Publications
297 results found
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
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- Citations: 1
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
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- Citations: 3
Saglani S, Gregory LG, Manghera AK, et al., 2018, Inception of early life allergen induced airway hyperresponsiveness is reliant on IL-13+CD4+ T cells, Science Immunology, Vol: 3, Pages: 1-12, 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
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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, 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.
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, 2018, PRO: Importance of Implementing Asthma Guidelines: An Evidence-Based Approach that Helps Ensure Consistent Management, Publisher: WILEY, Pages: S26-S28, ISSN: 8755-6863
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 [version 1; peer review: 2 approved], Wellcome Open Research, Vol: 3, 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.
Nagakumar P, Gambir N, Sanghani N, et al., 2018, Role of a prolonged inpatient admission when evaluating children with problematic severe asthma., European Respiratory Journal, Vol: 51, ISSN: 0903-1936
Belgrave D, Cassidy R, Custovic A, et al., 2018, Predictive Modelling Strategies to Understand Heterogeneous Manifestations of Asthma in Early Life, 16th IEEE International Conference on Machine Learning and Applications (ICMLA), Publisher: IEEE, Pages: 68-75
Wheezing is common among children and ~50% of those under 6 years of age are thought to experience at least one episode of wheeze. However, due to the heterogeneity of symptoms there are difficulties in treating and diagnosing these children. `Phenotype specific therapy' is one possible avenue of treatment, whereby we use significant pathology and physiology to identify and treat pre-schoolers with wheeze. By performing feature selection algorithms and predictive modelling techniques, this study will attempt to determine if it is possible to robustly distinguish patient diagnostic categories among pre-school children. Univariate feature analysis identified more objective variables and recursive feature elimination a larger number of subjective variables as important in distinguishing between patient categories. Predicative modelling saw a drop in performance when subjective variables were removed from analysis, indicating that these variables are important in distinguishing wheeze classes. We achieved 90%+ performance in AUC, sensitivity, specificity, and accuracy, and 80%+ in kappa statistic, in distinguishing ill from healthy patients. Developed in a synergistic statistical - machine learning approach, our methodologies propose also a novel ROC Cross Evaluation method for model post-processing and evaluation. Our predictive modelling's stability was assessed in computationally intensive Monte Carlo simulations.
Cook J, Martin-Alonso A, Sanghani N, et al., 2018, Children with Pre-School Wheeze Have Neutrophilic Airway Inflammation Associated with Bacteria and Viruses During Periods of Clinical Stability, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Jochmann A, Artusio L, Jamalzadeh A, et al., 2017, Electronic monitoring of adherence to inhaled corticosteroids: an essential tool in identifying severe asthma in children, European Respiratory Journal, Vol: 50, ISSN: 0903-1936
International guidelines recommend that severe asthma can only be diagnosed after contributory factors, including adherence, have been addressed. Accurate assessment of adherence is difficult in clinical practice. We hypothesised that electronic monitoring in children would identify nonadherence, thus delineating the small number with true severe asthma.Asthmatic children already prescribed inhaled corticosteroids were prospectively recruited and persistence of adherence assessed using electronic monitoring devices. Spirometry, airway inflammation and asthma control were measured at the start and end of the monitoring period.93 children (62 male; median age 12.4 years) were monitored for a median of 92 days. Median (range) monitored adherence was 74% (21-99%). We identified four groups: 1) good adherence during monitoring with improved control, 24% (likely previous poor adherence); 2) good adherence with poor control, 18% (severe therapy-resistant asthma); 3) poor adherence with good control, 26% (likely overtreated); and 4) poor adherence with poor control, 32%. No clinical parameter prior to monitoring distinguished these groups.Electronic monitoring is a useful tool for identifying children in whom a step up in treatment is indicated. Different approaches are needed in those who are controlled when adherent or who are nonadherent. Electronic monitoring is essential in a paediatric severe asthma clinic.
Nayeem A, Saglani S, Bush A, et al., 2017, Clinical and pathological characteristics of severely asthmatic children with persistent airflow limitation, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ Publishing Group, Pages: A45-A46, ISSN: 1468-3296
Introduction Severe therapy resistant asthma (STRA) in children is heterogeneous: many have normal lung function, however there is a group with persistent airflow limitation (PAL). Little is known about PAL in children and previous studies are limited by the definitions used. We hypothesised that when PAL is classified according to stringent criteria (post bronchodilator FEV1 z score <−1.96 after a one-month systemic steroid trial (ERM 2011,Ch 5; 51–59) this group would have distinct clinical, inflammatory and pathological characteristics compared to children without PAL.Methods Retrospective analysis of 103 STRA children. Patients were classified as STRA if they had ongoing poor control despite high dose inhaled corticosteroids plus at least one add on therapy having been assessed as part of a systematic protocol when modifiable factors such as poor adherence were identified and corrected. All children underwent bronchoscopy, bronchoalveolar lavage (BAL) and endobronchial biopsy and received intramuscular triamcinolone. Asthma control test score (ACT); inflammation (exhaled nitric oxide (FENO), induced sputum); spirometry (FEV1. FVC) were measured on the day of bronchoscopy and 4 weeks later. The best FEV1 in the year post triamcinolone was recorded.Results 26/103 (25.2%) STRA children were classified with PAL. There were no differences in the demographic characteristics between the groups. Fewer children with PAL had a previous Paediatric Intensive Care Unit admission (21.7% versus 47.1%); there were no other differences in asthma control. Children with PAL had a higher number of submucosal eosinophils (p=0.021) in endobronchial biopsies before triamcinolone, but there were no differences in airway luminal inflammation in BAL. However, there was a trend towards lower sputum eosinophils post, but not pre, triamcinolone in children with PAL (0.65% (0–17) versus 2.5% (0–42.8), p=0.054). There were no differences in blood eosinophils or FENO
Irving S, Bingham Y, Bossley C, et al., 2017, Change in lung clearance index and exhaled nitric oxide as markers of systemic corticosteroid response in children with severe asthma, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ Publishing Group, Pages: A44-A45, ISSN: 1468-3296
Introduction Children with severe therapy resistant asthma (STRA) have heterogeneous disease with variable response to steroids. Currently, spirometry (forced expiratory volume in 1 s (FEV1)) is most widely used to assess treatment response. We hypothesised lung clearance index (LCI) would more sensitively assess steroid response than FEV1 alone, using our multi-domain approach [JACI 2016;138:413–420] with the addition of LCI to measure response of distal airway disease.Methods 39 children with STRA were recruited during a clinically-indicated admission for bronchoscopy and intramuscular triamcinolone injection. Prior to triamcinolone, they performed LCI, spirometry, FeNO, and filled in the asthma control test (ACT). They were followed up at 4 weeks and these tests repeated. ACT was considered abnormal if <20, LCI if ≥7.1, FEV1 percent predicted below 80%, and FeNO if ≥24 parts per billion. Any domain which was abnormal at visit 2 was a non-response.Results 26/39 (67%) patients had at least a partial response, see Table. There was strongest concordance of Results between FeNO and LCI (70%). 11/39 (28%) of patients had a response in at least two domains, 4/39 (10%) at least three, and 1 patient responded in all four domains.Conclusions In this cohort, LCI, FeNO and FEV1 were equally likely to be abnormal at baseline. FeNO and LCI were most likely to respond, (36% and 33% respectively), whereas FEV1 was least responsive to systemic steroids. Using this multi-domain approach 67% improved over 4 weeks following treatment with systemic corticosteroid. The clinical significance of an LCI response remains to be determined. We speculate that this group may reflect a distal airway disease phenotype who may benefit from fine particle inhaled corticosteroids.
Bingham Y, Sanghani N, Irving S, et al., 2017, RELATIONSHIP BETWEEN EXHALED NITRIC OXIDE AND LUNG CLEARANCE INDEX IN PRE-SCHOOL CHILDREN WITH A RANGE OF RESPIRATORY SYMPTOMS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A131-A131, ISSN: 0040-6376
Wells C, Collins N, Bush A, et al., 2017, BENCHMARKING OF PAEDIATRIC DIFFICULT ASTHMA PHYSIOTHERAPY SERVICES, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A130-A130, ISSN: 0040-6376
Roberts G, Boyle R, Crane J, et al., 2017, Developments in the field of allergy in 2016 through the eyes of Clinical and Experimental Allergy, Clinical and Experimental Allergy, Vol: 47, Pages: 1512-1525, ISSN: 0954-7894
n this article, we described the development in the field of allergy as described by Clinical and Experimental Allergy in 2016. Experimental models of allergic disease, basic mechanisms, clinical mechanisms, allergens, asthma and rhinitis, and clinical allergy are all covered.
Bush A, Saglani S, Fleming L, 2017, Severe asthma: looking beyond the amount of medication, Lancet Respiratory Medicine, Vol: 5, Pages: 844-846, ISSN: 2213-2600
Alonso AM, Fainardi V, Saglani S, 2017, Severe therapy resistant asthma in children: translational approaches to uncover sub-phenotypes, Expert Review of Respiratory Medicine, Vol: 11, Pages: 867-874, ISSN: 1747-6348
Introduction: Paediatric severe therapy resistant asthma (STRA) affects a very small proportion of all children with asthma, but results in significant morbidity, has a high risk of mortality and utilises approximately half of all healthcare resources for childhood asthma. children with STRA need add-on ‘beyond guidelines’ therapies because of poor control despite maximal conventional treatments and optimisation of basic asthma management. however, STRA is heterogeneous with marked phenotypic variation between patients and mechanisms from adult severe asthma cannot be extrapolated to children.Areas covered: This review will cover our current knowledge of paediatric STRA pathophysiology, with examples of translational approaches that have been used to define sub-phenotypes including; 1. pre-clinical age-appropriate models using clinically relevant allergens, 2. in vitro techniques incorporating complex co-cultures of structural and inflammatory cells, and 3. techniques that allow detailed cellular immunophenotyping of small airway samples will be discussed. Studies using these approaches that have demonstrated the importance of the innate mediator IL-33 and vitamin D deficiency in severe steroid resistant disease will also be discussed.Expert commentary: These experimental approaches allow investigation of age and disease specific molecular pathways and the development of personalised therapies that can be stratified and targeted to sub-phenotypes of paediatric STRA.
Martin Alonso A, Saglani S, 2017, Mechanisms Mediating Pediatric Severe Asthma and Potential Novel Therapies, Frontiers in Pediatrics, Vol: 5, ISSN: 2296-2360
Although a rare disease, severe therapy-resistant asthma in children is a cause of significant morbidity and results in utilization of approximately 50% of health-care resources for asthma. Improving control for children with severe asthma is, therefore, an urgent unmet clinical need. As a group, children with severe asthma have severe and multiple allergies, steroid resistant airway eosinophilia, and significant structural changes of the airway wall (airway remodeling). Omalizumab is currently the only add-on therapy that is licensed for use in children with severe asthma. However, limitations of its use include ineligibility for approximately one-third of patients because of serum IgE levels outside the recommended range and lack of clinical efficacy in a further one-third. Pediatric severe asthma is thus markedly heterogeneous, but our current understanding of the different mechanisms underpinning various phenotypes is very limited. We know that there are distinctions between the factors that drive pediatric and adult disease since pediatric disease develops in the context of a maturing immune system and during lung growth and development. This review summarizes the current data that give insight into the pathophysiology of pediatric severe asthma and will highlight potential targets for novel therapies. It is apparent that in order to identify novel treatments for pediatric severe asthma, the challenge of undertaking mechanistic studies using age appropriate experimental models and airway samples from children needs to be accepted to allow a targeted approach of personalized medicine to be achieved.
Lloyd CM, Saglani S, 2017, Development of allergic immunity in early life, IMMUNOLOGICAL REVIEWS, Vol: 278, Pages: 101-115, ISSN: 0105-2896
The growth and maturity of the peripheral immune system and subsequent development of pulmonary immunity in early life is dictated by host, environmental and microbial factors. Dysregulation during the critical window of immune development in the postnatal years results in disease which impacts on lifelong lung health. Asthma is a common disease in childhood and is often preceded by wheezing illnesses during the preschool years. However, the mechanisms underlying development of wheeze and how and why only some children progress to asthma is unknown. Human studies to date have generally focused on peripheral immune development, with little assessment of local tissue pathology in young children. Moreover, mechanisms underlying the interactions between inflammation and tissue repair at mucosal surfaces in early life remain unknown. Disappointingly, mechanistic studies in mice have predominantly used adult models. This review will consider the aspects of the neonatal immune system which might contribute to the development of early life wheezing disorders and asthma, and discuss the external environmental factors which may influence this process.
Saglani S, Bush A, 2017, Asthma attacks in children: does blocking IgE reduce rhinoviral infections?, American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 941-942, ISSN: 1073-449X
Asthma attacks lead to impaired quality of life and mortality, but the rates of admission for acute asthma have changed little over the last 20 years(1). We know that a combination of allergen sensitization, allergen exposure and viral infections trigger attacks(2). Although usually these factors work together, a large allergen load alone can also be sufficient to trigger an attack [thunderstorm], and although viruses contribute to increased symptoms, in the context of atopic asthma, they are not the only culprit. Although Influenza viruses can be targeted by specific agents including vaccines, we lack strategies to treat most of the common respiratory viruses that result in asthma attacks, especially rhinovirus (RV). Interferon responses to rhinovirus are altered in asthmatics(3), but a recent study using nebulised interferon(4) failed to meet its primary end point suggesting interactions between allergic and antiviral immunity are key. Hence attention has turned to modulating the allergic components of asthma attacks. Reducing house dust mite allergen exposure with impermeable covers shows promise in sensitized children(5) and modulating the response to allergens with omalizumab(6) are examples of this approach.
Artiso L, Walker S, Fleming L, et al., 2017, Sputum eosinophil eroxidase (EPX) differentiates pediatric severe therapy resistant asthma (STRA) from difficult asthma (DA), Pediatric Pulmonology, Vol: 52, Pages: S105-S106, ISSN: 1099-0496
Saglani S, 2017, Childhood severe asthma: New insights on remodelling and biomarkers, PAEDIATRIC RESPIRATORY REVIEWS, Vol: 24, Pages: 11-13, ISSN: 1526-0542
Severe asthma in children is characterised by severe and multiple aeroallergen sensitisation, food allergy, eosinophilic airway inflammation and airway remodelling. However, it is a heterogeneous disease with considerable variability in the manifestation of each of these characteristics between patients. Recent data from mechanistic studies that have used translational approaches including neonatal mouse models and airway bronchoscopic samples, have shown specific molecular mediators that drive remodelling and steroid resistance in paediatric severe asthma will be discussed. The importance of undertaking studies using age appropriate models and primary cells from children to identify novel therapeutic targets will be highlighted.
Saglani S, 2017, Obesity, Systemic Inflammation and Respiratory Disease, Publisher: WILEY, Pages: S89-S91, ISSN: 8755-6863
Saglani S, 2017, Novel Treatments for Acute Asthma, Publisher: WILEY, Pages: S25-S27, ISSN: 8755-6863
Andersson CK, Adams A, Nagakumar P, et al., 2017, Intra-epithelial neutrophils in paediatric severe asthma are associated with better lung function, Journal of Allergy and Clinical Immunology, Vol: 139, Pages: 1819-1829.e11, ISSN: 1097-6825
BACKGROUND: Neutrophils and IL-17A have been linked mechanistically in models of allergic airways disease and have been associated with asthma severity. However, their role in paediatric asthma is unknown. OBJECTIVES: To investigate the role of neutrophils and the IL-17A pathway in mediating paediatric severe therapy resistant asthma (STRA). METHODS: Children with STRA (n=51, age 12.6 (6 -16.3) years) and non-asthmatic controls (n=15, age 4.75 (1.6-16) years) underwent clinically indicated fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial brushings and biopsy. Neutrophils, IL-17A and IL-17RA expressing cells and levels of IL-17A and IL-22 were quantified in BAL and biopsies and related to clinical features. Primary bronchial epithelial cells (PBECs) were stimulated with IL-17A and/or IL-22, with and without Budesonide. RESULTS: Children with STRA had increased intra-epithelial neutrophils, which positively correlated with FEV1 %predicted (r=0.43, p=0.008). Neutrophil-high patients also had better symptom control, despite lower dose maintenance inhaled steroids. Submucosal neutrophils were not increased in STRA. Submucosal and epithelial IL-17A positive cells and BAL IL-17A and IL-22 levels were similar in STRA and controls. However, there were significantly more IL-17RA positive cells in the submucosa and epithelium in children with STRA compared to controls (p=0.001). Stimulation of PBECs with IL-17A enhanced mRNA expression of IL-17RA and increased release of IL-8, even in the presence of Budesonide. CONCLUSIONS: A proportion of children with STRA exhibit increased intra-epithelial airway neutrophilia that correlated with better lung function. STRA was additionally characterised by increased airway IL-17RA expression. These data suggest a potential beneficial rather than adverse role for neutrophils in paediatric severe asthma pathophysiology.
Bush A, Fleming L, Saglani S, 2017, Severe asthma in children, Respirology, Vol: 22, Pages: 886-897, ISSN: 1323-7799
Most children with asthma have their disease easily controlled if low-dose inhaled corticosteroids (ICSs) are regularly and correctly administered. If a child presents with asthma which is apparently resistant to therapy with high-dose ICS and other controllers, then they have problematic severe asthma. However, in light of the UK National Review of Asthma Deaths, definitions of severe asthma based solely on the levels of prescribed treatment are too narrow. A detailed assessment of all such children should be performed. First, the diagnosis of asthma should be confirmed, then co-morbidities assessed. Next, a nurse-led assessment further characterizes the problem, conventionally categorizing the child as either having difficult asthma or severe therapy-resistant asthma. Here, we reassess in particular the interactions between, and management of, these two categories, highlighting that this dichotomous classification may need reconsideration. We use bronchoscopy and an intramuscular steroid injection to determine if the child has steroid-resistant asthma, using a novel, multidomain approach because the adult definition does not apply to around half the children we see. Finally, we highlight some mechanistic data which have emerged from this protocol such as the absence of T-helper 2 (TH2) cytokines even in eosinophilic severe asthma and the potential role of the innate epithelial cytokine IL-33, novel data on lineage negative innate lymphoid cells, which we can measure in induced sputum, and demonstrating that intraepithelial neutrophils are associated with better, not worse asthma outcomes. Severe paediatric asthma is very different from severe asthma in adults, and approaches must not be uncritically extrapolated from adult disease to children.
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