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Middeldorp CM, Felix JF, Mahajan A, et al., 2019, The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia: design, results and future prospects, European Journal of Epidemiology, Vol: 34, Pages: 279-300, ISSN: 0393-2990
The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
Bousquet J, Bedbrook A, Czarlewski W, et al., 2019, Guidance to 2018 good practice: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma, CLINICAL AND TRANSLATIONAL ALLERGY, Vol: 9, ISSN: 2045-7022
AimsMobile Airways Sentinel NetworK (MASK) belongs to the Fondation Partenariale MACVIA-LR of Montpellier, France and aims to provide an active and healthy life to rhinitis sufferers and to those with asthma multimorbidity across the life cycle, whatever their gender or socio-economic status, in order to reduce health and social inequities incurred by the disease and to improve the digital transformation of health and care. The ultimate goal is to change the management strategy in chronic diseases.MethodsMASK implements ICT technologies for individualized and predictive medicine to develop novel care pathways by a multi-disciplinary group centred around the patients.StakeholdersInclude patients, health care professionals (pharmacists and physicians), authorities, patient’s associations, private and public sectors.ResultsMASK is deployed in 23 countries and 17 languages. 26,000 users have registered.
Wang R, Simpson A, Custovic A, et al., 2019, Individual risk assessment tool for school-age asthma prediction in UK birth cohort, Clinical and Experimental Allergy, Vol: 49, Pages: 292-298, ISSN: 0954-7894
BACKGROUND: Current published asthma predictive tools have moderate positive likelihood ratios (+LR) but high negative likelihood ratios (-LR) based on their recommended cut-offs, which limit their clinical usefulness. OBJECTIVE: To develop a simple clinically applicable asthma prediction tool within a population-based birth cohort. METHOD: Children from the Manchester Asthma and Allergy Study (MAAS) attended follow-up at ages 3, 8 and 11 years. Data on preschool wheeze were extracted from primary-care records. Parents completed validated respiratory questionnaires. Children were skin prick tested (SPT). Asthma at 8/11 years (school-age) was defined as parentally reported (a) physician-diagnosed asthma and wheeze in the previous 12 months or (b) ≥3 wheeze attacks in the previous 12 months. An asthma prediction tool (MAAS APT) was developed using logistic regression of characteristics at age 3 years to predict school-age asthma. RESULTS: Of 336 children with physician-confirmed wheeze by age 3 years, 117(35%) had school-age asthma. Logistic regression selected 5 significant risk factors which formed the basis of the MAAS APT: wheeze after exercise; wheeze causing breathlessness; cough on exertion; current eczema and SPT sensitisation(maximum score 5). A total of 281(84%) children had complete data at age 3 years and were used to test the MAAS APT. Children scoring ≥3 were at high risk of having asthma at school-age (PPV > 75%; +LR 6.3, -LR 0.6), whereas children who had a score of 0 had very low risk(PPV 9.3%; LR 0.2). CONCLUSION: MAAS APT is a simple asthma prediction tool which could easily be applied in clinical and research settings.
Bousquet J, Hellings PW, Agache I, et al., 2019, Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 864-879, ISSN: 0091-6749
Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.
Saglani S, Custovic A, 2019, Childhood asthma: Advances using machine learning and mechanistic studies, American Journal of Respiratory and Critical Care Medicine, Vol: 199, ISSN: 1073-449X
A paradigm shift brought by the recognition that childhood asthma is a heterogeneous condition comprising several endotypes underpinned by different pathophysiology, coupled with advances in understanding important causal mechanisms, offers a real opportunity for a step change to reduce the burden of the disease on individual children, families and society. Data-driven approaches have provided a framework for revealing hidden structure within large datasets. One way of bridging findings from data-driven analyses into clinical practice is to link "phenotypes" identified using such techniques with a specific pathology. Epidemiological studies have provided important clues about mechanistic avenues that should be pursued to identify interventions to prevent asthma development or alter its natural history. Findings from cohort studies followed by mechanistic studies in humans and in neonatal mouse models have suggested that environments such as traditional farming may provide protection by modulating innate immune responses, and that impaired innate immunity may increase asthma susceptibility. The key question of which component of these exposures can be translated into interventions requires confirmation. Increasing mechanistic evidence is demonstrating that shaping the airway microbiome in early life may modulate immune function to confer protection. If we are to make advances, we have to foster cross-disciplinary collaborations between data scientists who turn "big data" into useful information about the hidden structures within large dataset which may help disaggregate "asthma", with medical professionals and basic scientists who provide critical clinical and mechanistic insights about the mechanisms underpinning the architecture of the heterogeneity, to deliver mechanism-based stratified treatments and prevention.
Papadopoulos NG, Custovic A, Cabana MD, et al., 2019, Pediatric asthma: An unmet need for more effective, focused treatments, Pediatric Allergy and Immunology, Vol: 30, Pages: 7-16, ISSN: 1399-3038
BackgroundDespite remarkable advances in our understanding of asthma, there are still several unmet needs associated with the management of pediatric asthma.MethodsA two‐day, face‐to‐face meeting was held in London, United Kingdom, on October 28 and 29, 2017, involving a group of international expert clinicians and scientists in asthma management to discuss the challenges and unmet needs that remain to be addressed in pediatric asthma.ResultsThese unmet needs include a lack of clinical efficacy and safety evidence, and limited availability of non‐steroid‐based alternative therapies in patients <6 years of age. An increased focus on children is needed in the context of clinical practice guidelines for asthma; current pediatric practice relies mostly on extrapolations from adult recommendations. Furthermore, no uniform definition of pediatric asthma exists, which hampers timely and robust diagnosis of the condition in affected patients.ConclusionsThere is a need for a uniform definition of pediatric asthma, clearly distinguishable from adult asthma. Furthermore, guidelines which provide specific treatment recommendations for the management of pediatric asthma are also needed. Clinical trials and real‐world evidence studies assessing anti‐immunoglobulin E (IgE) therapies and other monoclonal antibodies in children <6 years of age with asthma may provide further information regarding the most appropriate treatment options in these vulnerable patients. Early intervention with anti‐IgE and non‐steroid‐based alternative therapies may delay disease progression, leading to improved clinical outcomes.
Mahmoud O, Granell R, Tilling K, et al., 2018, Association of height growth in puberty with lung function: a longitudinal study, American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 1539-1548, ISSN: 1073-449X
RATIONALE: Puberty may influence lung function, but the precise role of pubertal height growth in lung development is unclear. OBJECTIVES: To examine associations of timing of puberty and peak velocity of pubertal height growth with lung function in adolescence and early-adulthood. METHODS: Longitudinal analyses of repeat height measurements from age 5-20 years for a British birth cohort with 4,772 males and 4,849 females were conducted to characterise height growth trajectories, and derive pubertal age and peak height velocity using the validated SuperImposition by Translation and Rotation (SITAR) model. Association of these estimates with pre-bronchodilator and post-bronchodilator spirometry measures: FEV1; FVC; FEV1/FVC; FEF25-75 at age 15 and 24 years were investigated using multivariable regression models adjusted for lung function at age 8 years, height and age at time of outcome measurements, and potential confounders. MEASUREMENTS AND MAIN RESULTS: Later pubertal age and greater peak velocity were associated with higher FEV1 and FVC at 24 years in both sexes. A 1-year advanced pubertal age was associated with a 263 ml higher FVC (95% confidence interval: 167, 360) for males (n=567), 100 ml (50, 150) for females (n=990). A 1-cm/year increase in peak velocity was associated with 145 ml (56, 234) and 50 ml (2, 99) increase in FVC for males and females respectively. No associations were found with FEV1/FVC. CONCLUSIONS: Later onset and greater peak velocity of height growth in puberty are associated with increased FEV1 and FVC in young adults but there was no evidence of dysanapsis of pubertal lung growth.
Fontanella S, Frainay C, Murray CS, et al., 2018, Machine learning to identify pairwise interactions between specific IgE antibodies and their association with asthma: A cross-sectional analysis within a population-based birth cohort, PLoS Medicine, Vol: 15, Pages: 1-22, ISSN: 1549-1277
BackgroundThe relationship between allergic sensitisation and asthma is complex; the data about the strength of this association are conflicting. We propose that the discrepancies arise in part because allergic sensitisation may not be a single entity (as considered conventionally) but a collection of several different classes of sensitisation. We hypothesise that pairings between immunoglobulin E (IgE) antibodies to individual allergenic molecules (components), rather than IgE responses to ‘informative’ molecules, are associated with increased risk of asthma.Methods and findingsIn a cross-sectional analysis among 461 children aged 11 years participating in a population-based birth cohort, we measured serum-specific IgE responses to 112 allergen components using a multiplex array (ImmunoCAP Immuno‑Solid phase Allergy Chip [ISAC]). We characterised sensitivity to 44 active components (specific immunoglobulin E [sIgE] > 0.30 units in at least 5% of children) among the 213 (46.2%) participants sensitised to at least one of these 44 components. We adopted several machine learning methodologies that offer a powerful framework to investigate the highly complex sIgE–asthma relationship. Firstly, we applied network analysis and hierarchical clustering (HC) to explore the connectivity structure of component-specific IgEs and identify clusters of component-specific sensitisation (‘component clusters’). Of the 44 components included in the model, 33 grouped in seven clusters (C.sIgE-1–7), and the remaining 11 formed singleton clusters. Cluster membership mapped closely to the structural homology of proteins and/or their biological source. Components in the pathogenesis-related (PR)-10 proteins cluster (C.sIgE-5) were central to the network and mediated connections between components from grass (C.sIgE-4), trees (C.sIgE-6), and profilin clusters (C.sIgE-7) with those in mite (C.sIgE-1), lipocalins (C.sIgE-3), and peanut clusters (C.sIgE-2)
Jolliffe DA, Greiller CL, Mein CA, et al., 2018, Vitamin D receptor genotype influences risk of upper respiratory infection, British Journal of Nutrition, Vol: 120, Pages: 891-900, ISSN: 1475-2662
SNP in the vitamin D receptor (VDR) gene is associated with risk of lower respiratory infections. The influence of genetic variation in the vitamin D pathway resulting in susceptibility to upper respiratory infections (URI) has not been investigated. We evaluated the influence of thirty-three SNP in eleven vitamin D pathway genes (DBP, DHCR7, RXRA, CYP2R1, CYP27B1, CYP24A1, CYP3A4, CYP27A1, LRP2, CUBN and VDR) resulting in URI risk in 725 adults in London, UK, using an additive model with adjustment for potential confounders and correction for multiple comparisons. Significant associations in this cohort were investigated in a validation cohort of 737 children in Manchester, UK. In all, three SNP in VDR (rs4334089, rs11568820 and rs7970314) and one SNP in CYP3A4 (rs2740574) were associated with risk of URI in the discovery cohort after adjusting for potential confounders and correcting for multiple comparisons (adjusted incidence rate ratio per additional minor allele ≥1·15, P for trend ≤0·030). This association was replicated for rs4334089 in the validation cohort (P for trend=0·048) but not for rs11568820, rs7970314 or rs2740574. Carriage of the minor allele of the rs4334089 SNP in VDR was associated with increased susceptibility to URI in children and adult cohorts in the United Kingdom.
Bousquet J, Arnavielhe S, Bedbrook A, et al., 2018, MASK 2017: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma multimorbidity using real-world-evidence, Clinical and Translational Allergy, Vol: 8, ISSN: 2045-7022
mHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential to profoundly affect healthcare and health outcomes. However, it may be disruptive and results achieved are not always reaching the goals. Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline using the best evidence-based approach to care pathways suited to real-life using mobile technology in allergic rhinitis (AR) and asthma multimorbidity. Patients largely use over-the-counter medications dispensed in pharmacies. Shared decision making centered around the patient and based on self-management should be the norm. Mobile Airways Sentinel networK (MASK), the Phase 3 ARIA initiative, is based on the freely available MASK app (the Allergy Diary, Android and iOS platforms). MASK is available in 16 languages and deployed in 23 countries. The present paper provides an overview of the methods used in MASK and the key results obtained to date. These include a novel phenotypic characterization of the patients, confirmation of the impact of allergic rhinitis on work productivity and treatment patterns in real life. Most patients appear to self-medicate, are often non-adherent and do not follow guidelines. Moreover, the Allergy Diary is able to distinguish between AR medications. The potential usefulness of MASK will be further explored by POLLAR (Impact of Air Pollution on Asthma and Rhinitis), a new Horizon 2020 project using the Allergy Diary.
Tang HHF, Teo SM, Belgrave DCM, et al., 2018, Trajectories of childhood immune development and respiratory health relevant to asthma and allergy, eLife, Vol: 7, ISSN: 2050-084X
Events in early life contribute to subsequent risk of asthma; however, the causes andtrajectories of childhood wheeze are heterogeneous and do not always result in asthma. Similarly,not all atopic individuals develop wheeze, and vice versa. The reasons for these differences areunclear. Using unsupervised model-based cluster analysis, we identified latent clusters within aprospective birth cohort with deep immunological and respiratory phenotyping. We characterisedeach cluster in terms of immunological profile and disease risk, and replicated our results inexternal cohorts from the UK and USA. We discovered three distinct trajectories, one of which is ahigh-risk ‘atopic’ cluster with increased propensity for allergic diseases throughout childhood.Atopy contributes varyingly to later wheeze depending on cluster membership. Our findingsdemonstrate the utility of unsupervised analysis in elucidating heterogeneity in asthmapathogenesis and provide a foundation for improving management and prevention of childhoodasthma.
Howard R, Belgrave D, Papastamoulis P, et al., 2018, Evolution of IgE responses to multiple allergen components throughout childhood, Journal of Allergy and Clinical Immunology, Vol: 142, Pages: 1322-1330, ISSN: 0091-6749
BACKGROUND: There is a paucity of information about longitudinal patterns of IgE responses to allergenic proteins (components) from multiple sources. OBJECTIVE: To investigate temporal patterns of component-specific IgE responses from infancy to adolescence, and their relationship with allergic diseases. METHODS: In a population-based birth cohort, we measured IgE to 112 components at 6 follow-ups during childhood. We used a Bayesian method to discover cross-sectional sensitization patterns and their longitudinal trajectories, and related these patterns to asthma and rhinitis in adolescence. RESULTS: We identified one sensitization cluster at age one, 3 at age three, 4 at ages five and eight, 5 at age 11, and six at age 16 years. "Broad" cluster was the only cluster present at every follow-up, comprising of components from multiple sources. "Dust mite" cluster formed at age three and remained unchanged to adolescence. At age three, a single-component "Grass" cluster emerged, which at age five absorbed additional grass components and Fel d 1 to form the "Grass/cat" cluster. Two new clusters formed at age 11: "Cat" cluster and "PR-10/profilin" (which divided at age 16 into "PR-10" and "Profilin"). The strongest contemporaneous associate of asthma at age 16 years was sensitization to "Dust mite" cluster (OR [95% CI]: 2.6 [1.2-6.1], P<0.05), but the strongest early-life predictor of subsequent asthma was sensitization to "Grass/cat" cluster (3.5 [1.6-7.4], P<0.01). CONCLUSIONS: We describe the architecture of the evolution of IgE responses to multiple allergen components throughout childhood, which may facilitate development of better diagnostic and prognostic biomarkers for allergic diseases.
Oksel C, Haider S, Fontanella S, et al., 2018, Classification of Pediatric Asthma: From Phenotype Discovery to Clinical Practice, FRONTIERS IN PEDIATRICS, Vol: 6, ISSN: 2296-2360
Advances in big data analytics have created an opportunity for a step change in unraveling mechanisms underlying the development of complex diseases such as asthma, providing valuable insights that drive better diagnostic decision-making in clinical practice, and opening up paths to individualized treatment plans. However, translating findings from data-driven analyses into meaningful insights and actionable solutions requires approaches and tools which move beyond mining and patterning longitudinal data. The purpose of this review is to summarize recent advances in phenotyping of asthma, to discuss key hurdles currently hampering the translation of phenotypic variation into mechanistic insights and clinical setting, and to suggest potential solutions that may address these limitations and accelerate moving discoveries into practice. In order to advance the field of phenotypic discovery, greater focus should be placed on investigating the extent of within-phenotype variation. We advocate a more cautious modeling approach by “supervising” the findings to delineate more precisely the characteristics of the individual trajectories assigned to each phenotype. Furthermore, it is important to employ different methods within a study to compare the stability of derived phenotypes, and to assess the immutability of individual assignments to phenotypes. If we are to make a step change toward precision (stratified or personalized) medicine and capitalize on the available big data assets, we have to develop genuine cross-disciplinary collaborations, wherein data scientists who turn data into information using algorithms and machine learning, team up with medical professionals who provide deep insights on specific subjects from a clinical perspective.
Nakamura T, Haider S, Custovic A, 2018, Understanding the heterogeneity of atopic dermatitis in childhood, Current Allergy and Clinical Immunology, Vol: 31, Pages: 124-130, ISSN: 1609-3607
No universally accepted definition of atopic dermatitis (AD) exists in epidemiological studies, and no objective test that can unequivocally confirm the diagnosis. The heterogeneity of AD is now broadly accepted, but there is no consensus on what the best approach is to disaggregate this complex condition, and how best to identify different AD endotypes. One approach is to use data-driven techniques to uncover the unobserved (ie latent) structure in the data set(s) to identify homogenous groups of individuals in the heterogeneous AD population. Since AD usually starts early in life, and its clinical features may progress, remit or relapse over time, analyses assessing trajectories related to their presence or absence over time may help us understand AD heterogeneity. However, studies that used unsupervised methods such as latent class analysis to discover AD ‘phenotypes’ have reported inconsistent findings. If we are to use data-driven analyses to uncover patterns of AD with different long-term consequences, then the discovered ‘phenotypes’ must be consistent and reproducible. We therefore need to understand the reasons for the inconsistencies between different studies. We suggest that in addition to capturing a simple presence or absence of symptoms, more detailed clinical features, such as the severity and medication used, should be assessed in longitudinal studies. Ultimately, the objective is to move from ‘deep phenotyping’ to more informative genetic studies, followed by functional studies to understand mechanisms. In this way, the identification of novel therapeutic targets could be facilitated.
Waage J, Standl M, Curtin JA, et al., 2018, Author correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis, Nature Genetics, ISSN: 1061-4036
In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.
Bahri R, Custovic A, Korosec P, et al., 2018, Mast cell activation test in the diagnosis of allergic disease and anaphylaxis, Journal of Allergy and Clinical Immunology, Vol: 142, Pages: 485-496.e16, ISSN: 0091-6749
BackgroundFood allergy is an increasing public health issue and the most common cause of life-threatening anaphylactic reactions. Conventional allergy tests assess for the presence of allergen-specific IgE, significantly overestimating the rate of true clinical allergy and resulting in overdiagnosis and adverse effect on health-related quality of life.ObjectiveTo undertake initial validation and assessment of a novel diagnostic tool, we used the mast cell activation test (MAT).MethodsPrimary human blood-derived mast cells (MCs) were generated from peripheral blood precursors, sensitized with patients' sera, and then incubated with allergen. MC degranulation was assessed by means of flow cytometry and mediator release. We compared the diagnostic performance of MATs with that of existing diagnostic tools to assess in a cohort of peanut-sensitized subjects undergoing double-blind, placebo-controlled challenge.ResultsHuman blood-derived MCs sensitized with sera from patients with peanut, grass pollen, and Hymenoptera (wasp venom) allergy demonstrated allergen-specific and dose-dependent degranulation, as determined based on both expression of surface activation markers (CD63 and CD107a) and functional assays (prostaglandin D2 and β-hexosaminidase release). In this cohort of peanut-sensitized subjects, the MAT was found to have superior discrimination performance compared with other testing modalities, including component-resolved diagnostics and basophil activation tests. Using functional principle component analysis, we identified 5 clusters or patterns of reactivity in the resulting dose-response curves, which at preliminary analysis corresponded to the reaction phenotypes seen at challenge.ConclusionThe MAT is a robust tool that can confer superior diagnostic performance compared with existing allergy diagnostics and might be useful to explore differences in effector cell function between basophils and MCs during allergic reactions.
Waage J, Standl M, Curtin JA, et al., 2018, Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis, Nature Genetics, Vol: 50, Pages: 1072-1080, ISSN: 1061-4036
Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, and with increasing incidence in westernized countries.1,2 To elucidate the genetic architecture and understand disease mechanisms of allergic rhinitis, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implied genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants of importance for antigen binding. We further performed GWASs of allergic sensitization against inhalant allergens and non-allergic rhinitis suggesting shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.
Samreth D, Arnavielhe S, Ingenrieth F, et al., 2018, Geolocation with respect to personal privacy for the Allergy Diary app - a MASK study, World Allergy Organization Journal, Vol: 11, ISSN: 1939-4551
Background: Collecting data on the localization of users is a key issue for the MASK (Mobile Airways Sentinel networK: the Allergy Diary) App. Data anonymization is a method of sanitization for privacy. The European Commission's Article 29 Working Party stated that geolocation information is personal data.To assess geolocation using the MASK method and to compare two anonymization methods in the MASK database to find an optimal privacy method. Methods: Geolocation was studied for all people who used the Allergy Diary App from December 2015 to November 2017 and who reported medical outcomes. Two different anonymization methods have been evaluated: Noise addition (randomization) and k-anonymity (generalization). Results: Ninety-three thousand one hundred and sixteen days of VAS were collected from 8535 users and 54,500 (58.5%) were geolocalized, corresponding to 5428 users. Noise addition was found to be less accurate than k-anonymity using MASK data to protect the users' life privacy. Discussion: k-anonymity is an acceptable method for the anonymization of MASK data and results can be used for other databases.
Belgrave DCM, Granell R, Turner SW, et al., 2018, Lung function trajectories from pre-school age to adulthood and their associations with early life factors: a retrospective analysis of three population-based birth cohort studies, Lancet Respiratory Medicine, Vol: 6, Pages: 526-534, ISSN: 2213-2600
BackgroundMaximal lung function in early adulthood is an important determinant of mortality and COPD. We investigated whether distinct trajectories of lung function are present during childhood and whether these extend to adulthood and infancy.MethodsTo ascertain trajectories of FEV1, we studied two population-based birth cohorts (MAAS and ALSPAC) with repeat spirometry from childhood into early adulthood (1046 participants from 5–16 years and 1390 participants from 8–24 years). We used a third cohort (PIAF) with repeat lung function measures in infancy (V'maxFRC) and childhood (FEV1; 196 participants from 1 month to 18 years of age) to investigate whether these childhood trajectories extend from early life. We identified trajectories using latent profile modelling. We created an allele score to investigate genetic associations of trajectories, and constructed a multivariable model to identify their early-life predictors.FindingsWe identified four childhood FEV1 trajectories: persistently high, normal, below average, and persistently low. The persistently low trajectory (129 [5%] of 2436 participants) was associated with persistent wheezing and asthma throughout follow-up. In genetic analysis, compared with the normal trajectory, the pooled relative risk ratio per allele was 0·96 (95% CI 0·92–1·01; p=0·13) for persistently high, 1·01 (0·99–1·02; p=0·49) for below average, and 1·05 (0·98–1·13; p=0·13) for persistently low. Most children in the low V'maxFRC trajectory in infancy did not progress to the low FEV1 trajectory in childhood. Early-life factors associated with the persistently low trajectory included recurrent wheeze with severe wheezing exacerbations, early allergic sensitisation, and tobacco smoke exposure.InterpretationReduction of childhood smoke exposure and minimisation of the risk of early-life sensitisation and wheezing exacerbations migh
Schwarze J, Openshaw P, Jha A, et al., 2018, Influenza burden, prevention and treatment in asthma - a scoping review by the EAACI Influenza in Asthma Task Force, Allergy, Vol: 73, Pages: 1151-1181, ISSN: 0105-4538
To address uncertainties in the prevention and management of influenza in people with asthma, we performed a scoping review of the published literature on influenza burden; current vaccine recommendations; vaccination coverage; immunogenicity, efficacy, effectiveness and safety of influenza vaccines; and the benefits of antiviral drugs in people with asthma. We found significant variation in the reported rates of influenza detection in individuals with acute asthma exacerbations making it unclear to what degree influenza causes exacerbations of underlying asthma. The strongest evidence of an association was seen in studies of children. Countries in the European Union currently recommend influenza vaccination of adults with asthma; however, coverage varied between regions. Coverage was lower among children with asthma. Limited data suggest that good seroprotection and seroconversion can be achieved in both children and adults with asthma and that vaccination confers a degree of protection against influenza illness and asthma related morbidity to children with asthma. There were insufficient data to determine efficacy in adults. Overall, influenza vaccines appeared to be safe for people with asthma. We identify knowledge gaps and make recommendations on future research needs in relation to influenza in patients with asthma. This article is protected by copyright. All rights reserved.
Haider S, Custovic A, 2018, Big data and multiomics for asthma cure: the case for, 17th International Congress of Pediatric Pulmonology, Publisher: Wiley, Pages: S11-S12, ISSN: 1099-0496
Oksel C, Custovic A, 2018, Allergy for the respiratory pediatrician: which tests and interventions are useful?, 17th International Congress of Pediatric Pulmonology, Publisher: Wiley, Pages: S56-S57, ISSN: 1099-0496
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.
Custovic A, Belgrave D, Lin L, et al., 2018, Cytokine responses to rhinovirus and development of asthma, allergic sensitization and respiratory infections during childhood, American Journal of Respiratory and Critical Care Medicine, Vol: 197, Pages: 1265-1274, ISSN: 1073-449X
BACKGROUND: Immunophenotypes of anti-viral responses, and their relationship with asthma, allergy and lower respiratory tract infections (LRTIs) are poorly understood. We characterized multiple cytokine responses of peripheral-blood mononuclear cells to rhinovirus stimulation, and their relationship with clinical outcomes. METHODS: In a population-based birth cohort, we measured 28 cytokines post-stimulation with rhinovirus-16 in 307 children aged 11 years. We used machine learning to identify patterns of cytokine responses, and related these patterns to clinical outcomes using longitudinal models. We also ascertained phytohaemagglutinin-induced TH2-cytokine responses [PHA-TH2]. RESULTS: We identified six clusters of children based on their rhinovirus-16 responses, which were differentiated by the expression of four cytokine/chemokine groups: interferon-related-(IFN); pro-inflammatory-(Inflam); TH2-chemokine-(TH2-chem); regulatory-(Reg). Clusters differed in their clinical characteristics. Children with IFNmodInflamhighestTH2-chemhighestReghighestrhinovirus-16-induced pattern had PHA-TH2lowresponse, and a very low asthma risk (OR:0.08 [95%CI 0.01-0.81], P=0.03). Two clusters had high risk of asthma and allergic sensitization, but with different trajectories from infancy to adolescence. The IFNlowestInflamhighTH2-chemlowRegmodcluster exhibited PHA-TH2lowestresponse, and was associated with early-onset asthma and sensitization, and the highest risk of asthma exacerbations (1.37 [1.07-1.76], P=0.014) and LRTI hospitalizations (2.40 [1.26-4.58], P=0.008) throughout childhood. In contrast, cluster with IFNhighestInflammodTH2-chemmodReghighrhinovirus-16-cytokine pattern was characterized by PHA-TH2highestresponse, and a low prevalence of asthma/sensitization in infancy which increased sharply to become the highest among all clusters by adolescence (but with low risk of asthma exacerbations). CONCLUSIONS: Early-onset troublesome asthma with early-life sensitization, later-
Korošec P, Gibbs BF, Rijavec M, et al., 2018, Important and specific role for basophils in acute allergic reactions, Clinical and Experimental Allergy, Vol: 48, Pages: 502-512, ISSN: 0954-7894
IgE‐mediated allergic reactions involve the activation of effector cells, predominantly through the high‐affinity IgE receptor (FcεRI) on mast cells and basophils. Although the mast cell is considered the major effector cell during acute allergic reactions, more recent studies indicate a potentially important and specific role for basophils and their migration which occurs rapidly upon allergen challenge in humans undergoing anaphylaxis. We review the evidence for a role of basophils in contributing to clinical symptoms of anaphylaxis and discuss the possibility that basophil trafficking during anaphylaxis might be a pathogenic (to target organs) or protective (preventing degranulation in circulation) response. Finally, we examine the potential role of basophils in asthma exacerbations. Understanding the factors that regulate basophil trafficking and activation might lead to new diagnostic and therapeutic strategies in anaphylaxis and asthma.
Gore C, Gore RB, Fontanella S, et al., 2018, Temperature-controlled laminar airflow (TLA) device in the treatment of children with severe atopic eczema: Open-label, proof-of-concept study, Clinical and Experimental Allergy, Vol: 48, Pages: 594-603, ISSN: 0954-7894
BACKGROUND: Children with severe, persistent atopic eczema (AE) have limited treatment options, often requiring systemic immunosuppression. OBJECTIVE: To evaluate the effect of the temperature-controlled laminar airflow (TLA) treatment in children/adolescents with severe AE. METHODS: We recruited 15 children aged 2-16 years with longstanding, severe AE and sensitization to ≥1 perennial inhalant allergen. Run-in period of 6-10 weeks (3 visits), was followed by 12-month treatment with overnight TLA (Airsonett® , Sweden). The primary outcome was eczema severity (SCORAD-Index and Investigator Global Assessment-IGA). Secondary outcomes included child/family dermatology quality of life and family impact questionnaires (CDQLI, FDQLI, DFI), patient oriented eczema measure (POEM), medication requirements, and healthcare contacts. The study is registered as ISRCTN65865773. RESULTS: There was a significant reduction in AE severity ascertained by SCORAD and IGA during the 12-month intervention period (P<0.001). SCORAD was reduced from a median of 34.9 [interquartile range 28.75-45.15] at baseline to 17.2 [12.95-32.3] at the final visit, and IGA improved significantly from 4 [3-4] to 2 [1-3]. We observed a significant improvement in FDQLI (16.0 [12.25-19.0] to 12 [8-18], P=0.023) and DFI (P=0.011), but not CDQLI or POEM. Compared to 6-month period prior to enrollment, there was a significant reduction at six months after the start of the intervention in potent topical corticosteroids (P=0.033). The exploratory cluster analysis revealed two strongly divergent patterns of response, with 9 patients classified as responders, and 6 as non-responders. CONCLUSION AND CLINICAL RELEVANCE: Addition of TLA device to standard pharmacological treatment may be an effective add-on to the management of difficult-to-control AE. This article is protected by copyright. All rights reserved.
Custovic A, Oksel C, 2018, Development of allergic sensitization and its relevance to paediatric asthma, Current Opinion in Allergy and Clinical Immunology, Vol: 18, Pages: 109-116, ISSN: 1473-6322
Purpose of review: The purpose of this review is to summarize the recent evidence on the distinct atopic phenotypes and their relationship with childhood asthma. We start by considering definitions and phenotypic classification of atopy and then review evidence on its association with asthma in children.Recent findings: It is now well recognised that both asthma and atopy are complex entities encompassing various different sub-groups that also differ in the way they interconnect. The lack of gold standards for diagnostic markers of atopy and asthma further adds to the existing complexity over diagnostic accuracy and definitions. Although recent statistical phenotyping studies contributed significantly to our understanding of these heterogeneous disorders, translating these findings into meaningful information and effective therapies requires further work on understanding underpinning biological mechanisms. Summary: The disaggregation of allergic sensitization may help predict how the allergic disease is likely to progress. One of the important questions is how best to incorporate tests for the assessment of allergic sensitisation into diagnostic algorithms for asthma, both in terms of confirming asthma diagnosis, and the assessment of future risk.
Ziyab AH, Hankinson J, Ewart S, et al., 2018, Epistasis between FLG and IL4R genes on the risk of allergic sensitization: results from two population-based birth cohort studies, Scientific Reports, Vol: 8, ISSN: 2045-2322
Immune-specifc genes as well as genes responsible for the formation and integrity of the epidermalbarrier have been implicated in the pathogeneses of allergic sensitization. This study sought todetermine whether an epistatic efect (gene-gene interaction) between genetic variants withininterleukin 4 receptor (IL4R) and flaggrin (FLG) genes predispose to the development of allergicsensitization. Data from two birth cohort studies were analyzed, namely the Isle of Wight (IOW;n=1,456) and the Manchester Asthma and Allergy Study (MAAS; n=1,058). In the IOW study, oneinteraction term (IL4R rs3024676×FLG variants) showed statistical signifcance (interaction term:P=0.003). To illustrate the observed epistasis, stratifed analyses were performed, which showed thatFLG variants were associated with allergic sensitization only among IL4R rs3024676 homozygotes (OR,1.97; 95% CI, 1.27–3.05; P=0.003). In contrast, FLG variants efect was masked among IL4R rs3024676heterozygotes (OR, 0.53; 95% CI, 0.22–1.32; P=0.175). Similar results were demonstrated in the MAASstudy. Epistasis between immune (IL4R) and skin (FLG) regulatory genes exist in the pathogenesis ofallergic sensitization. Hence, genetic susceptibility towards defective epidermal barrier and deviatedimmune responses could work together in the development of allergic sensitization.
Wise SK, Lin SY, Toskala E, et al., 2018, International consensus statement on allergy and rhinology: allergic rhinitis., International Forum of Allergy and Rhinology, Vol: 8, Pages: 108-352, ISSN: 2042-6976
BACKGROUND: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR). METHODS: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. RESULTS: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR. CONCLUSION: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding.
Valovirta E, Petersen TH, Piotrowska T, et al., 2018, Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 141, Pages: 529-538.e13, ISSN: 0091-6749
BackgroundAllergy immunotherapy targets the immunological cause of allergic rhinoconjunctivitis and allergic asthma and has the potential to alter the natural course of allergic disease.ObjectiveThe primary objective was to investigate the effect of the SQ grass sublingual immunotherapy tablet compared with placebo on the risk of developing asthma.MethodsA total of 812 children (5-12 years), with a clinically relevant history of grass pollen allergic rhinoconjunctivitis and no medical history or signs of asthma, were included in the randomized, double-blind, placebo-controlled trial, comprising 3 years of treatment and 2 years of follow-up.ResultsThere was no difference in time to onset of asthma, defined by prespecified asthma criteria relying on documented reversible impairment of lung function (primary endpoint). Treatment with the SQ grass sublingual immunotherapy tablet significantly reduced the risk of experiencing asthma symptoms or using asthma medication at the end of trial (odds ratio = 0.66, P < .036), during the 2-year posttreatment follow-up, and during the entire 5-year trial period. Also, grass allergic rhinoconjunctivitis symptoms were 22% to 30% reduced (P < .005 for all 5 years). At the end of the trial, the use of allergic rhinoconjunctivitis pharmacotherapy was significantly less (27% relative difference to placebo, P < .001). Total IgE, grass pollen–specific IgE, and skin prick test reactivity to grass pollen were all reduced compared to placebo.ConclusionsTreatment with the SQ grass sublingual immunotherapy tablet reduced the risk of experiencing asthma symptoms and using asthma medication, and had a positive, long-term clinical effect on rhinoconjunctivitis symptoms and medication use but did not show an effect on the time to onset of asthma.
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