Nintedanib in children and adolescents with fibrosing interstitial lung diseases.

Childhood interstitial lung disease comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. Patients aged 6-17 years with fibrosing ILD on HRCT and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary endpoints were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24. Twenty-six patients received nintedanib and 13 placebo. The geometric mean (gCV%) AUCτ,ss for nintedanib was 175 µg×h·L-1 (85.1) in patients aged 6-11 years and 160 µg×h·L-1 (82.7) in patients aged 12-17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean (se) changes in FVC % predicted at week 24 were 0.3 (1.3) in the nintedanib group and -0.9 (1.8) in the placebo group. In conclusion, in children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.

Community-based asthma assessment in young children: adaptations for a multicentre longitudinal study in South Asia.

Background: Systematic assessment of childhood asthma is challenging in low- and middle-income country (LMIC) settings due to the lack of standardised and validated methodologies. We describe the contextual challenges and adaptation strategies in the implementation of a community-based asthma assessment in four resource-constrained settings in Bangladesh, India, and Pakistan. Method: We followed a group of children of age 6-8 years for 12 months to record their respiratory health outcomes. The study participants were enrolled at four study sites of the 'Aetiology of Neonatal Infection in South Asia (ANISA)' study. We standardised the research methods for the sites, trained field staff for uniform data collection and provided a 'Child Card' to the caregiver to record the illness history of the participants. We visited the children on three different occasions to collect data on respiratory-related illnesses. The lung function of the children was assessed in the outreach clinics using portable spirometers before and after 6-minute exercise, and capillary blood was examined under light microscopes to determine eosinophil levels. Results: We enrolled 1512 children, 95.5% (1476/1512) of them completed the follow-up, and 81.5% (1232/1512) participants attended the lung function assessment tests. Pre- and post-exercise spirometry was performed successfully in 88.6% (1091/1232) and 85.7% (1056/1232) of children who attempted these tests. Limited access to health care services, shortage of skilled human resources, and cultural diversity were the main challenges in adopting uniform procedures across all sites. Designing the study implementation plan based on the local contexts and providing extensive training of the healthcare workers helped us to overcome these challenges. Conclusion: This study can be seen as a large-scale feasibility assessment of applying spirometry and exercise challenge tests in community settings of LMICs and provides confidence to build capacity to evaluate children's respiratory outcomes in future translational research studies.

SARS-CoV-2 tests, confirmed infections and COVID-19-related hospital admissions in children and young people: birth cohort study.

BACKGROUND: There have been no population-based studies of SARS-CoV-2 testing, PCR-confirmed infections and COVID-19-related hospital admissions across the full paediatric age range. We examine the epidemiology of SARS-CoV-2 in children and young people (CYP) aged <23 years. METHODS: We used a birth cohort of all children born in Scotland since 1997, constructed via linkage between vital statistics, hospital records and SARS-CoV-2 surveillance data. We calculated risks of tests and PCR-confirmed infections per 1000 CYP-years between August and December 2020, and COVID-19-related hospital admissions per 100 000 CYP-years between February and December 2020. We used Poisson and Cox proportional hazards regression models to determine risk factors. RESULTS: Among the 1 226 855 CYP in the cohort, there were 378 402 tests (a rate of 770.8/1000 CYP-years (95% CI 768.4 to 773.3)), 19 005 PCR-confirmed infections (179.4/1000 CYP-years (176.9 to 182.0)) and 346 admissions (29.4/100 000 CYP-years (26.3 to 32.8)). Infants had the highest COVID-19-related admission rates. The presence of chronic conditions, particularly multiple types of conditions, was strongly associated with COVID-19-related admissions across all ages. Overall, 49% of admitted CYP had at least one chronic condition recorded. CONCLUSIONS: Infants and CYP with chronic conditions are at highest risk of admission with COVID-19. Half of admitted CYP had chronic conditions. Studies examining COVID-19 vaccine effectiveness among children with chronic conditions and whether maternal vaccine during pregnancy prevents COVID-19 admissions in infants are urgently needed.

Air Pollution, housing and respirfatory tract Infections in Children: NatIonal birth Cohort study (PICNIC): study protocol.

INTRODUCTION: Respiratory tract infections (RTIs) are the most common reason for hospital admission among children <5 years in the UK. The relative contribution of ambient air pollution exposure and adverse housing conditions to RTI admissions in young children is unclear and has not been assessed in a UK context. METHODS AND ANALYSIS: The aim of the PICNIC study (Air Pollution, housing and respiratory tract Infections in Children: NatIonal birth Cohort Study) is to quantify the extent to which in-utero, infant and childhood exposures to ambient air pollution and adverse housing conditions are associated with risk of RTI admissions in children <5 years old. We will use national administrative data birth cohorts, including data from all children born in England in 2005-2014 and in Scotland in 1997-2020, created via linkage between civil registration, maternity and hospital admission data sets. We will further enhance these cohorts via linkage to census data on housing conditions and socioeconomic position and small area-level data on ambient air pollution and building characteristics. We will use time-to-event analyses to examine the association between air pollution, housing characteristics and the risk of RTI admissions in children, calculate population attributable fractions for ambient air pollution and housing characteristics, and use causal mediation analyses to explore the mechanisms through which housing and air pollution influence the risk of infant RTI admission. ETHICS, EXPECTED IMPACT AND DISSEMINATION: To date, we have obtained approval from six ethics and information governance committees in England and two in Scotland. Our results will inform parents, national and local governments, the National Health Service and voluntary sector organisations of the relative contribution of adverse housing conditions and air pollution to RTI admissions in young children. We will publish our results in open-access journals and present our results to the public via parent groups and social media and on the PICNIC website. Code and metadata will be published on GitHub.