211 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, ISSN: 0105-4538
In a recent review on childhood asthma, we proposed that knowledge gaps will only be addressed by integrating technological advances and human knowledge across diverse disciplines, with a patient at its center (1). So, how far have we come in turning “big data” into actionable information to address some of the most important questions in asthma today, including clinical and mechanistic insights about the architecture of asthma heterogeneity, to inform personalized treatments? In this Update focusing on publications in the American Thoracic Society journals, we review the progress made in 2019 on understanding asthma epidemiology and risk factors, mechanisms underpinning different disease subtypes, therapeutic options and prediction of treatment responses, and highlight areas for future research.
Bingham Y, Sanghani N, Cook J, et al., 2020, Electronic adherence monitoring identifies severe preschool wheezers who are steroid responsive., Pediatric Pulmonology, ISSN: 1099-0496
Little is known about adherence to inhaled corticosteroids (ICS) in preschool children with troublesome wheeze. Children with aeroallergen senitization, or those reporting multiple trigger wheeze (MTW), are more likely to respond to ICS. We hypothesized that adherence to ICS and symptom control are only positively related in atopic children, or those reporting MTW. Patients aged 1 to 5 years with recurrent wheeze prescribed ICS were recruited from a tertiary respiratory clinic. Clinical phenotype and aeroallergen senitization were determined, and adherence assessed using an electronic monitoring device (Smartinhaler). Symptom control (test for respiratory and asthma control in kids [TRACK]), quality of life (PACQLQ), airway inflammation (offline exhaled nitric oxide) were assessed at baseline and follow-up. Forty-eight children (mean age 3.7 years; SD, 1.2) were monitored for a median of 112 (interquartile range [IQR], 91-126) days. At baseline n = 29 reported episodic viral wheeze and n = 19 reported MTW. Twenty-four out of 48 (50%) wheezers had suboptimal ICS adherence (<80%). Median adherence was 64% (IQR, 38-84). There was a significant increase in TRACK and PACQLQ in the group as a whole, unrelated to adherence. In subgroup analysis only atopic wheezers with moderate or good adherence ≥ 60% had a significant increase in TRACK. There was no relationship between clinical phenotype, and adherence or TRACK. In this pilot study, overall adherence to ICS was suboptimal and was positively related to symptom control in atopic wheezers only. Assessments of adherence are important in preschool troublesome wheezers before therapy escalation to help identify those with an ICS responsive phenotype.
Wang K, Elliot J, Saglani S, et al., 2020, IN LOW BIRTH INFANTS, THE AIRWAY SMOOTH MUSCLE LAYER COMPRISES AN INCREASED NUMBER OF SMALLER CELLS AND PROPORTIONALLY GREATER EXTRACELLULAR MATRIX, Publisher: WILEY, Pages: 208-208, ISSN: 1323-7799
Foster W, Grime C, Tan H-L, et al., 2020, Enhanced frequency and function of follicular T cells in the tonsils of house dust mite sensitized children, Allergy, Vol: 75, Pages: 1240-1243, ISSN: 0105-4538
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
Broadbent L, Manzoor S, Zarcone MC, et al., 2020, Comparative primary paediatric nasal epithelial cell culture differentiation and RSV-induced cytopathogenesis following culture in two commercial media, PLoS One, Vol: 15, Pages: 1-12, ISSN: 1932-6203
The culture of differentiated human airway epithelial cells allows the study of pathogen-host interactions and innate immune responses in a physiologically relevant in vitro model. As the use of primary cell culture has gained popularity the availability of the reagents needed to generate these cultures has increased. In this study we assessed two different media, Promocell and PneumaCult, during the differentiation and maintenance of well-differentiated primary nasal epithelial cell cultures (WD-PNECs). We compared and contrasted the consequences of these media on WD-PNEC morphological and physiological characteristics and their responses to respiratory syncytial virus (RSV) infection. We found that cultures generated using PneumaCult resulted in greater total numbers of smaller, tightly packed, pseudostratified cells. However, cultures from both media resulted in similar proportions of ciliated and goblet cells. There were no differences in RSV growth kinetics, although more ciliated cells were infected in the PneumaCult cultures. There was also significantly more IL-29/IFNλ1 secreted from PneumaCult compared to Promocell cultures following infection. In conclusion, the type of medium used for the differentiation of primary human airway epithelial cells may impact experimental results.
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
Byrne A, powell J, O'Sullivan B, et al., 2020, Dynamics of human monocytes and airway macrophages during healthy aging and post-transplant, Journal of Experimental Medicine, Vol: 217, Pages: 1-9, ISSN: 0022-1007
The ontogeny of airway macrophages (AMs) in human lung and their contribution to disease are poorly mapped out. In mice, aging is associated with an increasing proportion of peripherally, as opposed to perinatally derived AMs. We sought to understand AM ontogeny in human lung during healthy aging and after transplant. We characterized monocyte/macrophage populations from the peripheral blood and airways of healthy volunteers across infancy/childhood (2–12 yr), maturity (20–50 yr), and older adulthood (>50 yr). Single-cell RNA sequencing (scRNA-seq) was performed on airway inflammatory cells isolated from sex-mismatched lung transplant recipients. During healthy aging, the proportions of blood and bronchoalveolar lavage (BAL) classical monocytes peak in adulthood and decline in older adults. scRNA-seq of BAL cells from lung transplant recipients indicates that after transplant, the majority of AMs are recipient derived. These data show that during aging, the peripheral monocyte phenotype is consistent with that found in the airways and, furthermore, that the majority of human AMs after transplant are derived from circulating monocytes.
Bush A, Saglani S, 2020, Medical algorithm: diagnosis and treatment of preschool asthma, Allergy, ISSN: 0105-4538
Roberts G, Almqvist C, Boyle R, et al., 2019, Developments in the mechanisms of allergy in 2018 through the eyes of Clinical and Experimental Allergy, Part I., Clin Exp Allergy, Vol: 49, Pages: 1541-1549
In the first of two linked articles, we describe the development in the mechanisms underlying allergy as described by Clinical & Experimental Allergy and other journals in 2018. Experimental models of allergic disease, basic mechanisms and clinical mechanisms are all covered.
Roberts G, Almqvist C, Boyle R, et al., 2019, Developments in the field of clinical allergy in 2018 through the eyes of Clinical and Experimental Allergy, Part II., Clin Exp Allergy, Vol: 49, Pages: 1550-1557
In this article, we describe developments in the field of clinical allergy as described by Clinical and Experimental Allergy in 2018; epidemiology, asthma and rhinitis, clinical allergy and allergens are all covered.
Babalis D, Saglani S, Cornelius V, 2019, To fund or not to fund a paediatric severe asthma trial: that is the question, Publisher: BMC
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, 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
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
Lloyd CM, Saglani S, 2019, Opening the Window of Immune Opportunity: Treating Childhood Asthma, TRENDS IN IMMUNOLOGY, Vol: 40, Pages: 786-798, ISSN: 1471-4906
Oksel C, Granell R, Haider S, et al., 2019, Distinguishing wheezing phenotypes from infancy to adolescence: a pooled analysis of five birth cohorts, Annals of the American Thoracic Society, Vol: 16, Pages: 868-876, ISSN: 2329-6933
RATIONALE: Pooling data from multiple cohorts and extending the time-frame across childhood should minimize study-specific effects, enabling better characterization of the childhood wheezing. OBJECTIVE: To analyze wheezing patterns from early childhood to adolescence using combined data from five birth cohorts. METHODS: We used latent class analysis to derive wheeze phenotypes among 7719 participants from five birth cohorts with complete report of wheeze at five time-periods. We tested the association of derived phenotypes with late asthma outcomes and lung function, and investigated the uncertainty in phenotype assignment. RESULTS: We identified five phenotypes: Never/Infrequent wheeze (52.1%), Early-onset pre-school remitting (23.9%), Early-onset mid-childhood remitting (9%), Persistent (7.9%) and Late-onset wheeze (7.1%). Compared to the Never/infrequent wheeze, all phenotypes had higher odds of asthma and lower FEV1 and FEV1/FVC in adolescence. The association with asthma was strongest for Persistent wheeze (adjusted odds ratio 56.54, 95%CI 43.75-73.06). We observed considerable within-class heterogeneity at individual level, with 913 (12%) children having low membership probability (<0.60) of any phenotype. Class membership certainty was highest in Persistent and Never/infrequent, and lowest in Late-onset wheeze (with 51% of participants having membership probabilities<0.80). Individual wheezing patterns were particularly heterogeneous in Late-onset wheeze, while many children assigned to Early-onset pre-school remitting class reported wheezing at later time points. CONCLUSIONS: All wheeze phenotypes had significantly diminished lung function in school-age, suggesting that the notion that early-life episodic wheeze has a benign prognosis may not be true for a proportion of transient wheezers. We observed considerable within-phenotype heterogeneity in individual wheezing patterns.
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.
Saglani S, 2019, Noninvasive Assessments of Airway Inflammation and Infection in Asthma and Wheezing Disorders, Publisher: WILEY, Pages: S36-S38, ISSN: 8755-6863
Saglani S, 2019, Difficult to Treat Asthma, Publisher: WILEY, Pages: S32-S34, ISSN: 8755-6863
Oksel C, Custovic A, Granell R, et al., 2019, Causes of variability in latent phenotypes of childhood wheeze, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 1783-1790.e11, ISSN: 0091-6749
BackgroundLatent class analysis (LCA) has been used extensively to identify (latent) phenotypes of childhood wheezing. However, the number and trajectory of discovered phenotypes differed substantially between studies.ObjectiveWe sought to investigate sources of variability affecting the classification of phenotypes, identify key time points for data collection to understand wheeze heterogeneity, and ascertain the association of childhood wheeze phenotypes with asthma and lung function in adulthood.MethodsWe used LCA to derive wheeze phenotypes among 3167 participants in the ALSPAC cohort who had complete information on current wheeze recorded at 14 time points from birth to age 16½ years. We examined the effects of sample size and data collection age and intervals on the results and identified time points. We examined the associations of derived phenotypes with asthma and lung function at age 23 to 24 years.ResultsA relatively large sample size (>2000) underestimated the number of phenotypes under some conditions (eg, number of time points <11). Increasing the number of data points resulted in an increase in the optimal number of phenotypes, but an identical number of randomly selected follow-up points led to different solutions. A variable selection algorithm identified 8 informative time points (months 18, 42, 57, 81, 91, 140, 157, and 166). The proportion of asthmatic patients at age 23 to 24 years differed between phenotypes, whereas lung function was lower among persistent wheezers.ConclusionsSample size, frequency, and timing of data collection have a major influence on the number and type of wheeze phenotypes identified by using LCA in longitudinal data.
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
Saglani S, Menzie-Gow AN, 2019, Approaches to Asthma Diagnosis in Children and Adults, FRONTIERS IN PEDIATRICS, Vol: 7, ISSN: 2296-2360
Bloom C, Saglani S, Feary J, et al., 2019, Changing prevalence of current asthma and inhaled corticosteroid treatment in the UK: population based cohort 2006 to 2016, European Respiratory Journal, Vol: 53, ISSN: 0903-1936
BACKGROUND:Asthma is the most common respiratory disorder in the UK, yet we have incomplete knowledge on the prevalence of current disease, treatment and exacerbations.METHODS:We used UK electronic healthcare records, 2006 to 2016, to estimate the prevalence of current asthma by year, gender and age (<5, 5-11, 12-17, 18-24, 25-54 and ≥55 years), and the proportion prescribed inhaled corticosteroids (ICS) and additional asthma-therapy, treated for exacerbations and other asthma care markers. RESULTS:Overall current asthma prevalence was 6.5% in 2016 (7.2% in 2006). Prevalence fell in those under 45 years. The lowest prevalence and largest absolute decrease was in children under 5-years. In 2016, 80% of current asthma patients were managed on ICS, (65% in 2006); this increase occurred in all ages, primarily due to an increase in low-dose ICS. During this time there was an increase in all age-groups in the proportion prescribed additional asthma-therapy, treated for an exacerbation within primary care, given an annual asthma review or management plan. Hospitalised exacerbations showed minimal change over time.CONCLUSION:Asthma remains highly prevalent and a significant healthcare burden. In those with a diagnosis, there was an increase in ICS prescriptions and treatment of exacerbations across all age-groups. This may reflect a trend towards more aggressive asthma management within primary care. An apparent decline in prevalence was observed in those aged under 45 years, particularly in children under 5 years.
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
Selby L, Saglani S, 2019, Severe asthma in children: therapeutic considerations, Current Opinion in Allergy and Clinical Immunology, Vol: 19, Pages: 132-140, ISSN: 1473-6322
Purpose of review Children with poor asthma control despite maximal maintenance therapy have problematic severe asthma(PSA). A step-wise approach including objective adherence monitoring and a detailed multidisciplinaryteam assessment to identify modifiable factors contributing to poor control is needed prior to consideringtherapy escalation. Pathophysiological phenotyping in those with true severe therapy-resistant asthma(STRA) and the current array of add-on therapies will be discussed.Recent findingsAdherence monitoring using electronic devices has shown that only 20–30% of children with PSA haveSTRA and need additional therapies. Omalizumab and mepolizumab are licensed for children with STRAaged 6 years and older. Although robust safety and efficacy data, with reduced exacerbations, areavailable for omalizumab, biomarkers predicting response to treatment are lacking. Paediatric safety dataare available for mepolizumab, but efficacy data are unknown for those aged 6–11 years and minimal forthose 12 years and older. A sub-group of children with STRA have neutrophilia, but the clinicalsignificance and contribution to disease severity remains uncertain.SummaryMost children with PSA have steroid sensitive disease which improves with adherence to maintenanceinhaled corticosteroids. Add-on therapies are only needed for the minority with STRA. Paediatric efficacydata of novel biologics and biomarkers that identify the optimal add-on for each child are lacking. If weare to progress toward individualized therapy for STRA, pragmatic clinical trials of biologics in accuratelyphenotyped children are needed.
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
Wang K, Elliot J, Saglani S, et al., 2019, THICKENING OF THE AIRWAY SMOOTH MUSCLE LAYER FROM LATE GESTATION TO CHILDHOOD IS FACILITATED BY INCREASED MEAN CELL VOLUME, Publisher: WILEY, Pages: 76-76, ISSN: 1323-7799
Saglani S, Custovic A, 2019, Childhood asthma: Advances using machine learning and mechanistic studies, American Journal of Respiratory and Critical Care Medicine, Vol: 199, ISSN: 1073-449X
A paradigm shift brought by the recognition that childhood asthma is a heterogeneous condition comprising several endotypes underpinned by different pathophysiology, coupled with advances in understanding important causal mechanisms, offers a real opportunity for a step change to reduce the burden of the disease on individual children, families and society. Data-driven approaches have provided a framework for revealing hidden structure within large datasets. One way of bridging findings from data-driven analyses into clinical practice is to link "phenotypes" identified using such techniques with a specific pathology. Epidemiological studies have provided important clues about mechanistic avenues that should be pursued to identify interventions to prevent asthma development or alter its natural history. Findings from cohort studies followed by mechanistic studies in humans and in neonatal mouse models have suggested that environments such as traditional farming may provide protection by modulating innate immune responses, and that impaired innate immunity may increase asthma susceptibility. The key question of which component of these exposures can be translated into interventions requires confirmation. Increasing mechanistic evidence is demonstrating that shaping the airway microbiome in early life may modulate immune function to confer protection. If we are to make advances, we have to foster cross-disciplinary collaborations between data scientists who turn "big data" into useful information about the hidden structures within large dataset which may help disaggregate "asthma", with medical professionals and basic scientists who provide critical clinical and mechanistic insights about the mechanisms underpinning the architecture of the heterogeneity, to deliver mechanism-based stratified treatments and prevention.
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