Objectives There is increasing evidence to support the use of personalised medicine-led prescribing in young people's asthma. However, there is limited knowledge on the views of young people with respect to the motivation and acceptability for genotype directed therapy. Methods Young people aged 12–18 years old participating in the PACT pragmatic randomised controlled trial assessing asthma prescribing according to Arg16Gly β2 adrenoceptor genotype1 completed online questionnaires exploring their views on personalised medicine. Results 241 online questionnaires were distributed to adolescents who participated in the PACT trial and 186 questionnaires were returned (response rate 77.2%). The majority were happy to be approached to participate in this trial (n = 185, 99.4%). There was almost unanimous agreement that asthma control improved over the course of the study irrespective of the trial arm (n = 185, 99.4%). The majority believed that asthma research would help doctors understand and treat asthma better (n = 181, 97.3%). A small minority had concerns about the use and storage of their DNA for research (n = 12, 6.4%). 36 participants (19.4%) had concerns about having to stop or change their asthma medication. The most important motivating factor was attributed to believing the study would benefit other patients in future (n = 97, 52.2%), followed by curiosity regarding their genetic type and best treatment for asthma (n = 32, 17.2%). Very few had key motivating factors of receiving better care by taking part (n = 1, 0.5%), for closer monitoring (n= 2, 1.1%) or because they thought their asthma would get worse unless they took part (n = 1, 0.5%). Conclusion Adolescents find personalised medicine based asthma treatment trials to be largely acceptable without major concerns regarding the use and storage of DNA for research. The key motivating factor was altruism. The majority felt their asthma improved, which may be attributed to the trial effect. It would be beneficial to investigate parental views and views of communities from different geographical locations, and ethnic and socioeconomic groups. Reference Ruffles, et al. Asthma prescribing according to Arg16Gly beta-2 genotype: a randomised trial in adolescents, European Respiratory Journal, 2021.

ObjectiveHousehold damp exposure is an important public health issue. We aimed to assess the impact of the location of household damp on respiratory outcomes during early life.MethodsHousehold damp exposure was ascertained in children recruited to the GO-CHILD multicentre birth cohort study. The frequency of respiratory symptoms, infections, healthcare utilisation and medication prescription for wheezing were collected by postal questionnaires at 12 and 24 months. Log binomial and ordered logistic regression models were fitted to the data.ResultsFollow-up was obtained in 1344 children between August 2010 and January 2016. Visible damp was present in a quarter of households (25.3%) with 1 in 12 children’s bedrooms affected (8.3%). Damp in the bathroom, kitchen or living room was not associated with any respiratory or infection-related outcomes. Damp in the child’s bedroom was associated with an increased risk of dry cough (8.7% vs 5.7%) (adjusted relative risk 1.56, 95% CI 1.07 to 2.27; p=0.021) and odds of primary care attendance for cough and wheeze (7.6% vs 4.4%) (adjusted OR 1.37, 95% CI 1.07 to 1.76; p=0.009). There were also increased risk of inhaled corticosteroid (13.3% vs 5.9%) (adjusted RR 2.22, 95% CI 1.04 to 4.74; p=0.038) and reliever inhaler (8.3% vs 5.8%) (adjusted RR 2.01, 95% CI 1.21 to 2.79; p=0.018) prescription.ConclusionDamp in the child’s bedroom was associated with increased respiratory morbidity. In children presenting with recurrent respiratory symptoms, clinicians should enquire about both the existence and location of damp, the presence of which can help prioritise those families requiring urgent household damp assessment and remediation works.

BACKGROUND:Long-acting beta2-agonists (LABA) in combination with inhaled corticosteroids (ICS) are commonly used to treat asthma, however, some children lack response to the addition of LABA. This might be partially due to the presence of the Arg16Gly polymorphism, encoded by rs1042713 G>A in the ADRB2 gene. Carrying the A allele (Arg16) at this variant has been associated with an increased risk of exacerbations despite LABA treatment. We investigated whether genotype-guided treatment improved asthma-related outcomes. METHODS:We conducted an individual participant data meta-analysis of two randomised controlled trials: PUFFIN (Dutch and Swiss 6-18 year-olds) and PACT (English and Scottish 12-18 year-olds). Children with uncontrolled asthma despite ICS who required a step-up in treatment were included. Participants were randomised to genotype-guided treatment or the control group with a follow-up of at least 6 months. Genotype-guided treatment consisted of adding LABA for children with ADRB2 Gly16/Gly16, whilst children with ADRB2 Arg16/Arg16 or Arg16/Gly16 were treated with double dose ICS (PUFFIN) or add-on montelukast (PACT). The primary outcome was a change in asthma control; secondary outcomes included exacerbation rate and time to exacerbation. Repeated measures mixed models and Cox regression were used. RESULTS:Fifty-nine out of 102 (PUFFIN) and 59 out of 91 (PACT) children had at least one Arg (A allele). Amongst all 193 children, no difference was observed in asthma control between the study groups. However, genotype-guided treatment resulted in lower asthma exacerbation rates (-0.08 (95%CI -0.16 to -0.00, p = 0.04)) compared to the control group. CONCLUSION:Genotype-guided step-up treatment for children with uncontrolled asthma on ICS may lower asthma exacerbation rates and may be useful for personalising asthma care.

INTRODUCTION:Respiratory infections and wheeze have a considerable impact on the health of young children and consume significant healthcare resources. We aimed to evaluate the effect of environmental factors on respiratory infections and symptoms in early childhood. METHODS:Environmental risk factors including: daycare attendance; breastfeeding; siblings; damp within the home; environmental tobacco smoke (ETS); child's bedroom flooring; animal exposure; road traffic density around child's home; and solid fuel pollution within home were assessed in children recruited to the GO-CHILD multicentre prospective birth cohort study. Follow-up information on respiratory infections (bronchiolitis, pneumonia, otitis media and cold or flu), wheeze and cough symptoms, healthcare utilisation and medication prescription was collected by postal questionnaires at 12 and 24 months. Log binomial and ordered logistic regression models were fitted to the data. RESULTS:Follow-up was obtained on 1344 children. Daycare was associated with increased odds of pneumonia (odds ratio [OR] = 2.39, 95% confidence interval [CI]: 1.04-5.49), bronchiolitis (OR = 1.40, 1.02-1.90), otitis media (OR = 1.68, 1.32-2.14) and emergency department attendance for wheeze (RR = 1.81, 1.17-2.80). Breastfeeding beyond 6 months was associated with a reduced odds of bronchiolitis (OR = 0.55, 0.39-0.77) and otitis media (OR = 0.75, 0.59-0.99). Siblings at home was associated with an increased odds of bronchiolitis (OR = 1.65, 1.18-2.32) and risk of reliever inhaler prescription (RR = 1.37, 1.02-1.85). Visible damp was associated with an increased odds of wheeze (OR = 1.85, 1.11-3.19), and risk of reliever inhaler (RR = 1.73, 1.04-2.89) and inhaled corticosteroid prescription (RR = 2.61, 1.03-6.59). ETS exposure was associated with an increased odds of primary care attendance for cough or wheeze (OR = 1.52, 1.11-2.08). Dense traffic around the child's home was associated with an increased odds of bronchiolitis (OR = 1.32, 1.08-2.29). CONCLUSION:Environmental factors likely influence the wide variation in infection frequency and symptoms observed in early childhood. Larger population studies are necessary to further inform and guide public health policy to decrease the burden of respiratory infections and wheeze in young children.

Introduction: Respiratory infection and wheeze are a common cause of morbidity in early childhood. We studied the association between environmental factors and the risk of respiratory infections and symptoms in young children. Methods: 2312 Pregnant women were recruited to the GO-CHILD multi-centre birth cohort study from England and Scotland. Information on exposure to environmental factors, respiratory infections, symptoms, medication prescription and healthcare utilisation was obtained by follow-up questionnaires at 12 and 24 months after birth. Results: Follow-up was obtained in 1344 children. Breastfeeding beyond six months was associated with a reduced risk of bronchiolitis (RR 0.62, 95%CI 0.44-0.87; p=0.006) and otitis media (RR 0.58, 95%CI 0.43-0.78; p<0.001). Daycare was associated with an increased risk of pneumonia (RR 2.16, 95%CI 1.02-4.52; p=0.042) and emergency department attendance for wheeze (RR 1.73, 95%CI 1.16-2.60; p=0.008). Visible damp was associated with an increased risk of reliever inhaler (RR 2.01, 95%CI 1.21-2.79; p=0.018) and inhaled corticosteroid prescription (RR 2.22, 95%CI 1.04-4.74; p=0.038). Dense traffic was associated with an increased risk of bronchiolitis (RR 1.41, 95%CI 1.00-1.99; p=0.048). Environmental tobacco smoke exposure was associated with an increased risk of wheeze (RR 1.36, 95%CI 1.11-1.67; p=0.009) and dry cough (RR 1.61, 95%CI 1.05-2.45; p=0.003). Conclusion: Potentially modifiable environmental factors contribute to the risk of respiratory infections and symptoms in early childhood. The study informs on the benefits of breastfeeding and avoiding exposure to damp, vehicle emissions and secondhand smoke to mitigate these conditions.

Mannose‐binding lectin (MBL) is an important component of the innate immune system. Polymorphisms in the MBL2 gene and promoter region are directly associated with MBL‐deficiency. We sought to determine the association between MBL genotype on the frequency of common childhood respiratory infections, respiratory symptoms, and atopic outcomes in early childhood.

Background Protracted bacterial bronchitis (PBB) is a leading cause of chronic wet cough in children. The current standard treatment in European and American guidelines is 2 weeks of antibiotics, but the optimal duration of therapy is unknown. We describe the first randomised controlled trial to assess the duration of antibiotic treatment in children with chronic wet cough and suspected PBB. We hypothesise that 4 weeks of amoxicillin-clavulanate is superior to 2 weeks for improving clinical outcomes. Methods Our parallel, double-blind, placebo-controlled, randomised controlled trial was completed in four Australian hospitals. Children aged 2 months to 19 years with chronic (>4 weeks duration) wet cough, and suspected PBB were randomly assigned (1:1) using permuted block randomisation (stratified by age and site) to 4 weeks of amoxicillin- clavulanate (25-35 mg/kg twice daily oral suspension; 4-week group) or 2 weeks of amoxicillin-clavulanate followed by 2 weeks of placebo (2-week group). The children, caregivers, all the study coordinators, and investigators were masked to treatment assignment until data analysis was completed. The primary outcome was clinical cure (cough resolution) by day 28. Secondary outcomes were recurrence of PBB at 6 months, time to next exacerbation, change in Parent-proxy Cough-Specific Quality-of-Life (PC-QoL) score from baseline to day 28 and from day 28 to 7 months, adverse events, nasal swab bacteriology, and antimicrobial resistance. Analyses followed the intention-to-treat principle. This trial is complete and registered with Australian/New Zealand Registry, ACTRN12616001725459. Findings Between March 8, 2017, and Sept 30, 2019, 106 children were randomly assigned (52 in the 4-week group, median age 2middot2 years [IQR 1middot3-4middot1]; 54 in the 2-week group, median age 1middot7 years [1middot2-3middot8]) with 90 children completing the 4-week treatment. By day 28, the primary endpoint of clinical cure in the 4-week group (32 [62%] of 52 patients) was not significantly different to the 2-week group (38 [70%] of 54 patients; adjusted relative risk 0middot87 [95% CI 0middot60 to 1middot28]; p=0middot49). Time to next wet cough exacerbation was significantly longer in the 4-week group than the 2-week group (median 150 days [IQR 38-181] vs 36 days [15-181]; adjusted hazard ratio 0middot47 [0middot25 to 0middot90]; p=0middot02). The rate of recurrence of PBB at 6 months was 17 (53%) of 32 patients in the 4-week group vs 28 (74%) of 38 patients in the 2-week group, but the difference between the groups was not significant (adjusted odds ratio 0middot39 [0middot14 to 1middot04]; p=0middot07). PC-QoL significantly improved from baseline to day 28 in both groups, but there was no significant difference between them (mean difference in change -0middot2 [95% CI -1middot0 to 0middot6]; p=0middot64). From day 28 to 7 months, median PC-QoL remained stable in both groups with no difference in change between them. Data on respiratory pathogens and antimicrobial resistance (paired swabs available for 48 children) were similar between groups. Adverse events occurred in 13 (25%) children in the 2-week group and ten (19%) in the 4-week group (p=0middot57). Interpretation A 4-week course of amoxicillin-clavulanate for treating children with chronic wet cough and suspected PBB confers little advantage compared with a 2-week course in achieving clinical cure by 28 days. However, as a 4-week duration led to a longer cough-free period, identifying children who would benefit from a longer antibiotic course is a priority. Funding Queensland Children's Hospital Foundation. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Introduction The A allele of rs1042713 (Arg16 amino acid) in the β 2 -adrenoreceptor is associated with poor response to long-acting β 2 -agonist (LABA) in young people with asthma. Our aim was to assess whether the prescribing of second-line controller with LABA or a leukotriene receptor antagonist according to Arg16Gly genotype would result in improvements in Pediatric Asthma-Related Quality of Life Questionnaire (PAQLQ). Methods We performed a pragmatic randomised controlled trial (RCT) via a primary care clinical research network covering England and Scotland. We enrolled participants aged 12–18 years with asthma taking inhaled corticosteroids. 241 participants (mean± sd age 14.7±1.91 years) were randomised (1:1) to receive personalised care (genotype directed prescribing) or standard guideline care. Following a 4-week run-in participants were followed for 12 months. The primary outcome measure was change in PAQLQ. Asthma control, asthma exacerbation frequency and healthcare utilisation were secondary outcomes. Results Genotype-directed prescribing resulted in an improvement in PAQLQ compared to standard care (0.16, 95% CI 0.00–0.31; p=0.049), although this improvement was below the pre-determined clinical threshold of 0.25. The AA genotype was associated with a larger improvement in PAQLQ with personalised versus standard care (0.42, 95% CI 0.02–0.81; p=0.041). Conclusion This is the first RCT demonstrating that genotype-driven asthma prescribing is associated with a significant improvement in a clinical outcome compared to standard care. Adolescents with the AA homozygous genotype benefited most. The potential role of such β 2 -adrenoceptor genotype directed therapy in younger and more severe childhood asthma warrants further exploration.

We appreciate the interest shown by J.F.M. van Boven and co-workers in our study. PACT [1] was first and foremost designed as a pragmatic randomised controlled trial (RCT) reflecting current UK primary care practice. While addition of controller treatment for those in the personalised care group with poor control was guided by the study algorithm, the decisions with respect to monotherapy versus combination therapy, inhaler type and use of a spacer was down to the discretion of the participant's primary care team. A pragmatic trial design was used to elucidate potential effects of genotype directed asthma prescribing in a real life primary care setting https://bit.ly/2PpYavS

Introduction: The optimal duration of antibiotic treatment for children with protracted bacterial bronchitis (PBB), a common cause of chronic wet cough in children, is controversial. Effective management may reduce the risk of chronic suppurative disease (e.g. bronchiectasis). Objective: To determine whether 4-wks of amoxicillin-clavulanate is superior to 2-wks for improved clinical outcomes in children with suspected PBB. Methods: Multi-center, double-blind, placebo-controlled, RCT in Australian children aged 2-mo to 19-yrs with suspected PBB. Children were randomized to either 4-wks of amoxicillin-clavulanate or 2-wks of amoxicillin-clavulanate followed by 2-wks placebo. Follow-up was for 6-mo. Our primary outcome was cough resolution within 28-days. Recurrence of PBB, parent-proxy cough specific quality of life (PC-QoL) score at 28-days and time to first exacerbation were secondary outcomes. Results: 106 children were randomized, median age 2.0-yrs. There was no difference in cough resolution by 28-days between the groups (4-wks=61.5% vs 2-wks=71.4%) (RR 0.87, 95% CI0.59-1.29; p=0.50). Longer antibiotic treatment resulted in a non-significant increase in time to next wet cough exacerbation (150-wks vs 48-wks; p=0.094) and reduced PBB recurrence (74% vs 53%; p=0.074) in those whose cough resolved by day-28. PC-QoL improved by a median of 2.0 across both groups. Conclusion: A 4-wk course of amoxicillin-clavulanate in children with suspected PBB confers little advantage compared to a 2-wk course. A non-inferiority RCT is required to support our findings but until such data is available, children suspected of having PBB should be treated with the current standard 2-wks.

Background and objective Long-term data on children with PBB has been identified as a research priority. We describe the 5-year outcomes for children with PBB to ascertain the presence of chronic respiratory disease (bronchiectasis, recurrent PBB and asthma) and identify the risk factors for these. Methods Prospective cohort study was undertaken at the Queensland Children's Hospital, Brisbane, Australia, of 166 children with PBB and 28 controls (undergoing bronchoscopy for symptoms other than chronic wet cough). Monitoring was by monthly contact via research staff. Clinical review, spirometry and CT chest were performed as clinically indicated. Results A total of 194 children were included in the analysis. Median duration of follow-up was 59 months (IQR: 50-71 months) post-index PBB episode, 67.5% had ongoing symptoms and 9.6% had bronchiectasis. Significant predictors of bronchiectasis were recurrent PBB in year 1 of follow-up (ORadj= 9.6, 95% CI: 1.8-50.1) and the presence ofHaemophilus influenzaein the BAL (ORadj= 5.1, 95% CI: 1.4-19.1). Clinician-diagnosed asthma at final follow-up was present in 27.1% of children with PBB. A significant BDR (FEV(1)improvement >12%) was obtained in 63.5% of the children who underwent reversibility testing. Positive allergen-specific IgE (ORadj= 14.8, 95% CI: 2.2-100.8) at baseline and bronchomalacia (ORadj= 5.9, 95% CI: 1.2-29.7) were significant predictors of asthma diagnosis. Spirometry parameters were in the normal range. Conclusion As a significant proportion of children with PBB have ongoing symptoms at 5 years, and outcomes include bronchiectasis and asthma, they should be carefully followed up clinically. Defining biomarkers, endotypes and mechanistic studies elucidating the different outcomes are now required.