159 results found
Andersson CK, Iwasaki J, Cook J, et al., 2020, Impaired airway epithelial cell wound-healing capacity is associated with airway remodelling following RSV infection in severe preschool wheeze., Allergy
BACKGROUND: Respiratory syncytial virus (RSV) causes exacerbations of asthma and preschool wheeze (PSW). However, the anti-viral and repair responses of the bronchial epithelium in children with severe therapy resistant asthma (STRA) and PSW are poorly understood. METHODS: Children with STRA (age 12 [6-16] years), PSW (age 2 [1-5] years) and non-asthmatic controls (age 7 [2-14] years) underwent bronchoscopy with endobronchial brushings and biopsies. Anti-viral, wound injury responses were quantified in biopsies and primary bronchial epithelial cells (PBECs) in response to RSV, poly(I:C), house dust mite (HDM) or IL-33 using RT-qPCR, Luminex and live cell imaging. Collagen deposition and tissue expression of epithelial growth factor receptor (EGFR), IL-33 and receptor ST2 was investigated in bronchial biopsies. RESULTS: PBECs from STRA and PSW had increased TLR3 gene expression and increased secretion of anti-viral and pro-inflammatory cytokines (IFN-γ, IL-6 and IL-13) in response to RSV compared to controls. Exposure of PBECs to concomitant TLR3 agonist poly(I:C) and HDM resulted in a significant reduction in epithelial cell proliferation in PSW compared to controls. Wound-healing was also impaired in PSW compared to controls at baseline and following IL-33 stimulation. In addition, tissue EGFR expression was significantly reduced in PSW and correlated with collagen deposition in endobronchial biopsies. CONCLUSIONS: Despite increased anti-viral responses, preschool children with severe wheeze had impaired airway epithelial proliferative responses following damage. This might be connected to the low expression of EGFR in PSW which may affect epithelial function and contribute to asthma pathogenesis.
Abdel-Aziz MI, Brinkman P, Vijverberg SJH, et al., 2020, eNose breathprints as a surrogate biomarker for classifying asthma patients by atopy., J Allergy Clin Immunol
BACKGROUND: Electronic noses (eNose) are emerging point-of-care tools that may help in the subphenotyping of chronic respiratory diseases, such as asthma. OBJECTIVE: We aimed to investigate whether eNoses can classify atopy in paediatric and adult asthma patients. METHODS: Asthmatic/wheezing participants from 4 independent cohorts were included; BreathCloud (n=429), U-BIOPRED adults (n=96), U-BIOPRED paediatrics (n=100), and PACMAN2 (n=30). Atopy was defined as a positive skin prick test (≥3mm) and/or a positive specific IgE (≥0.35kU/L) for common allergens. Exhaled breath profiles were measured using either an integrated eNose platform or the SpiroNose. Data were divided into 2 training and 2 validation sets according to the technology used. Supervised data analysis involved the use of 3 different machine learning algorithms to classify atopic versus non-atopic patients with reporting area under receiver operating characteristic curves (AUCs-ROC) as a measure of model performance. In addition, an unsupervised approach was performed using Bayesian network (BN) to reveal data-driven relationships between eNose volatile organic compounds (VOCs) profiles and asthma characteristics. RESULTS: Breath profiles of 655 participants (n=601 asthmatics and 54 pre-school wheezing children, 68.2% atopic) were included in this study. Machine learning models utilizing VOCs profiles discriminated between atopic vs non-atopic participants with AUCs-ROC of at least 0.84 and 0.72 in the training and validation sets respectively. The unsupervised approach revealed that breath profiles classifying atopy are not confounded by other patient characteristics. CONCLUSION: eNoses accurately detect atopy in asthmatic and wheezing patients in cohorts with different age groups, and could be used in asthma phenotyping.
Bush A, Levy M, Fleming L, 2020, Steroid-filled rant: or another fashion accessory?, Arch Dis Child
Turner P, Fleming L, Saglani S, et al., 2020, Safety of live attenuated influenza vaccine in children with moderate-severe asthma, Journal of Allergy and Clinical Immunology, Vol: 145, Pages: 1157-1164.e6, ISSN: 0091-6749
Background:Live attenuated influenza vaccine (LAIV) is recommended for annual influenza vaccination in children from age 2 years. However, some guidelines recommend against its use in children with asthma or recurrent wheeze due to concerns over its potential to induce wheezing. Objective: To assess the safety of LAIV in children with moderate-severe asthma, and in preschool children with recurrent wheeze. Methods: Prospective, multi-center, open label, phase IV intervention studyin 14 specialist UK clinics.LAIV was administered under medical supervision, with follow-up of asthma symptoms 72 hours and 4 weeks late, using validated questionnaires.Clinical Trials.gov registration NCT02866942, EU Clinical Trials registration 2016-002352-24. Results: 478 young people (median 9.3, range 2–18 years) with physician-diagnosed asthma or recurrent wheeze were recruited, including 208 (44%) prescribed high-dose inhaled corticosteroids and 122 (31%) with severe asthma.There was no significant change in asthma symptoms in the 4 weeks following administration (median change 0, P=.26, McNemar’s test), with no impact of level of baseline asthma control/symptoms in predicting either a worsening of asthma or exacerbation following LAIV using a regression model. 47 subjects (14.7%, 95%CI 11% to 19.1%) reported a severe asthma exacerbation in the four weeks following immunization, requiring short course of systemic corticosteroids; in four cases, this occurred within 72 hours of vaccine. No association with asthma severity, baseline lung function or asthma control was identified.Conclusions: LAIV appears to be well-tolerated in the vast majority of children with asthma or recurrent wheeze, includingthosewhose asthma is categorized as severe or poorly controlled
Roberts G, Fontanella S, Selby A, et al., 2020, Connectivity patterns between multiple allergen specific IgE antibodies and their association with severe asthma., J Allergy Clin Immunol
BACKGROUND: Allergic sensitization is associated with severe asthma, but assessment of sensitization is not recommended by most guidelines. OBJECTIVE: We hypothesized that patterns of IgE responses to multiple allergenic proteins differ between sensitized participants with mild/moderate and severe asthma. METHODS: IgE to 112 allergenic molecules (components, c-sIgE) was measured using multiplex array among 509 adults and 140 school-age and 131 preschool children with asthma/wheeze from the Unbiased BIOmarkers for the PREDiction of respiratory diseases outcomes cohort, of whom 595 had severe disease. We applied clustering methods to identify co-occurrence patterns of components (component clusters) and patterns of sensitization among participants (sensitization clusters). Network analysis techniques explored the connectivity structure of c-sIgE, and differential network analysis looked for differences in c-sIgE interactions between severe and mild/moderate asthma. RESULTS: Four sensitization clusters were identified, but with no difference between disease severity groups. Similarly, component clusters were not associated with asthma severity. None of the c-sIgE were identified as associates of severe asthma. The key difference between school children and adults with mild/moderate compared with those with severe asthma was in the network of connections between c-sIgE. Participants with severe asthma had higher connectivity among components, but these connections were weaker. The mild/moderate network had fewer connections, but the connections were stronger. Connectivity between components with no structural homology tended to co-occur among participants with severe asthma. Results were independent from the different sample sizes of mild/moderate and severe groups. CONCLUSIONS: The patterns of interactions between IgE to multiple allergenic proteins are predictors of asthma severity among school children and adults with allergic asthma.
Hew M, Menzies-Gow A, Hull JH, et al., 2020, Systematic Assessment of Difficult-to-Treat Asthma: Principles and Perspectives., J Allergy Clin Immunol Pract
Difficult-to-treat asthma affects a minority of adults and children with asthma but represents a challenging mix of misdiagnosis, multimorbidity, inadequate self-management, severe airway pathobiology, and treatment complications. Management of these patients extends beyond asthma pharmacotherapy, because multiple other patient-related domains need to be addressed as well. Such complexity can hinder adequate clinical assessment even when performed in specialist practice. Systematic assessment undertaken by specialized multidisciplinary teams brings a broad range of resources to bear on patients with difficult-to-treat asthma. Although the concept of systematic assessment is not new, practices vary considerably and implementation is not universal. Nevertheless, assessment protocols are already in place in several institutions worldwide, and outcomes after such assessments have been highly encouraging. This review discusses the rationale, components, and benefits of systematic assessment, outlining its clinical utility and the available evidence for improved outcomes. It describes a range of service configurations and assessment approaches, drawing examples from severe asthma centers around the world to highlight common essential elements. It also provides a framework for establishing such services and discusses practical considerations for implementation.
Irving S, Fleming L, Ahmad F, et al., 2020, Lung clearance index and steroid response in pediatric severe asthma, PEDIATRIC PULMONOLOGY, Vol: 55, Pages: 890-898, ISSN: 8755-6863
Levy ML, Fleming L, 2020, Asthma reviews in children: what have we learned?, THORAX, Vol: 75, Pages: 98-99, ISSN: 0040-6376
Cruz AA, Riley JH, Barisal AT, et al., 2020, Asthma similarities across ProAR (Brazil) and U-BIOPRED (Europe) adult cohorts of contrasting locations, ethnicity and socioeconomic status, RESPIRATORY MEDICINE, Vol: 161, ISSN: 0954-6111
Östling J, van Geest M, Schofield JPR, et al., 2019, IL-17-high asthma with features of a psoriasis immunophenotype, Journal of Allergy and Clinical Immunology, Vol: 144, Pages: 1198-1213, ISSN: 0091-6749
BACKGROUND: The role of interleukin-17 immunity is well established in inflammatory diseases like psoriasis and inflammatory bowel disease but not in asthma where further study is required. OBJECTIVE: To undertake a deep-phenotyping study of asthmatics with up-regulated interleukin-17 immunity. METHODS: Whole genome transcriptomic analysis was performed using epithelial brushings, bronchial biopsies (91 asthmatics patients and 46 healthy controls) and whole blood samples (n=498) from the U-BIOPRED cohort. Gene signatures induced in vitro by interleukin-17 and interleukin-13 in bronchial epithelial cells were used to identify patients with interleukin-17-high and interleukin-13-high phenotypes of asthma. RESULTS: 22 out of 91 patients were identified with interleukin-17 and 9 patients with interleukin-13 gene signatures. The interleukin-17-high asthmatics were characterised by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis, the differentially expressed genes in interleukin-17-high patients were shared with those reported as altered in psoriasis lesions, and included genes regulating epithelial barrier function and defence mechanisms, such as interleukin-1β, interleukin-6, interleukin-8, and beta-defensin. CONCLUSION: The interleukin-17-high asthma phenotype, characterized by bronchial epithelial dysfunction, upregulated anti-microbial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway which should be considered as a biomarker for this phenotype in further studies, including clinical trials targeting interleukin-17.
Fleming L, Heaney L, 2019, Severe asthma-perspectives from adult and pediatric pulmonology, Frontiers in Pediatrics, Vol: 7, Pages: 389-389, ISSN: 2296-2360
Both adults and children with severe asthma represent a small proportion of the asthma population; however, they consume disproportionate resources. For both groups it is important to confirm the diagnosis of severe asthma and ensure that modifiable factors such as adherence have, as far as possible, been addressed. Most children can be controlled on inhaled corticosteroids and long term oral corticosteroid use is rare, in contrast to adults where steroid related morbidity accounts for a large proportion of the costs of severe asthma. Atopic sensitization is very common in children with severe asthma as are other atopic conditions such as allergic rhinitis and hay fever which can impact on asthma control. In adults, the role of allergic driven disease, even in those with co-existent evidence of sensitization, is unclear. There is currently an exciting pipeline of novel biologicals, particularly directed at Type 2 inflammation, which afford the possibility of improved asthma control and reduced treatment side effects for people with asthma. However, not all drugs will work for all patients and accurate phenotyping is essential. In adults the terms T2 high and T2 low asthma have been coined to describe groups of patients based on the presence/absence of eosinophilic inflammation and T-helper 2 (TH2) cytokines. Bronchoscopic studies in children with severe asthma have demonstrated that these children are predominantly eosinophilic but the cytokine patterns do not fit the T2 high paradigm suggesting other steroid resistant pathways are driving the eosinophilic inflammation. It remains to be seen whether treatments developed for adult severe asthma will be effective in children and which biomarkers will predict response.
Grime C, Garbato G, Rosenthal M, et al., 2019, Low prevalence of obstructive sleep apnoea in paediatric severe therapy resistant asthma, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Selby L, Saglani S, Bush A, et al., 2019, Assessment of adrenal function using low and standard dose synacthen tests in a cohort of paediatric asthma patients, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Mcmurray A, Cunningham S, Fleming L, 2019, Defining Near Fatal asthma - an international eDelphi study, European-Respiratory-Society (ERS) International Congress, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Selby L, Jamalzadeh A, Hall P, et al., 2019, Adherence, airway inflammation and adrenal suppression in children with asthma, European-Respiratory-Society (ERS) International Congress, 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, European-Respiratory-Society (ERS) International Congress, 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
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
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
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., 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”.
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
Bush A, Fleming L, 2019, 46 - Severe Asthma, Kendig's Disorders of the Respiratory Tract in Children, Pages: 722-736.e5, ISBN: 9780323448871
© 2019 Elsevier Inc. All rights reserved. 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.
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