Handling of Inhaled Particulate Matter by Alveolar Macrophages in Children with Cystic Fibrosis

Phd thesisBackground: Children with Cystic Fibrosis (CF) are vulnerable to the effects of inhaled carbonaceous pollutants, but the underlying mechanism remains unclear. In CF, bacterial phagocytosis by alveolar macrophages (AM) is impaired, with increased airway prostanoid levels. Since particulate matter (PM) clearance is mainly by AM phagocytosis, I hypothesised that in CF, the amount of inhaled carbon phagocytosed by AMs is reduced, with increased phagocytosis-inhibitory Prostaglandin-E2 (PGE2) production, secondary to increased AM cyclooxygenase-2 (COX-2) expression. Methods: Children with CF and healthy controls carried portable aethalometers to monitor their personal carbon exposure. AMs were obtained by sputum induction. Carbon areas of 50 AMs per participant were quantified using image analysis. Purified populations of AM were exposed to diesel exhaust particles (DEP) to compare phagocytosis in both groups. Addition of PGE2 to the cell-DEP culture assessed its phagocytosis effects. AM COX-2 expression was determined by flow cytometry. Urinary prostanoid metabolites, as prostanoids production markers, were measured by mass spectrometry. Data were analysed by Mann-Whitney/Wilcoxon and paired t-tests. Results: Despite no significant difference in median personal carbon exposure (CF 1394 ng/m3, n=25 vs control 1587 ng/m3, n=21; p=0.83); in vivo AM carbon was lower in CF (median 0.12 μm2 vs 0.30 μm2, p<0.001). AMs from both groups demonstrated considerable DEP uptake in vitro (CF median fold change 72 vs control 40); addition of PGE2 attenuated DEP uptake (mean difference -3.88 μm2, p<0.001). AM COX-2 expression was increased in CF (MFI median 10217 vs 8142; p<0.05), who also had higher urinary concentrations of PGE2 metabolites (median 35965 pg/mg creat vs 15873 pg/mg creat, p<0.001). Conclusion: AM phagocytosis of carbon is impaired in CF in vivo, but comparable with controls in vitro, suggesting inhibitory constituents are present in CF airways. Since COX-2 expression and PGE2 production are increased in CF, I conclude that PGE2 is inhibitory on CF AM function

Severe Paediatric Asthma Collaborative in Europe (SPACE):protocol for a European registry

The development of new asthma biologics and receptor blockers for the treatment of paediatric severe asthma raises challenges. It is unclear whether there are sufficient children in Europe to recruit into randomised placebo-controlled trials to establish efficacy and safety in this age group. In February 2016, the European Respiratory Society funded a clinical research collaboration entitled “Severe Paediatric Asthma Collaborative in Europe” (SPACE). We now report the SPACE protocol for a prospective pan-European observational study of paediatric severe asthma. Inclusion criteria are: 1) age 6–17 years, 2) severe asthma managed at a specialised centre for ≥6 months, 3)clinical and spirometry evidence of asthma, and 4) reaching a pre-defined treatment threshold. The exclusion criterion is the presence of conditions which mimic asthma symptoms. Eligible children will be prospectively recruited into a registry, recording demographics, comorbidities, quality of life, family history, neonatal history, smoking history, asthma background, investigations, and treatment. Follow-up will provide longitudinal data on asthma control and treatment changes. The SPACE registry, by identifying well-phenotyped children eligible for clinical trials, and the amount of overlap in eligibility criteria, will inform the design of European trials in paediatric severe asthma, and facilitate observational research where data from single centres are limited

First analysis of the Severe Paediatric Asthma Collaborative in Europe registry.

New biologics are being continually developed for paediatric asthma, but it is unclear whether there are sufficient numbers of children in Europe with severe asthma and poor control to recruit to trials needed for registration. To address these questions, the European Respiratory Society funded the Severe Paediatric Asthma Collaborative in Europe (SPACE), a severe asthma registry. We report the first analysis of the SPACE registry, which includes data from 10 paediatric respiratory centres across Europe. Data from 80 children with a clinical diagnosis of severe asthma who were receiving both high-dose inhaled corticosteroid and long-acting β2-agonist were entered into the registry between January 2019 and January 2020. Suboptimal control was defined by either asthma control test, or Global Initiative for Asthma criteria, or ≥2 severe exacerbations in the previous 12 months, or a combination. Overall, 62 out of 80 (77%) children had suboptimal asthma control, of whom 29 were not prescribed a biologic. However, in 24 there was an option for starting a licensed biologic. 33 children with suboptimal control were prescribed a biologic (omalizumab (n=24), or mepolizumab (n=7), or dupilumab (n=2)), and for 29 there was an option to switch to a different biologic. We conclude that the SPACE registry provides data that will support the planning of studies of asthma biologics. Not all children on biologics achieve good asthma control, and there is need for new trial designs addressing biologic switching

Novel therapies for severe asthma in children and adults.

The heterogeneous nature of asthma requires personalised treatments. Monoclonal antibody treatments showed good efficacy, and should be considered when symptoms are poorly controlled despite good inhaler technique, compliance and controlled comorbidities. http://ow.ly/UWpg30hImQh

Key paediatric messages from the 2018 European Respiratory Society International Congress

In this article, the Group Chairs and early career members of the European Respiratory Society (ERS) Paediatric Assembly highlight some of the most interesting findings in the field of paediatrics which were presented at the 2018 international ERS Congress.</p