively produced greater amounts of IL-6, IL-1β, and prostaglandin E(2), but similar levels of IL-8 and soluble intracellular adhesion molecule-1 compared with healthy cells, and this profile was maintained through repeated passage. Stimulation with LPS or cytomix elicited similar levels of IL-8 in CF and non-CF cells. In contrast, exposure to HRV1b resulted in a marked increase in IL-8 production from CF compared with non-CF cells. CF cells also exhibited reduced apoptosis and increased viral replication compared with non-CF cells after exposure to HRV1b. We conclude that CF and healthy AECs have similar basal and stimulated expression of IL-8 in response to proinflammatory stimuli, but elevated IL-8 release in response to HRV infection. The elevated IL-8, together with dampened apoptotic responses by CF cells to HRV, could contribute to augmented airway inflammation in the setting of recurrent viral infections early in life.