Publications
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Nagakumar P, Artusio L, Fainardi V, et al., 2017, Role of airway Ilc2 And Ilc3 compared to Th2 And Th17 cells in paediatric severe therapy resistant asthma (stra), International Conference of the American-Thoracic-Society (ATS), Publisher: American Thoracic Society, ISSN: 1073-449X
Edwards MR, Saglani S, Schwarze J, et al., 2017, Addressing unmet needs in understanding asthma mechanisms: From the European Asthma Research and Innovation Partnership (EARIP) Work Package (WP)2 collaborators, European Respiratory Journal, Vol: 49, ISSN: 1399-3003
Asthma is a heterogeneous, complex disease with clinical phenotypes that incorporate persistent symptoms and acute exacerbations. It affects many millions of Europeans throughout their education and working lives and puts a heavy cost on European productivity. There is a wide spectrum of disease severity and control. Therapeutic advances have been slow despite greater understanding of basic mechanisms and the lack of satisfactory preventative and disease modifying management for asthma constitutes a significant unmet clinical need. Preventing, treating and ultimately curing asthma requires co-ordinated research and innovation across Europe. The European Asthma Research and Innovation Partnership (EARIP) is an FP7-funded programme which has taken a co-ordinated and integrated approach to analysing the future of asthma research and development. This report aims to identify the mechanistic areas in which investment is required to bring about significant improvements in asthma outcomes.
Cook J, Beresford F, Fainardi V, et al., 2017, Managing the pediatric patient with refractory asthma: a multidisciplinary approach, Journal of Asthma and Allergy, Vol: 10, Pages: 123-130, ISSN: 1178-6965
Children with asthma that is refractory to high levels of prescribed treatment are described as having problematic severe asthma. Those in whom persistent symptoms result from a failure of basic asthma management are described as having “difficult asthma”, while those who remain symptomatic despite these factors having been addressed are described as having “severe therapy-resistant asthma” (STRA). The majority of children have difficult asthma; asthma that is poorly controlled because of a failure to get the basics of asthma management right. Modifiable factors including nonadherence to medication, persistent adverse environmental exposures, and psychosocial factors often contribute to poor control in these patients. As our skill in identifying and addressing modifiable factors has improved, we have found that a progressively smaller proportion of our clinic patients is categorized as having true STRA, resulting in an infrequent resort to escalation of treatment. Many of the modifiable factors associated with the diagnosis of difficult asthma can be identified in a general pediatric clinic. Characterization of more complex factors, however, requires the time, skill, and expertise of multiple health care professionals within the asthma multidisciplinary team. In this review, we will describe the structured approach adopted by The Royal Brompton Hospital in the management of the child with problematic severe asthma. We highlight the roles of members of the multidisciplinary team at various stages of assessment and focus on prominent themes in the identification and treatment of modifiable factors.
Prakash YS, Halayko AJ, Gosens R, et al., 2017, An Official American Thoracic Society Research Statement: Current Challenges Facing Research and Therapeutic Advances in Airway Remodeling., Am J Respir Crit Care Med, Vol: 195, Pages: e4-e19
BACKGROUND: Airway remodeling (AR) is a prominent feature of asthma and other obstructive lung diseases that is minimally affected by current treatments. The goals of this Official American Thoracic Society (ATS) Research Statement are to discuss the scientific, technological, economic, and regulatory issues that deter progress of AR research and development of therapeutics targeting AR and to propose approaches and solutions to these specific problems. This Statement is not intended to provide clinical practice recommendations on any disease in which AR is observed and/or plays a role. METHODS: An international multidisciplinary group from within academia, industry, and the National Institutes of Health, with expertise in multimodal approaches to the study of airway structure and function, pulmonary research and clinical practice in obstructive lung disease, and drug discovery platforms was invited to participate in one internet-based and one face-to-face meeting to address the above-stated goals. Although the majority of the analysis related to AR was in asthma, AR in other diseases was also discussed and considered in the recommendations. A literature search of PubMed was performed to support conclusions. The search was not a systematic review of the evidence. RESULTS: Multiple conceptual, logistical, economic, and regulatory deterrents were identified that limit the performance of AR research and impede accelerated, intensive development of AR-focused therapeutics. Complementary solutions that leverage expertise of academia and industry were proposed to address them. CONCLUSIONS: To date, numerous factors related to the intrinsic difficulty in performing AR research, and economic forces that are disincentives for the pursuit of AR treatments, have thwarted the ability to understand AR pathology and mechanisms and to address it clinically. This ATS Research Statement identifies potential solutions for each of these factors and emphasizes the importance of educati
Fleming L, Saglani S, Bush A, 2016, Asthma attacks: should we nail our colours to the mast (cell)?, European Respiratory Journal, Vol: 48, Pages: 1261-1264, ISSN: 1399-3003
Why do only some asthmatic children exacerbate, what is the underlying pathology, and how should we treat them? http://ow.ly/Mrik304eIVU
Roberts G, Boyle R, Bryce PJ, et al., 2016, Developments in the field of clinical allergy in 2015 through the eyes of Clinical and Experimental Allergy, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 46, Pages: 1389-1397, ISSN: 0954-7894
Del Giacco SR, Bakirtas A, Bel E, et al., 2016, Allergy in severe asthma, Allergy, Vol: 72, Pages: 207-220, ISSN: 0105-4538
It is well recognized that atopic sensitization is an important risk factor for asthma, both in adults and in children. However, the role of allergy in severe asthma is still under debate. The term 'Severe Asthma' encompasses a highly heterogeneous group of patients who require treatment on steps 4-5 of GINA guidelines to prevent their asthma from becoming 'uncontrolled', or whose disease remains 'uncontrolled' despite this therapy. Epidemiological studies on emergency room visits and hospital admissions for asthma suggest the important role of allergy in asthma exacerbations. In addition, allergic asthma in childhood is often associated with severe asthma in adulthood. A strong association exists between asthma exacerbations and respiratory viral infections, and interaction between viruses and allergy further increases the risk of asthma exacerbations. Furthermore, fungal allergy has been shown to play an important role in severe asthma. Other contributing factors include smoking, pollution and work-related exposures. The 'Allergy and Asthma Severity' EAACI Task Force examined the current evidence and produced this position document on the role of allergy in severe asthma.
Downing B, Irving S, Bingham Y, et al., 2016, The feasibility of lung clearance index (LCI) in a clinical setting in pre-school children, European Respiratory Journal, Vol: 48, Pages: 1074-1080, ISSN: 1399-3003
Introduction: Lung function testing in pre-school children in the clinical setting ischallenging. Most cannot perform spirometry and many infant lung function tests requiresedation. Lung clearance index (LCI) derived from the multiple breath washout (MBW) testhas been shown to be sensitive to early disease changes but may be time consuming and soa shortened test (LCI0.5) may be more feasible in young children. We sought to establishfeasibility of MBW in unsedated pre-school children in a clinic setting, and hypothesised useof LCI0.5 would increase success rates.Methods: 116 pre-school children (28 healthy controls, 88 respiratory disease), median age4.0 (range 2-6) years performed MBW test unsedated in a clinic setting, using sulphurhexafluoride (SF6) as a tracer gas and an adapted photoacoustic gas analyser.Results: 81/116 (70%) completed LCI and 72% completed LCI0.5. Test success increasedsignificantly in patients over 3 years (0% <2.5yrs, 33% 2.5-3yrs, 70%>3yrs, p<0.0001). LCIwas elevated in those with respiratory disease compared with healthy controls.Conclusions: MBW is feasible in a clinic setting in unsedated pre-schoolers, particularly inthose over 3 years old, and LCI is raised in those with respiratory disease. Use of LCI0.5 didnot increase success rate in pre-schoolers.
Roberts G, Boyle R, Bryce PJ, et al., 2016, Developments in the field of allergy mechanisms in 2015 through the eyes of Clinical & Experimental Allergy, CLINICAL AND EXPERIMENTAL ALLERGY, Vol: 46, Pages: 1248-1257, ISSN: 0954-7894
Irving S, Fleming L, Saglani S, et al., 2016, Scond may better discriminate severe therapy resistant asthma (STRA) from mild-moderate asthma than lung clearance index (LCI), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Cook J, Bush A, Saglani S, et al., 2016, Higher doses of inhaled steroid are associated with bacterial bronchitis in children with severe therapy resistant asthma (STRA), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Hall P, Winch D, Jamalzadeh A, et al., 2016, Safeguarding concerns are common in children with problematic severe asthma, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Jamalzadeh A, Jochmann A, Artusio L, et al., 2016, Improvements in asthma control following a period of electronic monitoring are sustained, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Fainardi V, Nagakumar P, Saglani S, et al., 2016, IL-4 and IL-13 secreting Type 2 innate lymphoid cells are present in human cord blood, Pediatric Pulmonology, Vol: 51, Pages: S84-S84, ISSN: 8755-6863
Saglani S, 2016, "Personalized medicine" and new designer drugs for children with asthma, Pediatric Pulmonology, Vol: 51, Pages: S29-S29, ISSN: 8755-6863
Saglani S, Fleming L, 2016, How to manage a child with difficult asthma?, Expert Review of Respiratory Medicine, Vol: 10, Pages: 873-879, ISSN: 1747-6348
Introduction: Children with difficult asthma have significant morbidity and fail to achieve asthma control despite being prescribed high dose maintenance treatment. If control remains poor after diagnostic confirmation, detailed assessments of the reasons for asthma being difficult-to-control are needed. Underlying modifiable factors including non-adherence to medication, persistent environmental exposures that trigger asthma symptoms and psychosocial factors contribute to poor control in these patients. Areas covered: The focus of this review is to provide a practical approach to the diagnosis and management of difficult asthma including an overview of long term assessments to identify potential progression to true, severe asthma. A multi-disciplinary team is critical to enable modifiable factors to be identified and addressed. Significant resources are required to manage paediatric difficult asthma optimally and only specialist centres should be tasked with the assessment of these patients. Although this may have an impact on healthcare resources, long term benefits for lung health are significant. Expert commentary: The management of paediatric difficult asthma is not simple and involves numerous professionals with varied expertise. However, if it is not undertaken with the appropriate skills, there is a significant risk of children receiving inappropriate invasive investigations and therapies that will have no impact on morbidity.
Saglani S, 2016, HOW TO MANAGE A CHILD WITH DIFFICULT ASTHMA?, Pediatric Pulmonology, Vol: 51, Pages: S21-S21, ISSN: 8755-6863
Saglani S, 2016, EPITHELIAL CYTOKINES AND PULMONARY ALLERGIC INFLAMMATION, Pediatric Pulmonology, Vol: 51, Pages: S20-S20, ISSN: 8755-6863
Bossley CJ, Fleming L, Ullmann N, et al., 2016, Assessment of corticosteroid response in pediatric patients with severe asthma by using a multidomain approach., Journal of Allergy and Clinical Immunology, Vol: 138, Pages: 413-420.e6, ISSN: 1097-6825
BACKGROUND: There is no agreed upon definition of systemic corticosteroid response in asthmatic children. Moreover, pediatric severe therapy-resistant asthma (STRA) is heterogeneous, and thus response to steroids is unlikely to be uniform in all patients. OBJECTIVE: We sought to evaluate the utility of a multidomain approach incorporating symptoms, lung function, and inflammation to determine steroid responsiveness in pediatric patients with STRA. METHODS: Eighty-two children (median age, 12 years) with STRA received a clinically indicated dose of intramuscular steroid. Changes in 4 separate domains were assessed 4 weeks after intramuscular triamcinolone acetonide: normalization of (1) symptoms (Asthma Control Test score, >19/25 or 50% increase), (2) spirometric results (FEV1 ≥80% of predicted value or ≥15% increase), (3) fraction of exhaled nitric oxide levels (<24 ppb), and (4) sputum eosinophil counts (<2.5%). Fifty-four of 82 children had complete data in all 4 domains. RESULTS: Twenty-three (43%) of 54 children had a symptom response, 29 (54%) of 54 had a lung function response, 28 (52%) of 54 had a fraction of exhaled nitric oxide response, and 29 (54%) of 54 had a sputum eosinophil response. Although a similar proportion of children responded to systemic corticosteroids in each domain, there were no reliable predictors of a response pattern. Seven (13%) of 54 were complete responders (response in all domains), 8 (15%) of 54 were nonresponders (no response in any domain), and 39 (72%) of 54 were partial responders (response in ≥1 domain). CONCLUSIONS: A multidomain evaluation of systemic steroid responsiveness using pragmatic clinical assessments confirms childhood STRA is heterogeneous and that a complete response in symptoms and inflammatory and physiologic parameters is rare. Individual response patterns to systemic steroids might be useful in guiding the choice of add-on therapies in each child as a step toward achieving pe
Fleming L, Koo M, Bossley CJ, et al., 2016, The utility of a multidomain assessment of steroid response for predicting clinical response to omalizumab, Journal of Allergy and Clinical Immunology, Vol: 138, Pages: 292-294, ISSN: 1097-6825
Cook J, Saglani S, 2016, Pathogenesis and prevention strategies of severe asthma exacerbations in children, Current Opinion in Pulmonary Medicine, Vol: 22, Pages: 25-31, ISSN: 1531-6971
Purpose of review: Exacerbations of asthma in children are most frequently precipitated by respiratory infections with a seasonal pattern. However, management takes little account of the underlying infective or other precipitant abnormality.Recent findings: Interactions between environmental triggers, the airway microbiome and innate immune responses are key determinants of exacerbations. Elevated innate cytokines interleukin (IL)-33 and IL-25, and abnormal molecular responses in the interferon pathway are associated with rhinoviral infections. Exacerbations caused by fungal allergens also induce IL-33, highlighting this as an attractive therapeutic target. An equal contribution of bacterial and viral infection during exacerbations, particularly in preschool children, has become increasingly apparent, but some organisms may be protective. Investigation of mechanisms underlying infection-related exacerbations especially in preschool children is needed.Progressive loss of lung function from exacerbations is most pronounced in children aged 6–11 years, and low FEV1 is now recognized as a key predictor for the development of chronic obstructive pulmonary disease and premature death. Although prevention of exacerbations is critical, suboptimal patient education, prescription and adherence to maintenance therapy, and a lack of predictive biomarkers, remain key unaddressed issues in children.Summary: Precipitants and predictors of exacerbations, together with the child's age and clinical phenotype, need to be used to achieve individualized management in preference to the current uniform approach for all.
Koo S, Gupta A, Fainardi V, et al., 2016, Ethnic variation in response to IM Triamcinolone in children with severe therapy-resistant asthma, Chest, Vol: 149, Pages: 98-105, ISSN: 0012-3692
BackgroundAlthough ethnicity may influence response to treatment of patients with asthma, this approach is controversial. The objective of this study was to determine if ethnicity influences the response to IM steroid use (eliminating adherence as an issue).MethodsChildren with severe therapy-resistant asthma who had previously undergone a detailed assessment (including a nurse-led hospital and home visit in which potentially modifiable factors had been identified and addressed) were admitted for further evaluation; this evaluation included assessment of steroid response. Children were classified as white, black, Asian, or mixed white/black. Steroid responsiveness was defined according to symptoms (Asthma Control Test), inflammation (sputum eosinophil count and exhaled nitric oxide), and spirometry (FEV1); these variables were measured before and 4 weeks after IM triamcinolone use. Data were collected regarding exacerbations. Fractional exhaled nitric oxide (Feno) response was defined as a decrease to < 24 parts per billion (ppb).ResultsSeventy-nine subjects were identified (white, n = 54 [68%]; black, n = 16 [20%]; Asian, n = 5 [6%]; and mixed white/black, n = 4 [5%]). After administration of triamcinolone, there was a significant drop in median Feno in white children (46.8 to 23.1 ppb; P < .001) but not in black children (52.2 to 34.5 ppb; P = .58). More black children than white children (86.7%) were Feno nonresponders (86.7% vs 45.3%; P < .05), and more black children had exacerbations compared with white children (61% vs 17%; P < .05).ConclusionsBlack children with asthma were less likely to report an Feno response and had more exacerbations 4 weeks after administration of triamcinolone than white children. Further research is needed to understand the mechanisms of these differences, but they cannot be due to differences in adherence or access to care.
Saglani S, Lloyd CM, 2016, Prostacyclin as a potential novel means to manipulate type 2 innate lymphoid cell function, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 2-4, ISSN: 1535-4970
Johnston S, Edwards MR, Schwarze J, et al., 2016, Where Next In Asthma Research? A Review Of Current Understanding And Future Focus To Prevent And Cure Asthma, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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Grime CJ, Saglani S, Lloyd CM, et al., 2016, Children With Obstructive Sleep Apnoea Have Lower T-Regulatory Cells In The Upper Airway And Peripherally Compared To Controls, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Jochmann A, Artusio L, Robson K, et al., 2015, Infection and inflammation in induced sputum from preschool children with chronic airways diseases., Pediatric Pulmonology, Vol: 51, Pages: 778-786, ISSN: 8755-6863
BACKGROUND: We hypothesized airway inflammation can be detected non-invasively by induced sputum (IS) or peripheral blood eosinophilia, and IS can detect bacterial and viral infection in preschool children with airway disease, with results comparable to broncho-alveolar lavage (BAL). METHODS: Preschool children with cystic fibrosis, recurrent wheeze, or wet cough underwent IS with nebulized hypertonic saline, chest physiotherapy, and oropharyngeal suction. Samples were analyzed for inflammation by cytology and bacterial culture, viral detection by PCR. Results were compared to BAL and blood in a sub-group undergoing clinically indicated bronchoscopy. RESULTS: 64 children (median age 33 [7-76] months) underwent IS without adverse events. IS was obtained from 61/64. Twenty out of sixty-four underwent BAL and IS, no IS was obtained in 2/23. Thirteen out of twenty-one (62%) had matching bacteria and viruses, 4/21 had positive BAL bacterial growth with negative IS, and 3/21 had negative BAL growth with positive IS. 67% of sputum samples were processed for cytology, 46% had <80% squamous cells; the proportion of squamous cells reduced with increasing age (r = -0.55, P < 0.01). IS was significantly more neutrophilic and less eosinophilic than BAL; 2/21 IS samples contained eosinophils compared to 17/23 BAL. There was a positive correlation between blood and BAL eosinophilia (r = 0.75, P < 0.01). CONCLUSION: IS from preschool children can be used to assess infection. BAL and IS culture concurred in approximately two-thirds. However, inflammation was measureable in only one-third of IS samples and the cell differential was predominantly neutrophilic compared to BAL. Blood eosinophils may provide a better reflection of lower airway eosinophilia in this age group. Pediatr Pulmonol. 2016;51:778-786. © 2015 WileyPeriodicals, Inc.
Mckeon S, Saglani S, Bush A, et al., 2015, The relationship between invasive and non-invasive measures of inflammation in children with severe therapy-resistant asthma, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ Publishing Group, Pages: A124-A125, ISSN: 1468-3296
Background Children with severe therapy-resistant asthma (STRA) are refractory to treatment despite optimal management. Assessment of airway inflammation to phenotype these patients can enable targeted therapy. Samples obtained at bronchoscopy provide the most direct measure of lower airway inflammation; however, non-invasive measures (induced sputum and exhaled nitric oxide (FeNO)) are of greater clinical utility. We have previously demonstrated a poor relationship between blood and bronchoalveolar lavage (BAL) eosinophilic phenotype using clinical cut-offs for children (blood eosinophils 1.0 × 109/L).1 Recent studies of the anti-IL-5 antibody mepolizumab have used a lower cut point (0.3 × 109/L) for blood eosinophils.2 The aim of this study was to assess the concordance between BAL and non-invasive measures of inflammation.Methods 113 children (aged 4–17 years) with STRA underwent bronchoscopy at the Royal Brompton Hospital. They had all previously been assessed and potentially modifiable factors such as poor adherence had been addressed. Inflammation was measured invasively using BAL cytology and non-invasively by blood eosinophils, induced sputum cytology, and FeNO. The eosinophilic phenotype was defined as BAL eosinophils >1.19%; blood eosinophils ≥0.3 × 109/L; sputum eosinophils ≥2.5%; and FeNO >35ppb. The relationship between measures was assessed using Spearman rank correlation and Receiver Operator Characteristic (ROC) curves were constructed to determine which cut points best determined BAL eosinophilia and positive and negative predictive values (PPV and NPV) calculated.Results The predominant phenotype in all samples was eosinophilic. There was 75.6–77.8% concordance between the eosinophilic phenotype in BAL and each of the non-invasive measures.Blood and BAL eosinophils had the strongest correlation (r = 0.57, p < 0.001, n = 84). Weaker correlations were found between the other measures. The most promising pr
Downing B, Irving S, Bingham Y, et al., 2015, Feasibility of measuring lung clearance index (LCI) in a clinic setting in preschool children with a range of airway diseases, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ Publishing Group, Pages: A116-A116, ISSN: 1468-3296
Introduction and objectives LCI is a measurement of lung function (in particular distal airway disease) derived from the multiple breath washout (MBW) test (Eur Resp J 2013; 41:507–22). Although practical in a research setting, feasibility in a clinic setting (with limited time and without using sedation) in young children is not known. We looked at success rates of LCI, and LCI0.5 (a shortened washout which can be accomplished more quickly) in preschool children (aged 2–6 years) with recurrent wheeze (Eur Resp J 2008; 32:1096–110), cystic fibrosis (CF), recurrent cough/infections, and healthy controls. Our hypothesis (based on other research performed in this field (Thorax 2012; 68:586–587) was that shortened LCI0.5 would be more feasible than full LCI, and that the test would be more feasible in older preschool children than younger.
Saglani S, Lloyd CM, 2015, Novel concepts in airway inflammation and remodelling in asthma, EUROPEAN RESPIRATORY JOURNAL, Vol: 46, Pages: 1796-1804, ISSN: 0903-1936
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Ahmad F, Irving S, Alton E, et al., 2015, Multiple breath washouts in children can be shortened without compromising quality, European Respiratory Journal, Vol: 46, Pages: 1814-1816, ISSN: 1399-3003
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