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BackgroundAsthma-associated single nucleotide polymorphisms from large genome-wide association studies only explain a fraction of genetic heritability. Likely causes of the missing heritability include broad phenotype definitions and gene-environment interactions (GxE). The mechanisms underlying GxE in asthma are poorly understood. Previous GxE studies on pet ownership showed discordant results.ObjectivesWe sought to study the GxE between the 17q12-21 locus and pet ownership in infancy in relation to wheeze.MethodsWheezing classes derived from 5 UK-based birth cohorts (latent class analysis) were used to study GxE between the 17q12-21 asthma-risk variant rs2305480 and dog and cat ownership in infancy, using multinomial logistic regression. A total of 9149 children had both pet ownership and genotype data available. Summary statistics from individual analyses were meta-analyzed.Resultsrs2305480 G allele was associated with increased risk of persistent wheeze (additive model odds ratio, 1.37; 95% CI, 1.25-1.51). There was no evidence of an association between dog or cat ownership and wheeze. We found significant evidence of a GxE interaction between rs2305480 and dog ownership (P = 8.3 × 10−4) on persistent wheeze; among dog owners, the G allele was no longer associated with an increased risk of persistent wheeze (additive model odds ratio, 0.95; 95% CI, 0.73-1.24). For those without pets, G allele was associated with increased risk of persistent wheeze (odds ratio, 1.61; 95% CI, 1.40-1.86). Among cat owners, no such dampening of the genetic effect was observed.ConclusionsAmong dog owners, rs2305480 G was no longer associated with an increased risk of persistent wheeze (or asthma). Early-life environmental exposures may therefore attenuate likelihood of asthma in those carrying 17q12-21 risk alleles.

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.

BackgroundEffectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies.MethodsCOMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients’ and carers’ views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria.ResultsBoth adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately).ConclusionsThis patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

RATIONALE Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. OBJECTIVE To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. METHODS Oropharyngeal swabs, from the Unbiased BIOmarkers for the Prediction of REspiratory Disease outcomes pediatric asthma/wheezing cohort, were characterized by 16S rRNA gene sequencing and unsupervised hierarchical clustering was performed on the Bray-Curtis β-diversity. Enrichment scores (ESs) of the MSigDB Hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessing the frequency of exacerbations. MEASUREMENTS AND MAIN RESULTS Oropharyngeal samples of 241 children (age range: 1-17 years, 40% female) revealed 4 taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia and Haemophilus, respectively. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1 % predicted post-salbutamol, and the annual asthma exacerbation frequency during follow-up. The Veillonella-cluster was the most allergic and included highest percentage of children with ≥2 exacerbations/year during follow-up. The oropharyngeal clusters were different in the ESs of transforming growth factor β (highest in Veillonella-cluster) and Wnt/β-Catenin signaling (highest in Haemophilus-cluster) transcriptomic pathways in blood (all q-values < 0.05). CONCLUSION The analysis of the oropharyngeal microbiota of children with asthma/wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with exacerbations' risk and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiological insights and potentially new treatment approaches.

Background: Effector cells assays provide an overall measure of responsiveness to allergen, but the lack of reliable and high-throughput assays limits the clinical utility. We aimed to develop a high-throughput basophil activation test based on human progenitor cell-derived basophils (PCB) and investigate the role of PCB activation test (PCBAT) in allergic diseases. Methods: Progenitor cell-derived basophils were differentiated from CD34+ progenitor cells and sensitized with sera from subjects sensitized to cat, peanut or atopic controls. Sensitized PCBs were stimulated with increasing concentrations of the corresponding allergens in vitro. Degranulation was assessed by measuring CD63 expression using flow cytometry. The correlations between PCBAT and clinical allergy were assessed. Results: Following passive sensitization of the mature PCBs with serum and allergen stimulation, an allergen specific dose-dependent increase in CD63 expression was observed. Sera from subjects sensitized to cat (n = 35, of which 17 subjects had clinical reactivity quantified using inhaled allergen challenge), peanut allergic (n = 30, of which 15 subjects had clinical reactivity validated using double blind, placebo controlled food challenges [DBPCFC]), peanut-sensitized but tolerant subjects (n = 5) were used to sensitize PCBs. PCBAT area under the curve (AUC) correlated with sIgE (r2 =.49, p =.001) in subjects sensitized to cat (sIgE ≥ 0.35KU/L). The provocation concentration of inhaled cat allergen (PC20) correlated with PCBAT AUC (r2 =.33, p =.016). In subjects sensitized to peanut, PCBAT AUC was highly correlated with sIgE to Ara h 2 (r2 =.59, p 2 =.57, p =.001) and IgE to Ara h1 (r2 =.55, p =.007), but not with sIgE to whole peanut or Ara h2. All peanut-sensitized but tolerant subjects showed no reaction to peanut on PCBAT. Conclusion: Progenitor cell-derived basophils activation test is a high-throughput assay, which correlates with clinical allergy and may confer a powerful alternative tool in allergy testing.

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.

ObjectiveTo understand community seroprevalence of SARS-CoV-2 in children and adolescents. This is vital to understanding the susceptibility of this cohort to COVID-19 and to inform public health policy for disease control such as immunisation.DesignWe conducted a community-based cross-sectional seroprevalence study in participants aged 0–18 years old recruiting from seven regions in England between October 2019 and June 2021 and collecting extensive demographic and symptom data. Serum samples were tested for antibodies against SARS-CoV-2 spike and nucleocapsid proteins using Roche assays processed at UK Health Security Agency laboratories. Prevalence estimates were calculated for six time periods and were standardised by age group, ethnicity and National Health Service region.ResultsPost-first wave (June–August 2020), the (anti-spike IgG) adjusted seroprevalence was 5.2%, varying from 0.9% (participants 10–14 years old) to 9.5% (participants 5–9 years old). By April–June 2021, this had increased to 19.9%, varying from 13.9% (participants 0–4 years old) to 32.7% (participants 15–18 years old). Minority ethnic groups had higher risk of SARS-CoV-2 seropositivity than white participants (OR 1.4, 95% CI 1.0 to 2.0), after adjusting for sex, age, region, time period, deprivation and urban/rural geography. In children ConclusionsApproximately one-third of participants aged 15–18 years old had evidence of antibodies against SARS-CoV-2 prior to the introduction of widespread vaccination. These data demonstrate that ethnic background is independently associated with risk of SARS-CoV-2 infection in children.Trial registration numberNCT04061382.

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.

Genome-wide and epigenome-wide association studies have identified genetic variants and differentially methylated nucleotides associated with childhood asthma. Incorporation of such genomic data may improve performance of childhood asthma prediction models which use phenotypic and environmental data. Using genome-wide genotype and methylation data at birth from the Isle of Wight Birth Cohort (n = 1456), a polygenic risk score (PRS), and newborn (nMRS) and childhood (cMRS) methylation risk scores, were developed to predict childhood asthma diagnosis. Each risk score was integrated with two previously published childhood asthma prediction models (CAPE and CAPP) and were validated in the Manchester Asthma and Allergy Study. Individually, the genomic risk scores demonstrated modest-to-moderate discriminative performance (area under the receiver operating characteristic curve, AUC: PRS = 0.64, nMRS = 0.55, cMRS = 0.54), and their integration only marginally improved the performance of the CAPE (AUC: 0.75 vs. 0.71) and CAPP models (AUC: 0.84 vs. 0.82). The limited predictive performance of each genomic risk score individually and their inability to substantially improve upon the performance of the CAPE and CAPP models suggests that genetic and epigenetic predictors of the broad phenotype of asthma are unlikely to have clinical utility. Hence, further studies predicting specific asthma endotypes are warranted.

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.

BackgroundWheeze is common in early life and often transient. It is difficult to identify which children will experience persistent symptoms and subsequently develop asthma. Machine learning approaches have the potential for better predictive performance and generalisability over existing childhood asthma prediction models.ObjectiveTo apply machine learning approaches for predicting school-age asthma (age 10) in early life (Childhood Asthma Prediction in Early life, CAPE model) and at preschool age (Childhood Asthma Prediction at Preschool age, CAPP model).MethodsData on clinical symptoms and environmental exposures were collected from children enrolled in the Isle of Wight Birth Cohort (N=1368, ∼15% asthma prevalence). Recursive Feature Elimination (RFE) identified the optimal subset of features predictive of school-age asthma for each model. Seven state-of-the-art machine learning classification algorithms were used to develop the models and the results were compared. To optimize the models, training was performed by applying 5-fold cross-validation, imputation and resampling. Predictive performances were evaluated on the test set and externally validated in the Manchester Asthma and Allergy Study (MAAS) cohort.ResultsRFE identified eight and 12 predictors for the CAPE and CAPP models, respectively. The best predictive performance was demonstrated by a Support Vector Machine (SVM) algorithm for both the CAPE model (area under the receiver operating curve, AUC=0.71) and CAPP model (AUC=0.82). Both models demonstrated good generalisability in MAAS (CAPE 8YR=0.71, 11YR=0.71, CAPP 8YR=0.83, 11YR=0.79).ConclusionUsing machine learning approaches improved upon the predictive performance of existing regression-based models, with good generalisability and ability to rule in asthma.

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.

Introduction and Objectives Fractional exhaled Nitric Oxide (FeNO) is an essential test for asthma diagnosis in the NICE algorithm (NG80). A characteristic feature of asthma is the variability of symptoms and signs. Within the setting of our Rapid Access Diagnostics for Asthma (RADicA) research clinic, we investigated whether repeat testing of FeNO in those with borderline or negative results improved diagnostic certainty. Methods Adults and children with symptoms of cough, wheeze, breathlessness or chest tightness were referred by primary care for a comprehensive assessment. FeNO (NIOX VERO, Circassia) was measured on two separate occasions a minimum of 5 days apart prior to starting inhaled corticosteroids. FeNO result was classified according to NG80 for adults (FeNO ≥ 40ppb positive, 25–39ppb borderline, Results 112 participants (66% adult, 56% female) achieved FeNO on at least one of these visits; 86 completed both measures. FeNO levels were similar between the two visits (V1 median 22ppb [IQR 54ppb], V2 median 23.5ppb [IQR 45ppb], p=0.52; r=0.91 p Conclusions Although there was a strong correlation between FeNO measured on 2 separate occasions prior to starting treatment, almost one in four of those with a borderline test went on to have a positive test when given the opportunity to repeat. Repeating FeNO in those with a borderline result would reduce the proportion of patients requiring referral to secondary care, at low cost.

Background The defining feature of asthma is variability in symptoms and airflow obstruction over time. Historical variation in forced expiratory volume in 1 second (FEV1) is a diagnostic indicator in asthma. We aimed to investigate the variability of spirometry measurements between diagnostic visits in untreated patients with a high clinical suspicion of asthma. Method Patients with symptoms consistent with asthma, but diagnosis- and treatment-naive, were prospectively recruited from primary care. Clinical history and examination were carried out, then spirometry and fractional exhaled nitric oxide (FeNO) measured on two visits. An asthma diagnosis was confirmed or refuted using full diagnostic testing and assessment of response to inhaled corticosteroids. Results Of 116 patients, 81% completed spirometry measurements on both clinical visits [58.5% adults, 43.6% male, mean (SD) age: 23.5 (15.6) years]. The median (IQR) duration between clinics was 21 (15–28) days. Of these, 59.6% had definite asthma, 30.9% did not have asthma, and 9.5% could not be classified. The change in FEV1:FVC and% change in FEV1 (difference between-visits/the lower measurement) was higher in asthmatics [median (IQR): 2.9 (1.3–5.3)% and 6.9 (2.6–11.3)%, respectively] compared to non-asthmatics [1.6 (0.6–3.7)% and 4.3 (1.8–6.5)% respectively, p=0.02]. The% change in FEV1 correlated with% change in FENO between visits in adults (r=0.45, p=0.001). Seventeen (18%) patients had ≥12% change in FEV1 between visits, of which 76.5% were asthmatics (accounting for 23% of all asthma patients) and 11.8% were non-astmatics. Seven (of which 6 asthmatics) patients had FEV1:FVC straddling the fixed diagnostic cutoff (70%) between clinic visits. Conclusion Clinically meaningful variability in spirometry was observed in one-fifth of patients with confirmed but untreated asthma between clinical visits, and so may be useful in asthma diagnosis for a minority. This variability in airflow correlated with that in inflammation (FeNO). Validation of novel tests more sensitive to change in both parameters, and/or more targetted test-timing (e.g. morning/evening) may increase the utility of this diagnostic strategy.

Background National guidance for asthma diagnosis in children within the UK (NICE NG80 2017) requires children to perform multiple sequential objective tests. All tests within the diagnostic algorithm require forced or prolonged expiratory manoeuvres. The feasibility of children completing the tests is unknown. We investigate feasibility of completing the required tests and the impact this will have on completing the algorithm. Methods Symptomatic children aged five to sixteen years with suspected asthma were referred into the RADicA (Rapid Access Diagnostics in Asthma) study. Fractional exhaled nitric oxide (FeNO), spirometry, and bronchodilator reversibility (BDR) were performed during the visit. Children were then asked to complete peak expiratory flow (PEFv) measurements twice a day for two weeks using an electronic peak flow meter. All tests were performed by trained staff experienced in paediatric lung function measurements at a tertiary respiratory centre. Results Fifty-two children [median (IQR) age 9(7–12)yrs, 54% male] were recruited. Of these, only 33(63.5%) successfully completed all four tests. This reduced to 17(50%) in children under twelve years. All children completed spirometry and BDR. 40(77%) completed PEF monitoring, poor compliance was the main reason for failure to complete this test. 42(81%) completed FeNO, inability to perform the test was the reason for failure in all of our children. Of those under twelve years (n 34), only 24(71%) could perform FeNO despite clear instructions and multiple attempts during the initial visit. We were able to complete the sequential diagnostic algorithm in 67% of all children, this reduced to 56% in those under twelve years. This improved to 79% and 74% if additional FeNO practice was provided at a subsequent visit. Conclusions Significant proportion of children failed to complete the paediatric diagnostic algorithm recommended by NICE, despite multiple visits in a tertiary setting with experienced staff. We have concerns over the feasibility of the paediatric algorithm within a primary care setting. Diagnostic tools with less demand on technique are urgently required in this age group.

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.

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.Objective: To investigate associations of circulating allergy-related chemokines with development of asthma and sensitisation 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 a population-based birth cohort. Samples were available from cord blood at birth (n=376) and age 1 (n=195) and 8 years (n=334). Cross-sectional and longitudinal association analyses were performed in relation to asthma and allergic sensitisation, as well as allergic phenotype clusters previously derived using machine learning in the same study population.Results: In children with asthma and/or allergic sensitisation, CCL18 levels at ages 1 and/or 8 were consistently elevated. In a longitudinal model which included information on asthma from 4 time-points (ages 5, 8, 11 and 16 years), we observed a significant association between increasing levels of CCL18 at age 1 year and a higher risk of asthma from early school age to adolescence (OR=2.9, 95% CI 1.1-7.6, p=0.028). We observed similar associations in longitudinal models for allergic sensitisation. Asthma later in life was preceded by increased CXCL10 levels after birth, and decreased CXCL11 levels at birth. Conclusion: Elevated CCL18 levels throughout childhood foreshadow the development of asthma and allergic sensitisation. The Th1-associated chemokines CXCL10 and CXCL11 were also associated with development of both outcomes, with differential temporal effects.

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: Fractional exhaled nitric oxide (FeNO) is a common biomarker used in the diagnosis and monitoring of asthma in children. Little is known about the variability of FeNO beyond one week in healthy or asthmatic children. We investigated the medium-term variability of FeNO in children with and without asthma. Methods: Children from the Manchester Asthma and Allergy Study attended follow-up at the age of 11 years on two occasions. Skin prick testing was completed. FeNO and spirometry were measured on each visit. Clinically significant FeNO variability (∆FeNO) was defined according to ATS 2011 recommendations. Results: Of the 425 children who had FeNO measured on two occasions [median (IQR) 20 (9-47) days apart], 11% had current asthma and 33% were atopic. Mean (SD) FeNO in children with current asthma [37.5 (31.6) ppb] or atopy [34.6 (32.2) ppb] was higher than those without [16.7 (21.0) ppb and 10.9 (9.4) ppb, respectively, p Conclusion: Increased medium-term variability of FeNO were observed in children with current wheeze and atopy compared to those without. History of hayfever, asthma medication use and atopy were independent confounding factors for clinically significant variability in FeNO.

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.