249 results found
Byrne AJ, Saglani S, Snelgrove RJ, 2021, An Alarmin Role for P2Y13R During Viral Driven Asthma Exacerbations., Am J Respir Crit Care Med
Custovic A, Siddiqui S, Saglani S, 2021, Considering biomarkers in asthma disease severity., J Allergy Clin Immunol
Amongst patients with asthma, reliance on the type/dose of prescribed medication and symptom control does not adequately capture those at risk of adverse outcomes, and we need biomarkers for risk and treatment stratification which are consistently accurate, readily quantifiable and reproducible. The majority of patients with severe asthma, regardless of age, have predominant type-2 (T2) inflammation mediated disease, making airway/blood eosinophils, FeNO, periostin and/or allergic sensitization potentially important biomarkers for severe disease. In both adult and pediatric asthma, there is scope to improve prediction of severe attacks by using a composite T2 biomarkers of blood eosinophils and FeNO. Technological advances in component-resolved diagnostics (CRD) microarray technologies coupled with the development of interpretation software offer a possibility to use CRD as biomarkers of asthma severity amongst sensitized asthmatics. Genetic predisposition and polygenic risk scores of relevant traits (e.g., lung function, host immune responses, biomarkers of exposure from the indoor and outdoor environment, infection and microbial dysbiosis) may also contribute to prediction algorithms. We challenge the idea that asthma can be accurately defined in an individual patient by a discrete and static "endotype" (e.g., T2-high asthma). As we traverse the new era of molecular endotyping in asthma, we need to understand how relevant mechanisms impact patient outcomes, and in parallel develop new tools and approaches to stratify therapies and define individual patient trajectories.
Bush A, Fitzpatrick AM, Saglani S, et al., 2021, Difficult-to-Treat Asthma Management in School-Age Children., J Allergy Clin Immunol Pract
The World Health Organization divides severe asthma into three categories: untreated severe asthma; difficult-to-treat severe asthma; and severe, therapy-resistant asthma. The apparent frequency of severe asthma in the general population of asthmatic children is probably around 5%. Upon referral of these children, it is important to evaluate the diagnosis of asthma carefully before modifying management and applying a long-term monitoring plan. Identification of pathophysiologic phenotypes using objective biomarkers is essential in our routine assessments of severe asthma. Although conventional pharmacologic approaches should be attempted first, there is growing recognition that children with difficult-to-treat asthma may have unique clinical phenotypes that may necessitate alternative treatment approaches including asthma biologics. These new medications, especially those with effects on multiple pathologic features of asthma, raise the hope that new treatment strategies could induce remission. Besides introducing new medications, the opportunity for closer monitoring is feasible with advances in digital health. Therefore, we have the opportunity to improve response to medications, individualize treatment, and monitor response along with potential steps to prevent severe asthma.
Saglani S, Bingham Y, Balfour-Lynn I, et al., 2021, Blood eosinophils in managing preschool wheeze: Lessons learnt from a proof-of-concept trial, Pediatric Allergy and Immunology, ISSN: 0905-6157
BackgroundManagement of preschool wheeze is based predominantly on symptom patterns.ObjectiveTo determine whether personalizing therapy using blood eosinophils or airway bacterial infection results in fewer attacks compared with standard care.MethodsA proof-of-concept, randomized trial to investigate whether the prescription of inhaled corticosteroids (ICS) guided by blood eosinophils, or targeted antibiotics for airway bacterial infection, results in fewer unscheduled healthcare visits (UHCVs) compared with standard care. Children aged 1–5 years with ≥2 wheeze attacks in the previous year were categorized as episodic viral wheeze (EVW) or multiple trigger wheeze (MTW). The intervention group was prescribed ICS if blood eosinophils ≥3%, or targeted antibiotics if there is positive culture on induced sputum/cough swab. The control group received standard care. The primary outcome was UHCV at 4 months.Results60 children, with a median age of 36.5 (range 14–61) months, were randomized. Median blood eosinophils were 5.2 (range 0–21)%, 27 of 60 (45%) children were atopic, and 8 of 60 (13%) had airway bacterial infection. There was no relationship between EVW, MTW and either blood eosinophils, atopic status or infection. 67% in each group were prescribed ICS. 15 of 30 control subjects and 16 of 30 patients in the intervention group had UHCV over 4 months (p = .8). The time to first UHCV was similar. 50% returned adherence monitors; in those, median ICS adherence was 67%. There were no differences in any parameter between those who did and did not have an UHCV.ConclusionClinical phenotype was unrelated to allergen sensitization or blood eosinophils. ICS treatment determined by blood eosinophils did not impact UHCV, but ICS adherence was poor.
Nichols A-L, Sonnappa-Naik M, Gardner L, et al., 2021, COVID-19 and delivery of difficult asthma services, ARCHIVES OF DISEASE IN CHILDHOOD, ISSN: 0003-9888
Ko J, Jamalzadeh A, Makhecha S, et al., 2021, REAL LIFE EXPERIENCE WITH MEPOLIZUMAB AND COMPARISON WITH OMALIZUMAB IN CHILDREN WITH SEVERE ASTHMA, Publisher: BMJ PUBLISHING GROUP, Pages: A176-A177, ISSN: 0040-6376
In the pathogenesis of asthma in children there is a pivotal role for a type 2 inflammatory response to early life exposures or events. Interactions between infections, atopy, genetic susceptibility, and environmental exposures (such as farmyard environment, air pollution, tobacco smoke exposure) influence the development of wheezing illness and the risk for progression to asthma. The immune system, lung function and the microbiome in gut and airways develop in parallel and dysbiosis of the microbiome may be a critical factor in asthma development. Increased infant weight gain and preterm birth are other risk factors for development of asthma and reduced lung function. The complex interplay between these factors explains the heterogeneity of asthma in children. Subgroups of patients can be identified as phenotypes based on clinical parameters, or endotypes, based on a specific pathophysiological mechanism. Paediatric asthma phenotypes and endotypes may ultimately help to improve diagnosis of asthma, prediction of asthma development and treatment of individual children, based on clinical, temporal, developmental or inflammatory characteristics. Unbiased, data-driven clustering, using a multidimensional or systems biology approach may be needed to better define phenotypes. The present knowledge on inflammatory phenotypes of childhood asthma has now been successfully applied in the treatment with biologicals of children with severe therapy resistant asthma, and it is to be expected that more personalized treatment options may become available.
Creese H, Lai E, Mason K, et al., 2021, Disadvantage in early-life and persistent asthma in adolescents: a UK cohort study, THORAX, ISSN: 0040-6376
Scotney E, Burchett S, Goddard T, et al., 2021, Pediatric problematic severe asthma: Recent advances in management, Pediatric Allergy and Immunology, Vol: 32, Pages: 1405-1415, ISSN: 0905-6157
Problematic severe asthma remains a significant challenge to manage, accounting for the majority of healthcare utilization among children with asthma. The heterogeneity is recognized and the clinical phenotypes of “difficult-to-treat” asthma (DA) and “severe therapy-resistant asthma” (STRA) help to guide management. Recent evidence supports molecular distinctions between these phenotypes and shows poor correlations between peripheral and airway markers of inflammation, especially in STRA. Airway neutrophils in the context of childhood severe asthma have been explored, but their role in disease causation, protection, or as bystanders remain unknown, and thus, treatment implications are unclear. Several novel management strategies, including once-daily maintenance therapy, single-device maintenance and reliever therapy, and novel biological treatments are being increasingly used for DA and STRA. However, pediatric data for efficacy of novel treatments is scarce, and when available, is restricted to adolescents. The aim of this review is to highlight recent advances in objective biomarkers that aid stratification and management of childhood severe asthma and to highlight gaps in pediatric evidence. Specifically, the urgent need for efficacy studies to improve the management of problematic severe asthma in children younger than 12 years.
Porsbjerg C, Maitland-van der Zee AH, Brusselle G, et al., 2021, 3TR: a pan-European cross-disease research consortium aimed at improving personalised biological treatment of asthma and COPD, EUROPEAN RESPIRATORY JOURNAL, Vol: 58, ISSN: 0903-1936
Golebski K, Dankelman LHM, Björkander S, et al., 2021, Expert meeting report: towards a joint European roadmap to address the unmet needs and priorities of paediatric asthma patients on biologic therapy., ERJ Open Res, Vol: 7, ISSN: 2312-0541
A digital multidisciplinary European expert meeting took place on the 9 July 2020 to identify the unmet needs of paediatric severe asthma patients, and set the priorities for clinical and research activities ahead https://bit.ly/3CeLBHB.
Tanner N, Saglani S, Li AM, et al., 2021, Airway inflammation in severe asthmatics with acid gastro-oesophageal reflux, Thorax, ISSN: 0040-6376
The relationship between childhood asthma and gastro-oesophageal reflux (GOR) is contentious. Recent studies in adult asthmatics suggest that GOR is associated with worse control and differences in sputum proteomics related to epithelial integrity, systemic inflammation and host defence. We assessed 127 children with severe asthma undergoing bronchoscopy and pH study. There were no differences in asthma control or measures of airway inflammation or remodelling when those with acid GOR were compared with those without. These results suggest that acid GOR is not an important comorbidity in paediatric severe asthma.
Makhecha S, Jamalzadeh A, Irving S, et al., 2021, Paediatric severe asthma biologics service: from hospital to home, Archives of Disease in Childhood, Vol: 106, Pages: 900-902, ISSN: 0003-9888
Children with severe asthma may be treated with biologic agents normally requiring 2–4 weekly injections in hospital. In March 2020, due to COVID-19, we needed to minimise hospital visits. We assessed whether biologics could be given safely at home. The multidisciplinary team identified children to be considered for home administration. This was virtually observed using a video link, and home spirometry was also performed. Feedback was obtained from carers and young people. Of 23 patients receiving biologics, 16 (70%) families agreed to homecare administration, 14 administered by parents/patients and 2 by a local nursing team. Video calls for omalizumab were observed on 56 occasions, mepolizumab on 19 occasions over 4 months (April–July). Medication was administered inaccurately on 2/75 occasions without any adverse events. Virtually observed home biologic administration in severe asthmatic children, supported by video calls and home spirometry, is feasible, safe and is positively perceived by children and their families
Saglani S, 2021, Personalized Treatments for Severe Asthma., Publisher: WILEY, Pages: S18-S20, ISSN: 8755-6863
Saglani S, 2021, Clinical Adaptations in Pediatric Pulmonology Post Covid-19 in High Income Countries., Publisher: WILEY, Pages: S27-S29, ISSN: 8755-6863
Saglani S, 2021, Phenotype-based Management of Preschool Wheeze., Publisher: WILEY, Pages: S36-S37, ISSN: 8755-6863
Saglani S, Robinson P, Fontanella S, et al., 2021, Recurrent severe preschool wheeze: From pre-specified diagnostic labels to underlying endotypes, American Journal of Respiratory and Critical Care Medicine, Vol: 204, Pages: 523-535, ISSN: 1073-449X
Rationale: Preschool wheezing is heterogeneous, but the underlying mechanisms are poorly understood. Objectives: To investigate lower airway inflammation and infection in preschool children with different clinical diagnoses undergoing elective bronchoscopy/bronchoalveolar lavage-BAL. Methods: We recruited 136 children aged 1-5 years (105 recurrent severe wheeze-RSW; 31 non-wheeze respiratory disorders-NWRD). RSW were assigned as episodic viral-EVW or multiple trigger wheeze-MTW. We compared lower airway inflammation/infection in different clinical diagnoses and undertook data-driven analyses to determine clusters of pathophysiological features, and investigated their relationships with pre-specified diagnostic labels. Measurements and Main Results: Blood eosinophils and allergic sensitization were significantly higher in RSW than NWRD. Blood neutrophils, BAL eosinophils and neutrophils, and positive bacterial culture and virus detection rates were similar between groups. However, pathogen distribution differed significantly, with higher detection of rhinovirus in RSW and Moraxella in sensitized RSW. EVW and MTW did not differ in blood/BAL inflammation, or bacterial/virus detection. Partition Around Medoids algorithm revealed 4 clusters of pathophysiological features: (1) Atopic (17.9%); (2) Non-atopic, low infection rate, high inhaled corticosteroids-ICS (31.3%); (3) Non-atopic, high infection rate (23.1%); and (4) Non-atopic, low infection rate, no ICS (27.6%). Cluster allocation differed significantly between RSW and NWRD (RSW evenly distributed across clusters, 60% of NWRD assigned to cluster 4, p<0.001). There was no difference in cluster membership between EVW and MTW. Cluster 1 was dominated by Moraxella detection (p=0.04) and Cluster 3 by Haemophilus/Staphylococcus/ Streptococcus (p=0.02). Conclusions: We identified four clusters of severe preschool wheeze distinguished using sensitization, peripheral eosinophilia, lower airway neutrophilia and bacteriolog
Coughlin S, Parrott H, Wells C, et al., 2021, Acceptability of Home Spirometry in Children with Asthma: The NuvoAir Platform, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Agerskov N, Coughlin S, Parrott H, et al., 2021, Quality of unsupervised home spirometry in children with asthma, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, Pages: 1-1, ISSN: 1073-449X
Rationale: Spirometry is a standard test that is used to support clinical decision making in patients with asthma.Laboratory spirometry is associated with high quality data but is performed only when patients attend thehospital. Hand-held spirometry can be performed regularly at home allowing clinical trends to be identified. It isunclear whether children perform these tests regularly and achieve adequate quality when unsupervised bytrained personnel. The goal of this study was to evaluate adherence to, and quality of, home spirometry inpaediatric asthma patients using NuvoAir Home. Methods: A retrospective analysis of data from 39 paediatricasthma patients (age, 13±3.3) using the NuvoAir Home platform, from the Royal Brompton Hospital (London,UK), was performed. The platform consists of a smartphone application, Bluetooth spirometer, and clinicianportal that allows patient data to be shared with their healthcare team. The built-in coaching system on the Appprovides feedback to patients on the quality of spirometry (2017 ATS) and tips on how to improve during futuretests. Patients were provided instructions on how to use the NuvoAir Home platform by a specialist respiratoryphysiologist using remote consultation. All sessions were performed in the home setting. Children were asked toperform tests prior to clinical review (1 to 3 monthly). Data were analysed for patients that had used the in-homesolution for at least 90 days. Assessment of session quality was completed over 30 day intervals, analyzing theoverall session grade, FEV1 and FVC percent predicted. All data were analysed anonymously, with informedconsent from the study participants. Results: A total of 517 sessions, performed over a period of 210 days wereanalysed. 288 (55.7%) of the sessions were of acceptable quality (grade A-C, at least 2 attempts <200 mL FEV1and FVC variability). A higher proportion (76.9%) of sessions performed in the last 30 days of the study were ofacceptable quality, compar
Branchett WJ, Cook J, Oliver RA, et al., 2021, Airway macrophage-intrinsic TGF-β1 regulates pulmonary immunity during early life allergen exposure, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 1892-1906, ISSN: 0091-6749
BackgroundEarly life represents a major risk window for asthma development. However, the mechanisms controlling the threshold for establishment of allergic airway inflammation in early life are incompletely understood. Airway macrophages (AMs) regulate pulmonary allergic responses and undergo TGF-β–dependent postnatal development, but the role of AM maturation factors such as TGF-β in controlling the threshold for pathogenic immune responses to inhaled allergens remains unclear.ObjectiveOur aim was to test the hypothesis that AM-derived TGF-β1 regulates pathogenic immunity to inhaled allergen in early life.MethodsConditional knockout (Tgfb1ΔCD11c) mice, with TGF-β1 deficiency in AMs and other CD11c+ cells, were analyzed throughout early life and following neonatal house dust mite (HDM) inhalation. The roles of specific chemokine receptors were determined by using in vivo blocking antibodies.ResultsAM-intrinsic TGF-β1 was redundant for initial population of the neonatal lung with AMs, but AMs from Tgfb1ΔCD11c mice failed to adopt a mature homeostatic AM phenotype in the first weeks of life. Evidence of constitutive TGF-β1 signaling was also observed in pediatric human AMs. TGF-β1–deficient AMs expressed enhanced levels of monocyte-attractant chemokines, and accordingly, Tgfb1ΔCD11c mice exposed to HDM throughout early life accumulated CCR2-dependent inflammatory CD11c+ mononuclear phagocytes into the airway niche that expressed the proallergic chemokine CCL8. Tgfb1ΔCD11c mice displayed augmented TH2, group 2 innate lymphoid cell, and airway remodeling responses to HDM, which were ameliorated by blockade of the CCL8 receptor CCR8.ConclusionOur results highlight a causal relationship between AM maturity, chemokines, and pathogenic immunity to environmental stimuli in early life and identify TGF-β1 as a key regulator of this.
Bloom C, Franklin C, Bush A, et al., 2021, Burden of preschool wheeze and progression to asthma in the UK: population-based cohort 2007 to 2017, Journal of Allergy and Clinical Immunology, Vol: 147, Pages: 1949-1958, ISSN: 0091-6749
BackgroundWheeze is one of the most common symptoms of preschool children (age 1 to 5 years), yet we have little understanding of the burden in the UK.ObjectivesDetermine prevalence and pattern of physician-confirmed preschool wheeze, related healthcare utilisation, and factors associated with progression to school-age asthma.MethodsWe used nationally representative primary and secondary care electronic medical records between 2007-2017 to identify preschool children with wheeze. Factors associated with asthma progression were identified in a nested cohort of children with follow-up from 1-2 years of age, until at least 8 years of age.ResultsFrom 1,021,624 preschool children, 69,261 were identified with wheeze. Prevalence of preschool wheeze was 7.7% in 2017. Wheeze events were lowest in August and highest in late-autumn/early-winter. During median follow-up of 2.0 years (IQR 1.2-4.0), 15.8% attended an emergency department, and 13.9% had a hospital admission, for a respiratory disorder. The nested cohort with prolonged follow-up identified 15,085 children; 35.5% progressed to asthma between 5-8 years old. Of children with preschool wheeze, without an asthma diagnosis, 34.9% were prescribed inhaled corticosteroids, and 15.6% oral corticosteroids. The factors most strongly associated with progression to asthma were wheeze frequency and severity, atopy, prematurity, maternal asthma severity and first reported wheeze event occurring in September.ConclusionsPreschool wheeze causes considerable healthcare burden, a large number of children are prescribed asthma medication and have unplanned secondary care visits. Multiple factors influence progression to asthma, including first wheeze event occurring in September.
Saglani S, Scotney E, Bonner K, 2021, Factors and Mechanisms contributing to the development of preschool wheezing disorders, Expert Review of Respiratory Medicine, Vol: 15, Pages: 745-760, ISSN: 1747-6348
IntroductionHalf of all children will experience an episode of wheezing by their sixth birthday and acute episodes of wheezing in preschool children account for the majority of all childhood hospital admissions for wheeze. Recurrent preschool wheezing associates with early loss of lung function and a life-long impact on lung health.Areas coveredWe reviewed the literature on PubMed from August 2010–2020 focussing on factors associated with wheeze inception and persistence, paying specific attention to mechanistic studies that have investigated the impact of early life exposures in shaping immune responses in children with underlying susceptibility to wheezing. In particular, the role of early allergen sensitization, respiratory infections, and the impact of the environment on shaping the airway microbiome and resulting immune responses are discussed.Expert opinionThere is an abundance of associative data showing the role of in utero and postnatal factors influencing wheeze onset and persistence. However, mechanistic and stratified, biomarker-based interventional studies that confirm these associations are now needed if we are to impact the significant healthcare burden resulting from preschool wheezing disorders.
Wang K, Elliot J, Saglani S, et al., 2021, INCREASED BUT SMALLER AIRWAY SMOOTH MUSCLE CELLS IN LOW-BIRTHWEIGHT INFANTS, Publisher: WILEY, Pages: 78-78, ISSN: 1323-7799
Bacharier LB, Guilbert TW, Jartti T, et al., 2021, Which wheezing preschoolers should be treated for asthma?, Journal of Allergy and Clinical Immunology: In Practice, Pages: 1-8, ISSN: 2213-2198
Wheezing disorders in children younger than 5 years are common, but lack of clarity remains about which children should be treated to prevent symptoms and acute episodes. The aim of this review was to discuss a practical approach to deciding which children younger than 5 years with asthma should be treated, and if so, with which strategy. The importance of having a clear definition of "asthma" for this age group, determined by a collection of presenting respiratory symptoms, without assumptions about underlying mechanisms is addressed. Subsequent consideration should be given to timing, severity, and frequency of symptoms, together with assessment of objective biomarkers, including aeroallergen sensitization and blood eosinophils, to inform whether or not a preschooler with recurrent wheezing requires treatment. Numerous unanswered questions remain about the optimal management of nonallergic preschool wheezing and asthma, and areas of specific unmet need and future directions for research are highlighted.
Jamalzadeh A, Makhecha S, Irving S, et al., 2021, FROM HOSPITAL TO HOME: VIRTUALLY OBSERVED ADMINISTRATION OF BIOLOGICS IN CHILDREN WITH SEVERE ASTHMA DURING COVID-19, Publisher: BMJ PUBLISHING GROUP, Pages: A138-A139, ISSN: 0040-6376
Roberts G, Almqvist C, Boyle R, et al., 2020, Developments allergy in 2019 through the eyes of clinical and experimental allergy, part I mechanisms, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 50, Pages: 1294-1301, ISSN: 0954-7894
Roberts G, Almqvist C, Boyle R, et al., 2020, Developments allergy in 2019 through the eyes of Clinical and Experimental Allergy, Part II clinical allergy, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 50, Pages: 1302-1312, ISSN: 0954-7894
Creese H-M, Taylor-Robinson D, Saglani S, et al., 2020, Primary care of children and young people with asthma during the Covid-19 era, British Journal of General Practice, Vol: 70, Pages: 528-529, ISSN: 0960-1643
Around 1.1 million children and young people (CYP)currently receive treatment for asthma in the United Kingdom (UK)(1). The UK performs poorly compared with other European countries in children's outcomes of asthma management and has had amongst the highest number of reported asthma deaths in Europesince 1998 (2). We evaluate evidenceofthe impact of Covid-19 on CYP with asthma and consider what actionsgeneral practitioners can take to protect these children from serious harm.
Bush A, Saglani S, 2020, Preschool wheeze: Challenges and research prospects reply to: Dr Jartti and Colleagues; in response to our manuscript entitled: Medical algorithm: Diagnosis and treatment of preschool asthma, ALLERGY, Vol: 75, Pages: 2718-2718, ISSN: 0105-4538
Bush A, Saglani S, 2020, Medical algorithm: diagnosis and treatment of preschool asthma, Allergy, Vol: 75, Pages: 2711-2712, ISSN: 0105-4538
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