Spirometry parameters used to define small airways obstruction in population-based studies: systematic review protocol

IntroductionIn recent years, there has been increasing interest in the use of spirometry for the assessment of small airways obstruction (SAO) driven by the idea that these changes occur prior to development of established obstructive lung disease. Maximal mid-expiratory and distal flow rates have been widely used despite a lack of agreement regarding parameter selection or definition of an abnormal result. We aim to provide evidence from population-based studies, describing the different parameters, definitions of normal range and the resulting impact on prevalence estimates for SAO. Summarising this evidence is important to inform development of future studies in this area.Methods and analysisA systematic review of population-based studies will be conducted. MEDLINE, Web of Science and Google Scholar will be searched from database inception to May 2021. Primary outcomes will include the spirometry parameter used to define SAO, and the definition of an abnormal result. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed for study selection. Study methods will be assessed using the Newcastle-Ottawa scale and the Grading of Recommendations Assessment, Development and Evaluation working group methodology. Narrative synthesis will be conducted for all included studies. Meta-analysis will also be conducted for prevalence estimates and associated risk factors where data quality and availability allow. Random effects models will be used to conduct the meta-analysis and I2 statistics will be used to assess heterogeneity across studies. Where appropriate subgroup analysis will be conducted to explore heterogeneity.Ethics and disseminationThere is no requirement for ethical approval for this project. Findings will be disseminated via peer-reviewed publications and other formats, for example, conferences, congresses or symposia.PROSPERO registration numberCRD42021250206.

NOTCH3 contributes to rhinovirus-induced goblet cell hyperplasia in COPD airway epithelial cells

RationaleGoblet cell hyperplasia (GCH) is one of the cardinal features of chronic obstructive pulmonary disease (COPD) and contributes to airways obstruction. Rhinovirus (RV), which causes acute exacerbations in patients with COPD, also causes prolonged airways obstruction. Previously, we showed that RV enhances mucin gene expression and increases goblet cell number in a COPD mouse model. This study examines whether RV causes sustained GCH in relevant models of COPD.MethodsMucociliary-differentiated COPD and normal airway epithelial cell cultures and mice with normal or COPD phenotype were infected with RV or sham and examined for GCH by immunofluorescence and/or mucin gene expression. In some experiments, RV-infected COPD cells and mice with COPD phenotype were treated with γ-secretase inhibitor or interleukin-13 neutralising antibody and assessed for GCH. To determine the contribution of NOTCH1/3 in RV-induced GCH, COPD cells transduced with NOTCH1/3 shRNA were used.ResultsRV-infected COPD, but not normal cell cultures, showed sustained GCH and increased mucin genes expression. Microarray analysis indicated increased expression of NOTCH1, NOTCH3 and HEY1 only in RV-infected COPD cells. Blocking NOTCH3, but not NOTCH1, attenuated RV-induced GCH in vitro. Inhibition of NOTCH signalling by γ-secretase inhibitor, but not neutralising antibody to IL-13, abrogated RV-induced GCH and mucin gene expression.ConclusionsRV induces sustained GCH via NOTCH3 particularly in COPD cells or mice with COPD phenotype. This may be one of the mechanisms that may contribute to RV-induced prolonged airways obstruction in COPD.