Factors in childhood associated with lung function decline to adolescence in cystic fibrosis.

BACKGROUND: Despite improvements in general health and life expectancy in people with cystic fibrosis (CF), lung function decline continues unabated during adolescence and early adult life. METHODS: We examined factors present at age 5-years that predicted lung function decline from childhood to adolescence in a longitudinal study of Australasian children with CF followed from 1999 to 2017. RESULTS: Lung function trajectories were calculated for 119 children with CF from childhood (median 5.0 [25%-75%=5.0-5.1]) years) to early adolescence (median 12.5 [25%-75%=11.4-13.8] years). Lung function fell progressively, with mean (standard deviation) annual change -0.105 (0.049) for forced vital capacity (FVC) Z-score (p<0.001), -0.135 (0.048) for forced expiratory volume in 1-second (FEV1) Z-score (p<0.001), -1.277 (0.221) for FEV1/FVC% (p<0.001), and -0.136 (0.052) for forced expiratory flow between 25% and 75% of FVC Z-score (p<0.001). Factors present in childhood predicting lung function decline to adolescence, in multivariable analyses, were hospitalisation for respiratory exacerbations in the first 5-years of life (FEV1/FVC p = 0.001, FEF25-75p = 0.01) and bronchoalveolar lavage neutrophil elastase activity (FEV1/FVC% p = 0.001, FEV1p = 0.05, FEF25-75p = 0.02). No examined factor predicted a decline in the FVC Z-score. CONCLUSIONS: Action in the first 5-years of life to prevent and/or treat respiratory exacerbations and counteract neutrophilic inflammation in the lower airways may reduce lung function decline in children with CF, and these should be targets of future research.

Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.

Early markers of cystic fibrosis structural lung disease: follow-up of the ACFBAL cohort.

Little is known about early predictors of later cystic fibrosis (CF) structural lung disease. This study examined early predictors of progressive structural lung abnormalities in children who completed the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial at age 5-years and participated in an observational follow-up study (CF-FAB).Eight Australian and New Zealand CF centres participated in CF-FAB and provided follow-up chest computed-tomography (CT) scans for children who had completed the ACFBAL study with baseline scans at age 5-years. CT scans were annotated using PRAGMA-CF scoring. Ordinal regression analysis and linear regression were used to investigate associations between PRAGMA-CF (Perth-Rotterdam Annotated Grid Morphometric Analysis for CF) outcomes at follow-up and variables measured during the ACFBAL study.99 out of 157 ACFBAL children (mean±sd age 13±1.5 years) participated in the CF-FAB study. The probability of bronchiectasis at follow-up increased with airway disease severity on the baseline CT scan. In multiple regression (retaining factors at p<0.05) the extent of bronchiectasis at follow-up was associated with baseline atelectasis (OR 7.2, 95% CI 2.4-22; p≤ 0.001), bronchoalveolar lavage (BAL) log2 interleukin (IL)-8 (OR 1.2, 95% CI 1.05-1.5; p=0.010) and body mass index z-score (OR 0.49, 95% CI 0.24-1.00; p=0.05) at age 5 years. Percentage trapped air at follow-up was associated with BAL log2 IL-8 (coefficient 1.3, 95% CI 0.57-2.1; p<0.001) at age 5 years.The extent of airway disease, atelectasis, airway inflammation and poor nutritional status in early childhood are risk factors for progressive structural lung disease in adolescence.

PEBBLES study protocol: a randomised controlled trial to prevent atopic dermatitis, food allergy and sensitisation in infants with a family history of allergic disease using a skin barrier improvement strategy.

INTRODUCTION: The skin is an important barrier against environmental allergens, but infants have relatively impaired skin barrier function. There is evidence that impaired skin barrier function increases the risk of allergic sensitisation, atopic dermatitis (AD) and food allergy. We hypothesise that regular prophylactic use of emollients, particularly those that are designed to improve skin barrier structure and function, will help prevent these conditions. With the aim of determining if application of a ceramide-dominant emollient two times per day reduces the risk of AD and food allergy, we have commenced a multicentre phase III, outcome assessor blinded, randomised controlled trial of this emollient applied from birth to 6 months. METHODS AND ANALYSIS: Infants (n=760) with a family history of allergic disease will be recruited from maternity hospitals in Melbourne. The primary outcomes are as follows: the presence of AD, assessed using the UK Working Party criteria, and food allergy using food challenge, in the first 12 months of life as assessed by a blinded study outcome assessor. Secondary outcomes are as follows: food sensitisation (skin prick test), skin barrier function, AD severity, the presence of new onset AD after treatment cessation (between 6 and 12 months) and the presence of parent reported AD/eczema. Recruitment commenced in March 2018. ETHICS AND DISSEMINATION: The PEBBLES Study is approved by the Human Research Ethics Committees of the Royal Children's Hospital (RCH) (#37090A) and the Mercy Hospital for Women (2018-008). Parents or guardians will provide written informed consent. Outcomes will be disseminated through peer-reviewed publications and presented at scientific conferences. TRIAL REGISTRATION NUMBERS: ACTRN12617001380381 and NCT03667651.

How best to capture the respiratory consequences of prematurity?

Chronic respiratory morbidity is a common complication of premature birth, generally defined by the presence of bronchopulmonary dysplasia, both clinically and in trials of respiratory therapies. However, recent data have highlighted that bronchopulmonary dysplasia does not correlate with chronic respiratory morbidity in older children born preterm. Longitudinally evaluating pulmonary morbidity from early life through to childhood provides a more rational method of defining the continuum of chronic respiratory morbidity of prematurity, and offers new insights into the efficacy of neonatal respiratory interventions. The changing nature of preterm lung disease suggests that a multimodal approach using dynamic lung function assessment will be needed to assess the efficacy of a neonatal respiratory therapy and predict the long-term respiratory consequences of premature birth. Our aim is to review the literature regarding the long-term respiratory outcomes of neonatal respiratory strategies, the difficulties of assessing dynamic lung function in infants, and potential new solutions.

Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling.

BACKGROUND: Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed. OBJECTIVE: We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes. METHODS: We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both cis- and trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations. RESULTS: We tested the association between asthma and 17,190 genes that were found to have cis- and/or trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, LIMS1, TINF2, and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: B4GALT3, USMG5, P2RY13, and P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs. CONCLUSION: We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs.

Meta-analysis identifies seven susceptibility loci involved in the atopic march.

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

A prospective evaluation of the symptom-based screening approach to the management of children who are contacts of tuberculosis cases.

BACKGROUND: Child tuberculosis contact screening and management can enhance case finding and prevent tuberculosis disease. It is universally recommended but rarely implemented in tuberculosis-endemic settings. The World Health Organization (WHO)-recommended symptom-based screening approach could improve implementation but has not been prospectively evaluated. METHODS: We conducted a cohort study of children who were close contacts of pulmonary tuberculosis patients in Indonesia from August 2010 to December 2012. We performed clinical assessment, tuberculin skin test, and chest radiography in all eligible children irrespective of symptoms at baseline. Mycobacterial culture and Xpert MTB/RIF assay were performed on sputum from children with persistent symptoms of suspected tuberculosis. Children were managed according to WHO guidelines and were prospectively followed for 12 months. RESULTS: A total of 269 child contacts of 140 index cases were evaluated. At baseline, 21 (8%) children had tuberculosis diagnosed clinically; an additional 102 (38%) had evidence of infection without disease. Of children with any tuberculosis-related symptoms at baseline, 21% had tuberculosis diagnosed compared with none of the asymptomatic children (P < .001). After 12 months of follow-up, none of the 99 eligible young child contacts (<5 years) who received isoniazid preventive therapy (IPT) had developed disease compared with 4 of 149 (2.6%) asymptomatic older children who did not receive IPT. CONCLUSIONS: Symptom-based screening is an effective and simple approach to child tuberculosis contact management that can be implemented at the primary healthcare level.

Children with chronic cough: when is watchful waiting appropriate? development of likelihood ratios for assessing children with chronic cough.

BACKGROUND: Chronic cough is associated with poor quality of life and may signify a serious underlying disease. Differentiating nonspecific cough (when watchful waiting can be safely undertaken) from specific cough (treatment and further investigations are beneficial) would be clinically useful. In 326 children, we aimed to (1) determine how well cough pointers (used in guidelines) differentiate specific from nonspecific cough and (2) describe the clinical profile of children whose cough resolved without medications (spontaneous resolution). METHODS: A dataset from a multicenter study involving children newly referred for chronic cough (median duration, 3-4 months) was used to determine the sensitivity, specificity, predictive values, and likelihood ratios (LRs) of cough pointers (symptoms, signs, and simple investigations [chest radiography, spirometry]) recommended in guidelines. RESULTS: The pretest probability of specific cough was 88%. The absence of false-positive results meant that most pointers had strongly positive LRs. The most sensitive pointer (wet cough) had a positive LR of 26.2 (95% CI, 3.8-181.5). Although the absence of other individual pointers did not change the pretest probability much (negative LR close to 1), the absence of all pointers had a strongly negative LR of 0 (95% CI, 0-0.03). Children in the resolved spontaneously group were significantly more likely to be older, to be non-Indigenous, and to have a dry cough and a normal chest radiograph. CONCLUSIONS: Children with chronic dry cough without any cough pointers can be safely managed using the watchful waiting approach. The high pretest probability and high positive LRs of cough pointers support the use of individual cough pointers to identify high risk of specific cough in pediatric chronic cough guidelines. TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry; No.: 12607000526471; URL: www.anzctr.org.au.

Does migration affect asthma, rhinoconjunctivitis and eczema prevalence? Global findings from the international study of asthma and allergies in childhood.

BACKGROUND: Immigrants to Westernized countries adopt the prevalence of allergic diseases of native populations, yet no data are available on immigrants to low-income or low-disease prevalence countries. We investigated these questions using data from the International Study of Asthma and Allergies in Childhood. METHODS: Standardized questionnaires were completed by 13-14-year-old adolescents and by the parent/guardians of 6-7-year-old children. Questions on the symptom prevalence of asthma, rhinoconjunctivitis and eczema, and a wide range of factors postulated to be associated with these conditions, including birth in or not in the country and age at immigration, were asked. Odds ratios for risk of the three diseases according to immigration status were calculated using generalized linear mixed models. These were adjusted for: world region; language and gross national income; and individual risk factors including gender, maternal education, antibiotic and paracetamol use, maternal smoking, and diet. Effect modification by gross national income and by prevalence was examined. RESULTS: There were 326 691 adolescents from 48 countries and 208 523 children from 31 countries. Immigration was associated with a lower prevalence of asthma, rhinoconjunctivitis and eczema in both age groups than among those born in the country studied, and this association was mainly confined to high-prevalence/affluent countries. This reduced risk was greater in those who had lived fewer years in the host country. CONCLUSIONS: Recent migration to high prevalence/affluent countries is associated with a lower prevalence of allergic diseases. The protective pre-migration environment quickly decreases with increasing time in the host country.

Costs of bronchoalveolar lavage-directed therapy in the first 5 years of life for children with cystic fibrosis.

OBJECTIVES: To determine whether bronchoalveolar lavage (BAL)-directed therapy for infants and young children with cystic fibrosis (CF), rather than standard therapy, was justified on the grounds of a decrease in average costs and whether the use of BAL reduced treatment costs associated with hospital admissions. STUDY DESIGN: Costs were assessed in a randomized controlled trial conducted in Australia and New Zealand on infants diagnosed with CF after newborn screening and assigned to receive either BAL-directed or standard therapy until they reached 5 years of age. A health care funder perspective was adopted. Resource use measurement was based on standardized data collection forms administered for patients across all sites. Unit costs were obtained primarily from government schedules. RESULTS: Mean costs per child during the study period were Australian dollars (AUD)92 860 in BAL-directed therapy group and AUD90 958 in standard therapy group (mean difference AUD1902, 95% CI AUD-27 782 to 31 586, P = .90). Mean hospital costs per child during the study period were AUD57 302 in the BAL-directed therapy group and AUD66 590 in the standard therapy group (mean difference AUD-9288; 95% CI AUD-35 252 to 16 676, P = .48). CONCLUSIONS: BAL-directed therapy did not result in either lower mean hospital admission costs or mean costs overall compared with managing patients with CF by a standard protocol based upon clinical features and oropharyngeal culture results alone. Following on our previous findings that BAL-directed treatment offers no clinical advantage over standard therapy at age 5 years, flexible bronchoscopy with BAL cannot be recommended for the routine management of preschool children with CF on the basis of overall cost savings.

Trends in eczema, rhinitis, and rye grass sensitization in a longitudinal asthma cohort.

BACKGROUND: Atopic conditions are prevalent in the Western world, with limited long-term data on atopic trends in patients with asthma. OBJECTIVE: To describe the trends in eczema, rhinitis, and allergic sensitization in a longitudinal childhood asthma cohort. METHODS: Four hundred eighty-four patients were recruited at 7 years of age and followed regularly to 50 years of age. Subjects completed an interviewer-administered questionnaire to define current eczema and rhinitis. Skin prick testing to rye grass also was performed. RESULTS: The participation rate over the past 4 decades has been maintained at 72% to 91%. There was a decrease in the prevalence of eczema in the past 12 months in groups with viral-associated wheeze (21% to 8%, P = .002), asthma (47% to 18%, P < .001), and severe asthma (69% to 28%, P < .001) from 14 to 21 years of age. Conversely, there was an increase in the prevalence of rhinitis in the previous 12 months in groups without asthma (1% to 6%, P = .04; 1% to 20%, P = .008), with viral-associated wheeze (16% to 28%, P = .006; 16% to 49%, P < .001), and with asthma (45% to 56%, P = .2; 45% to 73%, P = .014) from recruitment to 10 and 14 years of age, respectively. There were 2 peaks in prevalence in the sensitization to rye grass in this cohort from 7 to 10 years of age and from 14 to 21 years of age in all groups. CONCLUSION: The adolescence phase appears to be an important period in the body's response to allergens whereby eczema decreases in prevalence, whereas rhinitis and rye grass sensitization increase in prevalence.

The association between childhood asthma and adult chronic obstructive pulmonary disease.

INTRODUCTION: There is epidemiological evidence to suggest that events in childhood influence lung growth and constitute a significant risk for adult COPD. The aim of the study is to evaluate for an association between childhood asthma and adult COPD. METHODS: This longitudinal, prospective study of 6-7-year-old children with asthma has been regularly reviewed every 7 years to the current analysis at 50 years of age. Participants completed respiratory questionnaires and lung function spirometry with postbronchodilator response. At the age of 50, subjects were classified to the following subgroups: non-asthmatics, asthma remission, current asthma and COPD which was defined by FEV1 to FVC ratio postbronchodilator of less than 0.7. RESULTS: Of the remaining survivors, 346 participated in the current study (participation rate of 76%) of whom 197 completed both questionnaire and lung function testing. As compared with children without symptoms of wheeze to the age of 7, (non-asthmatics) children with severe asthma had an adjusted 32 times higher risk for developing COPD (95% CI 3.4 to 269). In this cohort, 43% of the COPD group had never smoked. There was no evidence of a difference in the rate of decline in FEV1 (mL/year, 95th CI) between the COPD group (17, 10 to 23) and the other groups: non-asthmatics (16, 12 to 21), asthma remission (20, 16 to 24) and current asthma (19, 13 to 25). CONCLUSIONS: Children with severe asthma are at increased risk of developing COPD.

Outcomes of childhood asthma to the age of 50 years.

BACKGROUND: In 1964, The Melbourne Asthma Study was established to describe the spectrum and natural history of childhood asthma. OBJECTIVE: To describe the clinical and lung function outcome of childhood asthma to the age of 50 years. METHOD: Subjects were invited to complete an interviewer-administered questionnaire, skin prick testing, and measurement of lung function from the age of 7 years to the age of 50 years at 7-year intervals. RESULTS: Of 458 survivors (from the original 484 subjects at recruitment), 346 subjects (76%) participated, of whom, 197 completed lung function measurement. Asthma remission at the age of 50 years was 64% in those with wheezy bronchitis, 47% for those with persistent asthma, and 15% for those with severe asthma in childhood. Multivariable analysis identified severe asthma in childhood (odds ratio [OR] 11.9 [95% CI, 3.4-41.8]), female sex (OR 2.0 [95% CI, 1.1-3.6]), and childhood hay fever (OR 2.0 [95% CI, 1.0-4.0]) as risk factors for "current asthma" at age 50 years. There was no evidence of a difference in the rate of decline in FEV1 (mL/y, 95% CI) between the severe asthma group (15 mL/y [95% CI, 9-22 mL/y]) and all the other recruitment groups: control (16 mL/y [95% CI, 12-20 mL/y]), mild wheezy bronchitis (14 mL/y [95% CI, 8-19 mL/y]), wheezy bronchitis (16 mL/y [95% CI, 11-20 mL/y]), and persistent asthma (19 mL/y [95% CI, 13-24 mL/y]). CONCLUSION: The clinical and lung function outcome in adult life is strongly determined by asthma severity in childhood. The reduced lung function seen in adults is established in childhood and does not appear to decline more rapidly in adult years despite continuing symptoms.

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype.

BACKGROUND: To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. OBJECTIVE: We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. METHODS: We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). RESULTS: At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10(-9)) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10(-8)). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10(-7)) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10(-6)). CONCLUSION: By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

Increased rate of lung function decline in Australian adolescents with cystic fibrosis.

INTRODUCTION: Though baseline lung function as measured by spirometry in children with cystic fibrosis (CF) has improved, the annual rate of decline has not changed significantly during the critical period of adolescence. The aim of this study was to describe factors associated with longitudinal decline in lung function in a contemporary cohort of children with CF. METHODS: Best annual lung function data from children attending the CF service of the Royal Children's Hospital Melbourne were reviewed to determine rate of decline in FEV(1) up until time of transfer to an adult center. Mixed models were used to determine the influence of age, sex, genotype, newborn screening, respiratory hospitalization, CF related diabetes mellitus (CFRD), pancreatic insufficiency, Pseudomonas aeruginosa (PsA) infection, and body mass index (BMI) on lung function decline. RESULTS: Longitudinal lung function data (range 5-20 years) were obtained for 98 patients with CF (55 male). Overall, the annual rate of decline in FEV(1) % predicted for the entire cohort was 1.4% per annum though the greatest rate of FEV1 decline was seen during adolescence (2.6%). Increasing age, homozygous ΔF508 genotype, CFRD, mucoid PsA infection, pancreatic insufficiency and respiratory hospitalizations were all significant predictors of FEV1 decline. CONCLUSION: FEV(1) declines at its sharpest rate during adolescence even in the presence of newborn screening. Genotype, increasing age, CFRD, PsA infection, pancreatic insufficiency and a greater number of respiratory hospitalizations are all associated with an increased rate of lung function decline in Australian children and adolescents with cystic fibrosis.

Tracheal repair in children: reduction of mortality with advent of slide tracheoplasty.

BACKGROUND: Severe tracheal stenosis is a rare life-threatening condition that often requires early surgical intervention. The management of this anomaly has been associated with significant mortality and morbidity. We describe our experience with repair of this condition. METHODS: From 1986 to 2011, 20 patients underwent repair of tracheal stenosis at the Royal Children's Hospital (median age 4.9 months) and were retrospectively reviewed. RESULTS: Tracheal repair techniques used were as follows: patch tracheoplasty (n=8; 40%, 8 out of 20), slide tracheoplasty (n=7; 35%, 7 out of 20), end-to-end anastomosis (n=5; 25%, 5 out of 20). Six patients (30%, 6 out of 20) had coexisting congenital intracardiac anomalies. There were 12 pulmonary artery sling (60%, 12 out of 20) patients. Overall operative mortality was 15% (n=3; 3 out of 20). Operative mortality was 20% (n=2; 2 out of 10) from 1986 to 2001 and decreased to 10% (n=1; 1 out of 10) from 2002 to 2011. All early deaths occurred in patients who had undergone patch tracheoplasty. Since 2004, there were no operative deaths. Seven patients (35%, 7 out of 20) required tracheal reintervention postoperatively. There were three late deaths (17.6%, 3 out of 17) at 8, 9 and 22 months after surgery. At last follow-up (mean 5.3±6.6 years; range 1 month to 18 years), all 14 survivors remained asymptomatic. CONCLUSIONS: Repair of tracheal stenosis in children has been associated with high morbidity and mortality. Since the introduction of slide tracheoplasty, a multidisciplinary team approach and abandonment of patch tracheoplasty, the mortality has been reduced. Survival beyond 2 years after surgery is associated with an excellent outcome.

Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization.

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.