Publications by authors named "Angela Simpson"

148 Publications

Diagnosing asthma with and without aerosol generating procedures.

J Allergy Clin Immunol Pract 2021 Jul 21. Epub 2021 Jul 21.

Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Infection, Immunity & Respiratory Medicine, The University of Manchester, Manchester Academic Health Science Centre; NIHR Manchester Biomedical Research Unit and Manchester University NHS Foundation Trust. Electronic address:

Background: Asthma diagnostic guidelines require procedures with aerosol generating potential (AGPs) to guide decision-making. Restricted access to AGPs poses significant challenges in primary care and resource-poor countries, further amplified during the COVID-19 pandemic.

Objective: To establish an approach to asthma diagnosis that does not require AGPs.

Method: Symptomatic yet untreated (beyond as-required bronchodilator use) adults with clinician-suspected asthma and maximum 10 pack-year smoking history were recruited. Clinical history, physical examination, spirometry with bronchodilator reversibility, home peak flow monitoring and bronchial challenges were performed, and fractional exhaled nitric oxide and serum eosinophils measured. Tests were then repeated following treatment with inhaled corticosteroids before an asthma diagnosis was confirmed or refuted by an expert panel.

Results: 65 adults [mean (SD) age: 34.8 (12.2) years] were recruited. Five were excluded as "unclassifiable", due to borderline results or missing data. Of the remainder 36 were diagnosed with asthma and 24 were not. Using data from non-AGPs only (wheeze on auscultation and blood eosinophilia) and home peak flow variability, a "rule-in" diagnostic model provided comparable discriminative ability to the application of established guidelines. Clinical suspicion of asthma together with at least one positive non-AGP test provided a sensitivity of 55%, specificity 100%, positive predictive value 100% and negative predictive value 60%. Application of this model reduced the need for spirometry-based tests by one-third.

Conclusion: The proposed diagnostic algorithm may be clinically useful in "ruling-in" asthma in adults when access to AGPs is limited. This algorithm is not suitable for those with low clinical probability, with a significant smoking history, or where alternative diagnoses are more likely. This pragmatic approach to asthma diagnosis merits prospective validation.
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http://dx.doi.org/10.1016/j.jaip.2021.07.006DOI Listing
July 2021

The impact of a baked muffin matrix on the bioaccessibility and IgE reactivity of egg and peanut allergens.

Food Chem 2021 Nov 20;362:129879. Epub 2021 Apr 20.

Division of Infection, Immunity and Respiratory Medicine, Manchester Academic Health Sciences Centre, Manchester Institute of Biotechnology, University of Manchester, Manchester, UK. Electronic address:

Baked matrices, such as muffin, may help to promote tolerance to food allergens by modifying allergen structure, digestibility, and capacity to stimulate the immune responses. However, the impact of the muffin matrix on the bioaccessibility of allergens in the gastrointestinal tract is not well understood. Muffin containing egg and peanut was subjected to in vitro oral-gastro-duodenal digestion. During gastric digestion, the majority of the egg allergen Gal d 2 and the peanut allergens Ara h 1 and 3 were not bioaccessible. Subsequent duodenal digestion increased allergen bioaccessibility with Gal d 2 and the peanut allergen Ara h 2 proving highly resistant to digestion. The IgE reactivity of bioaccessible peanut allergens was retained to a greater extent than that of egg allergens after oral-gastric digestion. The starch and gluten-rich muffin matrix modifies allergen bioaccessiblity in a manner more similar to baked matrices such as bread, than low water activity matrices such as cookies.
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http://dx.doi.org/10.1016/j.foodchem.2021.129879DOI Listing
November 2021

Childhood CCL18, CXCL10 and CXCL11 levels differentially relate to and predict allergy development.

Pediatr Allergy Immunol 2021 Jun 7. Epub 2021 Jun 7.

Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.

Background: Chemokines are important mediators in immune cell recruitment, contributing to allergy development. However, extensive studies of chemokines in the circulation in relation to the presence and development of allergic diseases remain scarce. Our aim was to investigate associations of circulating allergy-related chemokines with the development of asthma and sensitization cross-sectionally and longitudinally in a population-based cohort.

Methods: The chemokines CCL17, CCL22, CXCL10, CXCL11 and CCL18 were measured in plasma samples from children in the Manchester Asthma and Allergy Study. Samples were available from cord blood at birth (n = 376), age 1 (n = 195) and age 8 (n = 334). Cross-sectional and longitudinal association analyses were performed in relation to asthma and allergic sensitization, as well as allergic phenotype clusters previously derived using machine learning in the same study population.

Results: In children with asthma and/or allergic sensitization, CCL18 levels were consistently elevated at 1 and/or 8 years of ages. In a longitudinal model including information on asthma from 4 time points (5, 8, 11 and 16 years of ages), we observed a significant association between increasing CCL18 levels at age 1 and a higher risk of asthma from early school age to adolescence (OR = 2.9, 95% CI 1.1-7.6, p = .028). We observed similar associations in longitudinal models for allergic sensitization. Asthma later in life was preceded by increased CXCL10 levels after birth and decreased CXCL11 levels at birth.

Conclusion: Elevated CCL18 levels throughout childhood precede the development of asthma and allergic sensitization. The Th1-associated chemokines CXCL10 and CXCL11 also associated with the development of both outcomes, with differential temporal effects.
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http://dx.doi.org/10.1111/pai.13574DOI Listing
June 2021

Genetics of Asthma and Allergic Diseases.

Handb Exp Pharmacol 2021 Jun 4. Epub 2021 Jun 4.

National Heart and Lung Institute, Imperial College London, London, UK.

Asthma genes have been identified through a range of approaches, from candidate gene association studies and family-based genome-wide linkage analyses to genome-wide association studies (GWAS). The first GWAS of asthma, reported in 2007, identified multiple markers on chromosome 17q21 as associates of the childhood-onset asthma. This remains the best replicated asthma locus to date. However, notwithstanding undeniable successes, genetic studies have produced relatively heterogeneous results with limited replication, and despite considerable promise, genetics of asthma and allergy has, so far, had limited impact on patient care, our understanding of disease mechanisms, and development of novel therapeutic targets. The paucity of precise replication in genetic studies of asthma is partly explained by the existence of numerous gene-environment interactions. Another important issue which is often overlooked is that of time of the assessment of the primary outcome(s) and the relevant environmental exposures. Most large GWASs use the broadest possible definition of asthma to increase the sample size, but the unwanted consequence of this is increased phenotypic heterogeneity, which dilutes effect sizes. One way of addressing this is to precisely define disease subtypes (e.g. by applying novel mathematical approaches to rich phenotypic data) and use these latent subtypes in genetic studies.
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http://dx.doi.org/10.1007/164_2021_484DOI Listing
June 2021

An Emotion Regulation and Impulse Control (ERIC) Intervention for Vulnerable Young People: A Multi-Sectoral Pilot Study.

Front Psychol 2021 1;12:554100. Epub 2021 Apr 1.

School of Psychology, Deakin University, Geelong, VIC, Australia.

There is a demonstrated link between the mental health and substance use comorbidities experienced by young adults, however the vast majority of psychological interventions are disorder specific. Novel psychological approaches that adequately acknowledge the psychosocial complexity and transdiagnostic needs of vulnerable young people are urgently needed. A modular skills-based program for emotion regulation and impulse control (ERIC) addresses this gap. The current one armed open trial was designed to evaluate the impact that 12 weeks exposure to ERIC alongside usual care had on young people's ability to regulate emotions, as well as examine potential moderating mechanisms. Seventy nine young people (50.6% male; = 19.30; = 2.94) were enrolled to the 12 week intervention period. Twenty one practitioners from youth and community health services delivered relevant ERIC modules adjunct to usual care. Linear mixed effects regression (with random intercept) was used to examine change over time across the primary outcome of emotion dysregulation and secondary outcomes of depression, anxiety, stress, experiential avoidance and mindfulness. Moderation analyses were conducted to test whether the magnitude of change in emotion dysregulation moderated change over time in secondary outcomes. Analyses revealed significant improvement in the primary outcome of emotion dysregulation with a moderate effect size (Mean Change = -10.24, 95% CI (-14.41, -6.06; Cohen's d = -0.53), in addition to decreases in the secondary outcomes of depression, anxiety, stress and experiential avoidance. No improvements in mindfulness were reported. Moderation analyses revealed that the residualised change over time in emotion dysregulation moderated the change over time in symptoms of distress, depression, anxiety, stress, experiential avoidance, and mindfulness. Reductions in the severity of emotion dysregulation, depression, anxiety, stress and experiential avoidance are promising, and were evident despite the complexity of the participants and the diversity of the service setting. The improvements found in each outcome were only observed for those young people whose emotion regulation also improved, providing preliminary evidence for the role of emotion regulation as a key treatment target in this population.
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http://dx.doi.org/10.3389/fpsyg.2021.554100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047628PMC
April 2021

Alterations in T and B cell function persist in convalescent COVID-19 patients.

Med (N Y) 2021 Jun 31;2(6):720-735.e4. Epub 2021 Mar 31.

Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity, and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester Academic Health Science Centre, Room 2.16, Core Technology Facility, 46 Grafton Street, Manchester, M13 9PL, UK.

Background: Emerging studies indicate that some coronavirus disease 2019 (COVID-19) patients suffer from persistent symptoms, including breathlessness and chronic fatigue; however, the long-term immune response in these patients presently remains ill-defined.

Methods: Here, we describe the phenotypic and functional characteristics of B and T cells in hospitalized COVID-19 patients during acute disease and at 3-6 months of convalescence.

Findings: We report that the alterations in B cell subsets observed in acute COVID-19 patients were largely recovered in convalescent patients. In contrast, T cells from convalescent patients displayed continued alterations with persistence of a cytotoxic program evident in CD8 T cells as well as elevated production of type 1 cytokines and interleukin-17 (IL-17). Interestingly, B cells from patients with acute COVID-19 displayed an IL-6/IL-10 cytokine imbalance in response to Toll-like receptor activation, skewed toward a pro-inflammatory phenotype. Whereas the frequency of IL-6 B cells was restored in convalescent patients irrespective of clinical outcome, the recovery of IL-10 B cells was associated with the resolution of lung pathology.

Conclusions: Our data detail lymphocyte alterations in previously hospitalized COVID-19 patients up to 6 months following hospital discharge and identify 3 subgroups of convalescent patients based on distinct lymphocyte phenotypes, with 1 subgroup associated with poorer clinical outcome. We propose that alterations in B and T cell function following hospitalization with COVID-19 could affect longer-term immunity and contribute to some persistent symptoms observed in convalescent COVID-19 patients.

Funding: Provided by UKRI, Lister Institute of Preventative Medicine, the Wellcome Trust, The Kennedy Trust for Rheumatology Research, and 3M Global Giving.
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http://dx.doi.org/10.1016/j.medj.2021.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011689PMC
June 2021

Asthma diagnosis: into the fourth dimension.

Thorax 2021 06 27;76(6):624-631. Epub 2021 Jan 27.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

Asthma is the most common chronic respiratory disease in the UK; however, the misdiagnosis rate is substantial. The lack of consistency in national guidelines and the paucity of data on the performance of diagnostic algorithms compound the challenges in asthma diagnosis. Asthma is a highly rhythmic disease, characterised by diurnal variability in clinical symptoms and pathogenesis. Asthma also varies day to day, seasonally and from year to year. As much as it is a hallmark for asthma, this variability also poses significant challenges to asthma diagnosis. Almost all established asthma diagnostic tools demonstrate diurnal variation, yet few are performed with standardised timing of measurements. The dichotomous interpretation of diagnostic outcomes using fixed cut-off values may further limit the accuracy of the tests, particularly when diurnal variability straddles cut-off values within a day, and careful interpretation beyond the 'positive' and 'negative' outcome is needed. The day-to-day and more long-term variations are less predictable and it is unclear whether performing asthma diagnostic tests during asymptomatic periods may influence diagnostic sensitivities. With the evolution of asthma diagnostic tools, home monitoring and digital apps, novel strategies are needed to bridge these gaps in knowledge, and circadian variability should be considered during the standardisation process. This review summarises the biological mechanisms of circadian rhythms in asthma and highlights novel data on the significance of time (the fourth dimension) in asthma diagnosis.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223645PMC
June 2021

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

Neurturin regulates the lung-resident macrophage inflammatory response to viral infection.

Life Sci Alliance 2020 12 5;3(12). Epub 2020 Oct 5.

The Lydia Becker Institute for Immunology and Inflammation, The University of Manchester, Manchester, UK

Lung-resident macrophages are crucial to the maintenance of health and in the defence against lower respiratory tract infections. Macrophages adapt to local environmental cues that drive their appropriate function; however, this is often dysregulated in many inflammatory lung pathologies. In mucosal tissues, neuro-immune interactions enable quick and efficient inflammatory responses to pathogenic threats. Although a number of factors that influence the antimicrobial response of lung macrophages are known, the role of neuronal factors is less well understood. Here, we show an intricate circuit involving the neurotrophic factor, neurturin (NRTN) on human lung macrophages that dampens pro-inflammatory cytokine release and modulates the type of matrix metalloproteinases produced in response to viral stimuli. This circuit involves type 1 interferon-induced up-regulation of RET that when combined with the glial cell line-derived neurotrophic factor (GDNF) receptor α2 (GFRα2) allows binding to epithelial-derived NRTN. Our research highlights a non-neuronal immunomodulatory role for NRTN and a novel process leading to a specific antimicrobial immune response by human lung-resident macrophages.
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http://dx.doi.org/10.26508/lsa.202000780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556752PMC
December 2020

Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19.

Sci Immunol 2020 09;5(51)

Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity & Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Room 2.16, Core Technology Facility, 46 Grafton Street, Manchester, M13 9PL, UK.

COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells (PBMCs) of hospitalized patients during the peak of the COVID-19 pandemic in the UK. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1 and IP-10, and most strikingly, modulation of CD14 monocyte phenotype and function. Modified features of CD14 monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, as well as enhanced expression of the cell cycle marker K-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of COVID-19 patients and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission suggesting immune-modulating therapies would be most beneficial at early timepoints.
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http://dx.doi.org/10.1126/sciimmunol.abd6197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857390PMC
September 2020

Phenotypic and functional translation of IL33 genetics in asthma.

J Allergy Clin Immunol 2021 01 19;147(1):144-157. Epub 2020 May 19.

Department of Health Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Leicester, United Kingdom.

Background: Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown.

Objective: This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function.

Methods: Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs.

Results: We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV, FEV/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function.

Conclusions: We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.
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http://dx.doi.org/10.1016/j.jaci.2020.04.051DOI Listing
January 2021

The Effect of the Food Matrix on the In Vitro Bio-Accessibility and IgE Reactivity of Peanut Allergens.

Mol Nutr Food Res 2020 07 29;64(14):e1901093. Epub 2020 Jun 29.

School of Biological Sciences, Manchester Institute of Biotechnology, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, M1 7DN, UK.

Scope: Factors such as food processing, the food matrix, and antacid medication may affect the bio-accessibility of proteins in the gastrointestinal tract and hence their allergenic activity. However, at present they are poorly understood.

Methods And Results: Roasted peanut flour was incorporated into either a chocolate dessert or cookie matrix and bio-accessibility were assessed using an in vitro digestion system comprising a model chew and simulated gastric and duodenal digestion. Protein digestion was monitored by SDS-PAGE and immunoreactivity analyzed by immunoblotting and immunoassay. IgE reactivity was assessed by immunoassay using serum panels from peanut-allergic subjects. Roasted peanut flour proteins proved highly digestible following gastro-duodenal digestion even when incurred into a food matrix, with only low molecular weight polypeptides of Mr < 8 kDa remaining. When gastric digestion was performed at pH 6.5 (simulating the effect of antacid medication), peanut proteins are not digested; subsequent duodenal digestion is also limited. IgE reactivity of the major peanut allergens Ara h 1, Ara h 2, and Ara h 6, although reduced, was retained after oral-gastro-duodenal digestion irrespective of digestion conditions employed.

Conclusion: Peanut allergen bio-accessibility is unaffected by the dessert or cookie matrices whilst high intra-gastric pH conditions render allergens more resistant to digestion.
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http://dx.doi.org/10.1002/mnfr.201901093DOI Listing
July 2020

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium.

JCI Insight 2020 04 23;5(8). Epub 2020 Apr 23.

Department of Human Development and.

The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-κB signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.
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http://dx.doi.org/10.1172/jci.insight.132446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205441PMC
April 2020

Asthma Diagnosis: The Changing Face of Guidelines.

Pulm Ther 2019 Dec 1;5(2):103-115. Epub 2019 Jul 1.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester, UK.

Asthma, the most common chronic respiratory disease, is frequently misdiagnosed, and accounts for a significant proportion of healthcare expenditure. This has driven the National Institute for Health and Care Excellence (NICE) in the United Kingdom (UK) to produce recent guidance; in places, this contrasts to that of the British Thoracic Society/Scottish Intercollegiate Guideline Network (BTS/SIGN), which have been producing their own guidance since 2003. Here we review the history of asthma diagnostic guidelines, and compare and review the evidence behind them, in adults and in children. We discuss the definitions of asthma and how these drive the concepts behind diagnostic strategies. We anticipate future directions in asthma diagnosis which will take into account the concepts of personalised medicine and disease endotypes. We also consider the utility of tests in use now and in the future, in particular novel tests relating to small airway inflammation and obstruction.
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http://dx.doi.org/10.1007/s41030-019-0093-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967246PMC
December 2019

Longitudinal trajectories of severe wheeze exacerbations from infancy to school age and their association with early-life risk factors and late asthma outcomes.

Clin Exp Allergy 2020 03 21;50(3):315-324. Epub 2020 Jan 21.

National Heart and Lung Institute, Imperial College of Science, Technology, and Medicine, London, UK.

Introduction: Exacerbation-prone asthma subtype has been reported in studies using data-driven methodologies. However, patterns of severe exacerbations have not been studied.

Objective: To investigate longitudinal trajectories of severe wheeze exacerbations from infancy to school age.

Methods: We 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.

Results: 498/887 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 (sR ) 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, FEV /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 (FEV /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 respectively, P < .001).

Conclusion: We have identified two distinct trajectories of severe exacerbations during childhood with different early-life risk factors and asthma-related outcomes in adolescence.
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http://dx.doi.org/10.1111/cea.13553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065181PMC
March 2020

Early-life inhalant allergen exposure, filaggrin genotype, and the development of sensitization from infancy to adolescence.

J Allergy Clin Immunol 2020 03 17;145(3):993-1001. Epub 2019 Oct 17.

Section of Paediatrics, Imperial College London, United Kingdom; National Heart and Lung Institute, Imperial College London, United Kingdom. Electronic address:

Background: We hypothesized that filaggrin (FLG) loss-of-function mutations modify the effect of allergen exposure on the development of allergic sensitization.

Objective: We sought to determine whether early-life exposure to inhalant allergens increases the risk of specific sensitization and whether FLG mutations modulate these odds.

Methods: In 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 6 FLG mutations.

Results: In the longitudinal multivariable model (age 1-16 years), we observed a significant interaction between FLG and Fel d 1 exposure on cat sensitization, with the effect of exposure being significantly greater among children with FLG mutations compared with those without (odds ratio, 1.36; 95% CI, 1.02-1.80; P = .035). The increase in risk of mite sensitization with increasing Der p 1 exposure was consistently greater among children with FLG mutations, but the interaction did not reach statistical significance. Different associations were observed for dogs: there was a significant interaction between FLG and dog ownership, but the risk of sensitization to any allergen was significantly lower among children with FLG mutations who were exposed to a dog in infancy (odds ratio, 0.16; 95% CI, 0.03-0.86; P = .03).

Conclusions: FLG loss-of-function mutations modify the relationship between allergen exposure and sensitization, but effects differ at different ages and between different allergens.
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http://dx.doi.org/10.1016/j.jaci.2019.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057264PMC
March 2020

Spidroins and Silk Fibers of Aquatic Spiders.

Sci Rep 2019 09 20;9(1):13656. Epub 2019 Sep 20.

Department of Evolution, Ecology, and Organismal Biology, University of California, Riverside, CA, 92591, USA.

Spiders are commonly found in terrestrial environments and many rely heavily on their silks for fitness related tasks such as reproduction and dispersal. Although rare, a few species occupy aquatic or semi-aquatic habitats and for them, silk-related specializations are also essential to survive in aquatic environments. Most spider silks studied to date are from cob-web and orb-web weaving species, leaving the silks from many other terrestrial spiders as well as water-associated spiders largely undescribed. Here, we characterize silks from three Dictynoidea species: the aquatic spiders Argyroneta aquatica and Desis marina as well as the terrestrial Badumna longinqua. From silk gland RNA-Seq libraries, we report a total of 47 different homologs of the spidroin (spider fibroin) gene family. Some of these 47 spidroins correspond to known spidroin types (aciniform, ampullate, cribellar, pyriform, and tubuliform), while other spidroins represent novel branches of the spidroin gene family. We also report a hydrophobic amino acid motif (GV) that, to date, is found only in the spidroins of aquatic and semi-aquatic spiders. Comparison of spider silk sequences to the silks from other water-associated arthropods, shows that there is a diversity of strategies to function in aquatic environments.
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http://dx.doi.org/10.1038/s41598-019-49587-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754431PMC
September 2019

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Hum Mol Genet 2019 10;28(19):3327-3338

Unidad de Investigacion Medica en Bioquımica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Although hundreds of genome-wide association studies-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 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (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 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 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 with 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 10 single nucleotide polymorphisms (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.
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http://dx.doi.org/10.1093/hmg/ddz161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859434PMC
October 2019

Differential associations of allergic disease genetic variants with developmental profiles of eczema, wheeze and rhinitis.

Clin Exp Allergy 2019 11 15;49(11):1475-1486. Epub 2019 Oct 15.

MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

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 birth 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 6345 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 = 3.3 × 10 , 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 And Clinical Relevance: We have shown complex, but distinct patterns of genetic associations with LCADs, suggesting that heterogeneous mechanisms underlie individual disease trajectories. Establishing the combination of allergic diseases with which each genetic variant is associated may inform therapeutic development and/or predictive modelling.
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http://dx.doi.org/10.1111/cea.13485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899469PMC
November 2019

Dust-mite inducing asthma: what advice can be given to patients?

Expert Rev Respir Med 2019 10 19;13(10):929-936. Epub 2019 Aug 19.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre , Manchester , UK.

: 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. : 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. : 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.
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http://dx.doi.org/10.1080/17476348.2019.1651647DOI Listing
October 2019

Does understanding endotypes translate to better asthma management options for all?

J Allergy Clin Immunol 2019 07 27;144(1):25-33. Epub 2019 May 27.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.

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.
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http://dx.doi.org/10.1016/j.jaci.2019.05.016DOI Listing
July 2019

Toward clinically applicable biomarkers for asthma: An EAACI position paper.

Allergy 2019 10;74(10):1835-1851

Allergy and Clinical Immunology Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

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 nonallergic 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 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.
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http://dx.doi.org/10.1111/all.13806DOI Listing
October 2019

Nocturnal asthma is affected by genetic interactions between RORA and NPSR1.

Pediatr Pulmonol 2019 06 29;54(6):847-857. Epub 2019 Mar 29.

Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.

Background: Neuropeptide S Receptor 1 ( NPSR1) and Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA ) interact biologically, are both known candidate genes for asthma, and are involved in controlling circadian rhythm. Thus, we assessed (1) whether interactions between RORA and NPSR1 specifically affect the nocturnal asthma phenotype and (2) how this may differ from other asthma phenotypes.

Methods: Interaction effects between 24 single-nucleotide polymorphisms (SNPs) in RORA and 35 SNPs in NPSR1 on asthma and nocturnal asthma symptoms were determined in 1432 subjects (763 asthmatics [192 with nocturnal asthma symptoms]; 669 controls) from the Multicenter Asthma Genetic in Childhood/International Study of Asthma and Allergies in Childhood studies. The results were validated and extended in children from the Manchester Asthma and Allergy Study (N = 723) and the Children Allergy Milieu Stockholm and Epidemiological cohort (N = 1646).

Results: RORA* NPSR1 interactions seemed to affect both asthma and nocturnal asthma. In stratified analyses, however, interactions mainly affected nocturnal asthma and less so asthma without nocturnal symptoms or asthma severity. Results were replicated in two independent cohorts and seemed to remain constant over time throughout youth.

Conclusion: RORA* NPSR1 interactions appear to be involved in mechanisms specific for nocturnal asthma. In contrast to previous studies focusing on the role of beta 2 receptor polymorphisms in nocturnal asthma as a feature of asthma control or severity in general, our data suggest that changes in circadian rhythm control are associated with nighttime asthma symptoms.
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http://dx.doi.org/10.1002/ppul.24292DOI Listing
June 2019

Distinguishing Wheezing Phenotypes from Infancy to Adolescence. A Pooled Analysis of Five Birth Cohorts.

Ann Am Thorac Soc 2019 07;16(7):868-876

1 Department of Paediatrics, and.

Pooling data from multiple cohorts and extending the time frame across childhood should minimize study-specific effects, enabling better characterization of childhood wheezing. To analyze wheezing patterns from early childhood to adolescence using combined data from five birth cohorts. We used latent class analysis to derive wheeze phenotypes among 7,719 participants from five birth cohorts with complete report of wheeze at five time periods. We tested the associations of derived phenotypes with late asthma outcomes and lung function, and investigated the uncertainty in phenotype assignment. We identified five phenotypes: never/infrequent wheeze (52.1%), early onset preschool remitting (23.9%), early onset midchildhood remitting (9%), persistent (7.9%), and late-onset wheeze (7.1%). Compared with the never/infrequent wheeze, all phenotypes had higher odds of asthma and lower forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity in adolescence. The association with asthma was strongest for persistent wheeze (adjusted odds ratio, 56.54; 95% confidence interval, 43.75-73.06). We observed considerable within-class heterogeneity at the 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, whereas many children assigned to early onset preschool remitting class reported wheezing at later time points. All wheeze phenotypes had significantly diminished lung function in school-age children, 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.
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http://dx.doi.org/10.1513/AnnalsATS.201811-837OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600832PMC
July 2019

Report from the National Institute of Allergy and Infectious Diseases workshop on "Atopic dermatitis and the atopic march: Mechanisms and interventions".

J Allergy Clin Immunol 2019 03 9;143(3):894-913. Epub 2019 Jan 9.

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Md.

Atopic dermatitis (AD) affects up to 20% of children worldwide and is an increasing public health problem, particularly in developed countries. Although AD in infants and young children can resolve, there is a well-recognized increased risk of sequential progression from AD to other atopic diseases, including food allergy (FA), allergic rhinitis, allergic asthma, and allergic rhinoconjunctivitis, a process referred to as the atopic march. The mechanisms underlying the development of AD and subsequent progression to other atopic comorbidities, particularly FA, are incompletely understood and the subject of intense investigation. Other major research objectives are the development of effective strategies to prevent AD and FA, as well as therapeutic interventions to inhibit the atopic march. In 2017, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop to discuss current understanding and important advances in these research areas and to identify gaps in knowledge and future research directions. International and national experts in the field were joined by representatives from several National Institutes of Health institutes. Summaries of workshop presentations, key conclusions, and recommendations are presented herein.
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http://dx.doi.org/10.1016/j.jaci.2019.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905466PMC
March 2019

Understanding problematic eating in out-of-home care: The role of attachment and emotion regulation.

Appetite 2019 04 26;135:33-42. Epub 2018 Dec 26.

Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Monash University, Locked Bag 29, Clayton, Vic 3168, Australia. Electronic address:

Children living in Out-of-Home Care (OoHC) are thought to be especially vulnerable to developing problematic eating behaviours due to their likelihood of having insecure attachment styles and emotion regulation deficits. Despite this increased risk, our understanding of problematic eating among children in OoHC is limited. Therefore, this study aimed to; (1) Explore the rate of problematic eating behaviours among children living in OoHC, specifically residential and foster care; (2) Investigate how carers manage problematic eating and (3) Understand carers' perceptions of the role of attachment and emotion regulation in relation to problematic eating in OoHC. Semi-structured interviews, focus groups, and surveys were conducted with residential care staff (n = 36) and foster carers (n = 8) in Victoria, Australia. Interviews were recorded, transcribed, and analysed for themes, and frequency data from the survey were generated. Residential and foster carers reported that approximately 38% of the children in their care displayed problematic eating behaviours at a clinical level. Both residential and foster carers commonly understood these behaviours as a function of the child's experiences of food deprivation and limited access to healthy foods prior to entering care which, they believe, has contributed to problems with regulating food intake and/or willingness to try new foods. Carers also commonly reported that the children in their care struggle to form attachments or regulate their emotions, which impacts carers ability to manage problematic eating. It is recommended that future interventions prioritise educating community service organisations (CSOs), responsible for delivering OoHC, to better recognise and address problematic eating behaviours. This will enable CSOs to train their residential and foster carers about how best to respond to and manage problematic eating behaviours.
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http://dx.doi.org/10.1016/j.appet.2018.12.027DOI Listing
April 2019

Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study.

Lancet Respir Med 2019 Jan 11;7(1):20-34. Epub 2018 Dec 11.

Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia.

Background: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.

Methods: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10 in stage 1. We set genome-wide significance at p less than 5 × 10. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.

Findings: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).

Interpretation: We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.

Funding: Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.
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http://dx.doi.org/10.1016/S2213-2600(18)30389-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314966PMC
January 2019

Individual risk assessment tool for school-age asthma prediction in UK birth cohort.

Clin Exp Allergy 2019 03 4;49(3):292-298. Epub 2019 Jan 4.

Division of Infection Immunity and Respiratory Medicine, School of Biological Sciences, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, The University of Manchester, Manchester, UK.

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.
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http://dx.doi.org/10.1111/cea.13319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446726PMC
March 2019

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 Med 2018 11 13;15(11):e1002691. Epub 2018 Nov 13.

Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom.

Background: The 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 Findings: In 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). We then used HC to identify four common 'sensitisation clusters' among study participants: (1) multiple sensitisation (sIgE to multiple components across all seven component clusters and singleton components), (2) predominantly dust mite sensitisation (IgE responses mainly to components from C.sIgE-1), (3) predominantly grass and tree sensitisation (sIgE to multiple components across C.sIgE-4-7), and (4) lower-grade sensitisation. We used a bipartite network to explore the relationship between component clusters, sensitisation clusters, and asthma, and the joint density-based nonparametric differential interaction network analysis and classification (JDINAC) to test whether pairwise interactions of component-specific IgEs are associated with asthma. JDINAC with pairwise interactions provided a good balance between sensitivity (0.84) and specificity (0.87), and outperformed penalised logistic regression with individual sIgE components in predicting asthma, with an area under the curve (AUC) of 0.94, compared with 0.73. We then inferred the differential network of pairwise component-specific IgE interactions, which demonstrated that 18 pairs of components predicted asthma. These findings were confirmed in an independent sample of children aged 8 years who participated in the same birth cohort but did not have component-resolved diagnostics (CRD) data at age 11 years. The main limitation of our study was the exclusion of potentially important allergens caused by both the ISAC chip resolution as well as the filtering step. Clustering and the network analyses might have provided different solutions if additional components had been available.

Conclusions: Interactions between pairs of sIgE components are associated with increased risk of asthma and may provide the basis for designing diagnostic tools for asthma.
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http://dx.doi.org/10.1371/journal.pmed.1002691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233916PMC
November 2018
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