ERS International Congress 2021: highlights from the Paediatric Assembly

In this review, Early Career Members of the European Respiratory Society (ERS) and the Chairs of the ERS Assembly 7: Paediatrics present the highlights in paediatric respiratory medicine from the ERS International Congress 2021. The eight scientific Groups of this Assembly cover respiratory physiology and sleep, asthma and allergy, cystic fibrosis (CF), respiratory infection and immunology, neonatology and intensive care, respiratory epidemiology, bronchology, and lung and airway development. We here describe new developments in lung function testing and sleep-disordered breathing diagnosis, early life exposures affecting pulmonary function in children and effect of COVID-19 on sleep and lung function. In paediatric asthma, we present the important role of the exposome in asthma development, and how biologics can provide better outcomes. We discuss new methods to assess distal airways in children with CF, as some details remain blind when using the lung clearance index. Moreover, we summarise the new ERS guidelines for bronchiectasis management in children and adolescents. We present interventions to reduce morbidity and monitor pulmonary function in newborns at risk of bronchopulmonary dysplasia and long-term chronic respiratory morbidity of this disease. In respiratory epidemiology, we characterise primary ciliary dyskinesia, identify early life determinants of respiratory health and describe the effect of COVID-19 preventive measures on respiratory symptoms. Also, we describe the epidemiology of interstitial lung diseases, possible consequences of tracheomalacia and a classification of diffuse alveolar haemorrhage in children. Finally, we highlight that the characterisation of genes and pathways involved in the development of a disease is essential to identify new biomarkers and therapeutic targets

Bronchiolitis needs a revisit: Distinguishing between virus entities and their treatments

Current data indicate that the “bronchiolitis” diagnosis comprises more than one condition. Clinically, pathophysiologically, and even genetically three main clusters of patients can be identified among children suffering from severe bronchiolitis (or first wheezing episode): (a) respiratory syncytial virus (RSV)-induced bronchiolitis, characterized by young age of the patient, mechanical obstruction of the airways due to mucus and cell debris, and increased risk of recurrent wheezing. For this illness, an effective prophylactic RSV-specific monoclonal antibody is available; (b) rhinovirus-induced wheezing, associated with atopic predisposition of the patient and high risk of subsequent asthma development, which may, however, be reversed with systemic corticosteroids in those with severe illness; and (c) wheeze due to other viruses, characteristically likely to be less frequent and severe. Clinically, it is important to distinguish between these partially overlapping patient groups as they are likely to respond to different treatments. It appears that the first episode of severe bronchiolitis in under 2-year-old children is a critical event and an important opportunity for designing secondary prevention strategies for asthma. As data have shown bronchiolitis cannot simply be diagnosed using a certain cutoff age, but instead, as we suggest, using the viral etiology as the differentiating factor.</p

The role of interferons in driving susceptibility to asthma following bronchiolitis:controversies and research gaps

Abstract Bronchiolitis is the most common cause of hospitalization in infancy and is associated with a higher risk for the development of childhood asthma. However, not all children hospitalized with bronchiolitis will develop asthma. The mechanisms underlying asthma development following bronchiolitis hospitalization are complex. Immune responses to respiratory viruses may underlie both bronchiolitis severity and long-term sequela (such as asthma). Interferons (IFNs) are important components of innate immune responses to respiratory viruses and could influence both asthma development and asthma exacerbations. However, the nature of the relationship between interferon production and wheezing illnesses is controversial. For example, low peripheral blood IFN responses at birth have been linked with recurrent wheeze and asthma development. In contrast, there is evidence that severe illnesses (e.g., hospitalization for bronchiolitis) are associated with increased IFN responses during acute infection (bronchiolitis hospitalization) and a higher risk for subsequent asthma diagnosis. Furthermore, mechanistic studies suggest that bronchial epithelial cells from asthmatic children have impaired IFN responses to respiratory viruses, which may enable increased viral replication followed by exaggerated secondary IFN responses. This review aims to discuss controversies around the role of IFNs as drivers of susceptibility to asthma development following bronchiolitis hospitalization. Past evidence from both mechanistic and cohort studies are discussed. We will highlight knowledge gaps that can inform future research study design

Respiratory virus type to guide predictive enrichment approaches in the management of the first episode of bronchiolitis:a systematic review

Abstract It has become clear that severe bronchiolitis is a heterogeneous disease; even so, current bronchiolitis management guidelines rely on the one-size-fits-all approach regarding achieving both short-term and chronic outcomes. It has been speculated that the use of molecular markers could guide more effective pharmacological management and achieve the prevention of chronic respiratory sequelae. Existing data suggest that asthma-like treatment (systemic corticosteroids and beta2-agonists) in infants with rhinovirus-induced bronchiolitis is associated with improved short-term and chronic outcomes, but robust data is still lacking. We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane’s Library to identify eligible randomized controlled trials to determine the efficacy of a personalized, virus-dependent application of systemic corticosteroids in children with severe bronchiolitis. Twelve studies with heterogeneous methodology were included. The analysis of the available results comparing the respiratory syncytial virus (RSV)-positive and RSV-negative children did not reveal significant differences in the associatons between systemic corticosteroid use in acute episode and duration of hospitalization (short-term outcome). However, this systematic review identified a trend of the positive association between the use of systematic corticosteroids and duration of hospitalization in RSV-negative infants hospitalized with the first episode of bronchiolitis (two studies). This evidence is not conclusive. Taken together, we suggest the design for future studies to assess the respiratory virus type in guiding predictive enrichment approaches in infants presenting with the first episode of bronchiolitis

ERS International Congress 2021 virtual: highlights from the Paediatric Assembly.

In this review, Early Career Members of the European Respiratory Society (ERS) and the Chairs of the Assembly 7 – Paediatrics Groups, present the highlights in paediatric respiratory medicine from the ERS International Congress 2021. The Groups cover respiratory physiology and sleep, asthma and allergy, cystic fibrosis (CF), respiratory infection and immunology, neonatology and intensive care, epidemiology, bronchology, and lung and airway development. We here describe new developments in lung function testing and sleep disordered breathing diagnosis, early life exposures affecting pulmonary function in children and effect of COVID-19 on sleep and lung function. In paediatric asthma, we present the important role of the exposome in asthma development, and how biologics can provide better outcomes. We discuss new methods to assess distal airways in children with CF, as some details remain blind when using Lung Clearance Index. Moreover, we summarise the new ERS guidelines for bronchiectasis management in children and adolescents. We present interventions to reduce morbidity and monitor pulmonary function in newborns at risk of bronchopulmonary dysplasia and long term chronic respiratory morbidity of this disease. In respiratory epidemiology, we characterise Primary Ciliary Dyskinesia, identify early life determinants of respiratory health and describe the effect of COVID-19 preventive measures on respiratory symptoms. Also, we describe the epidemiology of interstitial lung diseases, possible consequences of tracheomalacia and a classification of diffuse alveolar haemorrhage in children. Finally, we highlight that the characterisation of genes and pathways involved in the development of a disease is essential to identify new biomarkers and therapeutic targets

Preschool wheezing and asthma in children:a systematic review of guidelines and quality appraisal with the AGREE II instrument

Abstract Background: Asthma‐like symptoms in preschool children, such as wheezing and dyspnea, are common time‐ and resource‐consuming diagnostic and management challenges. Quality of wheezing and asthma recommendations varies. The purpose of this study, carried out by the European Academy of Allergy and Clinical Immunology (EAACI) Task Force for Preschool Wheeze, was to systematically review and assess the quality of guidelines for diagnosis and treatment of preschool wheezing and/or asthma. Methods: The Cochrane Library, MEDLINE, and EMBASE were searched until June 2018. The methodological rigor, quality, and transparency of relevant guidelines were assessed with the use of the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. Results: We identified 26 guidelines. The quality scores for each domain varied. Of all domains, clarity and presentation had the highest mean score, whereas applicability and stakeholder involvement had the lowest. The scores (median) for individual domains were as follows: score and purpose 86%; stakeholder involvement 49%; rigor of development 54%; clarity of presentation 85%; applicability 51%; and editorial independence 63%. Conclusion: Although several guidelines on asthma management in children are available, however, their quality varies. Additionally, there is a considerable gap in reliable recommendations on the management and treatment of non‐asthmatic preschool wheeze

IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo

Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell–derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation. Objectives: To assess whether rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway. Methods: We used a human experimental model of rhinovirus infection and novel airway sampling techniques to measure IL-4, IL-5, IL-13, and IL-33 levels in the asthmatic and healthy airways during a rhinovirus infection. Additionally, we cultured human T cells and type 2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirus- infected bronchial epithelial cells (BECs) to assess type 2 cytokine production in the presence or absence of IL-33 receptor blockade. Measurements and Main Results: IL-4, IL-5, IL-13, and IL-33 are all induced by rhinovirus in the asthmatic airway in vivo and relate to exacerbation severity. Further, induction of IL-33 correlates with viral load and IL-5 and IL-13 levels. Rhinovirus infection of human primary BECs induced IL-33, and culture of human T cells and ILC2s with supernatants of rhinovirus-infected BECs strongly induced type 2 cytokines. This induction was entirely dependent on IL-33. Conclusions: IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo. Virus-induced IL-33 and IL-33 – responsive T cells and ILC2s are key mechanistic links between viral infection and exacerbation of asthma. IL-33 inhibition is a novel therapeutic approach for asthma exacerbations

Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation

Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations