Publications
1495 results found
Faiz A, Mahbub RM, Boedijono FS, et al., 2023, IL-33 Expression Is Lower in Current Smokers at Both Transcriptomic and Protein Level., Am J Respir Crit Care Med
INTRODUCTION: IL-33 is a pro-inflammatory cytokine thought to play a role in the pathogenesis of asthma and COPD. A recent clinical trial using the anti-IL33 antibody showed a reduction in exacerbation and improved lung function in ex-smokers but not current smokers with COPD. In this study, we aimed to understand the effects of smoking status on IL-33. METHODS: We investigated the association of smoking status with the level of gene expression of IL33 in the airways in eight independent transcriptomic studies of lung airways. Additionally, we performed western blot and immunohistochemistry for IL-33 in lung tissue to assess protein levels. RESULTS: Across the bulk RNA-sequencing datasets, IL-33 gene expression and its signaling pathway were significantly lower in current- compared to ex- or never-smokers and increased upon smoking cessation (p<0.05). Single-cell sequencing showed that IL-33 is predominantly expressed in resting basal epithelial cells and decreases during the differentiation process triggered by smoke exposure. We also found a higher transitioning of this cellular sub-population into a more differentiated cell type during chronic smoking, potentially driving the reduction of IL-33. Protein analysis demonstrated lower IL-33 levels in lung tissue from COPD current- compared to ex-smokers and a lower proportion of IL-33 positive basal cells in current versus ex-smoking controls. CONCLUSION: We provide strong evidence that cigarette smoke leads to an overall reduction in IL33 expression in both transcriptomic and protein level and this may be due to the decrease in resting basal cells. Together, these findings may explain the clinical observation that a recent antibody-based anti-IL-33 treatment is more effective in ex- than current smokers with COPD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Tran HM, Lin Y-C, Tsai F-J, et al., 2023, Short-term mediating effects of PM2.5 on climate-associated COPD severity., Sci Total Environ, Vol: 903
The impact of short-term exposure to environmental factors such as temperature, relative humidity (RH), and fine particulate matter (PM2.5) on chronic obstructive pulmonary disease (COPD) remains unclear. The objective of this study is to investigate PM2.5 as a mediator in the relationship between short-term variations in RH and temperature and COPD severity. A cross-sectional study was conducted on 930 COPD patients in Taiwan from 2017 to 2022. Lung function, COPD Assessment Test (CAT) score, and modified Medical Research Council (mMRC) dyspnea scale were assessed. The mean and differences in 1-day, 7-day, and 30-day individual-level exposure to ambient RH, temperature, and PM2.5 were estimated. The associations between these factors and clinical outcomes were analyzed using linear regression models and generalized additive mixed models, adjusting for age, sex, smoking, and body mass index. In the total season, increases in RH difference were associated with increases in forced expiratory volume in 1 s (FEV1) / forced vital capacity (FVC), while increases in temperature difference were associated with decreases in FEV1 and FEV1/FVC. Increases in PM2.5 mean were associated with declines in FEV1. In the cold season, increases in temperature mean were associated with decreases in CAT and mMRC scores, while increases in PM2.5 mean were associated with declines in FEV1, FVC, and FEV1/FVC. In the warm season, increases in temperature difference were associated with decreases in FEV1 and FEV1/FVC, while increases in RH difference and PM2.5 mean were associated with decreases in CAT score. PM2.5 fully mediated the associations of temperature mean with FEV1/FVC in the cold season. In conclusion, PM2.5 mediates the effects of temperature and RH on clinical outcomes. Monitoring patients during low RH, extreme temperature, and high PM2.5 levels is crucial. Capsule of findings The significance of this study is that an increase in ambient RH and temperature, as well as PM2.
Tran HM, Tsai F-J, Lee Y-L, et al., 2023, The impact of air pollution on respiratory diseases in an era of climate change: A review of the current evidence., Sci Total Environ, Vol: 898
The impacts of climate change and air pollution on respiratory diseases present significant global health challenges. This review aims to investigate the effects of the interactions between these challenges focusing on respiratory diseases. Climate change is predicted to increase the frequency and intensity of extreme weather events amplifying air pollution levels and exacerbating respiratory diseases. Air pollution levels are projected to rise due to ongoing economic growth and population expansion in many areas worldwide, resulting in a greater burden of respiratory diseases. This is especially true among vulnerable populations like children, older adults, and those with pre-existing respiratory disorders. These challenges induce inflammation, create oxidative stress, and impair the immune system function of the lungs. Consequently, public health measures are required to mitigate the effects of climate change and air pollution on respiratory health. The review proposes that reducing greenhouse gas emissions contribute to slowing down climate change and lessening the severity of extreme weather events. Enhancing air quality through regulatory and technological innovations also helps reduce the morbidity of respiratory diseases. Moreover, policies and interventions aimed at improving healthcare access and social support can assist in decreasing the vulnerability of populations to the adverse health effects of air pollution and climate change. In conclusion, there is an urgent need for continuous research, establishment of policies, and public health efforts to tackle the complex and multi-dimensional challenges of climate change, air pollution, and respiratory health. Practical and comprehensive interventions can protect respiratory health and enhance public health outcomes for all.
Manullang A, Chung CL, Lee YL, et al., 2023, COPD with Eosinophilic Inflammation is Susceptible to Particulate Air Pollution Exposure, Aerosol and Air Quality Research, Vol: 23, ISSN: 1680-8584
Chronic obstructive pulmonary disease (COPD) has been linked to air pollution exposure. Air pollution has been associated with eosinophilic inflammation of respiratory disease. The objective of this study was to determine associations between air pollution and eosinophilic inflammation in COPD. A cross-sectional study was conducted on 291 COPD patients recruited from hospitals in Taipei between January 2014 and 2021, including 147 patients with eosinophil blood count ≥ 2% and 144 patients < 2%. Land use regression (LUR) model was used to estimate exposure levels to particulate matter with an aerodynamic diameter of < 10 µm (PM10), PM2.5 (< 10 µm), nitrogen oxides (NOx) and nitrogen dioxides (NO2). We investigated associations of air pollution with COPD outcomes by performing a linear regression approach. A two-pollutant approach was applied to examine the associations of PM10 or PM2.5 with NOx or NO2 in COPD with eosinophilic inflammation. An increase of 1 µg m–3 in PM10 was associated with a 0.62% (95% CI: –1.10%, –0.13%) decrease in the forced vital capacity (FVC) in COPD. An increase of 1 µg m–3 in PM2.5 was associated with a 0.38% (95% CI: –0.71%, –0.05%) decrease in the FVC. A 1 µg m–3 increase in PM10 was associated with a 0.92% (95% CI: –1.68%, –0.16%) decrease in the FVC in COPD patients with eosinophilic inflammation. A 1 µg m–3 increase in PM2.5 was associated with an increase of 0.26 points (95% CI: –1.68%, –0.16%) in the COPD Assessment Test (CAT) and a 0.03-times year–1 (95% CI: 0.01, 0.05) increase in the acute exacerbation (AE) of COPD eosinophilic inflammation. Associations of PM10 and PM2.5 with lung function decline in COPD eosinophilic inflammation were confirmed by the two-pollutant model. Exposure to particulate air pollution increased the risk of deleterious health outcomes in COPD with eosinophilic inflammation. COPD wi
Bertels X, Edris A, Garcia-Aymerich J, et al., 2023, Phenotyping asthma with airflow obstruction in middle-aged and older adults: a CADSET clinical research collaboration., BMJ Open Respir Res, Vol: 10
BACKGROUND: The prevalence and clinical profile of asthma with airflow obstruction (AO) remain uncertain. We aimed to phenotype AO in population- and clinic-based cohorts. METHODS: This cross-sectional multicohort study included adults ≥50 years from nine CADSET cohorts with spirometry data (N=69 789). AO was defined as ever diagnosed asthma with pre-BD or post-BD FEV1/FVC <0.7 in population-based and clinic-based cohorts, respectively. Clinical characteristics and comorbidities of AO were compared with asthma without airflow obstruction (asthma-only) and chronic obstructive pulmonary disease (COPD) without asthma history (COPD-only). ORs for comorbidities adjusted for age, sex, smoking status and body mass index (BMI) were meta-analysed using a random effects model. RESULTS: The prevalence of AO was 2.1% (95% CI 2.0% to 2.2%) in population-based, 21.1% (95% CI 18.6% to 23.8%) in asthma-based and 16.9% (95% CI 15.8% to 17.9%) in COPD-based cohorts. AO patients had more often clinically relevant dyspnoea (modified Medical Research Council score ≥2) than asthma-only (+14.4 and +14.7 percentage points) and COPD-only (+24.0 and +5.0 percentage points) in population-based and clinic-based cohorts, respectively. AO patients had more often elevated blood eosinophil counts (>300 cells/µL), although only significant in population-based cohorts. Compared with asthma-only, AO patients were more often men, current smokers, with a lower BMI, had less often obesity and had more often chronic bronchitis. Compared with COPD-only, AO patients were younger, less often current smokers and had less pack-years. In the general population, AO patients had a higher risk of coronary artery disease than asthma-only and COPD-only (OR=2.09 (95% CI 1.26 to 3.47) and OR=1.89 (95% CI 1.10 to 3.24), respectively) and of depression (OR=1.41 (95% CI 1.19 to 1.67)), osteoporosis (OR=2.30 (95% CI 1.43 to 3.72)) and gastro-oesophageal reflux disease
Annesi-Maesano I, Cecchi L, Biagioni B, et al., 2023, Is exposure to pollen a risk factor for moderate and severe asthma exacerbations?, Allergy, Vol: 78, Pages: 2121-2147
Limited number of studies have focused on the impact of pollen exposure on asthma. As a part of the EAACI Guidelines on Environment Science, this first systematic review on the relationship of pollen exposure to asthma exacerbations aimed to bridge this knowledge gap in view of implementing recommendations of prevention. We searched electronic iPubMed, Embase, and Web of Science databases using a set of MeSH terms and related synonyms and identified 73 eligible studies that were included for systemic review. When possible, meta-analyses were conducted. Overall meta-analysis suggests that outdoor pollen exposure may have an effect on asthma exacerbation, but caution is needed due to the low number of studies and their heterogeneity. The strongest associations were found between asthma attacks, asthma-related ED admissions or hospitalizations, and an increase in grass pollen concentration in the previous 2-day overall in children aged less than 18 years of age. Tree pollen may increase asthma-related ED visits or admissions lagged up to 7-day overall in individuals younger than 18 years. Rare data show that among subjects under 18 years of age, an exposure to grass pollen lagged up to 3 days may lower lung function. Further research considering effect modifiers of pollen sensitization, hay fever, asthma, air pollution, green spaces, and pre-existing medications is urgently warranted to better evaluate the impacts of pollen on asthma exacerbation. Preventive measures in relation to pollen exposure should be integrated in asthma control as pollen increase continues due to climate change.
Kermani NZ, Adcock IM, Djukanović R, et al., 2023, Systems biology in asthma., Precision Approaches to Heterogeneity in Asthma, Editors: Braiser, Jarjour, Pages: 215-235
The application of mathematical and computational analysis, together with the modelling of biological and physiological processes, is transforming our understanding of the pathophysiology of complex diseases. This systems biology approach incorporates large amounts of genomic, transcriptomic, proteomic, metabolomic, breathomic, metagenomic and imaging data from disease sites together with deep clinical phenotyping, including patient-reported outcomes. Integration of these datasets will provide a greater understanding of the molecular pathways associated with severe asthma in each individual patient and determine their personalised treatment regime. This chapter describes some of the data integration methods used to combine data sets and gives examples of the results obtained using single datasets and merging of multiple datasets (data fusion and data combination) from several consortia including the severe asthma research programme (SARP) and the Unbiased Biomarkers Predictive of Respiratory Disease Outcomes (U-BIOPRED) consortia. These results highlight the involvement of several different immune and inflammatory pathways and factors in distinct subsets of patients with severe asthma. These pathways often overlap in patients with distinct clinical features of asthma, which may explain the incomplete or no response in patients undergoing specific targeted therapy. Collaboration between groups will improve the predictions obtained using a systems medicine approach in severe asthma.
Liu Q, Weng J, Li C, et al., 2023, Attenuation of PM2.5-induced alveolar epithelial cells and lung injury through regulation of mitochondrial fission and fusion, Particle and Fibre Toxicology, Vol: 20, Pages: 1-18, ISSN: 1743-8977
BACKGROUND: Exposure to particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM2.5) is a risk factor for developing pulmonary diseases and the worsening of ongoing disease. Mitochondrial fission and fusion are essential processes underlying mitochondrial homeostasis in health and disease. We examined the role of mitochondrial fission and fusion in PM2.5-induced alveolar epithelial cell damage and lung injury. Key genes in these processes include dystrophin-related protein 1 (DRP1) and optic atrophy 1 (OPA1) respectively. METHODS: Alveolar epithelial (A549) cells were treated with PM2.5 (32 µg/ml) in the presence and absence of Mdivi-1 (10µM, a DRP1 inhibitor) or BGP-15 (10µM, an OPA1 activator). Results were validated using DRP1-knockdown (KD) and OPA1-overexpression (OE). Mice were injected intraperitoneally with Mdivi-1 (20 mg/kg), BGP-15 (20 mg/kg) or distilled water (control) one hour before intranasal instillation of PM2.5 (7.8 mg/kg) or distilled water for two consecutive days. RESULTS: PM2.5 exposure of A549 cells caused oxidative stress, enhanced inflammation, necroptosis, mitophagy and mitochondrial dysfunction indicated by abnormal mitochondrial morphology, decreased mitochondrial membrane potential (ΔΨm), reduced mitochondrial respiration and disrupted mitochondrial fission and fusion. Regulating mitochondrial fission and fusion pharmacologically using Mdivi-1 and BGP-15 and genetically using DRP1-KD and OPA1-OE prevented PM2.5-induced celluar damage in A549 cells. Mdivi-1 and BGP-15 attenuated PM2.5-induced acute lung injury in mice. CONCLUSION: Increased mitochondrial fission and decreased mitochondrial fusion may underlie PM2.5-induced alveolar epithelial cell damage in vitro and lung injury in vivo.
Abdel-Aziz MI, Thorsen J, Hashimoto S, et al., 2023, Oropharyngeal Microbiota Clusters in Children with Asthma or Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways, and Exacerbation Risk., Am J Respir Crit Care Med, Vol: 208, Pages: 142-154
Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis β-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-β (transforming growth factor-β) (highest in the Veillonella cluster) and Wnt/β-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microbiota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota
Raby KL, Michaeloudes C, Tonkin J, et al., 2023, Mechanisms of airway epithelial injury and abnormal repair in asthma and COPD, Frontiers in Immunology, Vol: 14, Pages: 1-14, ISSN: 1664-3224
The airway epithelium comprises of different cell types and acts as a physical barrier preventing pathogens, including inhaled particles and microbes, from entering the lungs. Goblet cells and submucosal glands produce mucus that traps pathogens, which are expelled from the respiratory tract by ciliated cells. Basal cells act as progenitor cells, differentiating into different epithelial cell types, to maintain homeostasis following injury. Adherens and tight junctions between cells maintain the epithelial barrier function and regulate the movement of molecules across it. In this review we discuss how abnormal epithelial structure and function, caused by chronic injury and abnormal repair, drives airway disease and specifically asthma and chronic obstructive pulmonary disease (COPD). In both diseases, inhaled allergens, pollutants and microbes disrupt junctional complexes and promote cell death, impairing the barrier function and leading to increased penetration of pathogens and a constant airway immune response. In asthma, the inflammatory response precipitates the epithelial injury and drives abnormal basal cell differentiation. This leads to reduced ciliated cells, goblet cell hyperplasia and increased epithelial mesenchymal transition, which contribute to impaired mucociliary clearance and airway remodelling. In COPD, chronic oxidative stress and inflammation trigger premature epithelial cell senescence, which contributes to loss of epithelial integrity and airway inflammation and remodelling. Increased numbers of basal cells showing deregulated differentiation, contributes to ciliary dysfunction and mucous hyperproduction in COPD airways. Defective antioxidant, antiviral and damage repair mechanisms, possibly due to genetic or epigenetic factors, may confer susceptibility to airway epithelial dysfunction in these diseases. The current evidence suggests that a constant cycle of injury and abnormal repair of the epithelium drives chronic airway inflammation and r
Brandsma J, Schofield JPR, Yang X, et al., 2023, Stratification of asthma by lipidomic profiling of induced sputum supernatant, Journal of Allergy and Clinical Immunology, Vol: 152, Pages: 117-125, ISSN: 0091-6749
BACKGROUND: Asthma is a chronic respiratory disease with significant heterogeneity in its clinical presentation and pathobiology. There is need for improved understanding of respiratory lipid metabolism in asthma patients and its relation to observable clinical features. OBJECTIVE: To perform a comprehensive, prospective, cross-sectional analysis of the lipid composition of induced sputum supernatant obtained from asthma patients with a range of disease severities, as well as healthy controls. METHODS: Induced sputum supernatant was collected from 211 asthmatic adults and 41 healthy individuals enrolled in the U-BIOPRED study. Sputum lipidomes were characterised by semi-quantitative shotgun mass spectrometry, and clustered using topological data analysis to identify lipid phenotypes. RESULTS: Shotgun lipidomics of induced sputum supernatant revealed a spectrum of nine molecular phenotypes, highlighting not just significant differences between the sputum lipidomes of asthmatics and healthy controls, but within the asthmatic population as well. Matching clinical, pathobiological, proteomic and transcriptomic data informed on the underlying disease processes. Sputum lipid phenotypes with higher levels of non-endogenous, cell-derived lipids were associated with significantly worse asthma severity, worse lung function, and elevated granulocyte counts. CONCLUSION: We propose a novel mechanism of increased lipid loading in the epithelial lining fluid of asthmatics, resulting from the secretion of extracellular vesicles by granulocytic inflammatory cells, which could reduce the ability of pulmonary surfactant to lower surface tension in asthmatic small airways, as well as compromise its role as an immune regulator. CLINICAL IMPLICATION: Immunomodulation of extracellular vesicle secretion in the lungs may provide a novel therapeutic target for severe asthma.
Khaleva E, Rattu A, Brightling C, et al., 2023, Definitions of non-response and response to biological therapy for severe asthma: a systematic review., ERJ Open Res, Vol: 9, ISSN: 2312-0541
BACKGROUND: Biologics have proven efficacy for patients with severe asthma but there is lack of consensus on defining response. We systematically reviewed and appraised methodologically developed, defined and evaluated definitions of non-response and response to biologics for severe asthma. METHODS: We searched four bibliographic databases from inception to 15 March 2021. Two reviewers screened references, extracted data, and assessed methodological quality of development, measurement properties of outcome measures and definitions of response based on COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). A modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach and narrative synthesis were undertaken. RESULTS: 13 studies reported three composite outcome measures, three asthma symptoms measures, one asthma control measure and one quality of life measure. Only four measures were developed with patient input; none were composite measures. Studies utilised 17 definitions of response: 10 out of 17 (58.8%) were based on minimal clinically important difference (MCID) or minimal important difference (MID) and 16 out of 17 (94.1%) had high-quality evidence. Results were limited by poor methodology for the development process and incomplete reporting of psychometric properties. Most measures rated "very low" to "low" for quality of measurement properties and none met all quality standards. CONCLUSIONS: This is the first review to synthesise evidence about definitions of response to biologics for severe asthma. While high-quality definitions are available, most are MCIDs or MIDs, which may be insufficient to justify continuation of biologics in terms of cost-effectiveness. There remains an unmet need for universally accepted, patient-centred, composite definitions to aid clinical decision making and comparability of responses to biologics.
Makrufardi F, Bai K-J, Suk C-W, et al., 2023, Alveolar deposition of inhaled fine particulate matter increased risk of severity of pulmonary tuberculosis in the upper and middle lobes., ERJ Open Res, Vol: 9, ISSN: 2312-0541
Inhaled PM2.5 associated with pulmonary tuberculosis https://bit.ly/3VXAKfq.
Kim H-K, Kang J-O, Lim JE, et al., 2023, Genetic differences according to onset age and lung function in asthma: a cluster analysis, Clinical and Translational Allergy, Vol: 13, Pages: 1-14, ISSN: 2045-7022
BACKGROUND: The extent of differences between genetic risks associated with various asthma subtypes is still unknown. To better understand the heterogeneity of asthma, we employed an unsupervised method to identify genetic variants specifically associated with asthma subtypes. Our goal was to gain insight into the genetic basis of asthma. METHODS: In this study, we utilized the UK Biobank dataset to select asthma patients (All asthma, n = 50,517) and controls (n = 283,410). We excluded 14,431 individuals who had no information on predicted values of forced expiratory volume in one second percent (FEV1%) and onset age, resulting in a final total of 36,086 asthma cases. We conducted k-means clustering based on asthma onset age and predicted FEV1% using these samples (n = 36,086). Cluster-specific genome-wide association studies were then performed, and heritability was estimated via linkage disequilibrium score regression. To further investigate the pathophysiology, we conducted eQTL analysis with GTEx and gene-set enrichment analysis with FUMA. RESULTS: Clustering resulted in four distinct clusters: early onset asthmanormalLF (early onset with normal lung function, n = 8172), early onset asthmareducedLF (early onset with reduced lung function, n = 8925), late-onset asthmanormalLF (late-onset with normal lung function, n = 12,481), and late-onset asthmareducedLF (late-onset with reduced lung function, n = 6508). Our GWASs in four clusters and in All asthma sample identified 5 novel loci, 14 novel signals, and 51 cluster-specific signals. Among clusters, early onset asthmanormalLF and late-onset asthmareducedLF were the least correlated (rg = 0.37). Early onset asthmareducedLF showed the highest heritability explained by common variants (h2 = 0.212) and was associated with the largest number of variants (71 single nucleotide polymorphisms). Further, the pathway analysis conducte
Lai K, Satia I, Song W-J, et al., 2023, Cough and cough hypersensitivity as treatable traits of asthma., Lancet Respir Med, Vol: 11, Pages: 650-662
Cough is a common and troublesome symptom in people with asthma and is often associated with poorer asthma control and exacerbations. Apart from asthma, other causes or comorbidities might underlie cough in asthma, such as rhinosinusitis and bronchiectasis. Eosinophilic inflammation and bronchoconstriction can lead to an acute episode of cough or worsen chronic cough. Cough hypersensitivity with laryngeal paraesthesia, allotussia, and hypertussia might underlie the cough of asthma through augmented sensory nerve excitability of upper-airway vagal sensory nerves. Cough associated with bronchoconstriction and type 2 inflammation should respond to inhaled corticosteroids and long-acting β-adrenoceptor agonist therapy. For cough hypersensitivity in adults, speech and language therapy and neuromodulators (eg, gabapentin) could be considered. In children, there is no consistent association of asthma with cough sensitivity or between cough and asthma severity. Further research is needed to realise the potential of cough as a measure of asthma control, to understand the mechanisms of cough in asthma, and to develop safe, effective treatments and a precision-medicine approach to the management of cough in asthma in children and adults.
Makrufardi F, Manullang A, Rusmawatiningtyas D, et al., 2023, Extreme weather and asthma: a systematic review and meta-analysis., Eur Respir Rev, Vol: 32
BACKGROUND: Climate change's influence on extreme weather events poses a significant threat to the morbidity and mortality of asthma patients. The aim of this study was to examine associations between extreme weather events and asthma-related outcomes. METHODS: A systematic literature search for relevant studies was performed using the PubMed, EMBASE, Web of Science and ProQuest databases. Fixed-effects and random-effects models were applied to estimate the effects of extreme weather events on asthma-related outcomes. RESULTS: We observed that extreme weather events were associated with increasing risks of general asthma outcomes with relative risks of 1.18-fold for asthma events (95% CI 1.13-1.24), 1.10-fold for asthma symptoms (95% CI 1.03-1.18) and 1.09-fold for asthma diagnoses (95% CI 1.00-1.19). Extreme weather events were associated with increased risks of acute asthma exacerbation with risk ratios of asthma emergency department visits of 1.25-fold (95% CI 1.14-1.37), of asthma hospital admissions of 1.10-fold (95% CI 1.04-1.17), of asthma outpatient visits of 1.19-fold (95% CI 1.06-1.34) and of asthma mortality of 2.10-fold (95% CI 1.35-3.27). Additionally, an increase in extreme weather events increased risk ratios of asthma events by 1.19-fold in children and 1.29-fold in females (95% CI 1.08-1.32 and 95% CI 0.98-1.69, respectively). Thunderstorms increased the risk ratio of asthma events by 1.24-fold (95% CI 1.13-1.36). CONCLUSIONS: Our study showed that extreme weather events more prominently increased the risk of asthma morbidity and mortality in children and females. Climate change is a critical concern for asthma control.
Laiman V, Hsiao T-C, Fang Y-T, et al., 2023, Hippo signaling pathway contributes to air pollution exposure-induced emphysema in ageing rats., J Hazard Mater, Vol: 452
Allam VSRR, Pavlidis S, Liu G, et al., 2023, Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma, Thorax, Vol: 78, Pages: 661-673, ISSN: 0040-6376
Background: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma.Methods: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo.Results: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity.Conclusion: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic
Versi A, Ivan FX, Abdel-Aziz MI, et al., 2023, Haemophilus influenzae and Moraxella catarrhalis in sputum of severe asthma with inflammasome and neutrophil activation, Allergy, ISSN: 0105-4538
BACKGROUND: Because of altered airway microbiome in asthma, we analysed the bacterial species in sputum of patients with severe asthma. METHODS: Whole genome sequencing was performed on induced sputum from non-smoking (SAn) and current or ex-smoker (SAs/ex) severe asthma patients, mild/moderate asthma (MMA) and healthy controls (HC). Data were analysed by asthma severity, inflammatory status and transcriptome-associated clusters (TACs). RESULTS: α-diversity at the species level was lower in SAn and SAs/ex, with an increase in Haemophilus influenzae and Moraxella catarrhalis, and Haemophilus influenzae and Tropheryma whipplei, respectively, compared to HC. In neutrophilic asthma, there was greater abundance of Haemophilus influenzae and Moraxella catarrhalis and in eosinophilic asthma, Tropheryma whipplei was increased. There was a reduction in α-diversity in TAC1 and TAC2 that expressed high levels of Haemophilus influenzae and Tropheryma whipplei, and Haemophilus influenzae and Moraxella catarrhalis, respectively, compared to HC. Sputum neutrophils correlated positively with Moraxella catarrhalis and negatively with Prevotella, Neisseria and Veillonella species and Haemophilus parainfluenzae. Sputum eosinophils correlated positively with Tropheryma whipplei which correlated with pack-years of smoking. α- and β-diversities were stable at one year. CONCLUSIONS: Haemophilus influenzae and Moraxella catarrhalis were more abundant in severe neutrophilic asthma and TAC2 linked to inflammasome and neutrophil activation, while Haemophilus influenzae and Tropheryma whipplei were highest in SAs/ex and in TAC1 associated with highest expression of IL-13 type 2 and ILC2 signatures with the abundance of Tropheryma whipplei correlating positively with sputum eosinophils. Whether these bacterial species drive the inflammatory response in asthma needs evaluation.
Pham DD, Lee J-H, Kwon H-S, et al., 2023, WITHDRAWN: Prospective direct comparison of biological treatments on severe eosinophilic asthma: Findings from the PRISM study., Ann Allergy Asthma Immunol
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Chung KF, 2023, Type-2-low severe asthma endotypes for new treatments: the new asthma frontier., Curr Opin Allergy Clin Immunol, Vol: 23, Pages: 199-204
PURPOSE OF REVIEW: Type-2 (T2)-high asthma represents a well defined group of severe eosinophilic asthma for which there are now effective biologic therapies targetting the interleukins (ILs) 4, 5 and 13, and Immunoglobulin E. T2-low asthma detected in the clinic by a low blood eosinophil count remains ill-defined and is the focus of this review. RECENT FINDINGS: By analysing transcriptomic and proteomic expression in sputum samples in U-BIOPRED cohort, both T2-high and -low molecular phenotypes have been described. Using clustering approaches, a neutrophilic-predominant cluster associated with activation markers of neutrophilic and inflammasome activation with interferon and tumour necrosis factor expression, together with a cluster of paucigranulocytic inflammation linked to oxidative phosphorylation and senescence pathways have been described. Using gene set variation analysis, specific molecular phenotypes driven by IL-6 trans-signalling pathway, or those by IL-6, IL-17 and IL-22 pathways were identified linked to a mixed granulocytic or neutrophilic inflammation. SUMMARY: Previous trials of antineutrophilic agents in asthma have failed because enrolled patients were not specifically chosen for these targeted treatments. Although the T2-low molecular pathways should be validated in other cohorts, the availability of targeted therapies indicated for other autoimmune conditions should encourage a trial of these respective biological therapies for these specific molecular phenotypes.
Wang R, Usmani OS, Chung KF, et al., 2023, Domiciliary Fractional Exhaled Nitric Oxide and Spirometry in Monitoring Asthma Control and Exacerbations., J Allergy Clin Immunol Pract, Vol: 11, Pages: 1787-1795.e5
BACKGROUND: Domiciliary measurements of airflow obstruction and inflammation may assist healthcare teams and patients in determining asthma control and facilitate self-management. OBJECTIVE: To evaluate parameters derived from domiciliary spirometry and fractional exhaled nitric oxide (Feno) in monitoring asthma exacerbations and control. METHODS: Patients with asthma were provided with hand-held spirometry and Feno devices in addition to their usual asthma care. Patients were instructed to perform twice-daily measurements for 1 month. Daily symptoms and medication change were reported through a mobile health system. The Asthma Control Questionnaire was completed at the end of the monitoring period. RESULTS: One hundred patients had spirometry, of which 60 were given additional Feno devices. Compliance rates for twice-daily measurements were poor (median [interquartile range], 43% [25%-62%] for spirometry; 30% [3%-48%] for Feno); at least 15% of patients took little or no spirometry measurements and 40% rarely measured Feno. The coefficient of variation (CV) values in FEV1 and Feno were higher, and the mean % personal best FEV1 lower in those who had major exacerbations compared with those without (P < .05). Feno CV and FEV1 CV were associated with asthma exacerbation during the monitoring period (area under the receiver-operating characteristic curve, 0.79 and 0.74, respectively). Higher Feno CV also predicted poorer asthma control (area under the receiver-operating characteristic curve, 0.71) at the end of the monitoring period. CONCLUSIONS: Compliance with domiciliary spirometry and Feno varied widely among patients even in the setting of a research study. However, despite significant missing data, Feno and FEV1 were associated with asthma exacerbations and control, making these measurements potentially clinically valuable if used.
Feng Y, Xie M, Liu Q, et al., 2023, Changes in targeted metabolomics in lung tissue of chronic obstructive pulmonary disease., Journal of Thoracic Disease, Vol: 15, Pages: 2544-2558, ISSN: 2072-1439
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common chronic lung disease and its incidence is steadily increasing. COPD patients and mouse models of COPD share some similarities in lung pathology and physiology. We performed this study to explore the potential metabolic pathways involved in the pathogenesis of COPD and to discover the COPD-associated biomarkers. Furthermore, we aimed to examine how much the mouse model of COPD was similar and different to human COPD in terms of the altered metabolites and pathways. METHODS: Twenty human lung tissue samples (ten COPD and ten controls) and twelve mice lung tissue samples (six COPD and six controls) were analyzed by targeted HM350 metabolomics, and multivariate and pathway analysis were performed by Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: The counts of many metabolites such as amino acids, carbohydrates and carnitines were changed in both COPD patients and mice compared to controls, respectively. While lipid metabolism was changed only in COPD mice. After KEGG analysis, we found these altered metabolites involved in COPD through aging, apoptosis, oxidative stress and inflammation pathways. CONCLUSIONS: The expressions of metabolites changed in both COPD patients and cigarette smoke exposed (CS-exposed) mice. And there were also some differences between COPD patients and mouse models due to the differences between species. Our study suggested the dysregulation in amino acid metabolism, energy production pathway and perhaps lipid metabolism may be significantly related to the pathogenesis of COPD.
Abubakkar-Waziri H, Kalaiarasan G, Wawman R, et al., 2023, SARS-CoV2 in public spaces in West London UK during COVID-19 pandemic, BMJ Open Respiratory Research, Vol: 10, ISSN: 2052-4439
Background: Spread of SARS-CoV2 by aerosol is considered an important mode of transmission over distances >2 m, particularly indoors.Objectives: We determined whether SARS-CoV2 could be detected in the air of enclosed/semi-enclosed public spaces.Methods and analysis: Between March 2021 and December 2021 during the easing of COVID-19 pandemic restrictions after a period of lockdown, we used total suspended and size-segregated particulate matter (PM) samplers for the detection of SARS-CoV2 in hospitals wards and waiting areas, on public transport, in a university campus and in a primary school in West London.Results: We collected 207 samples, of which 20 (9.7%) were positive for SARS-CoV2 using quantitative PCR. Positive samples were collected from hospital patient waiting areas, from hospital wards treating patients with COVID-19 using stationary samplers and from train carriages in London underground using personal samplers. Mean virus concentrations varied between 429 500 copies/m3 in the hospital emergency waiting area and the more frequent 164 000 copies/m3 found in other areas. There were more frequent positive samples from PM samplers in the PM2.5 fractions compared with PM10 and PM1. Culture on Vero cells of all collected samples gave negative results.Conclusion: During a period of partial opening during the COVID-19 pandemic in London, we detected SARS-CoV2 RNA in the air of hospital waiting areas and wards and of London Underground train carriage. More research is needed to determine the transmission potential of SARS-CoV2 detected in the air.
Kang YR, Huh J-Y, Oh J-Y, et al., 2023, Clinical Characteristics of Post-COVID-19 Persistent Cough in the Omicron Era., Allergy Asthma Immunol Res, Vol: 15, Pages: 395-405, ISSN: 2092-7355
Cough is one of the most common symptoms of acute coronavirus disease 2019, but cough may persist for weeks or months. This study aimed to examine the clinical characteristics of patients with post-coronavirus disease (COVID) persistent cough in the Omicron era. We conducted a pooled analysis comparing 3 different groups: 1) a prospective cohort of post-COVID cough (> 3 weeks; n = 55), 2) a retrospective cohort of post-COVID cough (> 3 weeks; n = 66), and 3) a prospective cohort of non-COVID chronic cough (CC) (> 8 weeks; n = 100). Cough and health status was assessed using patient-reported outcomes (PROs). Outcomes, including PROs and systemic symptoms, were longitudinally evaluated in the prospective post-COVID cough registry participants receiving usual care. A total of 121 patients with post-COVID cough and 100 with non-COVID CC were studied. Baseline cough-specific PRO scores did not significantly differ between post-COVID cough and non-COVID CC groups. There were no significant differences in chest imaging abnormality or lung function between groups. However, the proportions of patients with fractional exhaled nitric oxide (FeNO) ≥ 25 ppb were 44.7% in those with post-COVID cough and 22.7% in those with non-COVID CC, which were significantly different. In longitudinal assessment of the post-COVID registry (n = 43), cough-specific PROs, such as cough severity or Leicester Cough Questionnaire (LCQ) scores, significantly improved between visits 1 and 2 (visit interval: median 35 [interquartile range, IQR: 23-58] days). In the LCQ score, 83.3% of the patients showed improvement (change ≥ +1.3), but 7.1% had worsened (≤ -1.3). The number of systemic symptoms was median 4 (IQR: 2-7) at visit 1 but decreased to median 2 (IQR: 0-4) at visit 2. In summary, post-COVID persistent cough was similar in overall clinical characteristics to CC. Current cough guideline-based approaches may be effective in most patients with post-COVID cough. Measurement of Fe
Gaston B, Gardner DD, Mahan K, et al., 2023, Asthma innovations from the first International Collaborative Asthma Network forum., ERJ Open Res, Vol: 9, ISSN: 2312-0541
BACKGROUND: Many patients have uncontrolled asthma despite available treatments. Most of the new asthma therapies have focused on type 2 (T2) inflammation, leaving an unmet need for innovative research into mechanisms of asthma beyond T2 and immunity. An international group of investigators developed the International Collaborative Asthma Network (ICAN) with the goal of sharing innovative research on disease mechanisms, developing new technologies and therapies, organising pilot studies and engaging early-stage career investigators from across the world. This report describes the purpose, development and outcomes of the first ICAN forum. METHODS: Abstracts were solicited from interdisciplinary early-stage career investigators with innovative ideas beyond T2 inflammation for asthma and were selected for presentation at the forum. Breakout sessions were conducted to discuss innovation, collaboration and research translation. RESULTS: The abstracts were categorised into: 1) general omics and big data analysis; 2) lung-brain axis and airway neurology; 3) sex differences; 4) paediatric asthma; 5) new therapeutic targets inspired by airway epithelial biology; 6) new therapeutics targeting airway and circulating immune mediators; and 7) lung anatomy, physiology and imaging. Discussions revealed that research groups are looking for opportunities to further their findings using larger scale collaboration and the ability to translate their in vitro findings into clinical treatment. CONCLUSIONS: Through ICAN, teams that included interdisciplinary early-stage career investigators discussed innovation, collaboration and translation in asthma and severe asthma research. With a combination of fresh ideas and energetic, collaborative, global participation, ICAN has laid a firm foundation and model for future collaborative global asthma research.
Yang X, Chung KF, Huang K, 2023, Worldwide prevalence, risk factors and burden of chronic cough in the general population: a narrative review., J Thorac Dis, Vol: 15, Pages: 2300-2313, ISSN: 2072-1439
BACKGROUND AND OBJECTIVE: Chronic cough is one of the commonest complaints requiring medical attention that significantly impacts on the patient's quality of life. In this review, we focus on chronic cough prevalence, risk factors, and health burden among the general adult population based on recent reports, which will be helpful for a better understanding of the global burden of chronic cough. METHODS: A narrative search of Medline was performed for articles and their lists of references published using the keywords "chronic cough", "chronic bronchitis", "epidemiology", "prevalence", "risk factor", "burden", "quality of life", "adult" and "general population". KEY CONTENTS AND FINDINGS: Although there is a growing literature on the prevalence of chronic cough in the general population from different countries, the prevalence of chronic cough in different populations cannot be directly compared because of the use of varying definitions of chronic cough. Generally, the prevalence of chronic cough is higher in Europe and North America than in Asia. Regarding the risk factors for chronic cough, several have been identified, including age, smoking, asthma, allergic rhinitis, and rhinosinusitis, whereas for other imputed factors, such as occupational exposure, air pollution, and obesity, these remain inconclusive. Although chronic cough is usually not life-threatening, the physical and psychological impact of chronic cough is obvious, leading to substantial healthcare resource utilization, especially for the elderly or those with comorbidities. CONCLUSIONS: Chronic cough is a common symptom in the general population that can be associated with a deterioration of quality of life and with increased burden. The identification of risk factors and associated co-morbidities will help towards an improved management of this condition. There is an urgent need to apply the standard definition
Laiman V, Lo Y-C, Chen H-C, et al., 2023, Data on lung and intestinal microbiome after air pollution exposure in ageing rats, DATA IN BRIEF, Vol: 47, ISSN: 2352-3409
Rattu A, Khaleva E, Brightling C, et al., 2023, Identifying and appraising outcome measures for severe asthma: a systematic review., Eur Respir J, Vol: 61
BACKGROUND: Valid outcome measures are imperative to evaluate treatment response, yet the suitability of existing end-points for severe asthma is unclear. This review aimed to identify outcome measures for severe asthma and appraise the quality of their measurement properties. METHODS: A literature search was performed to identify "candidate" outcome measures published between 2018 and 2020. A modified Delphi exercise was conducted to select "key" outcome measures within healthcare professional, patient, pharmaceutical and regulatory stakeholder groups. Initial validation studies for "key" measures were rated against modified quality criteria from COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). The evidence was discussed at multi-stakeholder meetings to ratify "priority" outcome measures. Subsequently, four bibliographic databases were searched from inception to 20 July 2020 to identify development and validation studies for these end-points. Two reviewers screened records, extracted data, assessed their methodological quality and graded the evidence according to COSMIN. RESULTS: 96 outcome measures were identified as "candidates", 55 as "key" and 24 as "priority" for severe asthma, including clinical, healthcare utilisation, quality of life, asthma control and composite. 32 studies reported measurement properties of 17 "priority" end-points from the latter three domains. Only the Severe Asthma Questionnaire and Childhood Asthma Control Test were developed with input from severe asthma patients. The certainty of evidence was "low" to "very low" for most "priority" end-points across all measurement properties and none fulfilled all quality standards. CONCLUSIONS: Only two outcome measures had robust developmental data for severe asthma. This review informed development of core outcome measures sets for severe asthma.
Khaleva E, Rattu A, Brightling C, et al., 2023, Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA)., Eur Respir J, Vol: 61
BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.
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