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Ober C, McKennan CG, Magnaye KM, et al., 2020, Expression quantitative trait locus fine mapping of the 17q12-21 asthma locus in African American children: a genetic association and gene expression study, LANCET RESPIRATORY MEDICINE, Vol: 8, Pages: 482-492, ISSN: 2213-2600
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- Citations: 39
Turkalj M, Drkulec V, Haider S, et al., 2020, Association of bacterial load in drinking water and allergic diseases in childhood, Clinical and Experimental Allergy, Vol: 50, Pages: 733-740, ISSN: 0954-7894
BackgroundTreatment of drinking water may decrease microbial exposure.ObjectiveTo investigate whether bacterial load in drinking water is associated with altered risk of allergic diseases.MethodsWe recruited 1,110 schoolchildren aged 6‐16 years between 2011 and 2013 in Požega‐Slavonia County in Croatia, where we capitalized on a natural experiment whereby individuals receive drinking water through public mains supply or individual wells. We obtained data on microbial content of drinking water for all participants; 585 children were randomly selected for more detailed assessments, including skin prick testing. Since water supply was highly correlated with rural residence, we compared clinical outcomes across four groups (Rural/Individual, Rural/Public, Urban/Individual and Urban/Public). For each child, we derived quantitative index of microbial exposure (bacterial load in the drinking water measured during the child's first year of life).ResultsCumulative bacterial load in drinking water was higher (median [IQR]: 6390 [4190‐9550] vs 0 [0‐0]; P < .0001), and lifetime prevalence of allergic diseases was significantly lower among children with individual supply (5.5% vs 2.3%, P = .01; 14.4% vs 6.7%, P < .001; 25.2% vs 15.1%, P < .001; asthma, atopic dermatitis [AD] and rhinitis, respectively). Compared with the reference group (Urban/Public), there was a significant reduction in the risk of ever asthma, AD and rhinitis amongst rural children with individual supply: OR [95% CI]: 0.14 [0.03,0.67], P = .013; 0.20 [0.09,0.43], P < .001; 0.17 [0.10,0.32], P < .001. Protection was also observed in the Rural/Public group, but the effect was consistently highest among Rural/Individual children. In the quantitative analysis, the risk of allergic diseases decreased significantly with increasing bacterial load in drinking water in the first year of life (0.79 [0.70,0.88], P < .001; 0.90 [0.83,0.99], P = .025; 0.80 [0.74,0.86], P < .001; current whee
Hemingway H, Lyons R, Li Q, et al., 2020, A national initiative in data science for health: an evaluation of the UK Farr Institute, International Journal of Population Data Science, Vol: 5, Pages: 1-16, ISSN: 2399-4908
ObjectiveTo evaluate the extent to which the inter-institutional, inter-disciplinary mobilisation of data and skills in the Farr Institute contributed to establishing the emerging field of data science for health in the UK.Design and Outcome measuresWe evaluated evidence of six domains characterising a new field of science:defining central scientific challenges,demonstrating how the central challenges might be solved,creating novel interactions among groups of scientists,training new types of experts,re-organising universities,demonstrating impacts in society.We carried out citation, network and time trend analyses of publications, and a narrative review of infrastructure, methods and tools.SettingFour UK centres in London, North England, Scotland and Wales (23 university partners), 2013-2018.Results1. The Farr Institute helped define a central scientific challenge publishing a research corpus, demonstrating insights from electronic health record (EHR) and administrative data at each stage of the translational cycle in 593 papers with at least one Farr Institute author affiliation on PubMed. 2. The Farr Institute offered some demonstrations of how these scientific challenges might be solved: it established the first four ISO27001 certified trusted research environments in the UK, and approved more than 1000 research users, published on 102 unique EHR and administrative data sources, although there was no clear evidence of an increase in novel, sustained record linkages. The Farr Institute established open platforms for the EHR phenotyping algorithms and validations (>70 diseases, CALIBER). Sample sizes showed some evidence of increase but remained less than 10% of the UK population in primary care-hospital care linked studies. 3.The Farr Institute created novel interactions among researchers: the co-author publication network expanded from 944 unique co-authors (based on 67 publications in the first 30 months) to 3839 unique co-authors (545 papers in the final 30
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.
Simpson A, Brough HA, Haider S, et al., 2020, Early-life inhalant allergen exposure, filaggrin genotype and the development of sensitization from infancy to adolescence, Journal of Allergy and Clinical Immunology, Vol: 145, Pages: 993-1001, ISSN: 0091-6749
BackgroundWe hypothesized that filaggrin loss-of-function mutations modify the impact of allergen exposure on the development of allergic sensitization.ObjectiveTo determine whether early-life exposure to inhalant allergens increases the risk of specific sensitization, and whether filaggrin mutations modulate these odds.MethodsIn a population-based birth cohort, we measured mite, cat and dog allergen levels in dust samples collected from homes within the first year of life. Sensitization was assessed at 6 time-points between infancy and age 16 years. Genotyping was performed for six filaggrin mutations.ResultsIn the longitudinal multivariable model (age 1-16 years), we observed a significant interaction between filaggrin and Fel d 1 exposure on cat sensitization, with the effect of exposure being significantly greater among children with filaggrin mutations compared to those without (OR 1.36, 95% CI 1.02-1.80, p=0.035). The increase in risk of mite sensitization with increasing Der p 1 exposure was consistently higher among children with filaggrin mutations, but the interaction did not reach statistical significance. Different association were observed for dog: there was a significant interaction between filaggrin and dog ownership, but the risk of sensitization to any allergen was significantly lower among children with filaggrin mutations who were exposed to dog in infancy (OR 0.16, 95% CI 0.03–0.86, p=0.03).ConclusionsFilaggrin loss-of function mutations modify the relationship between allergen exposure and sensitization, but effects differ at different ages and between different allergens.
Akar-Ghibril N, Casale T, Custovic A, et al., 2020, Allergic endotypes and phenotypes of asthma, Journal of Allergy and Clinical Immunology: In Practice, Vol: 8, Pages: 429-440, ISSN: 2213-2198
Allergic asthma is defined as asthma associated with sensitization to aeroallergens, which leads to asthma symptoms and airway inflammation. Allergic asthma is the most common asthma phenotype. The onset of allergic asthma is most often in childhood and is usually accompanied by other comorbidities including atopic dermatitis and allergic rhinitis. It is often persistent although there is a wide variation in disease severity. It is a TH2-driven process. Biomarkers have been identified to distinguish patients with allergic asthma, particularly serum IgE levels, tests to indicate sensitization to aeroallergens such as specific IgE or skin prick test positivity, blood and sputum eosinophil levels, fraction of exhaled nitric oxide, and periostin. Treatments for allergic asthma include environmental control measures, allergen immunotherapy, and glucocorticoids. Biologics, targeting the TH2 pathway, have been shown to be effective in the treatment of allergic asthma.
Deliu M, Fontanella S, Haider S, et al., 2020, Longitudinal trajectories of severe wheeze exacerbations from infancy to school age and their association with early-life risk factors and late asthma outcomes, Clinical and Experimental Allergy, Vol: 50, Pages: 315-324, ISSN: 0954-7894
IntroductionExacerbation‐prone asthma subtype has been reported in studies using data‐driven methodologies. However, patterns of severe exacerbations have not been studied.ObjectiveTo investigate longitudinal trajectories of severe wheeze exacerbations from infancy to school age.MethodsWe applied longitudinal k‐means clustering to derive exacerbation trajectories among 887 participants from a population‐based birth cohort with severe wheeze exacerbations confirmed in healthcare records. We examined early‐life risk factors of the derived trajectories, and their asthma‐related outcomes and lung function in adolescence.Results498/887 children (56%) had physician‐confirmed wheeze by age 8 years, of whom 160 had at least one severe exacerbation. A two‐cluster model provided the optimal solution for severe exacerbation trajectories among these 160 children: “Infrequent exacerbations (IE)” (n = 150, 93.7%) and “Early‐onset frequent exacerbations (FE)” (n = 10, 6.3%). Shorter duration of breastfeeding was the strongest early‐life risk factor for FE (weeks, median [IQR]: FE, 0 [0‐1.75] vs. IE, 6 [0‐20], P < .001). Specific airway resistance (sRaw) was significantly higher in FE compared with IE trajectory throughout childhood. We then compared children in the two exacerbation trajectories with those who have never wheezed (NW, n = 389) or have wheezed but had no severe exacerbations (WNE, n = 338). At age 8 years, FEV1/FVC was significantly lower and FeNO significantly higher among FE children compared with all other groups. By adolescence (age 16), subjects in FE trajectory were significantly more likely to have current asthma (67% FE vs. 30% IE vs. 13% WNE, P < .001) and use inhaled corticosteroids (77% FE vs. 15% IE vs. 18% WNE, P < .001). Lung function was significantly diminished in the FE trajectory (FEV1/FVC, mean [95%CI]: 89.9% [89.3‐90.5] vs. 88.1% [87.3‐88.8] vs. 85.1% [83.4‐86.7] vs. 74.7% [61.5‐87.8], NW, WNE, IE, FE respective
Broadbent L, Manzoor S, Zarcone M, et al., 2020, Comparative primary paediatric nasal epithelial cell culture differentiation and RSV-induced cytopathogenesis following culture in two commercial media
<jats:title>Abstract</jats:title><jats:p>The culture of differentiated human airway epithelial cells allows the study of pathogen-host interactions and innate immune responses in a physiologically relevant <jats:italic>in vitro</jats:italic> 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. In conclusion, the type of medium used for the differentiation of primary human airway epithelial cells impacts experimental results.</jats:p>
Holguin F, Cardet JC, Chung KF, et al., 2020, Management of severe asthma: a European Respiratory Society/American Thoracic Society Guideline, European Respiratory Journal, Vol: 55, ISSN: 0903-1936
This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the Task Force's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on 6 specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: 1) Suggest using anti-IL5 and anti IL-5Rα for severe uncontrolled adult eosinophilic asthma phenotypes; 2) suggest using blood eosinophil cut-point of ≥150/μL to guide anti-IL5 initiation in adult patients with severe asthma; and 3) Suggest considering specific eosinophil (≥260/μL) and FeNO (≥19.5 ppb) cutoffs to identify adolescents or adults with the greatest likelihood or response to anti-IgE therapy; 4) Suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite GINA step 4-5 or NAEPP step 5 therapies; 5) Suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype; 6) Suggest using anti-IL4/13 for adult patients with severe eosinophilic asthma, and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These recommendations should be reconsidered as new evidence becomes available.
Custovic A, Martinez FD, 2020, The Epidemiology of Severe Childhood Asthma, SEVERE ASTHMA IN CHILDREN AND ADOLESCENTS: MECHANISMS AND MANAGEMENT, Editors: Forno, Saglani, Publisher: SPRINGER INTERNATIONAL PUBLISHING AG, Pages: 3-18, ISBN: 978-3-030-27433-7
Haider S, Nakamura T, Colicino S, et al., 2019, Different definitions of atopic dermatitis: Impact on prevalence estimates and associated risk factors, British Journal of Dermatology, Vol: 181, Pages: 1272-1279, ISSN: 1365-2133
BackgroundThere is no objective test that can unequivocally confirm the diagnosis of atopic dermatitis (AD), and no uniform clinical definition.ObjectiveTo investigate to what extent operational definitions of AD cause fluctuation in the prevalence estimates and the associated risk factors.MethodsWe first reviewed operational definitions of AD used in the literature. We then tested the impact of the choice of the most common definitions of “Cases” and “Controls” on AD prevalence estimates and associated risk factors (including filaggrin‐FLG mutations) among children aged 5 years in two population‐based birth cohorts: Manchester Asthma and Allergy Study (MAAS) and Asthma in Ashford. Model performance was measured by the percentage of children within an area of clinical indecision (defined as having a posterior probability of AD between 25% and 60%).ResultsWe identified 59 different definitions of AD across 45 reviewed studies. Of those, we chose 4 common “Case” definitions, and 2 definitions of “Controls”. The prevalence estimates using different case definitions ranged between 22% and 33% in MAAS, and 12% and 22% in Ashford. The area of clinical indecision ranged from 32% to 44% in MAAS, and from 9% to 29% in Ashford. Depending on the case definition used, the associations with FLG mutations varied (ORs [95% CI]: 1.8 [1.1‐2.9] to 2.2 [1.3‐3.7] (MAAS) and 1.7 [0.8‐3.7] to 2.3 [1.2‐4.5] (Ashford)). Associations with FLG mutations also differed when using the same “Case” definition, but different definitions of “Controls”.ConclusionUse of different definitions of AD results in substantial difference in prevalence estimates, the performance of prediction models, and association with risk factors.
Clark H, Granell R, Curtin JA, et al., 2019, Differential associations of allergic disease genetic variants with developmental profiles of eczema, wheeze and rhinitis, Clinical and Experimental Allergy, Vol: 49, Pages: 1475-1486, ISSN: 0954-7894
BACKGROUND: Allergic diseases (eczema, wheeze and rhinitis) in children often present as heterogeneous phenotypes. Understanding genetic associations of specific patterns of symptoms might facilitate understanding of the underlying biological mechanisms. OBJECTIVE: To examine associations between allergic disease-related variants identified in a recent genome-wide association study and latent classes of allergic diseases (LCADs) in two population-based birth cohorts. METHODS: Eight previously defined LCADs between 1 and 11 years: 'No disease', 'Atopic march', 'Persistent eczema and wheeze', 'Persistent eczema with later-onset rhinitis', 'Persistent wheeze with later-onset rhinitis', 'Transient wheeze', 'Eczema only' and 'Rhinitis only' were used as the study outcome. Weighted multinomial logistic regression was used to estimate associations between 135 SNPs (and a polygenic risk score, PRS) and LCADs among 6,345 individuals from The Avon Longitudinal Study of Parents and Children (ALSPAC). Heterogeneity across LCADs was assessed before and after Bonferroni correction. Results were replicated in Manchester Asthma and Allergy Study (MAAS) (n=896) and pooled in a meta-analysis. RESULTS: We found strong evidence for differential genetic associations across the LCADs; pooled PRS heterogeneity p-value=3.3x10-14 , excluding 'no disease' class. The associations between the PRS and LCADs in MAAS were remarkably similar to ALSPAC. Two SNPs (a protein truncating variant in FLG and a SNP within an intron of GSDMB) had evidence for differential association (pooled p-values≤ 0.006). The FLG locus was differentially associated across LCADs that included eczema, with stronger associations for LCADs with comorbid wheeze and rhinitis. The GSDMB locus in contrast was equally associated across LCADs that included wheeze. CONCLUSIONS & CLINICAL RELEVANCE: We have shown complex, but distinct patterns of genetic associations with LCADs, suggesting that heterogeneous mechanisms unde
Bradfield JP, Vogelezang S, Felix JF, et al., 2019, A trans-ancestral meta-analysis of Genome-wide Association Studies reveals loci associated with childhood obesity, Human Molecular Genetics, Vol: 28, Pages: 3327-3338, ISSN: 0964-6906
Although hundreds of GWAS-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity, and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of thirty studies consisting of up to 13,005 cases (≥95th percentile of BMI achieved 2-18 years old) and 15,599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1,888 cases and 4,689 controls from seven cohorts of European and North/South American ancestry. In addition to observing eighteen previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene: METTL15). The variant was nominally associated in only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than ten SNPs (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.
Diamant Z, Vijverberg S, Alving K, et al., 2019, Toward clinically applicable biomarkers for asthma: An EAACI position paper, Allergy, Vol: 74, Pages: 1835-1851, ISSN: 0105-4538
Inflammation, structural and functional abnormalities within the airways are key features of asthma. Although these processes are well-documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best-defined endotype, typically found in patients with allergic asthma, but surprisingly also in non-allergic patients with (severe) asthma. The etiology of asthma with non-type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology (EAACI) Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point-of-care) to support diagnosis, targeted treatment and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers.
Bousquet JJ, Schünemann HJ, Togias A, et al., 2019, Next-generation ARIA care pathways for rhinitis and asthma: a model for multimorbid chronic diseases, Clinical and Translational Allergy, Vol: 9, ISSN: 2045-7022
Background: In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy. Main body: As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted "patient activation", (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Santé as a Good Practice in the field of digitally-enabled, integrated, person-centred care. Conclusion: In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement.
Bourdin A, Bjermer L, Brightling C, et al., 2019, ERS/EAACI statement on severe exacerbations in asthma in adults: facts, priorities and key research questions, European Respiratory Journal, Vol: 54, Pages: 1-25, ISSN: 0903-1936
Despite the use of effective medications to control asthma, severe exacerbations in asthma are still a major health risk and require urgent action on the part of the patient and physician to prevent serious outcomes such as hospitalisation or death. Moreover, severe exacerbations are associated with substantial healthcare costs and psychological burden, including anxiety and fear for patients and their families. The European Academy of Allergy and Clinical Immunology (EAACI) and the European Respiratory Society (ERS) set up a task force to search for a clear definition of severe exacerbations, and to also define research questions and priorities. The statement includes comments from patients who were members of the task force.
Roche N, Anzueto A, Anticevich SB, et al., 2019, The importance of real-life research in respiratory medicine: manifesto of the Respiratory Effectiveness Group, European Respiratory Journal, Vol: 54, Pages: 1-6, ISSN: 0903-1936
Custovic A, Murray CS, Simpson A, 2019, Dust-mite inducing asthma: what advice can be given to patients?, Expert Review of Respiratory Medicine, Vol: 13, Pages: 929-936, ISSN: 1747-6348
Introduction: Amongst allergic asthmatics, high allergen exposure increases asthma severity. However, there is no consensus on the role of mite allergen avoidance in the management of asthma, and various guidelines differ in their recommendations.Areas covered: Several systematic reviews/meta-analyses on mite avoidance in the management of asthma have been published, and their findings have been used for a call to provide a recommendation in British guidelines that dust-mite control measures should not be recommended. However, there are several problems with such analysis (such as combining studies in adults and children), and we question whether these are appropriate tools to evaluate available evidence about mite allergen avoidance, and whether it is correct to rely disproportionately on the results of meta-analyses/systematic reviews to inform clinical practice in this area. Recent evidence in children suggests that mite–impermeable bed encasings reduce emergency hospital attendance with severe asthma exacerbations.Expert opinion: The practical questions include how to achieve a sufficient real-life reduction allergen exposure, and how to identify patients who will benefit from effective intervention. The intervention should start early in the natural history of asthma, and consideration for choosing patients should include using the titre of allergen-specific IgE antibodies or the size of skin test wheal as an indicator.
Powell E, Fontanella S, Boakes E, et al., 2019, Temporal association of the development of oropharyngeal microbiota with early life wheeze in a population-based birth cohort, EBioMedicine, Vol: 46, Pages: 486-498, ISSN: 2352-3964
Background A critical window in infancy has been proposed, during which the microbiota may affect subsequent health. The longitudinal development of the oropharyngeal microbiota is under-studied and may be associated with early-life wheeze. We aimed to investigate the temporal association of the development of the oropharyngeal microbiota with early-life wheeze.Methods A population-based birth cohort based in London, UK was followed for 24 months. We collected oropharyngeal swabs at six time-points. Microbiota was determined using sequencing of the V3-V5 region of the 16S rRNA-encoding gene. Medical records were reviewed for the outcome of doctor diagnosed wheeze. We used a time-varying model to investigate the temporal association between the development of microbiota and doctor-diagnosed wheeze. Findings 159 participants completed the study to 24 months and for 98 there was complete sequencing data at all timepoints and outcome data. Of these, 26 had doctor-diagnosed wheeze. We observed significant increase in the abundance of Neisseria between 9 and 24 months in children who developed wheeze (p=0∙003), while in those without wheezing there was a significant increment in the abundance of Granulicatella (p=0 ∙012) between 9 and 12 months, and of Prevotella (p=0 ∙018) after 18 months. Interpretation A temporal association between the respiratory commensal Granulicatella and also Prevotella with wheeze (negative), and between Neisseria and wheeze (positive) was identified in infants prior to one year of age. This adds to evidence for the proposed role of the microbiota in the development of wheeze.
Wise SK, Lin SY, Toskala E, et al., 2019, 国际过敏与鼻科学共识声明 : 变应性鼻炎, International Forum of Allergy & Rhinology, Vol: 8, Pages: 108-352, ISSN: 2042-6976
Polack FP, Stein RT, Custovic A, 2019, The syndrome we agreed to call bronchiolitis, Journal of Infectious Diseases, Vol: 220, Pages: 184-186, ISSN: 0022-1899
We are ignoring evidence suggesting that the diagnosis of bronchiolitis encompasses several diseases with distinct underlying mechanisms, considerable heterogeneity in treatment responses, and ultimately different therapeutic targets. Understanding this heterogeneity may be the only way to deliver appropriate, stratified treatments.
Oksel C, Granell R, Haider S, et al., 2019, Distinguishing wheezing phenotypes from infancy to adolescence: a pooled analysis of five birth cohorts, Annals of the American Thoracic Society, Vol: 16, Pages: 868-876, ISSN: 2329-6933
RATIONALE: Pooling data from multiple cohorts and extending the time-frame across childhood should minimize study-specific effects, enabling better characterization of the childhood wheezing. OBJECTIVE: To analyze wheezing patterns from early childhood to adolescence using combined data from five birth cohorts. METHODS: We used latent class analysis to derive wheeze phenotypes among 7719 participants from five birth cohorts with complete report of wheeze at five time-periods. We tested the association of derived phenotypes with late asthma outcomes and lung function, and investigated the uncertainty in phenotype assignment. RESULTS: We identified five phenotypes: Never/Infrequent wheeze (52.1%), Early-onset pre-school remitting (23.9%), Early-onset mid-childhood remitting (9%), Persistent (7.9%) and Late-onset wheeze (7.1%). Compared to the Never/infrequent wheeze, all phenotypes had higher odds of asthma and lower FEV1 and FEV1/FVC in adolescence. The association with asthma was strongest for Persistent wheeze (adjusted odds ratio 56.54, 95%CI 43.75-73.06). We observed considerable within-class heterogeneity at individual level, with 913 (12%) children having low membership probability (<0.60) of any phenotype. Class membership certainty was highest in Persistent and Never/infrequent, and lowest in Late-onset wheeze (with 51% of participants having membership probabilities<0.80). Individual wheezing patterns were particularly heterogeneous in Late-onset wheeze, while many children assigned to Early-onset pre-school remitting class reported wheezing at later time points. CONCLUSIONS: All wheeze phenotypes had significantly diminished lung function in school-age, suggesting that the notion that early-life episodic wheeze has a benign prognosis may not be true for a proportion of transient wheezers. We observed considerable within-phenotype heterogeneity in individual wheezing patterns.
Custovic A, Henderson J, Simpson A, 2019, Does understanding endotypes translate to better asthma management options for all?, Journal of Allergy and Clinical Immunology, Vol: 144, Pages: 25-33, ISSN: 0091-6749
Despite the development of novel treatments, improvement in the design of delivery devices, and new technologies for monitoring and improving adherence, the burden of asthma is not decreasing. Predicting an individual patient's response to asthma drugs remains challenging, and the provision of personalized treatment remains elusive. Although biomarkers, such as allergic sensitization and blood eosinophilia, might be important predictors of response to inhaled corticosteroids in preschool children, these relatively cheap and available investigations are seldom used in clinical practice to select patients for corticosteroid prescription. However, for the majority of patients, response to different treatments cannot be accurately predicted. One of the key factors preventing further advances is the reductionist view of asthma as a single disease, which is forcing patients with different asthma subtypes into a single group for empiric treatment. This inevitably results in treatment failures and, for some, an unacceptable risk/benefit ratio. The approach to asthma today is an example of the traditional symptom (diagnosis)-based, one-size-fits-all approach rather than a stratified approach, and our guidelines-driven management based on a unitary diagnosis might not be the optimal way to deliver care. The only way to deliver stratified medicine and find a cure is through the understanding of asthma endotypes. We propose that the way to discover endotypes, biomarkers, and personalized treatments is through the iterative process based on interpretation of big data analytics from birth and patient cohorts, responses to treatments in randomized controlled trials, and in vitro mechanistic studies using human samples and experimental animal models, with technological and methodological advances at its core.
Sonntag H-J, Filippi S, Pipis S, et al., 2019, Blood biomarkers of sensitization and asthma, Frontiers in Pediatrics, Vol: 7, ISSN: 2296-2360
Biomarkers are essential to determine different phenotypes of childhood asthma, andfor the prediction of response to treatments. In young preschool children with asthma,aeroallergen sensitization, and blood eosinophil count of 300/µL or greater may identifythose who can benefit from the daily use of inhaled corticosteroids (ICS). We proposethat every preschool child who is considered for ICS treatment should have these twofeatures measured as a minimum before a decision is made on the commencementof long-term preventive treatment. In practice, IgE-mediated sensitization should beconsidered as a quantifiable variable, i.e., we should use the titer of sIgE antibodies orthe size of skin prick test response. A number of other blood biomarkers may proveuseful (e.g., allergen-specific IgG/IgE antibody ratios amongst sensitized individuals,component-resolved diagnostics which measures sIgE response to a large number ofallergenic molecules, assessment of immune responses to viruses, level of serum CC16,etc.), but it remains unclear whether these can be translated into clinically useful tests.Going forward, a more integrated approach which takes into account multiple domainsof asthma, from the pattern of symptoms and blood biomarkers to genetic risk andlung function measures, is needed if we are to move toward a stratified approach toasthma management.
Dharmage SC, Perret JL, Custovic A, 2019, Epidemiology of asthma in children and adults, Frontiers in Pediatrics, Vol: 7, ISSN: 2296-2360
Asthma is a globally significant non-communicable disease with major public health consequences for both children and adults, including high morbidity, and mortality in severe cases. We have summarized the evidence on asthma trends, environmental determinants, and long-term impacts while comparing these epidemiological features across childhood asthma and adult asthma. While asthma incidence and prevalence are higher in children, morbidity, and mortality are higher in adults. Childhood asthma is more common in boys while adult asthma is more common in women, and the reversal of this sex difference in prevalence occurs around puberty suggesting sex hormones may play a role in the etiology of asthma. The global epidemic of asthma that has been observed in both children and adults is still continuing, especially in low to middle income countries, although it has subsided in some developed countries. As a heterogeneous disease, distinct asthma phenotypes, and endotypes need to be adequately characterized to develop more accurate and meaningful definitions for use in research and clinical settings. This may be facilitated by new clustering techniques such as latent class analysis, and computational phenotyping methods are being developed to retrieve information from electronic health records using natural language processing (NLP) algorithms to assist in the early diagnosis of asthma. While some important environmental determinants that trigger asthma are well-established, more work is needed to define the role of environmental exposures in the development of asthma in both children and adults. There is increasing evidence that investigation into possible gene-by-environment and environment-by-environment interactions may help to better uncover the determinants of asthma. Therefore, there is an urgent need to further investigate the interrelationship between environmental and genetic determinants to identify high risk groups and key modifiable exposures. For children, as
Gaertner VD, Michel S, Curtin JA, et al., 2019, Nocturnal asthma is affected by genetic interactions between <i>RORA</i> and <i>NPSR1</i>, PEDIATRIC PULMONOLOGY, Vol: 54, Pages: 847-857, ISSN: 8755-6863
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Oksel C, Custovic A, Granell R, et al., 2019, Causes of variability in latent phenotypes of childhood wheeze, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 1783-1790.e11, ISSN: 0091-6749
BackgroundLatent class analysis (LCA) has been used extensively to identify (latent) phenotypes of childhood wheezing. However, the number and trajectory of discovered phenotypes differed substantially between studies.ObjectiveWe sought to investigate sources of variability affecting the classification of phenotypes, identify key time points for data collection to understand wheeze heterogeneity, and ascertain the association of childhood wheeze phenotypes with asthma and lung function in adulthood.MethodsWe used LCA to derive wheeze phenotypes among 3167 participants in the ALSPAC cohort who had complete information on current wheeze recorded at 14 time points from birth to age 16½ years. We examined the effects of sample size and data collection age and intervals on the results and identified time points. We examined the associations of derived phenotypes with asthma and lung function at age 23 to 24 years.ResultsA relatively large sample size (>2000) underestimated the number of phenotypes under some conditions (eg, number of time points <11). Increasing the number of data points resulted in an increase in the optimal number of phenotypes, but an identical number of randomly selected follow-up points led to different solutions. A variable selection algorithm identified 8 informative time points (months 18, 42, 57, 81, 91, 140, 157, and 166). The proportion of asthmatic patients at age 23 to 24 years differed between phenotypes, whereas lung function was lower among persistent wheezers.ConclusionsSample size, frequency, and timing of data collection have a major influence on the number and type of wheeze phenotypes identified by using LCA in longitudinal data.
Menditto E, Costa E, Midão L, et al., 2019, Adherence to treatment in allergic rhinitis using mobile technology. the mask study, Clinical and Experimental Allergy, Vol: 49, Pages: 442-460, ISSN: 0954-7894
BACKGROUND: Mobile technology may help to better understand the adherence to treatment MASK-rhinitis (Mobile Airways Sentinel NetworK for allergic rhinitis) is a patient-centered ICT system. A mobile phone app (the Allergy Diary) central to MASK is available in 22 countries. OBJECTIVES: To assess the adherence to treatment in allergic rhinitis patients using the Allergy Diary App. METHODS: An observational cross-sectional study was carried out on all users who filled in the Allergy Diary from January 1, 2016 to August 1, 2017. Secondary adherence was assessed by using the modified Medication Possession Ratio (MPR) and the Proportion of days covered (PDC) approach. RESULTS: 12,143 users were registered. 6,949 users reported at least one VAS data recording. Among them, 1,887 users reported ≥ 7 VAS data. 1,195 subjects were included in the analysis of adherence. 136 (11.28%) users were adherent (MPR ≥70% and PDC ≤ 1.25), 51 (4.23%) were partly adherent (MPR ≥70% and PDC =1.50) and 176 (14.60%) were switchers. On the other hand, 832 (69.05%) users were non-adherent to medications (MPR<70%). Of those, the largest group was non-adherent to medications and the time interval was increased in 442 (36.68%) users. CONCLUSION AND CLINICAL RELEVANCE: Adherence to treatment is low. The relative efficacy of continuous versus on-demand treatment for AR symptoms is still a matter of debate.This study shows an approach for measuring retrospective adherence based on a mobile app. This represent a novel approach also for analyzing medication taking behavior in a real-world setting. This article is protected by copyright. All rights reserved.
Lenney W, Adachi Y, Bush A, et al., 2019, Asthma: moving toward a global children's charter, The Lancet Respiratory Medicine, Vol: 7, Pages: 299-300, ISSN: 2213-2600
Colicino S, Munblit D, Minelli C, et al., 2019, Validation of childhood asthma predictive tools: A systematic review, Clinical and Experimental Allergy, Vol: 49, Pages: 410-418, ISSN: 0954-7894
BACKGROUND: There is uncertainty about the clinical usefulness of currently available asthma predictive tools. Validation of predictive tools in different populations and clinical settings is an essential requirement for the assessment of their predictive performance, reproducibility and generalizability. We aimed to critically appraise asthma predictive tools which have been validated in external studies. METHODS: We searched MEDLINE and EMBASE (1946-2017) for all available childhood asthma prediction models and focused on externally validated predictive tools alongside the studies in which they were originally developed. We excluded non-English and non-original studies. PROSPERO registration number is CRD42016035727. RESULTS: From 946 screened papers, eight were included in the review. Statistical approaches for creation of prediction tools included chi-square tests, logistic regression models and the least absolute shrinkage and selection operator. Predictive models were developed and validated in general and high-risk populations. Only three prediction tools were externally validated: the Asthma Predictive Index, the PIAMA and the Leicester asthma prediction tool. A variety of predictors has been tested, but no studies examined the same combination. There was heterogeneity in definition of the primary outcome among development and validation studies, and no objective measurements were used for asthma diagnosis. The performance of tools varied at different ages of outcome assessment. We observed a discrepancy between the development and validation studies in the tools' predictive performance in terms of sensitivity and positive predictive values. CONCLUSIONS: Validated asthma predictive tools, reviewed in this paper, provided poor predictive accuracy with performance variation in sensitivity and positive predictive value.
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