235 results found
Tanner N, Saglani S, Li AM, et al., 2021, Airway inflammation in severe asthmatics with acid gastro-oesophageal reflux., Thorax
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., Arch Dis Child, Vol: 106, Pages: 900-902
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
Scotney E, Burchett S, Goddard T, et al., 2021, Pediatric problematic severe asthma: Recent advances in management, Pediatric Allergy and Immunology, 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.
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, 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
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.
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
Wells C, Cartwright M, Hirani S, et al., 2020, Identifying predictors for referral to a physiotherapy service for children with difficult asthma, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Fainardi V, Saglani S, 2020, An approach to the management of children with problematic severe asthma., Acta Biomed, Vol: 91
Children with poor asthma control despite high levels of prescribed treatment are described as having problematic severe asthma. Most of these children have steroid sensitive disease which improves with adherence to daily inhaled corticosteroids and after having removed modifiable factors like poor inhalation technique, persistent adverse environmental exposures and psychosocial factors. These children are described as having "difficult-to-treat asthma" while children with persistent symptoms despite above-mentioned factors having been addressed are described as having "severe therapy-resistant asthma". In this review, we will describe the 6-step approach to the diagnosis and management of a child with problematic severe asthma adopted by The Royal Brompton Hospital (London, UK). The role of a multidisciplinary team is crucial for identification and treatment of modifiable factors and comorbidities in order to avoid invasive examinations and useless pharmacological treatments. The current knowledge on add-on therapies will be discussed.
Davies B, Frost S, Rao S, et al., 2020, Accuracy of blood eosinophil count in predicting sputum eosinophils in children with problematic severe asthma (PSA), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bingham Y, Fleming L, Sanghani N, et al., 2020, Electronic monitoring of adherence to inhaled corticosteroids in preschool children with wheeze, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Scotney E, Saglani S, 2020, Diagnosis and Management of Problematic Severe Asthma., Acta Med Acad, Vol: 49, Pages: 117-129
This review will outline an evidence-based approach for diagnosing and managing children with problematic severe asthma (PSA). Children with PSA have uncontrolled asthma symptoms, despite maximal prescribed asthma treatment. These children have high morbidity and mortality and should be referred for specialist respiratory assessment and management. The first step in the assessment of a child with PSA is confirming the diagnosis of asthma using objective evidence. Following this, an assessment of inhaled corticosteroid adherence and a multi-disciplinary team approach is essential for separating difficult asthma (DA) from severe therapy resistant asthma (STRA). The majority of children have DA which entails uncontrolled asthma symptoms due to underlying modifiable factors including poor treatment adherence, poor inhaler technique, exposure to environmental allergens, co-morbid conditions and psycho-social factors. Approximately 20% of children with PSA have STRA, and have persistent asthma symptoms despite good treatment adherence and correction of modifiable factors. Children with STRA typically have multiple and severe aeroallergen sensitization, eosinophilic airway inflammation and high fraction exhaled nitric oxide (FeNO). Further investigation of children with STRA includes an assessment of systemic steroid responsiveness, this is important for confirming the diagnosis of STRA and guiding the choice of additional treatment. Biologics are an add on (immune targeted) therapy for STRA. The current biologics used in children target the T2 helper (Th2) pathway mediating eosinophilic, allergic asthma. CONCLUSION: Future clinical trials of biologics in children will be essential to help identify childhood specific biomarkers and to decide which biologic is best for which individual child.
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.
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, Vol: 75, Pages: 3195-3207, ISSN: 0105-4538
Bingham Y, Sanghani N, Cook J, et al., 2020, Electronic adherence monitoring identifies severe preschool wheezers who are steroid responsive., Pediatric Pulmonology, Vol: 55, Pages: 2254-2260, 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
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.