Publications
298 results found
Selby L, Jamalzadeh A, Hall P, et al., 2019, Adherence, airway inflammation and adrenal suppression in children with asthma, International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Jochmann A, Artusio L, Usemann J, et al., 2019, A three months period of electronic monitoring is sufficient to assess adherence and improve asthma control, International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Mcmurray A, Cunningham S, Fleming L, 2019, Defining Near Fatal asthma - an international eDelphi study, International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Grime C, Garbato G, Rosenthal M, et al., 2019, Low prevalence of obstructive sleep apnoea in paediatric severe therapy resistant asthma, International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Levy ML, Fleming L, Warner JO, et al., 2019, Paediatric asthma care in the UK: fragmented and fatally fallible., British Journal of General Practice, Vol: 69, Pages: 405-406, ISSN: 0960-1643
Saglani S, Fleming L, Sonnappa S, et al., 2019, Advances in the aetiology, management, and prevention of acute asthma attacks in children (vol 3, pg 354, 2019), LANCET CHILD & ADOLESCENT HEALTH, Vol: 3, Pages: E13-E13, ISSN: 2352-4642
Perotin J-M, Schofield JPR, Wilson SJ, et al., 2019, Epithelial dysregulation in obese severe asthmatics with gastro-oesophageal reflux, European Respiratory Journal, Vol: 53, ISSN: 0903-1936
Nagakumar P, Puttur F, Gregory LG, et al., 2019, Pulmonary type2 innate lymphoid cells in paediatric severe asthma: phenotype and response to steroids, European Respiratory Journal, Vol: 54, Pages: 1-14, ISSN: 0903-1936
Children with severe therapy resistant asthma (STRA) have poor control despite maximal treatment, while those with difficult asthma (DA) have poor control from failure to implement basic management including adherence to therapy. Although recognised as clinically distinct, the airway molecular phenotype, including the role of ILCs and their response to steroids in DA and STRA is unknown.Immunophenotyping of sputum and blood ILCs and T cells from STRA, DA and non-asthmatic controls was undertaken. Leukocytes were analysed longitudinally pre and post intramuscular triamcinolone in children with STRA. Cultured ILCs were also evaluated to assess steroid responsiveness in vitroAirway eosinophils, Th2 cells and ILC2s were significantly higher in STRA patients compared to DA and disease controls, while IL-17+ lymphoid cells were similar. ILC2s and Th2 cells were significantly reduced in vivo following intramuscular triamcinolone and in vitro with steroids. Asthma attacks and symptoms also reduced after systemic steroids despite persistence of steroid resistant IL-17+ cells and eosinophils.Paediatric STRA and DA have distinct airway molecular phenotypes with STRA characterised by elevated type2 cells. Systemic corticosteroids but not maintenance inhaled steroids resulted in improved symptom control and exacerbations concomitant with a reduction in functional ILC2s despite persistently elevated IL-17+ lymphoid cells.
Reddel HK, FitzGerald JM, Bateman ED, et al., 2019, GINA 2019: a fundamental change in asthma management, European Respiratory Journal, Vol: 53, Pages: 1-7, ISSN: 0903-1936
In April 2019, the Global Initiative for Asthma (GINA) (box 1) published new recommendations that might be considered the most fundamental change in asthma management in 30 years. The new recommendations follow a decade-long programme of work by GINA, prompted by concerns about the risks and consequences of the long-standing approach of commencing asthma treatment with short-acting β2-agonists (SABA) alone. These initiatives were aimed at obtaining evidence about effective treatment options for mild asthma and providing consistent messaging for patients and clinicians across the spectrum of asthma severity.
Kuo C-HS, Pavlidis S, Zhu J, et al., 2019, Contribution of airway eosinophils in airway wall remodeling in asthma: role of MMP-10 and MET, Allergy, Vol: 74, Pages: 1102-1112, ISSN: 0105-4538
BackgroundEosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma.MethodsWe analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate‐to‐severe asthma of the U‐BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry.ResultsUsing stringent false discovery rate analysis, MMP‐10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP‐10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less‐stringent conditions (raw P‐value < 0.05, log2 fold change > 0.5), we defined a 73‐gene set characteristic of the HE compared to the LE group. Thirty‐three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC‐chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS‐1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression.ConclusionPathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP‐10 likely play an important role in these processes.
Saglani S, Fleming L, Sonnappa S, et al., 2019, Advances in the aetiology, management, and prevention of acute asthma attacks in children, LANCET CHILD & ADOLESCENT HEALTH, Vol: 3, Pages: 354-364, ISSN: 2352-4642
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- Citations: 26
Robinson PFM, Pattaroni C, Cook J, et al., 2019, Lower airway microbiota associates with inflammatory phenotype in severe preschool wheeze, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 1607-1610.e, ISSN: 0091-6749
Saglani S, Bush A, Carroll W, et al., 2019, Biologics for paediatric severe asthma: Trick or TREAT?, The Lancet Respiratory Medicine, Vol: 7, Pages: 294-296, ISSN: 2213-2600
Fleming L, Lorenzen R, Stanek J, et al., 2019, Transitions in Care Model for a Senior-Level Clinical Immersion Experience, NURSE EDUCATOR, Vol: 45, Pages: 39-42, ISSN: 0363-3624
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- Citations: 1
Pearce CJ, Fleming L, Chan A, et al., 2019, IT'S LIKE TRYING TO FIT A PIECE INTO AN ALREADY NOT WORKING PUZZLE: NON ADHERENCE TO INHALED CORTICOSTEROIDS IN YOUNG PEOPLE WITH PROBLEMATIC ASTHMA: A QUALITATIVE STUDY (vol 25, pg 1, 2018), 15th International Congress of Behavioral Medicine, Publisher: SPRINGER, Pages: 115-115, ISSN: 1070-5503
Jevnikar Z, Östling J, Ax E, et al., 2019, Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 577-590, ISSN: 0091-6749
BACKGROUND: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) with asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthma is unclear. OBJECTIVE: To explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthma. METHODS: An IL-6TS gene signature, obtained from air-liquid interface (ALI) cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R, was used to stratify lung epithelium transcriptomic data (U-BIOPRED cohorts) by hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis and immunohistochemical analysis of bronchial biopsies. RESULTS: Activation of IL-6TS in ALI cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of IL-6TS High asthma patients with increased epithelial expression of IL-6TS inducible genes in absence of systemic inflammation. The IL-6TS High subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings, TLR pathway genes were up-regulated while the expression of tight junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, MMP3, MIP-1β, IL-8 and IL-1β. CONCLUSIONS: Local lung epithelial IL-6TS activation in absence of type 2 airway inflammation defines a novel subset of asthmatics and may drive airway inflammation and epithelial dysfunction in these patients.
Simpson AJ, Hekking P-P, Shaw DE, et al., 2019, Treatable traits in the European U-BIOPRED adult asthma cohorts, Allergy, Vol: 74, Pages: 406-411, ISSN: 0105-4538
Saglani S, Fleming L, Sonnappa S, et al., 2019, Recent advances in the aetiology, management and prevention of acute asthma attacks, Lancet Child and Adolescent Health, ISSN: 2352-4642
Acute attacks of wheeze or asthma remain among the most common reasons for paediatric hospital attendance and rates of severe attacks in the UK are among the highest in Europe. Although most attacks are precipitated by infection, there are critical differences in the underlying pathophysiology between preschool and school-aged children. Allergen sensitisation, airway eosinophilia and type 2 inflammation are predominant in older children, while phenotypes in younger children are variable, often including non-atopic, neutrophilic infection driven episodes. Currently, a universal approach is adopted towards management in all ages, but there is a need to make objective assessments of airway function, inflammation and infection both during the attack and in disease stability to identify “treatable traits” and target therapy if we are to improve outcomes. An assessment of risk factors that led to the attack and early, focussed follow-up is essential to ensure attacks are a “never event”.
Bush A, Fleming L, 2019, 46 - Severe Asthma, Kendig's Disorders of the Respiratory Tract in Children, Pages: 722-736.e5, ISBN: 9780323448871
Most pediatric asthma is easily treated with low-dose inhaled corticosteroids, occasionally combined with a long-acting bronchodilator, provided the medications are administered regularly and correctly. If the child does not respond to treatment, rather than escalating treatment uncritically, a detailed, protocolized assessment is mandatory. This should include a review of the diagnosis and assessment of the presence or otherwise of any extrapulmonary comorbidities, such as obesity, exercise-induced laryngeal obstruction and lifestyle and social factors, such as adherence, perhaps the most important cause of "treatment resistant asthma," and allergen and tobacco exposure; this enables successful management of 90% of referrals with apparent severe asthma. For the rest, bronchoscopic assessment of airway pathology is advisable, combined with a parenteral steroid trial, to deconstruct airway pathology by determining the presence and nature of any inflammation and whether there is fixed airflow obstruction. If inflammation is present, it is eosinophilic not neutrophilic but signature T-helper cell cytokines are difficult to detect, suggesting alternative pathways are important. There is no agreed upon pediatric definition of steroid responsiveness, and we advocate a multidomain approach. Other than for omalizumab, treatments for steroid-resistant asthma have no evidence base in children. The child with recurrent asthma attacks is particularly difficult to manage and is at high risk of further attacks and death from asthma. In summary, therapy-resistant asthma is rare but a really difficult problem when present. Most apparent therapy-resistant asthma can be successfully treated by optimizing basic management, especially ensuring adherence to standard therapy.
Pavlidis S, Takahashi K, Kwong FNK, et al., 2019, "T2-high" in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin, European Respiratory Journal, Vol: 53, ISSN: 0903-1936
BACKGROUND: Type-2 (T2) immune responses in airway epithelial cells (AECs) classifies mild-moderate asthma into a T2-high phenotype. We examined whether currently-available clinical biomarkers can predict AEC-defined T2-high phenotype within U-BIOPRED cohort. METHODS: The transcriptomic profile of AECs obtained from brushings of 103 patients with asthma and 44 healthy controls was obtained and gene set variation analysis used to determine the relative expression score of T2 asthma using a signature from IL-13-exposed AECs. RESULTS: 37% of asthmatics (45% non-smoking severe asthma, n=49, 33% of smoking or ex-smoking severe asthma, n=18 and 28% mild-moderate asthma, n=36) were T2-high using AEC gene expression. They were more symptomatic with higher levels of nitric oxide in exhaled breath (FeNO) and of blood and sputum eosinophils but not of serum IgE or periostin. Sputum eosinophilia correlated best with the T2-high signature. FeNO (≥30 ppb) and blood eosinophils (≥300/µL) gave a moderate prediction of T2-high asthma. Sputum IL-4, IL-5 and IL-13 protein levels did not correlate with gene expression. CONCLUSION: T2-high severe asthma can be predicted to some extent from raised levels of FeNO, blood and sputum eosinophil counts, but serum IgE or serum periostin were poor predictors. Better bedside biomarkers are needed to detect T2-high.
Abul MH, Naja AS, Fitzpatrick A, et al., 2019, Evaluation and management in children, SEVERE ASTHMA, Editors: Chung, Israel, Gibson, Hurst, Publisher: EUROPEAN RESPIRATORY SOCIETY, Pages: 246-264, ISBN: 978-1-84984-103-0
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- Citations: 1
Robinson PF, Pattaroni C, Cook J, et al., 2019, Lower Airway Microbiota Associates with Inflammatory Phenotype in Severe Preschool Wheeze, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Garcia-Marcos L, Edwards J, Kennington E, et al., 2018, Priorities for future research into asthma diagnostic tools: A PAN-EU consensus exercise from the European asthma research innovation partnership (EARIP), Clinical and Experimental Allergy, Vol: 48, Pages: 104-120, ISSN: 0954-7894
The diagnosis of asthma is currently based on clinical history, physical examination and lung function, and to date, there are no accurate objective tests either to confirm the diagnosis or to discriminate between different types of asthma. This consensus exercise reviews the state of the art in asthma diagnosis to identify opportunities for future investment based on the likelihood of their successful development, potential for widespread adoption and their perceived impact on asthma patients. Using a two-stage e-Delphi process and a summarizing workshop, a group of European asthma experts including health professionals, researchers, people with asthma and industry representatives ranked the potential impact of research investment in each technique or tool for asthma diagnosis and monitoring. After a systematic review of the literature, 21 statements were extracted and were subject of the two-stage Delphi process. Eleven statements were scored 3 or more and were further discussed and ranked in a face-to-face workshop. The three most important diagnostic/predictive tools ranked were as follows: “New biological markers of asthma (eg genomics, proteomics and metabolomics) as a tool for diagnosis and/or monitoring,” “Prediction of future asthma in preschool children with reasonable accuracy” and “Tools to measure volatile organic compounds (VOCs) in exhaled breath.”.
Pearce CJ, Fleming L, 2018, Adherence to medication in children and adolescents with asthma: methods for monitoring and intervention, Expert Review of Clinical Immunology, Vol: 14, Pages: 1055-1063, ISSN: 1744-666X
Introduction: Poor adherence in children with asthma is a major cause of asthma attacks and poor control, leads to large health-care costs, and has been identified as a factor in asthma deaths. However, it is difficult to detect and frequently overlooked leading to inappropriate escalation of asthma treatment. There is a need for cost effective ways to monitor adherence in order to intervene to change this modifiable behavior.Areas covered: Several measurement tools have been developed to assess adherence in adults and children with asthma. The current methods for measuring adherence, both subjective and objective, have several flaws and even the current gold standard, electronic monitoring devices (EMDs), has limitations. This review will outline and critique the adherence monitoring tools and highlight ways in which they have been used for the purpose of intervention.Expert commentary: Although advances have been made in adherence monitoring, we still have some way to go in creating the ideal monitoring tool. There are no validated tailored self-monitoring questionnaires for children with asthma and most objective measures, such as prescription refill rate and weighing canisters, overestimate adherence. Current EMDs, although useful, need improved accuracy to ensure that both actuation and inhalation are measured, and the devices need to be affordable for use in routine health-care practice.
Ananth S, Cook J, Gregory L, et al., 2018, LOWER AIRWAY PATHOLOGICAL PHENOTYPES DO NOT RELATE TO CLINICAL PHENOTYPES IN PRESCHOOL CHILDREN WITH SEVERE, RECURRENT WHEEZE, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A4-A4, ISSN: 0040-6376
Selby LA, Saglani S, Fleming L, et al., 2018, ASSESSMENT OF ADRENAL FUNCTION USING LOW DOSE AND STANDARD DOSE SYNACTHEN TESTS IN A COHORT OF PAEDIATRIC ASTHMA PATIENTS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A150-A151, ISSN: 0040-6376
Walsted E, Fleming L, Bush A, et al., 2018, UTILITY OF THE AIRWAY PERTURBATION DEVICE IN THE DIAGNOSTIC ASSESSMENT OF EXERTIONAL WHEEZE AND BREATHLESSNESS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A67-A68, ISSN: 0040-6376
King JA, Saglani S, Bush A, et al., 2018, CLINICAL CHARACTERISTICS OF PRE-SCHOOL CHILDREN WITH MANNOSE BINDING LECTIN DEFICIENCY UNDERGOING BRONCHOSCOPY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A152-A153, ISSN: 0040-6376
Kermani NZ, Pavlidis S, Saqi M, et al., 2018, Further resolution of non-T2 asthma subtypes from high-throughput sputum transciptomics data in U-BIOPRED, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: European Respiratory Society, Pages: 1-3, ISSN: 0903-1936
Background: Precision medicine of asthma requires understanding of its heterogeneity and molecular pathophysiology.Aim: Three sputum-derived transcriptomic clusters (TACs) were previously identified [Kuo at al. Eur Respir J.2017, 49] in the U-BIOPRED cohort: TAC1 consisting of T2 high patients with eosinophilia, TAC2 with neutrophilia and inflammasome activation and TAC3, a more heterogeneous cluster with mostly paucigranulocytic patients. We further refine TAC3.Methods: Gaussian mixture modelling for model-based clustering was applied to sputum gene expression of 104 asthmatic participants from the adult cohort to substructure TAC3. Gene set variation analysis (GSVA) was used to explore the enrichment of gene signatures across the TACs.Results: We again produce the three TACs (TAC1 N=23, TAC2 N=24) but TAC3 was further split into two groups (TAC3a N=28, TAC3b N=29), distinguished by distinct neutrophils and macrophages density and enrichment of IL13 stimulation, inflammasome activation and OXPHOS gene signatures (Figure), as well as IL-4 and LPS-stimulated macrophage gene signatures. However, there were no distinguishing clinical features.Conclusion: Identification of sub-structure of sputum TACs, particularly of TAC3, will help towards improved targeted therapies.
Brandsma J, Goss VM, Yang X, et al., 2018, Lipid phenotyping of lung epithelial lining fluid in healthy human volunteers, Metabolomics, Vol: 14, ISSN: 1573-3882
BackgroundLung epithelial lining fluid (ELF)—sampled through sputum induction—is a medium rich in cells, proteins and lipids. However, despite its key role in maintaining lung function, homeostasis and defences, the composition and biology of ELF, especially in respect of lipids, remain incompletely understood.ObjectivesTo characterise the induced sputum lipidome of healthy adult individuals, and to examine associations between different ELF lipid phenotypes and the demographic characteristics within the study cohort.MethodsInduced sputum samples were obtained from 41 healthy non-smoking adults, and their lipid compositions analysed using a combination of untargeted shotgun and liquid chromatography mass spectrometry methods. Topological data analysis (TDA) was used to group subjects with comparable sputum lipidomes in order to identify distinct ELF phenotypes.ResultsThe induced sputum lipidome was diverse, comprising a range of different molecular classes, including at least 75 glycerophospholipids, 13 sphingolipids, 5 sterol lipids and 12 neutral glycerolipids. TDA identified two distinct phenotypes differentiated by a higher total lipid content and specific enrichments of diacyl-glycerophosphocholines, -inositols and -glycerols in one group, with enrichments of sterols, glycolipids and sphingolipids in the other. Subjects presenting the lipid-rich ELF phenotype also had significantly higher BMI, but did not differ in respect of other demographic characteristics such as age or gender.ConclusionsWe provide the first evidence that the ELF lipidome varies significantly between healthy individuals and propose that such differences are related to weight status, highlighting the potential impact of (over)nutrition on lung lipid metabolism.
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