1,720,974 research outputs found
The role of airway tissue-resident memory T Cells in severe asthma
No full textThe growing realisation that severe asthma encompasses a collection of clinical phenotypes and endotypes, plus the variable response to current asthma therapies suggest underlying pathophysiological heterogeneity and complex immune molecular pathways.T cells are critical orchestrators of airway inflammation. However, the role of tissue-resident memory T (TRM) cells, localised to sites of inflammation in the airway epithelium, in the pathogenesis of severe asthma remains unknown. Therefore, this thesis aims to investigate the molecular heterogeneity of airway CD4+ and CD8+ TRM cells in severe asthma pathogenesis and extend this characterisation to the underlying clinical phenotypic nature of severe asthma compared to mild asthma.In the first section of this thesis, I undertook extensive clinical phenotypic characterisation of participants with difficult/severe and mild asthma (Chapter 3). Subsequent separate K-means clustering analysis of the difficult/severe and mild asthma cohorts identified 6 clinically relevant difficult/severe asthma clusters and 2 mild asthma clusters, reflecting severe disease heterogeneity (Chapter 4).For the second section of this thesis, bronchoalveolar (BAL) fluid samples collected from a proportion of severe and mild asthma participants were immunophenotyped using flow cytometry. This analysis suggested that CD103+CD4+ TRM and CD103+CD8+ TRM cells represented the dominant population in asthma. Subsequent bulk and single-cell RNA-seq of BAL memory CD4+ (Chapter 5) and CD8+ (Chapter 6) T cell populations were completed to investigate the molecular profiles of these cells in relation to asthma severity. The transcriptional profiling of BAL CD4+ T cells highlighted a novel population of cytotoxic CD103+CD4+ TRM cells enriched for transcripts linked to TCR activation, TH1-like cytotoxicity and pro-inflammatory molecular features, which was associated with increasing asthma severity in the male adult-onset severe asthma phenotype. In contrast, the transcriptional profiling of BAL CD8+ T cells revealed 9 transcriptionally distinct putative airway CD103+CD8+ TRM cell states across the spectrum of asthma severity, thus highlighting significant molecular heterogeneity. Strikingly, 3 airway CD8+ TRM cell states were unique to severe asthma and appeared to be highly proliferative with enhanced cytotoxicity, glucocorticoid insensitivity and pro-inflammatory molecular properties. Such superior functional properties of cytotoxic CD103+CD4+ TRM and CD103+CD8+ TRM cells suggest their role as key drivers of persistent airway inflammation, remodelling and glucocorticoid insensitivity in severe asthma.In conclusion, these novel findings indicate the need to look beyond the traditional T2 model of severe asthma to better understand disease heterogeneity. Future work will aim towards completing functional studies in vivo to better understand the molecular role of airway CD4+ and CD8+ TRM cell populations and their interactions in severe asthma
Dataset for The role of airway tissue-resident memory T cells in severe asthma
No full textDataset containing all data generated and used for the PhD thesis 'The Role of Airway Tissue-Resident Memory T Cells in Severe Asthma' and the published journal article titled 'Cytotoxic CD4+ tissue-resident memory T cells are associated with asthma severity', https://doi.org/10.1016/j.medj.2023.09.003.</span
Sex differences in difficult asthma; findings in the WATCH cohort
No full textBackground: Difficult asthma is comprised of many phenotypes, but how sex influences such patterns of disease remains unclear.
Aims: To assess how the nature of difficult asthma seen in clinical practice differs between males and females.
Methods: We studied patients enrolled (n=380) from a tertiary difficult asthma clinic (Southampton, UK) into a longitudinal Wessex AsThma CoHort (WATCH) assessing comparisons of core features stratified by sex.
Results: Two thirds of subjects were female. Male participants were significantly older (median age 59.5 years v 48; p<0.001), and were also older at diagnosis, (median age of 31.0 years v 15; p<0.001). Males were less likely to have a smoking history (p=0.003), more likely to have a history of non-CF bronchiectasis (p=0.003), and demonstrated a higher peripheral eosinophil count (p=0.018). Females were more likely to be salicylate sensitive (33.5% v 13.3%, p<0.001), and had higher obesity prevalence (52.3% v 36.8%, p=0.017). Females had poorer asthma control assessed by ACQ6 (p=0.010) and were more likely to have depression (42% v 27%; p=0.006), anxiety (36 % v 25%; p=0.039), dysfunctional breathing (60% v 42%; p=0.001) and vocal cord dysfunction (20% v 10%; p=0.023). FeNO, atopy, total IgE and fungal sensitisation did not differ by sex. Males demonstrated a greater reduction in FEV1 (p=0.029). Post bronchodilator spirometry was obstructive in males (post BD FEV1/FVC 62.05) but not females (post BD FEV1/FVC 70.68) (p<0.001), with greater small airways obstruction (Post BD FEF 25-75%= 41.95% predicted in males v 55.40 in females; p<0.001).
Conclusion: Some core characteristics of difficult asthma differ by sex supporting the need for sex-specific stratified treatment approache
Symptomatic GORD in difficult asthma is associated with worse asthma control and related comorbidities: Findings from WATCH
No full textBackground: Difficult asthma is associated with increased prevalence of gastro-oesophageal reflux disease (GORD). However, it is unclear how controlling comorbid GORD impacts difficult asthma.Aim: To evaluate the impact of effectively controlling GORD symptoms in difficult asthmatics in the Wessex AsThma Cohort of difficult asthma (WATCH) Southampton UK.Methods: A retrospective analysis was undertaken to compare the reported symptoms of GORD in 311 adult asthmatics on treatment for GORD. We compared patients with ongoing GORD symptoms against those with no symptoms using Chi square (categorical data) and Mann-Whitney U tests (continuous data).Results: 208 (67%) difficult asthmatics had GORD, of whom 175 were receiving treatment for GORD. Prevalence of symptomatic GORD in those having treatment did not differ by sex, but was associated with higher BMI, worse asthma control and symptoms of depression, rhinitis and cough.Conclusion: Inadequately controlled GORD in difficult asthma is associated with increased symptoms of asthma, and related comorbidities. This highlights multiple potential benefits of optimising GORD treatment in difficult asthmatics
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Clinical characteristics of the Wessex AsThma CoHort of difficult asthma (WATCH)
No full textBackground: The Wessex AsThma CoHort of difficult asthma (WATCH) is a large prospective observational cohort study established at University Hospital Southampton (UHS) UK in 2015. Patients are enrolled from the UHS tertiary difficult asthma clinic. Aim: WATCH aims to improve understanding of the nature of difficult asthma in clinical practice. Here we report enrolment clinical characteristics. Methods: Patients undergo extensive clinical characterisation and phenotyping at enrolment using collated historical data plus objective clinical measurements. 380 patients have been enrolled to date with annual follow-up thereafter. Results: (as below) Conclusion: The cohort predominantly consists of female, middle-aged, atopic and obese patients whose disease often began before adulthood. The cohort showed high prevalence for maintenance oral steroids and omalizumab. WATCH provides a well-characterised cohort of patients to facilitate real-life difficult asthma research
Does the nature of adult difficult asthma differ by age of onset? Findings from WATCH
No full textBackground: Phenotypic differences between early-onset (EODA) and adult-onset (AODA) difficult asthma in adulthood are not well described. Aim: To characterise EODA and AODA in difficult asthma. Methods: The Wessex AsThma CoHort of difficult asthma (WATCH) is a longitudinal study at University Hospital Southampton (UHS) UK set up in 2015. To date, 380 patients are enrolled from the UHS tertiary difficult asthma clinic. Clinical features of EODA (age ≤18 yrs) and AODA (age >18 yrs) are presented here. Results: Of 368 patients with available data, 51.6% had EODA and 48.4% AODA (median age of onset 4.0 yrs v 40.5 yrs respectively (
Asthma control is associated with smoking status: Findings from WATCH
No full textBackground: Difficult asthmatics with a history of smoking, experience increased lung reactivity. Associations between related comorbidities need further investigation.Aim: To evaluate the symptoms of difficult asthmatics in relation to smoking status, in the Wessex AsThma Cohort of difficult asthma (WATCH) Southampton, UK.Methods: The smoking status of 377 adult asthmatics in WATCH was assessed for asthma control, symptoms of hyperventilation and depression. A retrospective analysis compared smoking status of difficult asthmatics using Chi square (categorical data) and Kruskall-Wallis (continuous data).Results: 180 (48%) had a history of smoking, of whom 13 continued to smoke. Differences in smoking status were not associated with BMI, but did differ by sex, age and age at diagnosis. Asthma control and symptoms of hyperventilation in ex-smokers was comparable to that of never smokers. Current smoking was associated with increased symptoms of depression and decreased attentional control than ever smokers.Conclusion: Prevalence of smoking in difficult asthma is low, but is associated with lack of asthma and attentional control, hyperventilation and depression. These findings highlight the benefits of smoking cessation.<br/
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