Environmental risk factors for respiratory infection and wheeze in young children: A multicentre birth cohort study.

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.

Mannose-binding lectin genotype is associated with respiratory disease in young children: A multicenter cohort study.

BACKGROUND: 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. METHODS: MBL2 gene variants were analyzed in newborns recruited to the GO-CHILD multicenter prospective cohort study. Follow-up for respiratory infection and atopy diagnoses and symptoms, healthcare utilization, and medication prescription were conducted by postal questionnaires at 12 and 24 months. RESULTS: Genotyping and follow-up were completed in 1004 children. Genotypes associated with MBL-deficiency were associated with an increased risk of bronchiolitis (relative risk [RR] 1.95, 95% confidence interval [CI] 1.33-2.85) and pneumonia (RR 2.46, 95% CI 1.16-5.22). MBL-deficient genotypes were associated with an increased risk of wheeze with shortness of breath episodes (RR 1.22, 95% CI 1.04-1.43), emergency department attendance (RR 1.90 95% CI 1.13-3.19), and hospital admission (RR 2.01, 95% CI 1.04-3.89) for wheeze. MBL-deficient genotypes were associated with a reduced risk of developing atopic dermatitis (RR 0.72, 95% CI 0.53-0.98). CONCLUSION: The positive association between MBL-deficient genotypes and bronchiolitis and pneumonia, as well as a severe wheeze phenotype in some young children, supports the hypothesis that MBL is an important component of innate immunity in the vulnerable period before the maturation of the adaptive immune system. Identification of disease-modifying genotypes may help target preventative strategies in high-risk infants.

Duration of amoxicillin-clavulanate for protracted bacterial bronchitis in children (DACS): a multi-centre, double blind, randomised controlled trial.

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 2·2 years [IQR 1·3-4·1]; 54 in the 2-week group, median age 1·7 years [1·2-3·8]) 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 0·87 [95% CI 0·60 to 1·28]; p=0·49). 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 0·47 [0·25 to 0·90]; p=0·02). 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 0·39 [0·14 to 1·04]; p=0·07). PC-QoL significantly improved from baseline to day 28 in both groups, but there was no significant difference between them (mean difference in change -0·2 [95% CI -1·0 to 0·6]; p=0·64). 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=0·57). 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.

Asthma prescribing according to Arg16Gly beta-2 genotype: a randomised trial in adolescents.

INTRODUCTION: The A allele of rs1042713 (Arg16 amino acid) in the ß2-adrenoreceptor is associated with poor response to long-acting ß2-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 ß2-adrenoceptor genotype directed therapy in younger and more severe childhood asthma warrants further exploration.

Outcomes of protracted bacterial bronchitis in children: A 5-year prospective cohort study.

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 of Haemophilus influenzae in 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 (FEV1 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.

Recurrent cystic lymphangioma of the breast: case report and literature review.

Cystic lymphangioma is a rare congenital lymphatic malformation. We report a case of a 37-year-old female with recurrent cystic lymphangioma of the breast which has progressively developed during pregnancy and breast feeding.