Allergic sensitization impairs lung resident memory CD8 T-cell response and virus clearance.

BACKGROUND: Patients with asthma often suffer from frequent respiratory viral infections and reduced virus clearance. Lung resident memory T cells provide rapid protection against viral reinfections. OBJECTIVE: Because the development of resident memory T cells relies on the lung microenvironment, we investigated the impact of allergen sensitization on the development of virus-specific lung resident memory T cells and viral clearance. METHODS: Mice were sensitized with house dust mite extract followed by priming with X47 and a subsequent secondary influenza infection. Antiviral memory T-cell response and protection to viral infection was assessed before and after secondary influenza infection, respectively. Gene set variation analysis was performed on data sets from the U-BIOPRED asthma cohort using an IFN-γ-induced epithelial cell signature and a tissue resident memory T-cell signature. RESULTS: Viral loads were higher in lungs of sensitized compared with nonsensitized mice after secondary infection, indicating reduced virus clearance. X47 priming induced fewer antiviral lung resident memory CD8 T cells and resulted in lower pulmonary IFN-γ levels in the lungs of sensitized as compared with nonsensitized mice. Using data from the U-BIOPRED cohort, we found that patients with enrichment of epithelial IFN-γ-induced genes in nasal brushings and bronchial biopsies were also enriched in resident memory T-cell-associated genes, had more epithelial CD8 T cells, and reported significantly fewer exacerbations. CONCLUSIONS: The allergen-sensitized lung microenvironment interferes with the formation of antiviral resident memory CD8 T cells in lungs and virus clearance. Defective antiviral memory response might contribute to increased susceptibility of patients with asthma to viral exacerbations.

Physical activity end-points in trials of chronic respiratory diseases: summary of evidence.

Background: Physical activity contributes to improving respiratory symptoms. However, validated end-points are few, and there is limited consensus about what is a clinically meaningful improvement for patients. This review summarises the evidence to date on the range of physical activity end-points used in COPD, asthma and idiopathic pulmonary fibrosis (IPF) whilst evaluating their appropriateness as end-points in trials and their relation to patients' everyday life. Methods: Trials reporting physical activity end-points were collected using Citeline's database Trialtrove; this was supplemented by searches in PubMed. Results: The daily-patient-reported outcome (PRO)active and clinical visit-PROactive physical activity composite end-points appeared superior at capturing the full experience of physical activity in patients with COPD and were responsive to bronchodilator intervention. Time spent in moderate-to-vigorous physical activity is a recently validated end-point for IPF that correlates with exercise capacity and quality of life. Step count appears the best available physical activity measure for asthma, which consistently declines with worse disease status. However, evidence suggests a time lag before significant improvement in step count is seen which may reflect the impact of human behaviour on physical activity. Conclusions: Physical activity represents a challenging domain to accurately measure. This is the first review evaluating physical activity measures used specifically within the respiratory field. Whilst physical activity can be effectively captured using PROactive in patients with COPD, this review highlights the unmet need for novel patient-focused end-points in asthma and IPF which would offer opportunities to develop efficacious medicines with impact on patients' therapeutic care and quality of life.