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Rationale: The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear. Objectives: To investigate within-individual patterns of morbidity of eczema, wheeze, and rhinitis from birth to adolescence/early adulthood. Methods: We investigated onset, progression, and resolution of eczema, wheeze, and rhinitis using descriptive statistics, sequence mining, and latent Markov modeling in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (filaggrin [FLG] mutations and 17q21 variants), increase the risk of multimorbidity. Measurements and Main Results: Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema1wheeze1rhinitis was rare but significantly overrepresented (three to six times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern. FLG mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (FLG by 2- to 3-fold, rs7216389 risk variant by 1.4- to 1.7-fold). Latent Markov modeling revealed five latent states (no disease/low risk, mainly eczema, mainly wheeze, mainly rhinitis, multimorbidity). The most likely transition to multimorbidity was from eczema state (0.21). However, although this was one of the highest transition probabilities, only one-fifth of those with eczema transitioned to multimorbidity. Conclusions: Atopic diseases fit a multimorbidity framework, with no evidence for sequential atopic march progression. The highest transition to multimorbidity was from eczema, but most children with eczema (more than three-quarters) had no comorbidities.

Background: Although estimates of suboptimal adherence to oral corticosteroids in asthma range from 30% to 50%, no ideal method for measurement exists; the impact of poor adherence in severe asthma is likely to be particularly high. Research Questions: What is the prevalence of suboptimal adherence detected by self-reporting and direct measures? Is suboptimal adherence associated with disease activity? Study Design and Methods: Data were included from individuals with severe asthma taking part in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study and prescribed daily oral corticosteroids. Participants completed the Medication Adherence Report Scale, a five-item questionnaire used to grade adherence on a scale from 1 to 5, and provided a urine sample for analysis of prednisolone and metabolites by liquid chromatography-mass spectrometry. Results: Data from 166 participants were included in this study: mean (SD) age, 54.2 (± 11.9) years; FEV 1, 65.1% (± 20.5%) predicted; female, 58%; 37% completing the Medication Adherence Report Scale reported suboptimal adherence; and 43% with urinary corticosteroid data did not have detectable prednisolone or metabolites in their urine. Good adherence by both methods was detected in 49 of the 142 (35%) of participants in whom both methods were performed; adherence detection did not match between methods in 53%. Self-reported high adherers had better asthma control and quality of life, whereas directly measured high adherers had lower blood eosinophil levels. Interpretation: Low adherence is a common problem in severe asthma, whether measured directly or self-reported. We report poor agreement between the two methods, suggesting some disassociation between self-assessment of medication adherence and regular oral corticosteroid use, which suggests that each approach may provide complementary information in clinical practice.

Background Chemokines are important mediators in immune cell recruitment, contributing to allergy development. However, extensive studies of chemokines in the circulation in relation to the presence and development of allergic diseases remain scarce. Our aim was to investigate associations of circulating allergy-related chemokines with the development of asthma and sensitization cross-sectionally and longitudinally in a population-based cohort. Methods The chemokines CCL17, CCL22, CXCL10, CXCL11 and CCL18 were measured in plasma samples from children in the Manchester Asthma and Allergy Study. Samples were available from cord blood at birth (n = 376), age 1 (n = 195) and age 8 (n = 334). Cross-sectional and longitudinal association analyses were performed in relation to asthma and allergic sensitization, as well as allergic phenotype clusters previously derived using machine learning in the same study population. Results In children with asthma and/or allergic sensitization, CCL18 levels were consistently elevated at 1 and/or 8 years of ages. In a longitudinal model including information on asthma from 4 time points (5, 8, 11 and 16 years of ages), we observed a significant association between increasing CCL18 levels at age 1 and a higher risk of asthma from early school age to adolescence (OR = 2.9, 95% CI 1.1-7.6, p = .028). We observed similar associations in longitudinal models for allergic sensitization. Asthma later in life was preceded by increased CXCL10 levels after birth and decreased CXCL11 levels at birth. Conclusion Elevated CCL18 levels throughout childhood precede the development of asthma and allergic sensitization. The Th1-associated chemokines CXCL10 and CXCL11 also associated with the development of both outcomes, with differential temporal effects. Funding Agencies|MRCUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [MR/L012693/1, MR/K002449/2, MR/S025340/1]; Manchester Biomedical Research Centre (BRC); Swedish Research CouncilSwedish Research CouncilEuropean Commission [2016-01698]; Swedish Heart-Lung FoundationSwedish Heart-Lung Foundation [20140321]; Cancer and Allergy Foundation; Foundation Samariten; Ellen, Walter and Lennart Hesselman foundation

Objective: Cleft palate (CP) can affect breathing, leading to sleep-disordered breathing (SDB). Sleep position can affect SDB, but the optimum sleep position for infants with CP is unknown. We aimed to determine the design of a pragmatic study to investigate the effect of the 2 routinely advised sleep positions in infants with CP on oxygen saturations. Design: A multicentered observational cohort. Setting: Four UK-based cleft centers, 2 advising supine- and 2 side-lying sleep positions for infants with CP. Participants: Infants with isolated CP born July 1, 2015, and December 31, 2016. Of 48 eligible infants, 30 consented (17 side-lying; 13 supine). Interventions: Oxygen saturation (SpO2) and end-tidal carbon dioxide (ETCO2) home monitoring at age 1 and 3 months. Qualitative interviews of parents. Outcome Measures: Willingness to participate, recruitment, retention, and acceptability/success (>90 minutes recording) of SpO2 and ETCO2 monitoring. Results: SpO2 recordings were obtained during 50 sleep sessions on 24 babies (13 side-lying) at 1 month (34 sessions >90 minutes) and 50 sessions on 19 babies (10 side-lying) at 3 months (27 sessions >90 minutes). The ETCO2 monitoring was only achieved in 12 sessions at 1 month and 6 at 3 months; only 1 was >90 minutes long. The ETCO2 monitoring was reported by the majority as unacceptable. Parents consistently reported the topic of sleep position in CP to be of importance. Conclusions: This study has demonstrated that it is feasible to perform domiciliary oxygen saturation studies in a research setting and has suggested that there may be a difference in the effects of sleep position that requires further investigation. We propose a study with randomization is indicated, comparing side-lying with supine-lying sleep position, representing an important step toward better understanding of SDB in infants with CP.

Asthma is the most common chronic respiratory disease in the UK; however, the misdiagnosis rate is substantial. The lack of consistency in national guidelines and the paucity of data on the performance of diagnostic algorithms compound the challenges in asthma diagnosis. Asthma is a highly rhythmic disease, characterised by diurnal variability in clinical symptoms and pathogenesis. Asthma also varies day to day, seasonally and from year to year. As much as it is a hallmark for asthma, this variability also poses significant challenges to asthma diagnosis. Almost all established asthma diagnostic tools demonstrate diurnal variation, yet few are performed with standardised timing of measurements. The dichotomous interpretation of diagnostic outcomes using fixed cut-off values may further limit the accuracy of the tests, particularly when diurnal variability straddles cut-off values within a day, and careful interpretation beyond the ‘positive’ and ‘negative’ outcome is needed. The day-to-day and more long-term variations are less predictable and it is unclear whether performing asthma diagnostic tests during asymptomatic periods may influence diagnostic sensitivities. With the evolution of asthma diagnostic tools, home monitoring and digital apps, novel strategies are needed to bridge these gaps in knowledge, and circadian variability should be considered during the standardisation process. This review summarises the biological mechanisms of circadian rhythms in asthma and highlights novel data on the significance of time (the fourth dimension) in asthma diagnosis.

BACKGROUND: Electronic noses (eNoses) are emerging point-of-care tools that may help in the subphenotyping of chronic respiratory diseases such as asthma.OBJECTIVE: We aimed to investigate whether eNoses can classify atopy in pediatric and adult patients with asthma.METHODS: Participants with asthma and/or wheezing from 4 independent cohorts were included; BreathCloud participants (n = 429), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes adults (n = 96), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes pediatric participants (n = 100), and Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory Effects 2 participants (n = 30). Atopy was defined as a positive skin prick test result (≥3 mm) and/or a positive specific IgE level (≥0.35 kU/L) for common allergens. Exhaled breath profiles were measured by using either an integrated eNose platform or the SpiroNose. Data were divided into 2 training and 2 validation sets according to the technology used. Supervised data analysis involved the use of 3 different machine learning algorithms to classify patients with atopic versus nonatopic asthma with reporting of areas under the receiver operating characteristic curves as a measure of model performance. In addition, an unsupervised approach was performed by using a bayesian network to reveal data-driven relationships between eNose volatile organic compound profiles and asthma characteristics.RESULTS: Breath profiles of 655 participants (n = 601 adults and school-aged children with asthma and 54 preschool children with wheezing [68.2% of whom were atopic]) were included in this study. Machine learning models utilizing volatile organic compound profiles discriminated between atopic and nonatopic participants with areas under the receiver operating characteristic curves of at least 0.84 and 0.72 in the training and validation sets, respectively. The unsupervised approach revealed that breath profiles classifying atopy are not confounded by other patient characteristics.CONCLUSION: eNoses accurately detect atopy in individuals with asthma and wheezing in cohorts with different age groups and could be used in asthma phenotyping.

Rationale: Longitudinal modeling of current wheezing identified similar phenotypes, but their characteristics often differ between studies. Objectives: We propose that a more comprehensive description of wheeze may better describe trajectories than binary information on the presence/absence of wheezing. Methods: We derived six multidimensional variables of wheezing spells from birth to adolescence (including duration, temporal sequencing, and the extent of persistence/recurrence). We applied partition-around-medoids clustering on these variables to derive phenotypes in five birth cohorts. We investigated within- and between-phenotype differences compared with binary latent class analysis models and ascertained associations of these phenotypes with asthma and lung function and with polymorphisms in asthma loci 17q12-21 and CDHR3 (cadherin-related family member 3). Measurements and Main Results: Analysis among 7,719 participants with complete data identified five spell-based wheeze phenotypes with a high degree of certainty: never (54.1%), early-transient (ETW) (23.7%), late-onset (LOW) (6.9%), persistent (PEW) (8.3%), and a novel phenotype, intermittent wheeze (INT) (6.9%). FEV 1/FVC was lower in PEW and INT compared with ETW and LOW and declined from age 8 years to adulthood in INT. 17q12-21 and CDHR3 polymorphisms were associated with higher odds of PEW and INT, but not ETW or LOW. Latent class analysis- and spell-based phenotypes appeared similar, but within-phenotype individual trajectories and phenotype allocation differed substantially. The spell-based approach was much more robust in dealing with missing data, and the derived clusters were more stable and internally homogeneous. Conclusions: Modeling of spell variables identified a novel intermittent wheeze phenotype associated with lung function decline to early adulthood. Using multidimensional spell variables may better capture wheeze development and provide a more robust input for phenotype derivation.

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Background Understanding risk factors for peanut allergy (PA) is essential to develop effective preventive measures. Objective The objective was to ascertain associates and predictors of PA, and the relationship between PA and asthma severity. Methods In a population-based birth cohort, we investigated the association between objectively confirmed PA with early-life environmental exposures, filaggrin (FLG)-loss-of-function mutations and other atopic disease. We then examined the association of PA with longitudinal trajectories of sensitization, wheeze and allergic comorbidities, which were previously derived using machine learning. Finally, we ascertained the relationship between PA and asthma severity. Results PA was confirmed in 30/959 participants with evaluable data. In the multivariate analysis, eczema in infancy (OR = 4.4, 95% CI 1.5–13.2, p = 0.007), egg sensitization at age 3 years (OR = 9.7, 95% CI 3.3–29.9, p < 0.001) and early-life cat ownership (OR = 3.0, 95% CI 1.1–8.4, p = 0.04) were independent associates of PA. In the stratified analysis among 700 participants with genetic information, in children with early-life eczema there was no difference in FLG mutations between children with and without PA (3/18 [16.7%] vs. 42/220 [19.1%], p = 1.00). In contrast, among children without eczema, those with PA were almost eight times more likely to have FLG mutations (2/6 [33.3%] vs. 27/456 [5.9%], p = 0.049). We observed associations between PA and multiple allergic sensitization profiles derived using machine learning, with ~60-fold increase in risk among individuals assigned to multiple early sensitization. PA was significantly associated with persistent wheeze (but not other wheeze phenotypes), and with trajectories of atopic disease characterized by co-morbid persistent eczema and wheeze (but not with transient phenotypes). Children with PA were more likely to have asthma, but among asthmatics we found no evidence of an association between PA and asthma severity. Conclusions Peanut allergy is associated with multiple IgE sensitization and early-onset persistent eczema and wheeze. FLG loss-of-function mutations were associated with peanut allergy in children without eczema.

Background In a population-based birth cohort, we aimed to identify longitudinal trajectories of atopic dermatitis (AD) during childhood using data from different sources (validated questionnaires and healthcare records), investigate impact of different AD definitions on such trajectories and their relationships with various risk factors. Methods Of the 1184 children born into the study, 1083 had information on current AD on at least three follow-ups from birth to age 11 years and were included in the analysis for parentally-reported AD (PRAD). Data were transcribed from healthcare records of 916/1184 children, for the analysis of doctor-diagnosed AD (DDAD). We also derived composite definition (CDAD; at least 2 of 3 features: PRAD, DDAD, current use of AD treatment). Using latent class analysis (LCA), we determined longitudinal profiles of AD using the three definitions (PRAD, DDAD CDAD). FLG genotype was available for 803 Caucasian participants. Results For PRAD, LCA identified four AD classes ("No AD", "Persistent", "Early-onset remitting"" and "Late-onset"). For DDAD and CDAD, the optimal number of phenotypes was three ("No AD", "Persistent" and "Early-onset remitting"). Although AD classes at population level appeared similar in different models, a considerable proportion of children (n=485, 45%) moved between classes. The association with FLG genotype, atopic diseases, and early-life risk factors were inconsistent across different definitions, but the association with oral food challenge-confirmed peanut allergy was similar, with a 9 to 11-fold increase amongst children in the Persistent AD class. In a CDAD model, compared to Early-onset remitting class, those with Persistent AD were significantly more likely to have (at age 3 years) moderate/severe AD (OR=11.6, [95% CI 1.7-80.2]), polysensitisation (5.2, [1.3-21.2]), and current wheeze (4.8, [1.4-16.6]), and were less likely to be breastfed (0.2, [0.05-0.8]). Conclusions Standardised composite definitions of AD may help define AD cases with more precision and identify more consistent long-term trajectories.

Introduction: Amongst allergic asthmatics, high allergen exposure increases asthma severity. However, there is no consensus on the role of mite allergen avoidance in the management of asthma, and various guidelines differ in their recommendations.Areas covered: Several systematic reviews/meta-analyses on mite avoidance in the management of asthma have been published, and their findings have been used for a call to provide a recommendation in British guidelines that dust-mite control measures should not be recommended. However, there are several problems with such analysis (such as combining studies in adults and children), and we question whether these are appropriate tools to evaluate available evidence about mite allergen avoidance, and whether it is correct to rely disproportionately on the results of meta-analyses/systematic reviews to inform clinical practice in this area. Recent evidence in children suggests that mite–impermeable bed encasings reduce emergency hospital attendance with severe asthma exacerbations.Expert opinion: The practical questions include how to achieve a sufficient real-life reduction allergen exposure, and how to identify patients who will benefit from effective intervention. The intervention should start early in the natural history of asthma, and consideration for choosing patients should include using the titre of allergen-specific IgE antibodies or the size of skin test wheal as an indicator.

Spirometric restriction, defined as a reduced forced vital capacity (FVC) with a preserved FEVIn this longitudinal, multicohort, population-based study, we used data from the Tucson Children's Respiratory Study (TCRS), which recruited 1246 healthy infants at birth between April 1980, and October 1984, in Tucson, AZ, USA. Questionnaires were answered by the primary caregiver at enrolment, immediately after the child's birth, and multiple follow-up questionnaires were completed through childhood and adulthood. At the age of 22, 26, 32, and 36 years, lung function was measured with spirometry. At each survey, three mutually exclusive spirometric patterns were defined: (1) normal (FEVOf 1246 healthy infants included in TCRS, for the present study we included data for 652 participants who had at least one set of spirometry data, contributing up to 1668 observations. In the TCRS cohort, results from the multivariate models showed that maternal nutritional problems during pregnancy (RRR 2·48 [95% CI 1·30-4·76]; p=0·0062), being born small for gestational age (birthweight10th percentile; 3·26 [1·34-7·93]; p=0·0093), and being underweight in childhood (BMI-for-age5th percentile; 3·54 [1·35-9·26]; p=0·010) were independent predictors of spirometric restriction in adult life. Associations between being small for gestational age (p=0·0028) and underweight in childhood (p0·0001) with adult spirometric restriction were supported by the results of meta-analysis of data from all three cohorts. In the MAAS cohort, having a low lean BMI (ie,10th percentile) at age 11 years predicted adult (age 18 years) spirometric restriction (RRR 3·66 [1·48-9·02]; p=0·0048). These associations of spirometric restriction with small for gestational age, childhood underweight, and low lean BMI in childhood were verified in participants with spirometric restriction who had diminished total lung capacity, indicating that these factors specifically increase the risk of lung restriction.Poor growth and nutritional deficits in utero and throughout childhood precede and predict the development of spirometric restriction in adult life. Strategies to improve prenatal and childhood growth trajectories could help to prevent spirometric restriction and its associated morbidity and mortality burden.National Institutes of Health.

IntroductionThe craniofacial abnormalities found in infants with cleft palate (CP) decrease their airway patency and increase their risk of obstructive sleep apnoea (OSA). We hypothesise that optimising sleep position in infants with CP may improve airway patency and offer a ‘low-cost, high-impact’ intervention to prevent the negative impacts of OSA. Because cleft centres give inconsistent advice about sleep position: some recommend back-lying and others side-lying, we will compare these in a randomised controlled trial.Methods and analysisThe aim is to determine the clinical effectiveness of side-lying as compared with back-lying sleep positioning in terms of reducing oxygen desaturation resulting from OSA in 244 infants aged 3–5 weeks of age, diagnosed with an isolated CP in/by UK cleft centres. Primary outcome is the 4% Oxygen Desaturation Index measured using pulse oximetry during sleep.Research plan1. Multicentre randomised controlled trial of side-lying compared with back-lying sleep positioning in reducing oxygen desaturation resulting from OSA in infants with CP at one month of age. 2. Internal pilot questionnaire-based study to support parents and clinicians regarding study participation, seeking to identify and address any barriers to recruitment. Monitoring data from the internal pilot will be used in the final analysis. 3. Co-development of new UK recommendations with Cleft Lip and Palate Association (CLAPA) regarding sleep position for infants with CP.Ethics and disseminationThe study protocol has received the favourable opinion of the West Midlands-South Birmingham Research Ethics Committee. Study results will be published on affiliated webpages and in peer-reviewed publications and conference contributions.Trial registration numberNCT04478201.

IntroductionClinical recommendations for childhood asthma are often based on data extrapolated from studies conducted in adults, despite significant differences in mechanisms and response to treatments. The Paediatric Asthma in Real Life (PeARL) Think Tank aspires to develop recommendations based on the best available evidence from studies in children. An overview of systematic reviews (SRs) on paediatric asthma maintenance management and an SR of treatments for acute asthma attacks in children, requiring an emergency presentation with/without hospital admission will be conducted.Methods and analysisStandard methodology recommended by Cochrane will be followed. Maintenance pharmacotherapy of childhood asthma will be evaluated in an overview of SRs published after 2005 and including clinical trials or real-life studies. For evaluating pharmacotherapy of acute asthma attacks leading to an emergency presentation with/without hospital admission, we opted to conduct de novo synthesis in the absence of adequate up-to-date published SRs. For the SR of acute asthma pharmacotherapy, we will consider eligible SRs, clinical trials or real-life studies without time restrictions. Our evidence updates will be based on broad searches of Pubmed/Medline and the Cochrane Library. We will use A MeaSurement Tool to Assess systematic Reviews, V.2, Cochrane risk of bias 2 and REal Life EVidence AssessmeNt Tool to evaluate the methodological quality of SRs, controlled clinical trials and real-life studies, respectively.Next, we will further assess interventions for acute severe asthma attacks with positive clinical results in meta-analyses. We will include both controlled clinical trials and observational studies and will assess their quality using the previously mentioned tools. We will employ random effect models for conducting meta-analyses, and Grading of Recommendations Assessment, Development and Evaluation methodology to assess certainty in the body of evidence.Ethics and disseminationEthics approval is not required for SRs. Our findings will be published in peer reviewed journals and will inform clinical recommendations being developed by the PeARL Think Tank.PROSPERO registration numbersCRD42020132990, CRD42020171624.

Background Asthma diagnostic guidelines require procedures with aerosol-generating potential (aerosol-generating procedures [AGPs]) to guide decision making. Restricted access to AGPs poses significant challenges in primary care and resource-poor countries, further amplified during the coronavirus disease 2019 pandemic. Objective To establish an approach to asthma diagnosis that does not require AGPs. Method Symptomatic yet untreated (beyond as-required bronchodilator use) adults with clinician-suspected asthma and maximum 10 pack year smoking history were recruited. Clinical history, physical examination, spirometry with bronchodilator reversibility, home peak flow monitoring, and bronchial challenges were performed, and fractional exhaled nitric oxide and serum eosinophils measured. Tests were then repeated following treatment with inhaled corticosteroids before an asthma diagnosis was confirmed or refuted by an expert panel. Results A total of 65 adults (mean age, 34.8 ± 12.2 years) were recruited. Five were excluded as “unclassifiable,” because of borderline results or missing data. Of the remainder, 36 were diagnosed with asthma and 24 were not. Using data from non-AGPs only (wheeze on auscultation and blood eosinophilia) and home peak flow variability, a “rule-in” diagnostic model provided comparable discriminative ability to the application of established guidelines. Clinical suspicion of asthma together with at least 1 positive non-AGP test result provided a sensitivity of 55%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 60%. Application of this model reduced the need for spirometry-based tests by one-third. Conclusions The proposed diagnostic algorithm may be clinically useful in “ruling-in” asthma in adults when access to AGPs is limited. This algorithm is not suitable for those with low clinical probability, with a significant smoking history, or where alternative diagnoses are more likely. This pragmatic approach to asthma diagnosis merits prospective validation.

Acute exacerbations cause significant morbidity and mortality in children with asthma worldwide. Although exacerbations can be minor and transient, in some children they are recurrent and significantly adversely impact quality of life. Children with frequent exacerbations account for a disproportionate amount of unscheduled care in nonprimary health facilities. Frequent exacerbators are often prescribed controller medications, but poor adherence is common. Major predictors for asthma exacerbations include genetic, social, comorbid, biological, and environmental factors. Although virus infections are a key trigger for exacerbations, other environmental factors also significantly increase risk. A previous exacerbation is a major risk factor for future exacerbations and thus identifies children to target for prevention of future episodes. In this review, we discuss both modifiable and fixed factors associated with asthma exacerbations, how to assess children for risk, and which pharmacological and nonpharmacological interventions may be of benefit. Finally, we review the current evidence around treatment within the outpatient setting for an emerging exacerbation.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values, CP received funding from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. MMcC is a Wellcome Senior Investigator and an NIHR Senior Investigator. MMcC received funding from Wellcome (090532, 106130, 098381, 203141, 212259), NIDDK (U01DK105535), and NIHR (NF-SI-0617-10090). TGMV was supported by ZonMW (TOP 40-00812-9811010). DLC was supported by the American Diabetes Association Grant 1-17-PDF-077. SFAG is supported by the Daniel B. Burke Chair for Diabetes Research and NIH Grant R01 HD058886. NVT is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (2017 FI_B 00636), Generalitat de Catalunya -Fons Social Europeu. BK received personal funding from the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG -no. 322605). BF was supported by an Oak Foundation Fellowship. RMF and RNB are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). ATH is supported by a Wellcome Trust Senior Investigator award (grant number 098395/Z/12/Z). DM is supported by a Canada Research Chair. DLC was supported by the American Diabetes Association Grant 1-17-PDF077. JTL was supported by the Finnish Cultural Foundation. DIB received a KNAW Academy Professor Award (PAH/6635). MH received PhD scholarship funding from TARGET (http://target.ku.dk), The Danish Diabetes Academy (http://danishdiabetesacademy.dk) and the Copenhagen Graduate School of Health and Medical Sciences. VWVJ received funding from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and the European Research Council (ERC-2014-CoG-648916). ISF was supported by the European Research Council, Wellcome Trust (098497/Z/12/Z), Medical Research Council (MRC_MC_UU_12012/5), the NIHR Cambridge Biomedical Research Centre, the Botnar Foundation, the Bernard Wolfe Health Neuroscience Endowment and the European Community's Seventh Framework Programme (FP7/2007-2013) project Beta-JUDO n degrees 279153. IB acknowledges funding from Wellcome (WT206194). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). KC received funds from the French National Agency of Research, F-CRIN/FORCE. All funding for the studies that provided the underlying data for this manuscript can be found in S1 Text. The funders had no role in study design, data collection and analysis, data interpretation, decision to publish, or preparation of the manuscript.

Background: Allergic sensitization is associated with severe asthma, but assessment of sensitization is not recommended by most guidelines. Objective: We hypothesized that patterns of IgE responses to multiple allergenic proteins differ between sensitized participants with mild/moderate and severe asthma. Methods: IgE to 112 allergenic molecules (components, c-sIgE) was measured using multiplex array among 509 adults and 140 school-age and 131 preschool children with asthma/wheeze from the Unbiased BIOmarkers for the PREDiction of respiratory diseases outcomes cohort, of whom 595 had severe disease. We applied clustering methods to identify co-occurrence patterns of components (component clusters) and patterns of sensitization among participants (sensitization clusters). Network analysis techniques explored the connectivity structure of c-sIgE, and differential network analysis looked for differences in c-sIgE interactions between severe and mild/moderate asthma. Results: Four sensitization clusters were identified, but with no difference between disease severity groups. Similarly, component clusters were not associated with asthma severity. None of the c-sIgE were identified as associates of severe asthma. The key difference between school children and adults with mild/moderate compared with those with severe asthma was in the network of connections between c-sIgE. Participants with severe asthma had higher connectivity among components, but these connections were weaker. The mild/moderate network had fewer connections, but the connections were stronger. Connectivity between components with no structural homology tended to co-occur among participants with severe asthma. Results were independent from the different sample sizes of mild/moderate and severe groups. Conclusions: The patterns of interactions between IgE to multiple allergenic proteins are predictors of asthma severity among school children and adults with allergic asthma.

Background To date, few data on paediatric COVID-19 have been published, and most reports originate from China. This study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across Europe to inform physicians and health-care service planning during the ongoing pandemic. Methods This multicentre cohort study involved 82 participating health-care institutions across 25 European countries, using a well established research network—the Paediatric Tuberculosis Network European Trials Group (ptbnet)—that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. We included all individuals aged 18 years or younger with confirmed SARS-CoV-2 infection, detected at any anatomical site by RT-PCR, between April 1 and April 24, 2020, during the initial peak of the European COVID-19 pandemic. We explored factors associated with need for intensive care unit (ICU) admission and initiation of drug treatment for COVID-19 using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with ICU admission. Findings 582 individuals with PCR-confirmed SARS-CoV-2 infection were included, with a median age of 5·0 years (IQR 0·5–12·0) and a sex ratio of 1·15 males per female. 145 (25%) had pre-existing medical conditions. 363 (62%) individuals were admitted to hospital. 48 (8%) individuals required ICU admission, 25 (4%) mechanical ventilation (median duration 7 days, IQR 2–11, range 1–34), 19 (3%) inotropic support, and one ( Interpretation COVID-19 is generally a mild disease in children, including infants. However, a small proportion develop severe disease requiring ICU admission and prolonged ventilation, although fatal outcome is overall rare. The data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed. Funding ptbnet is supported by Deutsche Gesellschaft für Internationale Zusammenarbeit.

Several agents are used to clear secretions from the airways of people with cystic fibrosis. Mannitol increases mucociliary clearance, but its exact mechanism of action is unknown. The dry powder formulation of mannitol may be more convenient and easier to use compared with established agents which require delivery via a nebuliser. Phase III trials of inhaled dry powder mannitol for the treatment of cystic fibrosis have been completed and it is now available in Australia and some countries in Europe. This is an update of a previous review.To assess whether inhaled dry powder mannitol is well tolerated, whether it improves the quality of life and respiratory function in people with cystic fibrosis and which adverse events are associated with the treatment.We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic databases, handsearching relevant journals and abstracts from conferences. Date of last search: 12 December 2019.All randomised controlled studies comparing mannitol with placebo, active inhaled comparators (for example, hypertonic saline or dornase alfa) or with no treatment.Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias in included studies. The quality of the evidence was assessed using GRADE.Six studies (reported in 36 unique publications) were included with a total of 784 participants. Duration of treatment in the included studies ranged from 12 days to six months, with open-label treatment for an additional six months in two of the studies. Five studies compared mannitol with control (a very low dose of mannitol or non-respirable mannitol) and the final study compared mannitol to dornase alfa alone and to mannitol plus dornase alfa. Two large studies had a similar parallel design and provided data for 600 participants, which could be pooled where data for a particular outcome and time point were available. The remaining studies had much smaller sample sizes (ranging from 22 to 95) and data could not be pooled due to differences in design, interventions and population. Pooled evidence from the two large parallel studies was judged to be of low to moderate quality and from the smaller studies was judged to be of low to very low quality. In all studies, there was an initial test to see if participants tolerated mannitol, with only those who could tolerate the drug being randomised; therefore, the study results are not applicable to the cystic fibrosis population as a whole. While the published papers did not provide all the data required for our analysis, additional unpublished data were provided by the drug's manufacturer and the author of one of the studies. Pooling the large parallel studies comparing mannitol to control, up to and including six months, lung function (forced expiratory volume at one second) measured in both mL and % predicted was significantly improved in the mannitol group compared to the control group (moderate-quality evidence). Beneficial results were observed in these studies in adults and in both concomitant dornase alfa users and non-users in these studies. In the smaller studies, statistically significant improvements in lung function were also observed in the mannitol groups compared to the non-respirable mannitol groups; however, we judged this evidence to be of low to very low quality. For the comparisons of mannitol and control, we found no consistent differences in health-related quality of life in any of the domains except for burden of treatment, which was less for mannitol up to four months in the two pooled studies of a similar design; this difference was not maintained at six months. It should be noted that the tool used to measure health-related quality of life was not designed to assess mucolytics and pooling of the age-appropriate tools (as done in some of the included studies) may not be valid so results were judged to be low to very low quality and should be interpreted with caution. Cough, haemoptysis, bronchospasm, pharyngolaryngeal pain and post-tussive vomiting were the most commonly reported side effects in both treatment groups. Where rates of adverse events could be compared, statistically no significant differences were found between mannitol and control groups; although some of these events may have clinical relevance for people with CF. For the comparisons of mannitol to dornase alfa alone and to mannitol plus dornase alfa, very low-quality evidence from a 12-week cross-over study of 28 participants showed no statistically significant differences in the recorded domains of health-related quality of life or measures of lung function. Cough was the most common side effect in the mannitol alone arm but there was no occurrence of cough in the dornase alfa alone arm and the most commonly reported reason of withdrawal from the mannitol plus dornase alfa arm was pulmonary exacerbations. In terms of secondary outcomes of the review (pulmonary exacerbations, hospitalisations, symptoms, sputum microbiology), evidence provided by the included studies was more limited. For all comparisons, no consistent statistically significant and clinically meaningful differences were observed between mannitol and control treatments (including dornase alfa).There is moderate-quality evidence to show that treatment with mannitol over a six-month period is associated with an improvement in some measures of lung function in people with cystic fibrosis compared to control. There is low to very low-quality evidence suggesting no difference in quality of life for participants taking mannitol compared to control. This review provides very low-quality evidence suggesting no difference in lung function or quality of life comparing mannitol to dornase alfa alone and to mannitol plus dornase alfa. The clinical implications from this review suggest that mannitol could be considered as a treatment in cystic fibrosis; but further research is required in order to establish who may benefit most and whether this benefit is sustained in the longer term. Furthermore, studies comparing its efficacy against other (established) mucolytic therapies need to be undertaken before it can be considered for mainstream practice.پیشینه: عوامل دارویی متعددی برای پاک کردن ترشحات از مجاری هوایی مبتلایان به فیبروز سیستیک استفاده می‌شوند. مانیتول پاکسازی موکوسیلیاری را افزایش می‌دهد، اما مکانیسم دقیق عملکرد آن ناشناخته است. فرمولاسیون پودر خشک مانیتول در مقایسه با عوامل تائید شده شده که توسط نبولایزر تجویز می‌شوند، ممکن است برای استفاده، راحت‌تر و آسان‌تر باشد. کارآزمایی‌های فاز III پودر خشک استنشاقی مانیتول برای درمان فیبروز سیستیک به پایان رسیده و هم اکنون در استرالیا و برخی از کشورهای اروپایی در دسترس قرار دارد. این یک به‌روزرسانی از یک مرور کاکرین است که قبلا منتشر شده است. اهداف: ارزیابی اینکه آیا پودر خشک استنشاقی مانیتول به خوبی تحمل می‌شود، آیا کیفیت زندگی و عملکرد تنفسی را در افراد مبتلا به فیبروز سیستیک بهبود می‌بخشد یا اینکه چه عوارض جانبی با درمان همراه است. روش‌های جست‌وجو: ما پایگاه ثبت کارآزمایی‌های گروه فیبروز کیستیک و اختلالات ژنتیکی در کاکرین را جست‌وجو کردیم که شامل منابع شناسایی‌شده از طریق جست‌وجوهای جامع در پایگاه‌های اطلاعاتی الکترونیکی، جست‌وجوهای دستی در مجلات مربوطه، کتاب‌های چکیده و مجموعه مقالات کنفرانس‌ها است. تاریخ آخرین جست‌وجو: 12 دسامبر 2019. معیارهای انتخاب: تمام مطالعات تصادفی‌سازی و کنترل شده که به مقایسه مانیتول با دارونما (placebo)، مقایسه کننده‌های استنشاقی فعال (به عنوان مثال، سالین هیپرتونیک یا دورناز آلفا) یا عدم درمان پرداختند. گردآوری و تجزیه‌وتحلیل داده‌ها: نویسندگان به‌طور مستقل از هم مطالعات را برای ورود ارزیابی کردند، داده‌‌ها را استخراج کرده و خطر سوگیری (bias) را در مطالعات وارد شده ارزیابی کردند. کیفیت شواهد با استفاده از GRADE ارزیابی شد. نتایج اصلی: شش مطالعه (گزارش شده در 36 مقاله تکی) با 784 شرکت‌کننده وارد شدند. مدت زمان درمان در مطالعات وارد شده، از 12 روز تا شش ماه متغیر بود، با درمان برچسب باز به مدت شش ماه بیشتر در دو مطالعه. پنج مطالعه مانیتول را با کنترل (دوز بسیار کمی از مانیتول یا مانیتول غیرقابل تنفس) مقایسه کرده و مطالعه نهایی به مقایسه مانیتول با دورناز آلفا به تنهایی و مانیتول به اضافه دورناز آلفا پرداخت. دو مطالعه بزرگ از یک طراحی موازی مشابه برخوردار بوده و داده‌ها را برای 600 شرکت‌کننده ارائه کردند، که می‌توانست در جایی که داده‌ها برای یک پیامد و نقطه زمانی خاص در دسترس بودند، تجمیع شوند. مطالعات باقیمانده حجم نمونه‌های بسیار کمتری داشتند (از 22 تا 95) و به دلیل تفاوت‌ها در طراحی مطالعه، مداخلات و جمعیت، داده‌ها قابل تجمیع نبودند. شواهد تجمعی از دو مطالعه موازی بزرگ، كیفیت پایین تا متوسطی داشته و شواهد به دست آمده از مطالعات كوچكتر به نظر می‌رسید كه از كیفیت پائین تا بسیار پائینی برخوردار بودند. در تمام مطالعات، آزمایش اولیه‌ای وجود داشت تا مشخص شود که شرکت‌کنندگان قادر به تحمل مانیتول بودند یا خیر، فقط کسانی که می‌توانستند دارو را تحمل کنند، تصادفی‌سازی شدند؛بنابراین، نتایج مطالعه برای کل جمعیت مبتلا به فیبروز سیستیک کاربرد ندارند. در حالی که مقالات منتشر شده تمام داده‌های مورد نیاز را برای تجزیه‌و‌تحلیل ما ارائه نمی‌دهند، داده‌های منتشر نشده اضافی توسط سازنده دارو و نویسنده یکی از مطالعات ارائه شد. تجمیع مطالعات موازی بزرگ که به مقایسه مانیتول با کنترل، تا شش ماه و شامل 6 ماه پرداختند، نشان دادند که عملکرد ریه (حجم اجباری بازدمی در یک ثانیه)، اندازه‌گیری شده به هر دو صورت میلی‌لیتر و درصد پیش‌بینی شده، در گروه مانیتول نسبت به گروه کنترل به‌طور قابل توجهی بهبود یافت (شواهد با کیفیت متوسط). در این مطالعات نتایج مفیدی در بزرگسالان و در هر دو گروه مصرف کننده همزمان دورناز آلفا و کسانی که از آن استفاده نکردند، مشاهده شد. در مطالعات کوچکتر نیز پیشرفت‌های معنی‌داری از نظر آماری در عملکرد ریه در گروه مانیتول در مقایسه با گروه‌های مانیتول غیرقابل تنفس مشاهده شد. با این حال، این شواهد از کیفیت پایین تا بسیار پایینی برخوردار بودند. برای مقایسه‌های مانیتول و کنترل، ما تفاوت‌های پایداری را در کیفیت زندگی مرتبط با سلامت در هیچ یک از حوزه‌ها به جز بار (burden) درمان پیدا نکردیم، که برای مانیتول تا چهار ماه، در دو مطالعه تجمیع شده با طراحی مشابه، کمتر بود؛ این اختلاف در شش ماه باقی نماند. لازم به ذکر است که ابزار مورد استفاده برای سنجش کیفیت زندگی مرتبط با سلامت، که برای ارزیابی موکولیتیک‌ها و ادغام ابزارهای مناسب سن (همانطور که در برخی از مطالعات وارد شده انجام شد) طراحی نشده بود، ممکن است معتبر نباشد، بنابراین نتایج با کیفیت پایین تا بسیار پایین داوری شدند و باید با احتیاط تفسیر شوند. سرفه، هموپتیزی، برونکواسپاسم، درد فارنگولارنژیال و استفراغ پس از سرفه، شایع‌ترین عوارض جانبی در هر دو گروه درمانی بودند. در جایی که میزان عوارض جانبی با هم قابل مقایسه بودند، از نظر آماری تفاوت معنی‌داری بین مانیتول و گروه کنترل مشاهده نشد؛ اگرچه برخی از این حوادث ممکن است ارتباط بالینی برای افراد مبتلا به CF داشته باشند. برای مقایسه‌های مانیتول با دورناز آلفا به تنهایی و مانیتول به علاوه دورناز آلفا، شواهدی با کیفیت بسیار پایین از یک مطالعه متقاطع 12 هفته‌ای با 28 شرکت‌کننده به دست آمد که هیچ تفاوت آماری معنی‌داری را در حوزه‌های ثبت شده کیفیت زندگی مرتبط با سلامت یا معیارهای عملکرد ریه نشان ندادند. سرفه شایع‌ترین عارضه جانبی در بازوی مانیتول به تنهایی بود اما هیچ موردی از وقوع سرفه در بازوی دورناز آلفا به تنهایی وجود نداشت و شایع‌ترین دلیل خروج از بازوی مانیتول به علاوه دورناز آلفا، تشدید حملات ریوی گزارش شد. از نظر پیامدهای ثانویه مرور (تشدید حملات ریوی، بستری در بیمارستان، علائم، میکروبیولوژی خلط)، شواهد ارائه شده توسط مطالعات وارد شده، محدودتر بودند. برای همه مقایسه‌ها، هیچ تفاوتی معنی‌دار آماری پایداری و تفاوت بالینی قابل‌توجهی بین درمان‌های مانیتول و کنترل (از جمله دورناز آلفا) مشاهده نشد. نتیجه‌گیری‌های نویسندگان: شواهدی با کیفیت متوسط وجود دارد که نشان می‌دهد درمان با مانیتول در طول یک دوره شش ماهه، با بهبود برخی معیارهای عملکرد ریه در افراد مبتلا به فیبروز سیستیک در مقایسه با کنترل همراه است. شواهدی با کیفیت پایین تا بسیار پایین وجود دارد که نشان می‌دهد هیچ تفاوتی در کیفیت زندگی شرکت‌کنندگان تحت درمان با مانیتول در مقایسه با کنترل، وجود ندارد. این مرور شواهدی را با کیفیت بسیار پائین نشان می‌دهد که هیچ تفاوتی در عملکرد ریه یا کیفیت زندگی در مقایسه مانیتول با دورناز آلفا به تنهایی و با مانیتول به همراه دورناز آلفا وجود ندارد. کاربردهای بالینی این مرور پیشنهاد می‌کند که مانیتول می‌تواند به عنوان درمانی در فیبروز سیستیک در نظر گرفته شود؛ اما تحقیقات بیشتری لازم است تا مشخص شود چه کسی بیشترین نفع را از آن می‌برد و اینکه این سود در طولانی‌مدت پایدار است یا خیر. علاوه بر این، پیش از آنکه مانیتول در طبابت بالینی به کار گرفته شود، مطالعات مربوط به مقایسه اثربخشی آن در برابر سایر روش‌های درمانی موکولیتیک (اثبات شده) باید انجام شوند.

Background: Immunophenotypes of anti-viral responses, and their relationship with asthma, allergy and lower respiratory tract infections (LRTIs) are poorly understood. We characterized multiple cytokine responses of peripheral-blood mononuclear cells to rhinovirus stimulation, and their relationship with clinical outcomes. Methods: In a population-based birth cohort, we measured 28 cytokines post-stimulation with rhinovirus-16 in 307 children aged 11 years. We used machine learning to identify patterns of cytokine responses, and related these patterns to clinical outcomes using longitudinal models. We also ascertained phytohaemagglutinin-induced TH2-cytokine responses [PHA-TH2]. Results: We identified six clusters of children based on their rhinovirus-16 responses, which were differentiated by the expression of four cytokine/chemokine groups: interferon-related-(IFN); pro-inflammatory-(Inflam); TH2-chemokine-(TH2-chem); regulatory-(Reg). Clusters differed in their clinical characteristics. Children with IFNmodInflamhighestTH2-chemhighestReghighest rhinovirus-16-induced pattern had PHA-TH2low response, and a very low asthma risk (OR:0.08 [95%CI 0.01–0.81], P=0.03). Two clusters had high risk of asthma and allergic sensitization, but with different trajectories from infancy to adolescence. The IFNlowestInflamhighTH2-chemlowRegmod cluster exhibited PHA-TH2lowest response, and was associated with early-onset asthma and sensitization, and the highest risk of asthma exacerbations (1.37 [1.07–1.76], P=0.014) and LRTI hospitalizations (2.40 [1.26–4.58], P=0.008) throughout childhood. In contrast, cluster with IFNhighestInflammodTH2-chemmodReghigh rhinovirus-16-cytokine pattern was characterized by PHA-TH2highest response, and a low prevalence of asthma/sensitization in infancy which increased sharply to become the highest among all clusters by adolescence (but with low risk of asthma exacerbations). Conclusions: Early-onset troublesome asthma with early-life sensitization, later-onset milder allergic asthma, and disease protection are each associated with different patterns of rhinovirus-induced immune responses.

BACKGROUND: It is unclear whether asthma may affect susceptibility or severity of coronavirus disease 2019 (COVID-19) in children and how pediatric asthma services worldwide have responded to the pandemic. OBJECTIVE: To describe the impact of the COVID-19 pandemic on pediatric asthma services and on disease burden in their patients. METHODS: An online survey was sent to members of the Pediatric Asthma in Real Life think tank and the World Allergy Organization Pediatric Asthma Committee. It included questions on service provision, disease burden, and the clinical course of confirmed cases of COVID-19 infection among children with asthma. RESULTS: Ninety-one respondents, caring for an estimated population of more than 133,000 children with asthma, completed the survey. COVID-19 significantly impacted pediatric asthma services: 39% ceased physical appointments, 47% stopped accepting new patients, and 75% limited patients' visits. Consultations were almost halved to a median of 20 (interquartile range, 10-25) patients per week. Virtual clinics and helplines were launched in most centers. Better than expected disease control was reported in 20% (10%-40%) of patients, whereas control was negatively affected in only 10% (7.5%-12.5%). Adherence also appeared to increase. Only 15 confirmed cases of COVID-19 were reported among the population; the estimated incidence is not apparently different from the reports of general pediatric cohorts. CONCLUSIONS: Children with asthma do not appear to be disproportionately affected by COVID-19. Outcomes may even have improved, possibly through increased adherence and/or reduced exposures. Clinical services have rapidly responded to the pandemic by limiting and replacing physical appointments with virtual encounters. (C) 2020 American Academy of Allergy, Asthma & Immunology.

Introduction Exacerbation‐prone asthma subtype has been reported in studies using data‐driven methodologies. However, patterns of severe exacerbations have not been studied. Objective To investigate longitudinal trajectories of severe wheeze exacerbations from infancy to school age. Methods We applied longitudinal k‐means clustering to derive exacerbation trajectories among 887 participants from a population‐based birth cohort with severe wheeze exacerbations confirmed in healthcare records. We examined early‐life risk factors of the derived trajectories, and their asthma‐related outcomes and lung function in adolescence. Results 498/887 children (56%) had physician‐confirmed wheeze by age 8 years, of whom 160 had at least one severe exacerbation. A two‐cluster model provided the optimal solution for severe exacerbation trajectories among these 160 children: “Infrequent exacerbations (IE)” (n = 150, 93.7%) and “Early‐onset frequent exacerbations (FE)” (n = 10, 6.3%). Shorter duration of breastfeeding was the strongest early‐life risk factor for FE (weeks, median [IQR]: FE, 0 [0‐1.75] vs. IE, 6 [0‐20], P

Background Asthma prevalence is 339 million globally. ‘Severe asthma’ (SA) comprises subjects with uncontrolled asthma despite proper management. Objectives To compare asthma from diverse ethnicities and environments. Methods A cross-sectional analysis of two adult cohorts, a Brazilian (ProAR) and a European (U-BIOPRED). U-BIOPRED comprised of 311 non-smoking with Severe Asthma (SAn), 110 smokers or ex-smokers with SA (SAs) and 88 mild to moderate asthmatics (MMA) while ProAR included 544 SA and 452 MMA. Although these projects were independent, there were similarities in objectives and methodology, with ProAR adopting operating procedures of U-BIOPRED. Results Among SA subjects, age, weight, proportion of former smokers and FEV1 pre-bronchodilator were similar. The proportion of SA with a positive skin prick tests (SPT) to aeroallergens, the scores of sino-nasal symptoms and quality of life were comparable. In addition, blood eosinophil counts (EOS) and the % of subjects with EOS > 300 cells/μl were not different. The Europeans with SA however, were more severe with a greater proportion of continuous oral corticosteroids (OCS), worse symptoms and more frequent exacerbations. FEV1/FVC pre- and post-bronchodilator were lower among the Europeans. The MMA cohorts were less comparable in control and treatment, but similar in the proportion of allergic rhinitis, gastroesophageal reflux disease and EOS >3%. Conclusions ProAR and U-BIOPRED cohorts, with varying severity, ethnicity and environment have similarities, which provide the basis for global external validation of asthma phenotypes. This should stimulate collaboration between asthma consortia with the aim of understanding SA, which will lead to better management.

BACKGROUND: Pediatric asthma remains a public health challenge with enormous impact worldwide.OBJECTIVE: The aim of this study was to identify and prioritize unmet clinical needs in pediatric asthma, which could be used to guide future research and policy activities.METHODS: We first identified unmet needs through an open question survey administered to international experts in pediatric asthma who were members of the Pediatric Asthma in Real Life Think Tank. Prioritization of topics was then achieved through a second, extensive survey with global reach, of multiple stakeholders (leading experts, researchers, clinicians, patients, policy makers, and the pharmaceutical industry). Differences across responder groups were compared.RESULTS: A total of 57 unmet clinical need topics identified by international experts were prioritized by 412 participants from 5 continents and 60 countries. Prevention of disease progression and prediction of future risk, including persistence into adulthood, emerged as the most urgent research questions. Stratified care, based on biomarkers, clinical phenotypes, the children's age, and demographics were also highly rated. The identification of minimum diagnostic criteria in different age groups, cultural perceptions of asthma, and best treatment by age group were priorities for responders from low-middle income countries. There was good agreement across different stakeholder groups in all domains with some notable exceptions that highlight the importance of involving the whole range of stakeholders in formulation of recommendations.CONCLUSIONS: Different stakeholders agree in the majority of research and strategic (eg, prevention, personalized approach) priorities for pediatric asthma. Stakeholder diversity is crucial for highlighting divergent issues that future guidelines should consider. (c) 2020 American Academy of Allergy, Asthma & Immunology

Background Lung clearance index (LCI), measured using multiple breath inert gas washout (MBW) is a potentially useful test in infants with respiratory disease, particularly cystic fibrosis (CF). Clinical use is limited however by the need for specialist staff and equipment. We have previously described a novel method for infant MBW suitable for use outside of specialist laboratories. This study describes its performance in vivo in infants with CF and healthy controls, including a limited comparison with the respiratory mass spectrometer. Methods Children aged less than 2 years with CF and controls underwent MBW testing on a single occasion. The practical applicability of the system was determined by the number of successful duplicate tests and within-subject repeatability. Results Twenty-five children (seven with CF, 18 healthy controls, all sedated with chloral hydrate) attempted MBW. Twenty patients (seven with CF) successfully underwent duplicate testing (80% success rate). Mean within-subject coefficient of variation for functional residual capacity (FRC) was 7.2% and for LCI 5.9%. Comparison of LCI with the mass spectrometer was limited but gave very similar values for LCI and FRC in those patients who underwent technically adequate tests with both methods. Conclusions We have described a new MBW method that is feasible and reproducible in sedated infants. Results fall within the expected range, and well within accuracy limits set by international guidelines. This could provide a more accessible alternative to previously described systems for infant MBW, and overcomes many of the technical challenges inherent in conventional MBW.

No abstract available.

Rationale: Pooling data from multiple cohorts and extending the time frame across childhood should minimize study-specific effects, enabling better characterization of childhood wheezing. Objectives: To analyze wheezing patterns from early childhood to adolescence using combined data from five birth cohorts. Methods: We used latent class analysis to derive wheeze phenotypes among 7,719 participants from five birth cohorts with complete report of wheeze at five time periods. We tested the associations of derived phenotypes with late asthma outcomes and lung function, and investigated the uncertainty in phenotype assignment. Results: We identified five phenotypes: never/infrequent wheeze (52.1%), early onset preschool remitting (23.9%), early onset midchildhood remitting (9%), persistent (7.9%), and late-onset wheeze (7.1%). Compared with the never/infrequent wheeze, all phenotypes had higher odds of asthma and lower forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity in adolescence. The association with asthma was strongest for persistent wheeze (adjusted odds ratio, 56.54; 95% confidence interval, 43.75–73.06). We observed considerable within-class heterogeneity at the individual level, with 913 (12%) children having low membership probability (

Childhood wheezing is common particularly in children under the age of 6 years and in this age group is generally referred to as preschool wheezing. Particular diagnostic and treatment uncertainties exist in these young children due to the difficulty in obtaining objective evidence of reversible airways narrowing and inflammation. A diagnosis of asthma depends on the presence of relevant clinical signs and symptoms and the demonstration of reversible airways narrowing on lung function testing, which is difficult to perform in young children. Few treatments are available and inhaled corticosteroids are the recommended preventer treatment in most international asthma guidelines. There is, however, considerable controversy about its effectiveness in children with preschool wheeze and a corticosteroid responder phenotype has not been established. These diagnostic and treatment uncertainties in conjunction with the knowledge of corticosteroid side effects, in particular the reduction of growth velocity, have resulted in a variable approach to inhaled corticosteroid prescribing by medical practitioners and a reluctance in carers to regularly administer the treatment. Identifying children who are likely responders to corticosteroid therapy would be a major benefit in the management of this condition. Eosinophils have emerged as a promising biomarker of corticosteroid responsive airways disease, and evaluation of this biomarker in sputum has successfully been employed to direct management in adults with asthma. Obtaining sputum from young children is time consuming and difficult, and it is hard to justify more invasive procedures such as a bronchoscopy in young children routinely. Recently, in children, interest has shifted to assessing the value of less invasive biomarkers of likely corticosteroid response and the biomarker 'blood eosinophils' has emerged as an attractive candidate. The aim of this review was to summarize the evidence for blood eosinophils as a predictive biomarker for corticosteroid responsive disease with a particular focus on the difficult area of preschool wheeze.

Background The relationship between allergic sensitisation and asthma is complex; the data about the strength of this association are conflicting. We propose that the discrepancies arise in part because allergic sensitisation may not be a single entity (as considered conventionally) but a collection of several different classes of sensitisation. We hypothesise that pairings between immunoglobulin E (IgE) antibodies to individual allergenic molecules (components), rather than IgE responses to ‘informative’ molecules, are associated with increased risk of asthma. Methods and findings In a cross-sectional analysis among 461 children aged 11 years participating in a population-based birth cohort, we measured serum-specific IgE responses to 112 allergen components using a multiplex array (ImmunoCAP Immuno‑Solid phase Allergy Chip [ISAC]). We characterised sensitivity to 44 active components (specific immunoglobulin E [sIgE] > 0.30 units in at least 5% of children) among the 213 (46.2%) participants sensitised to at least one of these 44 components. We adopted several machine learning methodologies that offer a powerful framework to investigate the highly complex sIgE–asthma relationship. Firstly, we applied network analysis and hierarchical clustering (HC) to explore the connectivity structure of component-specific IgEs and identify clusters of component-specific sensitisation (‘component clusters’). Of the 44 components included in the model, 33 grouped in seven clusters (C.sIgE-1–7), and the remaining 11 formed singleton clusters. Cluster membership mapped closely to the structural homology of proteins and/or their biological source. Components in the pathogenesis-related (PR)-10 proteins cluster (C.sIgE-5) were central to the network and mediated connections between components from grass (C.sIgE-4), trees (C.sIgE-6), and profilin clusters (C.sIgE-7) with those in mite (C.sIgE-1), lipocalins (C.sIgE-3), and peanut clusters (C.sIgE-2). We then used HC to identify four common ‘sensitisation clusters’ among study participants: (1) multiple sensitisation (sIgE to multiple components across all seven component clusters and singleton components), (2) predominantly dust mite sensitisation (IgE responses mainly to components from C.sIgE-1), (3) predominantly grass and tree sensitisation (sIgE to multiple components across C.sIgE-4–7), and (4) lower-grade sensitisation. We used a bipartite network to explore the relationship between component clusters, sensitisation clusters, and asthma, and the joint density-based nonparametric differential interaction network analysis and classification (JDINAC) to test whether pairwise interactions of component-specific IgEs are associated with asthma. JDINAC with pairwise interactions provided a good balance between sensitivity (0.84) and specificity (0.87), and outperformed penalised logistic regression with individual sIgE components in predicting asthma, with an area under the curve (AUC) of 0.94, compared with 0.73. We then inferred the differential network of pairwise component-specific IgE interactions, which demonstrated that 18 pairs of components predicted asthma. These findings were confirmed in an independent sample of children aged 8 years who participated in the same birth cohort but did not have component-resolved diagnostics (CRD) data at age 11 years. The main limitation of our study was the exclusion of potentially important allergens caused by both the ISAC chip resolution as well as the filtering step. Clustering and the network analyses might have provided different solutions if additional components had been available. Conclusions Interactions between pairs of sIgE components are associated with increased risk of asthma and may provide the basis for designing diagnostic tools for asthma., Adnan Custovic and colleagues demonstrate that combinations of allergen sensitivities in children can be used to predict concurrent asthma diagnosis., Author summary Why was this study done? The relationship between allergic sensitisation and asthma is complex. Asthma prediction models based on the IgE responses to the whole allergen extracts exhibit relatively poor performance. This study examines the relationship between IgE responses to multiple allergen components in component-resolved diagnostics (CRD) and their associations with asthma. What did the researchers do and find? Serum-specific IgE responses to 112 allergen components were measured using a multiplex array among children in a population-based birth cohort. Researchers applied network analysis and hierarchical clustering (HC) to explore the connectivity structure of component-specific IgEs and identified seven clusters of component-specific sensitisation. Cluster membership mapped closely to the structural homology of proteins and/or their biological source. HC identified four ‘sensitisation clusters’ among study participants. The relationship between component clusters, sensitisation clusters, and asthma was explored using a bipartite network. The differential network of pairwise component-specific IgE interactions was inferred, which demonstrated that interactions among 18 pairs of allergen components predicted asthma with a good balance between sensitivity and specificity. For example, children with IgE antibodies to different allergenic proteins from both dog and cat, or horse and house dust mite, are at higher risk of developing asthma. What do these findings mean? IgE responses to multiple allergenic proteins are functionally coordinated and co-regulated. Pairwise interactions within this complex network predict clinical phenotypes. Interactions between pairs of sIgE components are associated with increased risk of asthma and provide the basis for designing diagnostic tools for asthma.

BACKGROUND: In a population-based sample of school-age children, we investigated factors associated with rhinitis, and differences between allergic and nonallergic rhinitis. Amongst children with asthma, we explored the association between rhinitis and asthma severity. METHODS: Children participating in a birth cohort study (n = 906) were reviewed at age 8 years. Asthma was defined as at least two of the following three features: physician-diagnosed asthma, currently using asthma medication and current wheeze. We measured lung function (plethysmography and spirometry) and airway hyper-reactivity (AHR; methacholine challenge). RESULTS: In the analysis adjusted for the presence of asthma, children with rhinitis had significantly higher AHR (P = 0.001). Maternal smoking and absence of breastfeeding were stronger predictors of nonallergic rhinitis, whereas current wheeze and eczema were stronger predictors of allergic rhinitis. Amongst asthmatics (n = 159), when compared to 76 children without rhinitis, those with rhinitis (n = 83) were 2.89-fold (95% CI 1.41-5.91) more likely to experience frequent attacks of wheezing, 3.44-fold (1.19-9.94) more likely to experience severe attacks of wheezing limiting speech, 10.14-fold (1.27-81.21) more likely to have frequent visits to their doctor because of asthma and nine-fold (1.11-72.83) more likely to miss school. Reported use of intranasal corticosteroids resulted in a numerically small, but consistent reduction in risk, rendering the associations between rhinitis and asthma severity nonsignificant. CONCLUSION: We observed differences in risk factors and severity between allergic and nonallergic rhinitis. In children with asthma, rhinitis had adverse impact on asthma severity. The use of intranasal corticosteroids resulted in a small, but consistent reduction in the risk.

BACKGROUND: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma. C.O. is supported by a NIH grant that supported the Hutterite studies (R01 HL085197). D.E. is supported by UK Medical Research Council Centre (G0600705). G.S. is supported by UK Medical Research Council Centre (G0600705). J.K. is funded by a Wellcome Trust 4-year PhD studentship in molecular, genetic, and life course epidemiology (WT083431MA). L.D. is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community’s Seventh Framework Programme FP7/2007-2013–Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 (no. MC 1226- 2009). N.T. is supported by UK Medical Research Council Centre (G0600705). R.V. was partly supported by an unrestricted personal grant from GlaxoSmithKline, NL. V.J. is supported by the Netherlands Organization for Health Research and Development (ZonMw 90700303, 916.10159). L. Duijts is supported by a European Respiratory Society/Marie Curie Joint Research Fellowship of the European Respiratory Society and the European Community’s Seventh Framework Programme (FP7/2007-2013-Marie Curie Actions under grant agreement RESPIRE, PCOFUND-GA-2008-229571 [no. MC 1226-2009]). M. T. Salam has received research support from the National Heart, Lung, and Blood Institute (NHLBI; 5R01HL61768 and 5R01HL76647); the Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048); and the Environmental Protection Agency (EPA; 5P01ES009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627), and the Hastings Foundation. J. Genuneit has received grant EuFP6 (018996 under IP LSH-2004-1.25- 1). Evans has received a grant in the form of the MRC New Investigator Award G0600705. B. St Pourcain has received research support with Autism Speaks (7132). O. Fuchs has received research support from the European Commission within Seventh Framework Programme (theme FP7-KBBE-2007- 1) as part of EFRAIM (Impact of exogenous factors in the development of Allergy, contract no. 211911), the European Respiratory Society for a long-term research fellowship (no. 675). F. D. Gilliand has received research support from the NHLBI (5R01HL61768 and 5R01HL76647), Southern California Environmental Health Sciences Center funded by the National Institute of Environmental Health Sciences (5P30ES007048), the Children’s Environmental Health Center funded by the National Institute of Environmental Health Sciences and the Environmental Protection Agency (5P01Es009581, R826708-01, and RD831861-01), the National Institute of Environmental Health Sciences (5P01ES011627)

BACKGROUND: Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalised management approach can be provided.OBJECTIVES: We stratified patients with moderate-to-severe asthma based on clinico-physiological parameters and performed an -omics analysis of sputum.METHODS: Partition-around-medoid clustering was applied to a training set of 266 asthma participants from the European U-BIOPRED adult cohort using 8 pre-specified clinic-physiological variables. This was repeated in a separate validation set of 152 asthmatics. The clusters were compared based on sputum proteomic and transcriptomic data.RESULTS: Four reproducible and stable clusters of asthmatics were identified. The training set cluster T1 consists of well-controlled moderate-to-severe asthmatics, while cluster T2 is a group of late-onset severe asthmatics with history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of non-smokers. Cluster T4 is predominantly composed of obese female uncontrolled severe asthmatics with increased exacerbations, but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters, T2, T3 and T4, had higher sputum eosinophilia than T1 with no differences in sputum neutrophil counts, exhaled nitric oxide and serum IgE levels.CONCLUSION: Clustering based on clinico-physiological parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.CLINICAL IMPLICATIONS: The definition of four distinct clusters of asthma linked to different pathobiological pathways provides a better template for the phenotyping and personalised treatment of severe asthma, where high unmet needs remain.CAPSULE SUMMARY: Unsupervised clustering of asthma on clinical features alone has led to the definition of four phenotypes. Sputum 'omics' analysis has revealed different biological pathways pointing towards potential new treatments.

ObjectiveTo produce study-specific portion sizes for 11-year-old children in a population-based birth cohort and to compare these study-specific portion sizes with previously published children's portion sizes, to assess their relevance today.DesignTwo multiple-pass 24 h dietary recalls were taken. The Food Standard Agency's photographic food atlas was used to quantify intakes. Study-specific food portion sizes were calculated for each food group. Portion sizes were calculated for all children and separately for boys and girls. The nutrient intake from the 24 h dietary recalls was analysed using study-specific and published portion sizes for individual participants. Agreement was assessed using Pearson's correlation, intra-class correlation coefficients and the Bland–Altman method.SettingBirth cohort study, UK.SubjectsChildren (mean age 11·3 years, n 264) and parents/guardians.ResultsA total of 124 food portion sizes were calculated. Differences in portion weights between boys and girls were seen only for seven food items. There was a significant positive relationship (P < 0·001) between intakes of each nutrient as determined by the two sets of portion sizes. Correlation coefficients ranged from 0·77 (protein) to 0·98 (β-carotene). The intra-class correlation coefficients showed good agreement between nutrient intakes determined by the study-specific and published portion sizes (P < 0·001).ConclusionsNutrient intakes calculated using portion sizes from our population were similar to those calculated from portion size data collected in a national survey, despite being collected over a decade later. The present study adds to the small amount of evidence regarding portion sizes in UK children and shows agreement with previously published paediatric portion sizes.

BACKGROUND: Allergic disease has been associated with altered intestinal microbiota. Therefore, probiotics have been suggested as a potential treatment for eczema. OBJECTIVE: We investigated whether dietary supplementation of infants with eczema at age 3-6 months with Lactobacillus paracasei CNCM I-2116 or Bifidobacterium lactis CNCM I-3446 had a treatment effect or altered allergic disease progression. METHODS: Primary outcome included eczema severity (SCORing Atopic Dermatitis, SCORAD) 3 months post-randomization. Secondary: SCORAD (other visits); infant dermatitis quality of life (IDQoL); gastrointestinal permeability; urinary eosinophilic protein X; allergen-sensitization; allergic symptoms (age 12, 18, 36 months). A total of 208 infants aged 3-6 months with physician-diagnosed eczema were recruited; 137/208 (SCORAD ? 10, consuming ? 200 mL standard formula/day) were randomized to daily supplements containing L. paracasei or B. lactis or placebo for a 3-month period, while receiving extensively hydrolysed whey-formula (dairy-free diet). There were two open observational groups, one group exclusively breastfed (n = 22) and the other, standard formula-fed (n = 49). TRIAL NUMBER: ISRCTN41490500. RESULTS: Eczema severity decreased significantly over time in all groups. No significant difference was observed between randomized groups after 12-week treatment-period (SCORAD-score pre-/post-intervention: B. lactis 25.9 [95% CI: 22.8-29.2] to 12.8 [9.4-16.6]; L. paracasei 25.4 [22.1-29] to 12.5 [9.2-16.4]; placebo 26.9 [23.4-30.6] to 11.8 [9.6-14.3]; P = 0.7). Results were similar when analysis was controlled for allergen-sensitization, or when only sensitized infants were analysed. No differences were found for secondary outcomes. No difference was observed in SCORAD-score between randomized and observational groups. CONCLUSION AND CLINICAL RELEVANCE: We found no benefit from supplementation with B. lactis or L. paracasei in the treatment of eczema, when given as an adjunct to basic topical treatment, and no effect on the progression of allergic disease from age 1 to 3 years.

Background: Allergic diseases have risen in prevalence over recent decades. The aetiology remains unclear but is likely to be a result of changing lifestyle and/or environment. A reduction in antioxidant intake, consequent to reduced intake of fresh fruits and vegetables, has been suggested as a possible cause. Objective: To investigate whether dietary antioxidant intake at age 5 was related to atopy at 5 and 8 years of age amongst children in an unselected birth cohort. Methods: Children were followed from birth. Parents completed a validated respiratory questionnaire and children were skin prick tested at 5 and 8 years of age. Serum IgE levels were measured at age 5. At age 5, antioxidant intake was assessed using a semi-quantitative food frequency questionnaire (FFQ). A nutrient analysis program computed nutrient intake, and frequency counts of foods high in the antioxidant vitamins A, C and E were assessed. Results: Eight hundred and sixty-one children completed both the respiratory and FFQ. Beta-carotene intake was associated with reduced risk of allergic sensitization at age 5 [0.80 (0.68–0.93)] and 8 [0.81 (0.70–0.94)]. In addition, beta-carotene intake was negatively associated with total IgE levels (P = 0.002). Vitamin E intake was associated with an increased risk of allergic sensitization [1.19 (1.02–1.39)], only at age 5. There was no association between antioxidant intakes and wheeze or eczema. Conclusion: Increased beta-carotene intake was associated with a reduced risk of allergic sensitization and lower IgE levels, in 5- and 8-year-old children. Dietary antioxidants may play a role in the development of allergic sensitization.

PURPOSE OF REVIEW: Asthma is characterised by variable airflow obstruction, airway inflammation and hyper-responsiveness. Persistent inflammation is thought to lead to 'remodelling' of the airway, which in turn leads to the progressive loss of lung function seen in asthmatics. It would appear logical that anti-inflammatory drugs such as inhaled corticosteroids (ICS) would influence the natural history of asthma by reducing inflammation, subsequent remodelling, and thus preventing the decline in lung function. This review will summarise the effects of ICS on the secondary prevention of asthma, lung function and remodelling. RECENT FINDINGS: Many published studies show a reduction in airway inflammation, improvement in clinical symptoms and prebronchodilator lung function whilst taking ICS. Few studies, however, examine their effect on the natural history of asthma. Several recent studies have targeted very young children with asthma using ICS, and despite their differing target populations and treatment strategies, have failed to show any difference in lung function. Studies in adults with mild persistent asthma show similar findings. ICS appear to reverse some of the processes involved in airway remodelling, but not all. SUMMARY: Although ICS are effective in controlling symptoms they do not appear to alter the natural history of asthma.

Background Skin prick tests (SPTs) and allergen-specific serum IgE (sIgE) measurements are the main diagnostic tools for confirming atopic sensitization. Results are usually reported as 'positive' or 'negative', using the same arbitrary cut-offs (SPT>3 mm, sIgE>0.35 kUA /l) across different ages and sexes. We investigated the influence of age and sex on the interpretation of allergy test in the context of childhood asthma. Methods In a population-based birth cohort (n = 1051), we ascertained the information on asthma/wheeze (validated questionnaires) and performed SPTs and sIgE measurement to inhalant allergens (dust mite, cat, dog) at follow-ups between ages three and 11 years. We investigated the association between quantitative sensitization (sum of SPT mean wheal diameters [MWD] and sIgE titres to the three allergens) and current wheeze and asthma across ages and sexes. Results We observed a significant association between the SPT MWD and sIgE titres and wheeze/asthma at most ages and for both sexes. However, the strength of this association was age- and sex-dependent. For SPTs, the strength of the association between MWD and asthma increased with increasing age; we observed the opposite pattern for sIgE titre. For any given SPT MWD/sIgE titre, boys were significantly more likely to express clinical symptoms, particularly in early life; this difference between males and females diminished with age and was no longer significant by age 11 years. Conclusions Age and sex should be taken into account when interpreting the results of skin tests and sIgE measurement, and age- and sex-specific normative data are needed for these allergy tests.

Sarah J. Nolan *, Judith Thornton , Clare S. Murray , Tiffany Dwyer 4 Department of Biostatistics, The University of Liverpool, Liverpool, UK Centre for Clinical Practice, National Institute for Health and Care Excellence, Manchester, UK Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, University of Manchester and University Hospital of South Manchester, Manchester, UK 4 Sydney Medical School, University of Sydney, Sydney, Australia

Multiple breath washout (MBW) in infants presents a number of technical challenges. Conventional MBW is based on simultaneous measurement of flow and gas concentrations. These two signals are aligned and combined to derive expired gas volumes from which lung volumes and measures of ventilation inhomogeneity are calculated. Accuracy of measurement becomes increasingly vulnerable to errors in gas signal alignment at fast respiratory rates. In this paper we describe an alternative method of performing MBW in infants. Expired gas is collected and analyzed to derive functional residual capacity (FRC) and lung clearance index (LCI). This eliminates the need for simultaneous measurement of flow, and integration of flow and gas signals, and significantly reduces deadspace.A highly accurate lung model incorporating BTPS conditions was used to generate realistic infant breathing parameters: FRC of 100-250 mls with respiratory rate of 20-60 min(-1) . In vitro accuracy of FRC measurement using the novel MBW method was assessed using the model.Overall mean error (standard deviation) of FRC measurement was -1.0 (3.3)% with 90% of tests falling within ±5%.FRC measurement using the novel method has superior accuracy in vitro than previously described systems. By uncoupling the measurement of gas volumes from real-time flow and gas measurement, this system offers an alternative method of MBW which is well suited to infants.

When standard doses of inhaled corticosteroids (ICS) fail to control symptoms in children aged >4 years, guidelines recommend the addition of a long-acting β2-agonist (LABA), with other treatment options being available if symptoms persist. To determine the proportion of initial ‘step-up’ episodes where LABAs were prescribed and to describe characteristics of individuals not stepped up with LABA. Between 1999 and 2011, initial step-up episodes from ICS monotherapy were identified in children aged 5–12 years with asthma and in receipt of ICS. Data sources were the Clinical Practice Research Datalink and Optimum Patient Care Research Database. Initial step-up episodes were identified in 10,793 children. ICS dose was increased in 6,252 children (58%), LABA was introduced in 3,436 (32%; including 1,107 where fixed dose combination inhaler (FDC) replaced the ICS inhaler), and leukotriene receptor antagonist (LTRA) was added in 1,105 (10%). Compared with children stepped up to any LABA, others were younger and prescribed lower doses of ICS and reliever medication. ICS dose increase was more likely in obese children and LTRA prescribing was more likely in children with rhinitis and in receipt of antibiotics. Compared with FDC, step-up to separate LABA inhaler was more likely in younger, obese children who were using less oral steroids. One-third of initial step-up episodes in children with asthma treated with ICS are to add LABA. Different characteristics of children prescribed therapies other than LABA suggest that prescribers tailor treatment in some clinical settings. Clinicians in the UK frequently opt to deviate from the guidelines for increasing treatment choices in children with asthma. When standard doses of inhaled corticosteroids (ICS) fail to control symptoms in children older than four years, guidelines recommend adding long-acting beta agonist (LABA), with other treatment options considered if symptoms persist. Stephen Turner at the University of Aberdeen and co-workers across the UK conducted a historical cohort study of treatment “step-up” choices in 10,793 children aged between 5 and 12. An increased dose of ICS was prescribed for 58% of the children. LABA was introduced for only 32%, combined in some cases with either a change of inhaler type or prescribing leukotriene receptor antagonist. Deviation from treatment guidelines appears to be an active decision based on patient characteristics including obesity, antibiotic therapy and rhinitis.

In the UK, almost 15% of the annual healthcare budget is set aside by the National Health Service (NHS) for specialised services . This significant resource (£14 billion last year) is directed towards a clearly defined pool of uncommon and complex conditions, and specifically supports small numbers of ‘centres of excellence’ with large catchment areas. In respiratory medicine, specialised commissioning has funded services for cystic fibrosis and pulmonary hypertension for some years. However, variations in commissioning arrangements for other complex conditions have led to variable service provision. In 2013, NHS England (NHSE) produced service specifications for an additional set of respiratory conditions, including severe asthma1 (figure 1), and these have fuelled a good deal of debate. Figure 1 Under specialised commissioning, patients fitting the criteria would be referred to their most geographically convenient regional specialist unit from either primary, secondary or tertiary care. The specialist units, based at an unspecified number of pre-existing centres, would act as concentrated centres of excellence located around the UK, with all other severe asthma services decommissioned in their existing form. To be commissioned as a specialist unit, centres must have access to all facilities outlined in the specification4 required to deliver full multidisciplinary team assessments over 2-day case visits and must be led by at least two consultant respiratory physicians with a special interest in severe asthma. We all recognise asthma to be a major source of physical and psychological morbidity and of indirect and healthcare expenditure. Indeed, preventative inhaler therapy is the largest drug cost faced by the NHS. It came as little surprise to us that the recent National Review of Asthma Deaths revealed failings across the whole spectrum of asthma care,2 with this report and other publications (such as the NHS Atlas of Variation3) also highlighting disparities in outcomes …

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. Refereed/Peer-reviewed

U-BIOPRED aims to characterise paediatric and adult severe asthma using conventional and innovative systems biology approaches.A total of 99 school-age children with severe asthma and 81 preschoolers with severe wheeze were compared with 49 school-age children with mild/moderate asthma and 53 preschoolers with mild/moderate wheeze in a cross-sectional study.Despite high-dose treatment, the severe cohorts had more severe exacerbations compared with the mild/moderate ones (annual medians: school-aged 3.0 versus 1.1, preschool 3.9 versus 1.8; pse school-age PAQLQ: 4.77±0.15 versus 5.80±0.19; preschool PACQLQ: 4.27±0.18 versus 6.04±0.18; both p≤0.001); however, mild/moderate cohorts also had significant morbidity. Impaired quality of life was associated with poor control and airway obstruction. Otherwise, the severe and mild/moderate cohorts were clinically very similar.Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life that is associated with poor control and airflow limitation: a very different phenotype from adult severe asthma. In-depth phenotyping of these children, integrating clinical data with high-dimensional biomarkers, may help to improve and tailor their clinical management.

Background: The rising prevalence of asthma and allergic disease remains unexplained. Several risk factors have been implicated including diet, in particular poly-unsaturated fats and antioxidant intake. Methods: A nested case–control study comparing the dietary intake of sensitized children with recurrent wheeze (age 3–5 years) and nonsensitized children who had never wheezed was carried out within an unselected population-based cohort. Cases and controls were matched for age, sex, parental atopy, indoor allergen exposure and pet ownership. Dietary intake was assessed using a validated semi-quantitative food frequency questionnaire and nutrient analysis program. Results: Thirty-seven case–control pairs (23 male, mean age 4.4 years) participated. Daily total polyunsaturated fat intake was significantly higher in sensitized wheezers (g/day, geometric mean, 95% confidence intervals: 7.1, 6.4–7.9) compared with nonsensitized nonwheezy children (5.6, 5.0–6.3, P = 0.003). Daily omega-3 and omega-6 fat intakes were not significantly different between the two groups. No significant differences were found in intake of any antioxidant or antioxidant cofactors between the groups. Conclusions: Young sensitized wheezy children had a significantly higher total polyunsaturated fat intake compared with nonsensitized nonwheezy children. However, we were unable to distinguish a significant difference in specific poly-unsaturated fat intakes. Otherwise the children in both groups had a very similar nutritional intake.

Distinct phenotypes can be identified in childhood wheezing illness. Within the context of a birth cohort study, we investigated the association between preschool lung function and phenotypes of wheeze. From parentally reported history of wheeze (interviewer-administered questionnaire, age 3 and 5 years), children were classified as never wheezers, transient early wheezers, late-onset wheezers, or persistent wheezers. Lung function (specific airway resistance [sRaw]; kPa/second) was assessed at age 3 (n = 463) and 5 years (n = 690). Persistent wheezers had markedly poorer lung function compared with other groups. In children who had wheezed by age 3, the risk of persistent wheeze increased with increased sRaw (odds ratio [OR] 5.2, 95% confidence interval [CI] 1.3-22.0; p = 0.02). In a multivariate model, increasing sRaw (OR 5.5, 95% CI 1.2-25.9; p = 0.03) and the child's sensitization (OR 2.8, 95% CI 1.3-5.8; p = 0.008) were significant independent predictors of persistent wheezing. We found no association between lung function at age 3 and late-onset wheeze in children who had not wheezed previously (OR 0.6, 95% CI 0.07-5.3; p = 0.64). In conclusion, poor lung function at age 3 predicted the subsequent persistence of symptoms in children who had wheezed within the first 3 years, but was not associated with the onset of wheeze after age 3 in children who had not wheezed previously.

The gut microbiota may be important in the postnatal development of the immune system and hence may influence the prevalence of atopic diseases. Bifidobacteria are the most numerous bacteria in the guts of infants, and the presence or absence of certain species could be important in determining the geographic incidence of atopic diseases. We compared the fecal populations of bifidobacteria from children aged 25 to 35 days in Ghana (which has a low prevalence of atopy), New Zealand, and the United Kingdom (high-prevalence countries). Natal origin influenced the detection of bifidobacterial species in that fecal samples from Ghana almost all containedBifidobacterium infantiswhereas those of the other children did not. Choosing species on the basis of our bacteriological results, we tested bifidobacterial preparations for their effects on cell surface markers and cytokine production by dendritic cells harvested from cord blood. Species-specific effects on the expression of the dendritic-cell activation marker CD83 and the production of interleukin-10 (IL-10) were observed. Whereas CD83 expression was increased and IL-10 production was induced byBifidobacterium bifidum,Bifidobacterium longum, andBifidobacterium pseudocatenulatum,B. infantisfailed to produce these effects. We concluded thatB. infantisdoes not trigger the activation of dendritic cells to the degree necessary to initiate an immune response but thatB. bifidum,B. longum, andB. pseudocatenulatuminduce a Th2-driven immune response. A hypothesis is presented to link our observations to the prevalence of atopic diseases in different countries.

Summary Background The development of a method to assess lung function in young children may provide new insight into asthma development. Plethysmographic measurement of specific airway resistance (sR aw ) is feasible in this age group. We aimed to identify risk factors associated with low lung function in early childhood in a prospective birth cohort. Methods Children were prenatally assigned to risk group according to parental atopic status (high risk, both parents atopic; medium risk, one parent atopic; low risk, neither parent atopic) and followed prospectively until age 3 years. We measured sR aw in 503 symptom-free children using whole-body plethysmography during tidal breathing. Findings 803 of 868 children attended the clinic, of whom 503 obtained satisfactory sR aw readings. 200 who wheezed at least once during first 3 years of life had significantly higher sR aw than the 303 who had never wheezed (mean difference 5·8%, 95% CI 2·2–9·3, p=0·002). For children who had never wheezed there were significant differences in sR aw between risk groups (p aw (geometric mean 1·17 kPa/s, 1·12–1·22) than children at medium risk (n=162; 1·02 kPa/s, 1·00–1·05) and at low risk (54; 1·04 kPa/s, 0·99–1·11). Atopic children (n=62) had significantly higher sR aw (1·15 kPa/s, 1·09–1·21) than those who were not atopic (232; 1·05 kPa/s, 1·02–1·07, p=0·002). For non-atopic children, those at high risk (58) had higher sR aw (1·13 kPa/s, 1·07–1·18) than those at medium risk (125, 1·01 kPa/s, 0·98–1·05) or at low risk (49, 1·04 kPa/s, 0·97–1·10, p=0·003). We showed a significant interaction between history of maternal asthma and child's atopic status (p=0·006). Interpretation Even in the absence of respiratory symptoms, children of atopic parents and those with personal atopy have impaired lung function in early life.

BACKGROUND: Many studies have investigated individual nutrients or foods as risk factors for allergic disease, but few have studied dietary patterns. We aimed to use principal component analysis (PCA) to determine dietary patterns in school age children and examine associations between these dietary patterns and wheeze, asthma and sensitization. METHODS: Participants in a population-based birth cohort attended review clinics at ages 8 and 11�yr. A validated questionnaire was interviewer-administered to collect information on parentally reported symptoms and doctor-diagnosed asthma. Atopic sensitization was ascertained by skin-prick tests. Current asthma was defined as doctor-diagnosed asthma and wheezing in the previous 12�months. A validated semi-quantitative food frequency questionnaire was completed at age 8�yr, and PCA was used to determine dietary patterns. RESULTS: Principal component analysis identified three dietary components, which based on their characteristics we termed as Traditional (mixed meat, fish, fruit and vegetables), Western (predominantly high fat content, processed foods) and Other (predominantly grains and nuts) dietary patterns. High adherence to the Western diet pattern was significantly associated with doctor-diagnosed asthma and current asthma at age 8�yr [aOR (95% CI): 2.19 (1.20-4.01), p�=�0.01; 2.59 (1.15-5.81), p�=�0.02; respectively]. A similar association was found for current asthma at age 11�yr [aOR (95% CI): 2.20 (1.07-4.51), p�=�0.03]. There was no evidence of an association between dietary patterns and current wheeze and allergic sensitization at either age 8 or 11�yr. CONCLUSION: School age children adhering strongly to a Western diet, high in fat and processed foods, had a higher risk of current asthma and doctor-diagnosed asthma.

Persistent acquired lobar overinflation (PALO) may complicate bronchopulmonary dysplasia (BPD). From infants admitted to the regional neonatal intensive care unit or who had been followed up at the chronic lung disease clinic in Liverpool over a 6.5-year period, 11 children with BPD and PALO were identified and details of their neonatal and subsequent outcome obtained. Their median gestational age was 29 weeks (range 24-33) and median birth weight was 1317 g (range 676-1968 g). All had received ventilatory support for severe neonatal respiratory distress syndrome for a median of 26 days (range 5-86). The median age the acquired lobar overinflation was detected was 82 days (range 45424 days). Nine patients required continued neonatal or paediatric intensive care re-admission for deteriorating respiratory function. Six children have subsequently died at a median age of 9.5 months (range 6.5-20). Five patients underwent bronchoscopy, four suggesting the presence of bronchomalacia. Three patients had ventilation-perfusion scans all showing that the overinflated lobe had no mismatch defect unlike other areas of the lung.The place of specific therapies for persistent acquired lobar overinflation is unclear. Surgery to remove the overinflated lobe in such cases may be inappropriate and the outcome of this complication of bronchopulmonary dysplasia appears to be poor.