Improved childhood asthma control after exposure reduction interventions for desert dust and anthropogenic air pollution: the MEDEA randomised controlled trial.

INTRODUCTION: Elevated particulate matter (PM) concentrations of anthropogenic and/or desert dust origin are associated with increased morbidity among children with asthma. OBJECTIVE: The Mitigating the Health Effects of Desert Dust Storms Using Exposure-Reduction Approaches randomised controlled trial assessed the impact of exposure reduction recommendations, including indoor air filtration, on childhood asthma control during high desert dust storms (DDS) season in Cyprus and Greece. DESIGN, PARTICIPANTS, INTERVENTIONS AND SETTING: Primary school children with asthma were randomised into three parallel groups: (a) no intervention (controls); (b) outdoor intervention (early alerts notifications, recommendations to stay indoors and limit outdoor physical activity during DDS) and (c) combined intervention (same as (b) combined with indoor air purification with high efficiency particulate air filters in children's homes and school classrooms. Asthma symptom control was assessed using the childhood Asthma Control Test (c-ACT), spirometry (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC)) and fractional exhaled nitric oxide (FeNO). RESULTS: In total, 182 children with asthma (age; mean=9.5, SD=1.63) were evaluated during 2019 and 2021. After three follow-up months, the combined intervention group demonstrated a significant improvement in c-ACT in comparison to controls (ß=2.63, 95% CI 0.72 to 4.54, p=0.007), which was more profound among atopic children (ß=3.56, 95% CI 0.04 to 7.07, p=0.047). Similarly, FEV1% predicted (ß=4.26, 95% CI 0.54 to 7.99, p=0.025), the need for any asthma medication and unscheduled clinician visits, but not FVC% and FeNO, were significantly improved in the combined intervention compared with controls. CONCLUSION: Recommendations to reduce exposure and use of indoor air filtration in areas with high PM pollution may improve symptom control and lung function in children with asthma. TRIAL REGISTRATION NUMBER: NCT03503812.

Body composition and respiratory outcomes in children: a population-based prospective cohort study.

BACKGROUND: Body composition might influence lung function and asthma in children, but its longitudinal relations are unclear. We aimed to identify critical periods for body composition changes during childhood and adolescence in relation to respiratory outcomes in adolescents. METHODS: In a population-based prospective cohort study, we measured body mass index, fat mass index (FMI), lean mass index (LMI) and the ratio of android fat mass divided by gynoid fat mass (A/G ratio) by dual-energy X-ray absorptiometry at 6, 10 and 13 years. At 13 years, lung function was measured by spirometry, and current asthma was assessed by questionnaire. RESULTS: Most prominently and consistently, higher FMI and A/G ratio at age 13 years were associated with lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and forced expiratory flow after exhaling 75% of FVC (FEF75) (range Z-score difference -0.13 (95% CI -0.16 to -0.10) to -0.08 (95% CI -0.11 to -0.05) per SD score increase), and higher LMI at all ages was associated with higher FEF75 (range Z-score difference 0.05 (95% CI 0.01 to 0.08) to 0.09 (95% CI 0.06 to 0.13)). Between the ages of 6 and 13 years, normal to high FMI and A/G ratio were associated with lower FEV1/FVC and FEF75 (range Z-score difference -0.20 (95% CI -0.30 to -0.10) to -0.17 (95% CI -0.28 to -0.06)) and high to high LMI with higher FEF75 (range Z-score difference0.32 (95% CI 0.23 to 0.41)). Body composition changes were not associated with asthma. CONCLUSION: Adolescents with higher total and abdominal fat indices may have impaired lung function, while those with a higher lean mass during childhood and adolescence may have better small airway function. Public health measures should focus on a healthy body composition in adolescents to minimise respiratory morbidity.

Use of inhaled corticosteroids and the risk of hospitalisation for pneumonia in children with asthma: a nationwide cohort study.

BACKGROUND: The potential association between the use of inhaled corticosteroids (ICS) and the risk of pneumonia among adults is disputed and paediatric-specific evidence is scarce. AIM: To assess the potential association between ICS, use and the risk of hospitalisation for pneumonia among children (age 2-17 years) with asthma. METHODS: This was a cohort study based on nationwide data from routine clinical practice in Sweden (January 2007 to November 2021). From 425 965 children with confirmed asthma, episodes of new ICS use and no use were identified using records of dispensed drugs. We adjusted for potential confounders with propensity score overlap weighting and the risk of a hospitalisation with pneumonia as primary diagnosis was estimated. Multiple subgroup and sensitivity analyses were also performed. RESULTS: We identified 249 351 ICS (mean follow-up of 0.9 years) and 214 840 no-use (mean follow-up of 0.7 years) episodes. During follow-up, 369 and 181 events of hospitalisation for pneumonia were observed in the ICS and no-use episodes, respectively. The weighted incidence rates of hospitalisation for pneumonia was 14.5 per 10 000 patient-years for ICS use episodes and 14.6 for no-use episodes. The weighted HR for hospitalisation for pneumonia associated with ICS use was 1.06 (95% CI 0.88 to 1.28) and the absolute rate difference was -0.06 (95% CI -2.83 to 2.72) events per 10 000 patient-years, compared with no use. CONCLUSIONS: In this nationwide cohort study, we found no evidence of an association between ICS use and the risk of hospitalisation for pneumonia among children with asthma, as compared with no use.

Influence of age on clinical characteristics, pharmacological management and exacerbations in children with asthma.

BACKGROUND: Asthma trials and guidelines often do not distinguish between adolescents and younger children. Using a large English data set, we evaluated the impact of age on asthma characteristics, management and exacerbations. METHODS: Primary care medical records, 2004-2021, were linked to hospital records. Children were categorised by age at diagnosis and followed until the next age bracket. Ages (based on management guidelines) were 5-8 years, 9-11 years and adolescents (12-16 years). Characteristics evaluated included body mass index, allergies and events before and after diagnosis (symptoms, medication). Exacerbation incidence was calculated. Multivariable Cox proportional hazards determined associations with exacerbations. RESULTS: 119 611 children were eligible: 61 940 (51.8%) 5-8 years, 32 316 (27.7%) 9-11 years and 25 355 (21.2%) adolescents. Several characteristics differed by age; children aged 5-8 years had the highest proportion with eczema, food/drug allergy and cough, but adolescents had the highest proportion with overweight/obesity, aeroallergen sensitisation, dyspnoea and short-acting-beta-agonist only use. Exacerbation rates were highest in the youngest children (per 100 person-years (95% CI): 5-8 years =13.7 (13.4-13.9), 9-11 years =10.0 (9.8-10.4), adolescents =6.7 (6.5-7.0)). Exacerbation risk factors also differed by age; 5-8 years: male, eczema and food/drug allergy were strongly associated, but for children ≥9 years old, obesity and aeroallergen sensitisation were strongly associated. For all children, higher socioeconomic deprivation was significantly associated with having an exacerbation. Delayed diagnosis was most common in children aged 5-8 years and was associated with increased exacerbations across all ages. CONCLUSION: Children's baseline characteristics and exacerbation rates varied according to their age group. Clinical guidelines should consider age at time of diagnosis more discretely than the broad range, 5-16 years, as this appears to impact on asthma severity and management.

Clinical implications of airway obstruction with normal or low FEV1 in childhood and adolescence.

BACKGROUND: Airway obstruction is defined by spirometry as a low forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio. This impaired ratio may originate from a low FEV1 (classic) or a normal FEV1 in combination with a large FVC (dysanaptic). The clinical implications of dysanaptic obstruction during childhood and adolescence in the general population remain unclear. AIMS: To investigate the association between airway obstruction with a low or normal FEV1 in childhood and adolescence, and asthma, wheezing and bronchial hyperresponsiveness (BHR). METHODS: In the BAMSE (Barn/Child, Allergy, Milieu, Stockholm, Epidemiology; Sweden) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy; the Netherlands) birth cohorts, obstruction (FEV1:FVC ratio less than the lower limit of normal, LLN) at ages 8, 12 (PIAMA only) or 16 years was classified as classic (FEV1

Association between socioeconomic deprivation, ethnicity and health outcomes in preschool children with recurrent wheeze in England: a retrospective cohort study.

BACKGROUND: Preschool-aged children have among the highest burden of acute wheeze. We investigated differences in healthcare use, treatment and outcomes for recurrent wheeze/asthma in preschoolers from different ethno-socioeconomic backgrounds. METHODS: Retrospective cohort study using data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics in England. We reported number of acute presentations and hospitalisations stratified by index of multiple deprivation (IMD) and ethnicity; and factors associated with treatment non-escalation, and hospitalisation rates using multivariable logistic and Poisson regression models. RESULTS: 194 291 preschool children were included. In children not trialled on asthma preventer medications, children from the most deprived IMD quintile (adjusted OR 1.67; 95% CI 1.53 to 1.83) and South Asian (1.77; 1.64 to 1.91) children were more likely to have high reliever usage and where specialist referral had not occurred, the odds of referral being indicated was higher in the most deprived quintile (1.39; 1.28 to 1.52) and South Asian (1.86; 1.72 to 2.01) children compared with the least deprived quintile and white children, respectively.Hospitalisation rates for wheeze/asthma were significantly higher in children from the most deprived quintile (adjusted IRR 1.20; 95% CI 1.13 to 1.27) compared with the least, and in South Asian (1.57; 1.44 to 1.70) and black (1.32; 1.22 to 1.42) compared with white children. CONCLUSIONS: We identified inequalities in wheeze/asthma treatment and morbidity in preschool children from more deprived, and non-white backgrounds. A multifaceted approach to tackle health inequality at both the national and local levels, which includes a more integrated and standardised approach to treatment, is needed to improve health outcomes in children with preschool wheeze/asthma.

Identification and treatment of persistent small airway dysfunction in paediatric patients with asthma: a retrospective cohort study.

BACKGROUND: Asthma is a common respiratory disease. In asthma, the small airways have more intensive inflammation and prominent airway remodelling, compared to the central airways. We aimed to investigate the predictive value of risk factors and the fractional concentration of exhaled nitric oxide (FeNO) for persistent small airway dysfunction (p-SAD), and compare the effects of different treatment modalities. METHODS: This retrospective cohort study included 248 children with asthma (aged 4-11 years). Binary logistic regression was used to analyse the risk factors for p-SAD. Correlations among FEV1/FVC, small airway function parameters, and FeNO levels in patients with asthma were analysed using Spearman's rank correlation. The receiver operating characteristic curve and the Delong test were used to analyse the predictive value of FeNO for p-SAD. Differences in the treatment effects of inhaled corticosteroids (ICS) and ICS with a long-acting beta-agonist (ICS/LABA) on p-SAD were analysed using Fisher's exact test. RESULTS: Asthmatic children with older age of receiving the regular treatment (OR 1.782, 95% CI 1.082-2.935), with younger age at the time of onset of suspected asthma symptoms (OR 0.602, 95% CI 0.365-0.993), with longer duration of using ICS or ICS/LABA (OR 1.642, 95% CI 1.170-2.305) and with worse asthma control (OR 3.893, 95% CI 1.699-8.922) had increased risk for p-SAD. Significant negative correlations of small airway function parameters with FeNO at a 200 mL/s flow rate (FeNO200), and the concentration of nitric oxide in the alveolar or acinar region (CaNO) were observed. The areas under the curve of FeNO200 (cut-off:10.5ppb), CaNO (cut-off:5.1ppb), and FeNO200 combined with CaNO were 0.743, 0.697, and 0.750, respectively, for asthma with p-SAD. After using ICS or ICS/LABA, switching to ICS/LABA was easier than continuing with ICS to improve small airway dysfunction (SAD) in the 8th month. CONCLUSIONS: Paediatric asthma with p-SAD is associated with older age at receiving regular treatment, younger age at the time of onset of suspected asthma symptoms, longer duration of using ICS or ICS/LABA, worse asthma control, and higher FeNO200 and CaNO levels, all of which can be combined with small airway function indicators to distinguish p-SAD from asthma. ICS/LABA improves SAD better than ICS alone.

Preterm or early term birth and long-term risk of asthma into midadulthood: a national cohort and cosibling study.

BACKGROUND: Preterm birth is associated with pulmonary complications early in life; however, long-term risks of asthma into adulthood are unclear. OBJECTIVE: To determine asthma risks from childhood into adulthood associated with gestational age at birth in a large population-based cohort. METHODS: A national cohort study was conducted of all 4 079 878 singletons born in Sweden during 1973-2013, followed up for asthma identified from primary care, specialty outpatient and inpatient diagnoses in nationwide registries through 2018 (up to 46 years). Cox regression was used to adjust for potential confounders, and cosibling analyses assessed the influence of unmeasured shared familial (genetic and/or environmental) factors. RESULTS: In 91.9 million person-years of follow-up, 607 760 (14.9%) persons were diagnosed with asthma. Preterm birth was associated with increased risk of asthma at ages <10 years (adjusted HR 1.73; 95% CI 1.70 to 1.75), 10-17 years (1.29; 1.27 to 1.32) and 18-46 years (1.19; 1.17 to 1.22). Across all ages, adjusted HRs further stratified were 3.01 (95% CI 2.88 to 3.15) for extremely preterm (22-27 weeks), 1.76 (1.72 to 1.79) for very or moderately preterm (28-33 weeks), 1.31 (1.29 to 1.32) for late preterm (34-36 weeks) and 1.13 (1.12 to 1.14) for early term (37-38 weeks), compared with full-term (39-41 weeks) birth. These findings were not explained by shared familial factors. Asthma risks were elevated after spontaneous or medically indicated preterm birth and with or without perinatal respiratory complications. CONCLUSIONS: In this large national cohort, preterm and early term birth were associated with increased risks of asthma from childhood into midadulthood. Persons born prematurely need long-term follow-up into adulthood for timely detection and treatment of asthma.

Recent trends in asthma diagnosis, preschool wheeze diagnosis and asthma exacerbations in English children and adolescents: a SABINA Jr study.

BACKGROUND: Asthma-related burden remains poorly characterised in children in the UK. We quantified recent trends in asthma prevalence and burden in a UK population-based cohort (1‒17-year-olds). METHODS: The Clinical Practice Research Datalink Aurum database (2008‒2018) was used to assess annual asthma incidence and prevalence in 1‒17-year-olds and preschool wheeze in 1‒5-year-olds, stratified by sex and age. During the same period, annual asthma exacerbation rates were assessed in those with either a diagnosis of preschool wheeze or asthma. RESULTS: Annual asthma incidence rates decreased by 51% from 1403.4 (95% CI 1383.7 to 1423.2) in 2008 to 688.0 (95% CI 676.3 to 699.9) per 105 person-years (PYs) in 2018, with the most pronounced decrease observed in 1‒5-year olds (decreasing by 65%, from 2556.9 (95% CI 2509.8 to 2604.7) to 892.3 (95% CI 866.9 to 918.3) per 105 PYs). The corresponding decreases for the 6‒11- and 12‒17-year-olds were 36% (1139.9 (95% CI 1110.6 to 1169.7) to 739.9 (95% CI 720.5 to 759.8)) and 20% (572.3 (95% CI 550.4 to 594.9) to 459.5 (95% CI 442.9 to 476.4)) per 105 PYs, respectively. The incidence of preschool wheeze decreased over time and was slightly more pronounced in the 1‒3 year-olds than in the 4-year-olds. Prevalence of asthma and preschool wheeze also decreased over time, from 18.0% overall in 2008 to 10.2% in 2018 for asthma. Exacerbation rates increased over time from 1.33 (95% CI 1.31 to 1.35) per 10 PYs in 2008 to 1.81 (95% CI 1.78 to 1.83) per 10 PYs in 2018. CONCLUSION: Paediatric asthma incidence decreased in the UK since 2008, particularly in 1-5-year-olds; this was accompanied by a decline in asthma prevalence. Preschool wheeze incidence also decreased in this age group. However, exacerbation rates have been increasing.

Respiratory and allergic outcomes among 5-year-old children exposed to pesticides.

BACKGROUND: Little is known about the effects of pesticides on children's respiratory and allergic outcomes. We evaluated associations of prenatal and current pesticide exposures with respiratory and allergic outcomes in children from the Infants' Environmental Health Study in Costa Rica. METHODS: Among 5-year-old children (n=303), we measured prenatal and current specific gravity-corrected urinary metabolite concentrations of insecticides (chlorpyrifos, pyrethroids), fungicides (mancozeb, pyrimethanil, thiabendazole) and 2,4-D. We collected information from caregivers on respiratory (ever doctor-diagnosed asthma and lower respiratory tract infections (LRTI), wheeze and cough during last 12 months) and allergic (nasal allergies, itchy rash, ever eczema) outcomes. We fitted separate multivariable logistic regression models for high (≥75th percentile (P75)) vs low (

Asthma symptoms, spirometry and air pollution exposure in schoolchildren in an informal settlement and an affluent area of Nairobi, Kenya.

BACKGROUND: Although 1 billion people live in informal (slum) settlements, the consequences for respiratory health of living in these settlements remain largely unknown. This study investigated whether children living in an informal settlement in Nairobi, Kenya are at increased risk of asthma symptoms. METHODS: Children attending schools in Mukuru (an informal settlement in Nairobi) and a more affluent area (Buruburu) were compared. Questionnaires quantified respiratory symptoms and environmental exposures; spirometry was performed; personal exposure to particulate matter (PM2.5) was estimated. RESULTS: 2373 children participated, 1277 in Mukuru (median age, IQR 11, 9-13 years, 53% girls), and 1096 in Buruburu (10, 8-12 years, 52% girls). Mukuru schoolchildren were from less affluent homes, had greater exposure to pollution sources and PM2.5. When compared with Buruburu schoolchildren, Mukuru schoolchildren had a greater prevalence of symptoms, 'current wheeze' (9.5% vs 6.4%, p=0.007) and 'trouble breathing' (16.3% vs 12.6%, p=0.01), and these symptoms were more severe and problematic. Diagnosed asthma was more common in Buruburu (2.8% vs 1.2%, p=0.004). Spirometry did not differ between Mukuru and Buruburu. Regardless of community, significant adverse associations were observed with self-reported exposure to 'vapours, dusts, gases, fumes', mosquito coil burning, adult smoker(s) in the home, refuse burning near homes and residential proximity to roads. CONCLUSION: Children living in informal settlements are more likely to develop wheezing symptoms consistent with asthma that are more severe but less likely to be diagnosed as asthma. Self-reported but not objectively measured air pollution exposure was associated with increased risk of asthma symptoms.

Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth.

BACKGROUND: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations. OBJECTIVE: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles. METHODS: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases. RESULTS: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (C5orf46) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels. CONCLUSIONS: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2.

Burden and unmet need for specialist care in poorly controlled and severe childhood asthma in a Danish nationwide cohort.

BACKGROUND: Asthma is a common disease in childhood and adolescence with lifelong consequences particularly among those at risk of severe disease, poor control and/or frequent exacerbations. Specialist care is recommended for at-risk children and adolescents, yet access to specialist management in free-to-access healthcare settings remains poorly understood. METHODS: A Danish nationwide cohort of children and adolescents aged 2-17 years with persistent asthma, defined as repeated redemption of inhaled corticosteroids (ICS) during 2015, were followed for two years, to identify at-risk children and adolescents comprising those with severe asthma (classified according to GINA 2020 guidelines), poor control (defined as use of 400/600 (ages 2-11/12 +) annual doses of short-acting bronchodilators), or frequent exacerbations (defined as use of oral steroids or hospitalization), and access to specialist care. The population is chosen due to detailed medical records in the setting of universal health care. RESULTS: The cohort comprised of 29,851 children and adolescents (59% boys), with a median age of 9 years. While 17% of children were on high dose ICS, 22% were on daily ICS below GINA low dose cut-off. Prevalence of severe asthma (3.0-6.5%) was lower than poor asthma control (6.4-25%); both declined from childhood to adolescence. Exacerbations occurred in 7.1-9.0% of children, with median number of exacerbations being 1 (IQR 1-1). Despite being classified as having mild-to-moderate asthma, 15% had poor asthma control and 3.8% experienced exacerbation(s), respectively. While 61% of children with severe asthma and 58% with exacerbation-prone disease were in specialist care, only 24% with uncontrolled disease were receiving specialist care. Of children and adolescents using high-dose ICS, 71% were managed in primary care, while the use of additional controllers was more common in specialist care. CONCLUSIONS: Throughout childhood and adolescence, there was a high prevalence of severe asthma and poor control, although their prevalence declined with age. We demonstrate a large unmet need for specialist care among children with at-risk asthma, particularly among those with poorly controlled asthma, even in a system with free-to-access, tax-funded healthcare.

Nasopharyngeal lipidomic endotypes of infants with bronchiolitis and risk of childhood asthma: a multicentre prospective study.

BACKGROUND: Bronchiolitis is the leading cause of hospitalisation of US infants and an important risk factor for childhood asthma. Recent evidence suggests that bronchiolitis is clinically heterogeneous. We sought to derive bronchiolitis endotypes by integrating clinical, virus and lipidomics data and to examine their relationship with subsequent asthma risk. METHODS: This is a multicentre prospective cohort study of infants (age <12 months) hospitalised for bronchiolitis. We identified endotypes by applying clustering approaches to clinical, virus and nasopharyngeal airway lipidomic data measured at hospitalisation. We then determined their longitudinal association with the risk for developing asthma by age 6 years by fitting a mixed-effects logistic regression model. To account for multiple comparisons of the lipidomics data, we computed the false discovery rate (FDR). To understand the underlying biological mechanism of the endotypes, we also applied pathway analyses to the lipidomics data. RESULTS: Of 917 infants with bronchiolitis (median age, 3 months), we identified clinically and biologically meaningful lipidomic endotypes: (A) cinicalclassiclipidmixed (n=263), (B) clinicalseverelipidsphingolipids-high (n=281), (C) clinicalmoderatelipidphospholipids-high (n=212) and (D) clinicalatopiclipidsphingolipids-low (n=161). Endotype A infants were characterised by 'classic' clinical presentation of bronchiolitis. Profile D infants were characterised by a higher proportion of parental asthma, IgE sensitisation and rhinovirus infection and low sphingolipids (eg, sphingomyelins, ceramides). Compared with endotype A, profile D infants had a significantly higher risk of asthma (22% vs 50%; unadjusted OR, 3.60; 95% CI 2.31 to 5.62; p<0.001). Additionally, endotype D had a significantly lower abundance of polyunsaturated fatty acids (eg, docosahexaenoic acid; FDR=0.01). The pathway analysis revealed that sphingolipid metabolism pathway was differentially expressed in endotype D (FDR=0.048). CONCLUSIONS: In this multicentre prospective cohort study of infants with bronchiolitis, integrated clustering of clinical, virus and lipidomic data identified clinically and biologically distinct endotypes that have a significantly differential risk for developing asthma.Delete.

Airway inflammation in severe asthmatics with acid gastro-oesophageal reflux.

The relationship between childhood asthma and gastro-oesophageal reflux (GOR) is contentious. Recent studies in adult asthmatics suggest that GOR is associated with worse control and differences in sputum proteomics related to epithelial integrity, systemic inflammation and host defence. We assessed 127 children with severe asthma undergoing bronchoscopy and pH study. There were no differences in asthma control or measures of airway inflammation or remodelling when those with acid GOR were compared with those without. These results suggest that acid GOR is not an important comorbidity in paediatric severe asthma.

Height and bone mineral content after inhaled corticosteroid use in the first 6 years of life.

BACKGROUND: Infants and young children might be particularly susceptible to the potential side effects from inhaled corticosteroid (ICS) on height and bone mineral content (BMC), but this has rarely been studied in long-term prospective studies. METHODS: Children from two Copenhagen Prospective Studies on Asthma in Childhood cohorts were included. ICS use was registered prospectively from birth to age 6 and the cumulative dose was calculated. Primary outcomes were height and BMC from dual-energy X-ray absorptiometry (DXA) scans at age 6. RESULTS: At age 6, a total of 930 children (84%) from the cohorts had a valid height measurement and 792 (71%) had a DXA scan. 291 children (31%) received a cumulated ICS dose equivalent to or above 10 weeks of standard treatment before age 6. We found an inverse association between ICS use and height, -0.26 cm (95% CI: -0.45 to -0.07) per 1 year standard treatment from 0 to 6 years of age, p=0.006. This effect was mainly driven by children with ongoing treatment between age 5 and 6 years (-0.31 cm (95% CI: -0.52 to -0.1), p=0.004), while there was no significant association in children who stopped treatment at least 1 year before age 6 (-0.09 cm (95% CI: -0.46 to 0.28), p=0.64). There was no association between ICS use and BMC at age 6. CONCLUSIONS: ICS use in early childhood was associated with reduced height at age 6 years but only in children with continued treatment in the sixth year of life.

Epinephrine (adrenaline) compared to selective beta-2-agonist in adults or children with acute asthma: a systematic review and meta-analysis.

BACKGROUND: International asthma guidelines recommend against epinephrine (adrenaline) administration in acute asthma unless associated with anaphylaxis or angio-oedema. However, administration of intramuscular epinephrine in addition to nebulised selective ß2-agonist is recommended for acute severe or life-threatening asthma in many prehospital guidelines. We conducted a systematic review to determine the efficacy of epinephrine in comparison to selective ß2-agonist in acute asthma. METHODS: We included peer-reviewed publications of randomised controlled trials (RCTs) that enrolled children or adults in any healthcare setting and compared epinephrine by any route to selective ß2-agonist by any route for an acute asthma exacerbation. The primary outcome was treatment failure, including hospitalisation, need for intubation or death. RESULTS: Thirty-eight of 1140 studies were included. Overall quality of evidence was low. Seventeen studies contributed data on 1299 participants to the meta-analysis. There was significant statistical heterogeneity, I2=56%. The pooled Peto's OR for treatment failure with epinephrine versus selective ß2-agonist was 0.99 (0.75 to 1.32), p=0.95. There was strong evidence that recruitment age group was associated with different estimates of the odds of treatment failure; with studies recruiting adults-only having lower odds of treatment failure with epinephrine. It was not possible to determine whether epinephrine in addition to selective ß2-agonist improved outcomes. CONCLUSION: The low-quality evidence available suggests that epinephrine and selective ß2-agonists have similar efficacy in acute asthma. There is a need for high-quality double-blind RCTs to determine whether addition of intramuscular epinephrine to inhaled or nebulised selective ß2-agonist improves outcome. PROSPERO REGISTRATION NUMBER: CRD42017079472.

Wheeze in the time of COVID-19: overcoming obstacles to an unusual diagnosis.

This case is an example of a rare cause of a common clinical presentation (persistent lobar collapse with wheeze). We describe patient management from primary care through to a national thoracic referral centre. We highlight the importance of objective testing to support an asthma diagnosis and the need to consider alternative or additional diagnoses if a patient does not respond to treatment or the clinical course is unexpected. We highlight the importance of follow-up X-ray to determine whether atelectasis has resolved, which was significantly delayed in this case due to COVID-19 restrictions. Though rare, an endobronchial tumour should be considered if atelectasis persists and when planning endoscopy for a presumed foreign body, especially if the clinical history and patient factors make a foreign body less likely. Greater awareness of this as a differential may expedite diagnoses for patients in future. We show how virtual, multicentre, multidisciplinary meetings can aid rapid diagnosis, surgical planning and coordination of follow-up across centres.

Sustained delivery of salbutamol from cubosomal gel for management of paediatric asthma: in vitro and in vivo evaluation.

AIM: In the current study, efforts are being made to formulate transdermal salbutamol-cubosomal gel to manage paediatric asthma. METHODS: Salbutamol-loaded cubosomal gels were prepared by melt emulsification and sonication. The cubosomal gels were characterised by morphology, particle size, zeta potential, entrapment efficacy, assay, viscosity, and texture profiles. Ex vivo permeation and pharmacokinetic studies were performed using rats. RESULTS: The mean cubosomal particle size (208-361 ± 12.5-32.5 nm), PDI (0.06-0.11 ± 0.01-0.02), viscosity (8527-9019 cp), and entrapment efficacy (76.3-91.0% w/w) increase with the level of monoolein. The ex vivo permeation study showed a biphasic release pattern, with salbutamol cleared from control gel within 8 h, while cubosomal gels showed sustained release up to 72 h. The pharmacokinetic profiles in the rat model showed 8.62-fold higher bioavailability with cubosomal gel. CONCLUSION: The study demonstrated the potential of cubosomal nanoparticle-laden gel to sustain the release of salbutamol to treat paediatric asthma.

An enhanced care package to improve asthma management in Malawian children: a randomised controlled trial.

BACKGROUND: Shortages of clinical staff make chronic asthma care challenging in low-income countries. We evaluated an outpatient asthma care package for children, including task-shifting of asthma management roles. METHODS: We conducted a non-blinded individually randomised controlled trial at a tertiary-level government hospital in Blantyre, Malawi. Children aged 6-15 years diagnosed with asthma were recruited from outpatient clinic, stratified by Childhood Asthma Control Test (cACT) score and allocated 1:1 from a concealed file, accessed during electronic questionnaire completion. The intervention, delivered by non-physicians, comprised clinical assessment, optimisation of inhaled treatment, individualised asthma education. The control group received standard care from outpatient physicians. Primary outcome for intention-to-treat analysis was change in cACT score at 3 months. Secondary outcomes included asthma exacerbations requiring emergency healthcare and school absence. FINDINGS: Between September 2018 and December 2019, 120 children (59 intervention; 61 control) were recruited; 65.8% males, with mean (SD) age 9.8 (2.8) years, mean (SD) baseline cACT 20.3 (2.6). At 3 months, intervention children (n=56) had a greater mean (SD) change in cACT score from baseline (2.7 (2.8) vs 0.6 (2.8)) compared with standard care participants (n=59); a difference of 2.1 points (95% CI: 1.1 to 3.1, p<0.001). Fewer intervention children attended emergency healthcare (7.3% vs 25.4%, p=0.02) and missed school (20.0% vs 62.7%, p<0.001) compared with standard care children. INTERPRETATION: The intervention resulted in decreased asthma symptoms and exacerbations. Wider scale-up could present substantial benefits for asthmatic patients in resource-limited settings. TRIAL REGISTRATION NUMBER: PACTR201807211617031.