191 results found
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, 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, 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
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, Bush A, Carroll W, et al., 2019, Biologics for paediatric severe asthma: Trick or TREAT?, The Lancet Respiratory Medicine, ISSN: 2213-2600
Bloom C, Saglani S, Feary J, et al., Changing prevalence of current asthma and inhaled corticosteroid treatment in the UK: population based cohort 2006 to 2016, European Respiratory Journal, 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.
Selby L, Saglani S, 2019, Severe asthma in children: therapeutic considerations, Current Opinion in Allergy and Clinical Immunology, ISSN: 1473-6322
Purpose of reviewChildren 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, 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
Robinson PFM, Pattaroni C, Cook J, et al., 2018, Lower airway microbiota associates with inflammatory phenotype in severe preschool wheeze, Journal of Allergy and Clinical Immunology, ISSN: 0091-6749
Saglani S, Custovic A, 2018, Childhood asthma: Advances using machine learning and mechanistic studies, American Journal of Respiratory and Critical Care Medicine, 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.
Oksel C, Custovic A, Granell R, et al., 2018, Causes of variability in latent phenotypes of childhood wheeze, Journal of Allergy and Clinical Immunology, 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.
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
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
Bloom CI, Feary J, Jarvis D, et al., 2018, CHANGING PREVALENCE OF CURRENT ASTHMA AND INHALED CORTICOSTEROID TREATMENT IN THE UK: POPULATION BASED COHORT 2006 TO 2016, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A63-A64, 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
Roberts G, Almqvist C, Boyle R, et al., 2018, Developments in the field of allergy in 2017 through the eyes of Clinical and Experimental Allergy, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 48, Pages: 1606-1621, ISSN: 0954-7894
Bush A, Saglani S, 2018, Structurally unsound? Why airways become asthmatic, American Journal of Respiratory Cell and Molecular Biology, Vol: 59, Pages: 405-406, ISSN: 1044-1549
Benn CS, Hornef M, Naik S, et al., 2018, Immunity in the Very Young: Challenges and Opportunities, IMMUNITY, Vol: 49, Pages: 377-378, ISSN: 1074-7613
Selby L, Beresford F, Saglani S, et al., 2018, Emotional distress in children with problematic severe asthma is associated with parental anxiety and depression, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wang K, Elliot J, Saglani S, et al., 2018, Thickening of the airway smooth muscle layer from late gestation to first year of life is accompanied by a reduction in smooth muscle cell density, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Saglani S, 2018, Inception of early life allergen induced airway hyperresponsiveness is reliant on IL-13+CD4+ T cells, Science Immunology, Vol: 3, ISSN: 2470-9468
Airway hyperresponsiveness (AHR) is a critical feature of wheezing and asthma in children, but the initiating immune mechanisms remain unconfirmed. We demonstrate that both recombinant interleukin-33 (rIL-33) and allergen [house dust mite (HDM) or Alternaria alternata] exposure from day 3 of life resulted in significantly increased pulmonary IL-13+CD4+ T cells, which were indispensable for the development of AHR. In contrast, adult mice had a predominance of pulmonary LinnegCD45+CD90+IL-13+ type 2 innate lymphoid cells (ILC2s) after administration of rIL-33. HDM exposure of neonatal IL-33 knockout (KO) mice still resulted in AHR. However, neonatal CD4creIL-13 KO mice (lacking IL-13+CD4+ T cells) exposed to allergen from day 3 of life were protected from AHR despite persistent pulmonary eosinophilia, elevated IL-33 levels, and IL-13+ ILCs. Moreover, neonatal mice were protected from AHR when inhaled Acinetobacter lwoffii (an environmental bacterial isolate found in cattle farms, which is known to protect from childhood asthma) was administered concurrent with HDM. A. lwoffii blocked the expansion of pulmonary IL-13+CD4+ T cells, whereas IL-13+ ILCs and IL-33 remained elevated. Administration of A. lwoffii mirrored the findings from the CD4creIL-13 KO mice, providing a translational approach for disease protection in early life. These data demonstrate that IL-13+CD4+ T cells, rather than IL-13+ ILCs or IL-33, are critical for inception of allergic AHR in early life.
Saglani S, 2018, Lung function in primary ciliary dyskinesia: breaking the myth that this is a mild disease, EUROPEAN RESPIRATORY JOURNAL, Vol: 52, ISSN: 0903-1936
Saglani S, 2018, Airway granulocytes in severe preschool wheeze: Predictive of school-age asthma attacks or disease protection, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 48, Pages: 760-761, ISSN: 0954-7894
Saglani S, 2018, PRO: Importance of Implementing Asthma Guidelines: An Evidence-Based Approach that Helps Ensure Consistent Management, Publisher: WILEY, Pages: S26-S28, ISSN: 8755-6863
Saglani S, 2018, Pro-Con Debate: Big Data and Multi-omics for Asthma Cure Con: Big Data and Multi-omics Alone Will Not Be Helpful to Cure Asthma: Hypothesis-Driven Mechanistic Research Is Essential, Publisher: WILEY, Pages: S12-S14, ISSN: 8755-6863
Saglani S, Rosenthal M, Bush A, 2018, Should oral corticosteroids be prescribed for preschool viral wheeze?, Lancet Respiratory Medicine, Vol: 6, Pages: E21-E21, ISSN: 2213-2600
Castro-Rodriguez JA, Saglani S, Rodriguez-Martinez CE, et al., 2018, The relationship between inflammation and remodeling in childhood asthma: a systematic review, Pediatric Pulmonology, Vol: 53, Pages: 824-835, ISSN: 1099-0496
OBJECTIVES: We aimed to perform a systematic review of all studies with direct measurements of both airway inflammation and remodeling in the subgroup of children with repeated wheezing and/or persistent asthma severe enough to warrant bronchoscopy, to address whether airway inflammation precedes remodeling or is a parallel process, and also to assess the impact of remodeling on lung function. METHODS: Four databases were searched up to June 2017. Two independent reviewers screened the literature and extracted relevant data. RESULTS: We found 526 references, and 39 studies (2390 children under 18 years old) were included. Airway inflammation (eosinophilic/neutrophilic) and remodeling were not present in wheezers at a mean age of 12 months, but in older pre-school children (mean 2.5 years), remodeling (mainly increased reticular basement membrane [RBM] thickness and increased area of airway smooth muscle) and also airway eosinophilia was reported. This was worse in school-age children. RBM thickness was similar in atopic and non-atopic preschool wheezers. Airway remodeling was correlated with lung function in seven studies, with FeNO in three, and with HRCT-scan in one. Eosinophilic inflammation was not seen in patients without remodeling. There were no invasive longitudinal or intervention studies. CONCLUSION: The relationship between inflammation and remodeling in children cannot be determined. Failure to demonstrate eosinophilic inflammation in the absence of remodeling is contrary to the hypothesis that inflammation causes these changes. We need reliable, non-invasive markers of remodeling in particular if this is to be addressed.
Turner S, Custovic A, Ghazal P, et al., 2018, Pulmonary epithelial barrier and immunological functions at birth and in early life - key determinants of the development of asthma? A description of the protocol for the Breathing Together study, Wellcome Open Research, ISSN: 2398-502X
Background. Childhood asthma is a common complex condition whose aetiology is thought to involve gene-environment interactions in early life occurring at the airway epithelium, associated with immune dysmaturation. It is not clear if abnormal airway epithelium cell (AEC) and cellular immune system functions associated with asthma are primary or secondary. To explore this, we will (i) recruit a birth cohort and observe the evolution of respiratory symptoms; (ii) recruit children with and without asthma symptoms; and (iii) use existing data from children in established STELAR birth cohorts. Novel pathways identified in the birth cohort will be sought in the children with established disease. Our over-arching hypothesis is that epithelium function is abnormal at birth in babies who subsequently develop asthma and progression is driven by abnormal interactions between the epithelium, genetic factors, the developing immune system, and the microbiome in the first years of life.Methods. One thousand babies will be recruited and nasal AEC collected at 5-10 days after birth for culture. Transcriptomes in AEC and blood leukocytes and the upper airway microbiome will be determined in babies and again at one and three years of age. In a subset of 100 individuals, AEC transcriptomes and microbiomes will also be assessed at three and six months. Individuals will be assigned a wheeze category at age three years. In a cross sectional study, 300 asthmatic and healthy children aged 1 to 16 years will have nasal and bronchial AEC collected for culture and transcriptome analysis, leukocyte transcriptome analysis, and upper and lower airway microbiomes ascertained. Genetic variants associated with asthma symptoms will be confirmed in the STELAR cohorts. Conclusions. This study is the first to comprehensively study the temporal relationship between aberrant AEC and immune cell function and asthma symptoms in the context of early gene-microbiome interactions.
Saglani S, Lloyd CM, Bush A, 2018, Biology and Assessment of Airway Inflammation, Kendig's Disorders of the Respiratory Tract in Children, Pages: 101-119.e4, ISBN: 9780323448871
© 2019 Elsevier Inc. All rights reserved. The nature and development airway inflammation may be driven by numerous factors, including pathogenic infections, pollution, or even relatively innocuous inhaled particles, such as allergens. A robust inflammatory response is essential to fight pathogens, but both active inflammation and efficient resolution are equally important. The failure of resolution or persistent proinflammatory immune responses results in chronic inflammatory airway diseases. These may be characterized by persistent neutrophilic inflammation, as is the case in cystic fibrosis and chronic suppurative lung diseases, or persistent eosinophilia, as is seen in allergic asthma. It is essential to accurately undertake an assessment of the airway inflammatory phenotype in chronic airways diseases to allow an understanding of the mechanisms mediating disease and identify appropriate therapeutic targets. It is also becoming increasingly important to phenotype airway inflammation in individual patients to allow targeted treatment as we move towards personalized therapies. This chapter will discuss what is known about the mechanisms driving chronic inflammatory airways diseases in children and provide an update on the methods used to investigate airway inflammation invasively and noninvasively in patients to allow phenotype driven and targeted therapies.
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