Publications
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Custovic A, Custovic D, Fontanella S, 2024, Understanding the heterogeneity of childhood allergic sensitization and its relationship with asthma., Curr Opin Allergy Clin Immunol, Vol: 24, Pages: 79-87
PURPOSE OF REVIEW: To review the current state of knowledge on the relationship between allergic sensitization and asthma; to lay out a roadmap for the development of IgE biomarkers that differentiate, in individual sensitized patients, whether their sensitization is important for current or future asthma symptoms, or has little or no relevance to the disease. RECENT FINDINGS: The evidence on the relationship between sensitization and asthma suggests that some subtypes of allergic sensitization are not associated with asthma symptoms, whilst others are pathologic. Interaction patterns between IgE antibodies to individual allergenic molecules on component-resolved diagnostics (CRD) multiplex arrays might be hallmarks by which different sensitization subtypes relevant to asthma can be distinguished. These different subtypes of sensitization are associated amongst sensitized individuals at all ages, with different clinical presentations (no disease, asthma as a single disease, and allergic multimorbidity); amongst sensitized preschool children with and without lower airway symptoms, with different risk of subsequent asthma development; and amongst sensitized patients with asthma, with differing levels of asthma severity. SUMMARY: The use of machine learning-based methodologies on complex CRD data can help us to design better diagnostic tools to help practising physicians differentiate between benign and clinically important sensitization.
Regis E, Fontanella S, Curtin JA, et al., 2024, Association between polymorphisms on chromosome 17q12-q21 and rhinovirus-induced interferon responses., J Allergy Clin Immunol
BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes on chromosome 17q12-q21 are associated with childhood-onset asthma and rhinovirus-induced wheeze. There are few mechanistic data linking chromosome 17q12-q21 to wheezing illness. OBJECTIVE: We investigated whether 17q12-q21 risk alleles were associated with impaired interferon responses to rhinovirus. METHODS: In a population-based birth cohort of European ancestry, we stimulated peripheral blood mononuclear cells with rhinovirus A1 (RV-A1) and rhinovirus A16 (RV-A16) and measured IFN and IFN-induced C-X-C motif chemokine ligand 10 (aka IP10) responses in supernatants. We investigated associations between virus-induced cytokines and 6 SNPs in 17q12-q21. Bayesian profile regression was applied to identify clusters of individuals with different immune response profiles and genetic variants. RESULTS: Five SNPs (in high linkage disequilibrium, r2 ≥ 0.8) were significantly associated with RV-A1-induced IFN-β (rs9303277, P = .010; rs11557467, P = .012; rs2290400, P = .006; rs7216389, P = .008; rs8079416, P = .005). A reduction in RV-A1-induced IFN-β was observed among individuals with asthma risk alleles. There were no significant associations for RV-A1-induced IFN-α or CXCL10, or for any RV-A16-induced IFN/CXCL10. Bayesian profile regression analysis identified 3 clusters that differed in IFN-β induction to RV-A1 (low, medium, high). The typical genetic profile of the cluster associated with low RV-A1-induced IFN-β responses was characterized by a very high probability of being homozygous for the asthma risk allele for all SNPs. Children with persistent wheeze were almost 3 times more likely to be in clusters with reduced/average RV-A1-induced IFN-β responses than in the high immune response cluster. CONCLUSIONS: Polymorphisms on chromosome 17q12-q21 are associated with rhinovirus-induced IFN-β, suggesting a novel mechanism-impaired IFN-&b
Melén E, Faner R, Allinson JP, et al., 2024, Lung-function trajectories: relevance and implementation in clinical practice, The Lancet, ISSN: 0140-6736
Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation.
Howard R, Fontanella S, Simpson A, et al., 2024, Component-specific clusters for diagnosis and prediction of allergic airway diseases., Clin Exp Allergy
BACKGROUND: Previous studies which applied machine learning on multiplex component-resolved diagnostics arrays identified clusters of allergen components which are biologically plausible and reflect the sources of allergenic proteins and their structural homogeneity. Sensitization to different clusters is associated with different clinical outcomes. OBJECTIVE: To investigate whether within different allergen component sensitization clusters, the internal within-cluster sensitization structure, including the number of c-sIgE responses and their distinct patterns, alters the risk of clinical expression of symptoms. METHODS: In a previous analysis in a population-based birth cohort, by clustering component-specific (c-s)IgEs, we derived allergen component clusters from infancy to adolescence. In the current analysis, we defined each subject's within-cluster sensitization structure which captured the total number of c-sIgE responses in each cluster and intra-cluster sensitization patterns. Associations between within-cluster sensitization patterns and clinical outcomes (asthma and rhinitis) in early-school age and adolescence were examined using logistic regression and binomial generalized additive models. RESULTS: Intra-cluster sensitization patterns revealed specific associations with asthma and rhinitis (both contemporaneously and longitudinally) that were previously unseen using binary sensitization to clusters. A more detailed description of the subjects' within-cluster c-sIgE responses in terms of the number of positive c-sIgEs and unique sensitization patterns added new information relevant to allergic diseases, both for diagnostic and prognostic purposes. For example, the increase in the number of within-cluster positive c-sIgEs at age 5 years was correlated with the increase in prevalence of asthma at ages 5 and 16 years, with the correlations being stronger in the prediction context (e.g. for the largest 'Broad' component cluster, contemporaneous
Turner PJ, Ansotegui IJ, Campbell DE, et al., 2024, Updated grading system for systemic allergic reactions: Joint Statement of the World Allergy Organization Anaphylaxis Committee and Allergen Immunotherapy Committee, The World Allergy Organization Journal, Vol: 17, ISSN: 1939-4551
There is a lack of consensus over the description and severity assignment of allergic adverse reactions to immunotherapy, although there seems to be a consensus at least in terms of using the World Allergy Organization (WAO) grading systems to describe local adverse events for Sublingual Immunotherapy (SLIT) and Systemic Allergic Reactions (SARs) to Subcutaneous Immunotherapy (SCIT) amongst the major national/regional allergy societies. In this manuscript, we propose a modification of the previous WAO Grading system for SARs, which aligns with the newly-proposed Consortium for Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions in Food Allergy (version 3.0). We hope this can facilitate a unified grading system appropriate to SARs due to allergen immunotherapy, independent of allergen and route of administration, and across clinical and research practice.
Duverdier A, Hurault G, Thomas K, et al., 2024, Evaluation of measurement errors in the patient‐oriented eczema measure (POEM) outcome, Clinical and Experimental Allergy, Vol: 54, Pages: 207-215, ISSN: 0954-7894
Background:The Patient-Oriented Eczema Measure (POEM) is the recommended core outcome instrument for atopic dermatitis (AD) symptoms. POEM is reported by recalling the presence/absence of seven symptoms in the last 7 days.Objective:To evaluate measurement errors in POEM recordings due to imperfect recall.Methods:Using data from a clinical trial of 247 AD patients aged 12–65 years, we analysed the reported POEM score (r-POEM) and the POEM derived from the corresponding daily scores for the same seven symptoms without weekly recall (d-POEM). We quantified recall error by comparing the r-POEM and d-POEM for 777 patient-weeks collected from 207 patients, and estimated two components of recall error: (1) recall bias due to systematic errors in measurements and (2) recall noise due to random errors in measurements, using a bespoke statistical model.Results:POEM scores have a relatively low recall bias, but a high recall noise. Recall bias was estimated at 1.2 points lower for the r-POEM on average than the d-POEM, with a recall noise of 5.7 points. For example, a patient with a recall-free POEM of 11 (moderate) could report their POEM score anywhere from 5 to 14 (with 95% probability) because of recall error. Model estimates suggested that patients tend to recall itch and dryness more often than experienced (positive bias of less than 1 day), but less often for the other symptoms (bleeding, cracking, flaking, oozing/weeping and sleep disturbance; negative bias ranging 1–4 days).Conclusions:In this clinical trial data set, we found that patients tended to slightly underestimate their symptoms when reporting POEM, with significant variation in how well they were able to recall the frequency of their symptoms every time they reported POEM. A large recall noise should be taken into consideration when interpreting POEM scores.
Farhan AJ, Kothalawala DM, Kurukulaaratchy RJ, et al., 2024, Response to correspondence: Prediction of adult asthma risk in early childhood using novel adult asthma predictive risk scores., Allergy
Ullah A, Granell R, Haider S, et al., 2024, Obstructive and restrictive spirometry from school age to adulthood: three birth cohort studies, EClinicalMedicine, Vol: 67, ISSN: 2589-5370
Background:Spirometric obstruction and restriction are two patterns of impaired lung function which are predictive of poor health. We investigated the development of these phenotypes and their transitions through childhood to early adulthood.Methods:In this study, we analysed pooled data from three UK population−based birth cohorts established between 1989 and 1995. We applied descriptive statistics, regression modelling and data-driven modelling to data from three population−based birth cohorts with at least three spirometry measures from childhood to adulthood (mid-school: 8–10 years, n = 8404; adolescence: 15–18, n = 5764; and early adulthood: 20–26, n = 4680). Participants were assigned to normal, restrictive, and obstructive spirometry based on adjusted regression residuals. We considered two transitions: from 8–10 to 15–18 and from 15–18 to 20–26 years.Findings:Obstructive phenotype was observed in ∼10%, and restrictive in ∼9%. A substantial proportion of children with impaired lung function in school age (between one third in obstructive and a half in restricted phenotype) improved and achieved normal and stable lung function to early adulthood. Of those with normal lung function in school-age, <5% declined to adulthood. Underweight restrictive and obese obstructive participants were less likely to transit to normal. Maternal smoking during pregnancy and current asthma diagnosis increased the risk of persistent obstruction and worsening. Significant associate of worsening in restrictive phenotypes was lower BMI at the first lung function assessment. Data-driven methodologies identified similar risk factors for obstructive and restrictive clusters.Interpretation:The worsening and improvement in obstructive and restrictive spirometry were observed at all ages. Maintaining optimal weight during childhood and reducing maternal smoking during pregnancy may reduce spirometry obstruction and restrictio
Haider S, Granell R, Curtin JA, et al., 2024, Identification of eczema clusters and their association with filaggrin and atopic comorbidities: analysis of 5 birth cohorts, British Journal of Dermatology, Vol: 190, Pages: 45-54, ISSN: 0007-0963
Background: Longitudinal modelling of the presence/absence of current eczema through childhood has identified similar phenotypes, but their characteristics often differ between studies. Objectives: We propose that more comprehensive description of longitudinal pattern of symptoms may better describe trajectories than binary information on eczema presence. Methods: We derived 6 multi-dimensional variables of eczema spells from birth to age 18 years (including duration, temporal sequencing, and the extent of persistence/recurrence). Spells were defined as consecutive observations eczema separated by no-eczema across 5 epochs in five birth cohorts: infancy (first year); early childhood (age 2-3 years); pre-school/early school age (4-5 years); middle childhood (8-10 years); adolescence (14-18 years). We applied Partition-Around-Medoids clustering on these variables to derive clusters of the temporal patterns of eczema. We then investigated the stability of the clusters, within-cluster homogeneity, and associated risk factors, including filaggrin mutations.Results: Analysis among 7,464 participants with complete data identified five clusters: 1) No eczema (NOE) (51%); 2) Early transient (ETE) (21.6%); (3) Late-onset (LOE) (8.1%); 4) Intermittent (INT) (7.5%); and 5) Persistent (PE) (11.8%) eczema. There was a very high agreement between assignment of individual children into clusters when using complete or imputed (n=15,848) data (adjusted Rand index=0.99), i.e., the clusters were very stable. Within-individual symptom patterns across clusters confirmed within−cluster homogeneity, with consistent patterns of symptoms among participants within each cluster, and no overlap between the clusters. Clusters were characterised by differences in associations with risk factors (e.g., parental eczema was associated with all clusters apart from LOE; sensitisation to inhalant allergens was associated with all clusters, with highest risk of PE). All clusters apart from LOE we
Tutino M, Hankinson J, Murray C, et al., 2023, Identification of differences in CD4+ T-cell gene expression between people with asthma and healthy controls., Sci Rep, Vol: 13
Functional enrichment analysis of genome-wide association study (GWAS)-summary statistics has suggested that CD4+ T-cells play an important role in asthma pathogenesis. Despite this, CD4+ T-cells are under-represented in asthma transcriptome studies. To fill the gap, 3'-RNA-Seq was used to generate gene expression data on CD4+ T-cells (isolated within 2 h from collection) from peripheral blood from participants with well-controlled asthma (n = 32) and healthy controls (n = 11). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify sets of co-expressed genes (modules) associated with the asthma phenotype. We identified three modules associated with asthma, which are strongly enriched for GWAS-identified asthma genes, antigen processing/presentation and immune response to viral infections. Through integration of publicly available eQTL and GWAS summary statistics (colocalisation), and protein-protein interaction (PPI) data, we identified PTPRC, a potential druggable target, as a putative master regulator of the asthma gene-expression profiles. Using a co-expression network approach, with integration of external genetic and PPI data, we showed that CD4+ T-cells from peripheral blood from asthmatics have different expression profiles, albeit small in magnitude, compared to healthy controls, for sets of genes involved in immune response to viral infections (upregulated) and antigen processing/presentation (downregulated).
Fontanella S, Cucco A, Custovic A, 2023, Breathing new life into asthma research: a review of machine learning and multi-omics approaches, Minerva Respiratory Medicine, Vol: 62, Pages: 163-176, ISSN: 2784-8477
INTRODUCTION: Asthma is a chronic respiratory disease that affects millions of people worldwide, and despite intensive study, the underlying molecular pathways are still unknown. Recent breakthroughs in machine learning and multi-omics technology provide new avenues for delving deeper into disease pathophysiology and identifying potential treatment targets. EVIDENCE ACQUISITION: We comprehensively reviewed the literature to explore the potential of machine learning and multi-omics approaches in asthma research. We searched the Scopus database using a combination of terms such as “asthma,” “machine learning”, and “multi-omics” and their synonyms. EVIDENCE SYNTHESIS: Our review revealed that machine learning and multi-omics approaches have been increasingly used to identify biomarkers, classify asthma subtypes, predict treatment outcomes, and understand the disease pathophysiology at the molecular level. CONCLUSIONS: Combining machine learning and multi-omics technologies holds tremendous potential for advancing our understanding of asthma pathogenesis and identifying novel therapeutic targets. Overall, this analysis demonstrates how these techniques have the potential to revitalize asthma research and improve patient outcomes. More study is needed, however, to confirm the utility of these approaches and understand how to build viable models that can be applied to clinical practice.
Custovic D, Fontanella S, Custovic A, 2023, Understanding progression from pre-school wheezing to school-age asthma: Can modern data approaches help?, Pediatr Allergy Immunol, Vol: 34
Preschool wheezing and childhood asthma create a heavy disease burden which is only exacerbated by the complexity of the conditions. Preschool wheezing exhibits both "curricular" and "aetiological" heterogeneity: that is, heterogeneity across patients both in the time-course of its development and in its underpinning pathological mechanisms. Since these are not fully understood, but clinical presentations across patients may nonetheless be similar, current diagnostic labels are imprecise-not mapping cleanly onto underlying disease mechanisms-and prognoses uncertain. These uncertainties also make a identifying new targets for therapeutic intervention difficult. In the past few decades, carefully designed birth cohort studies have collected "big data" on a large scale, incorporating not only a wealth of longitudinal clinical data, but also detailed information from modalities as varied as imaging, multiomics, and blood biomarkers. The profusion of big data has seen the proliferation of what we term "modern data approaches" (MDAs)-grouping together machine learning, artificial intelligence, and data science-to make sense and make use of this data. In this review, we survey applications of MDAs (with an emphasis on machine learning) in childhood wheeze and asthma, highlighting the extent of their successes in providing tools for prognosis, unpicking the curricular heterogeneity of these conditions, clarifying the limitations of current diagnostic criteria, and indicating directions of research for uncovering the etiology of the diseases underlying these conditions. Specifically, we focus on the trajectories of childhood wheeze phenotypes. Further, we provide an explainer of the nature and potential use of MDAs and emphasize the scope of what we can hope to achieve with them.
Farraia M, Mendes FC, Sokhatska O, et al., 2023, Component-resolved diagnosis in childhood and prediction of asthma in early adolescence: A birth cohort study., Pediatr Allergy Immunol, Vol: 34
INTRODUCTION: Component-resolved diagnosis (CRD) has been decisive in exploring the mechanisms of IgE sensitization, but the predictive ability to detect asthma has not been addressed. We aim to develop and evaluate the performance of a personalized predictive algorithm for asthma that integrates information on allergic sensitization using CRD. METHODS: One thousand one hundred one twenty-five children from the Generation XXI birth cohort were randomly selected to perform a screening test for allergic sensitization and a subsample was characterized using CRD against 112 allergen components. Allergen components were analyzed using volcano plots and partial least squares (PLS) analysis. Logistic regression was performed to assess the associations between the obtained latent components (LC) and allergic outcomes (asthma, rhinitis, eczema) including other potential predictors used in previous asthma risk scores. The accuracy of the model in predicting asthma was assessed using Receiver Operating Characteristic (ROC) curve statistics. RESULTS: In the PLS, the first LC was positively associated with asthma, rhinitis, and eczema. This LC was mainly driven by positive weights for Der p 1/2/23, Der f 1/2, and Fel d 1. The main components in the second LC were pollen and food allergens. History of early wheezing and parental allergy were included in the predictive model and the area under the curve improved to 0.82. CONCLUSIONS: This is the first approach to improve the clinical applicability of CRD by combining CRD and clinical data to predict asthma at 13 years. Sensitization to distinct allergen molecules seems relevant to improve the accuracy of asthma prediction models.
Farhan AJ, Kothalawala DM, Kurukulaaratchy RJ, et al., 2023, Prediction of adult asthma risk in early childhood using novel adult asthma predictive risk scores, Allergy, Vol: 78, Pages: 2969-2979, ISSN: 0105-4538
BackgroundNumerous risk scores have been developed to predict childhood asthma. However, they may not predict asthma beyond childhood. We aim to create childhood risk scores that predict development and persistence of asthma up to young adult life.MethodsThe Isle of Wight Birth Cohort (n = 1456) was prospectively assessed up to 26 years of age. Asthma predictive scores were developed based on factors during the first 4 years, using logistic regression and tested for sensitivity, specificity and area under the curve (AUC) for prediction of asthma at (i) 18 and (ii) 26 years, and persistent asthma (PA) (iii) at 10 and 18 years, and (iv) at 10, 18 and 26 years. Models were internally and externally validated.ResultsFour models were generated for prediction of each asthma outcome. ASthma PredIctive Risk scorE (ASPIRE)-1: a 2-factor model (recurrent wheeze [RW] and positive skin prick test [+SPT] at 4 years) for asthma at 18 years (sensitivity: 0.49, specificity: 0.80, AUC: 0.65). ASPIRE-2: a 3-factor model (RW, +SPT and maternal rhinitis) for asthma at 26 years (sensitivity: 0.60, specificity: 0.79, AUC: 0.73). ASPIRE-3: a 3-factor model (RW, +SPT and eczema at 4 years) for PA-18 (sensitivity: 0.63, specificity: 0.87, AUC: 0.77). ASPIRE-4: a 3-factor model (RW, +SPT at 4 years and recurrent chest infection at 2 years) for PA-26 (sensitivity: 0.68, specificity: 0.87, AUC: 0.80). ASPIRE-1 and ASPIRE-3 scores were replicated externally. Further assessments indicated that ASPIRE-1 can be used in place of ASPIRE-2-4 with same predictive accuracy.ConclusionASPIRE predicts persistent asthma up to young adult life.
Salehian S, Fleming L, Saglani S, et al., 2023, Phenotype and endotype based treatment of preschool wheeze, EXPERT REVIEW OF RESPIRATORY MEDICINE, ISSN: 1747-6348
Voraphani N, Stern DA, Ledford JG, et al., 2023, Circulating CC16 and asthma: a population-based, multi-cohort study from early childhood through adult life, American Journal of Respiratory and Critical Care Medicine, Vol: 208, ISSN: 1073-449X
RATIONALE: CC16 is an anti-inflammatory protein highly expressed in the airways. CC16 deficiency has been associated with lung function deficits, but its role in asthma has not been established conclusively. OBJECTIVES: To determine 1) the longitudinal association of circulating CC16 with the presence of active asthma from early childhood through adult life and 2) whether CC16 in early childhood predicts the clinical course of childhood asthma into adult life. METHODS: We assessed the association of circulating CC16 and asthma in three population-based birth cohorts: TCRS (years 6-36; N-participants=814, N-observations=3042), BAMSE (years 8-24; Ns=2547, 3438), and MAAS (years 5-18, Ns=745, 1626). Among 233 children who had asthma at the first survey in any of the cohorts, baseline CC16 was also tested for association with persistence of symptoms. MEASUREMENTS AND MAIN RESULTS: 1) After adjusting for covariates, CC16 deficits were associated with increased risk for the presence of asthma in all cohorts (meta-analyzed adjOR per 1-SD CC16 decrease: 1.20[95%CI 1.12-1.28];P<0.0001). The association was particularly strong for asthma with frequent symptoms (meta-analyzed adjRRR: 1.40[1.24-1.57];P<0.0001), was confirmed for both atopic and non-atopic asthma, and was independent of lung function impairment. 2) After adjustment for known predictors of persistent asthma, asthmatic children in the lowest CC16 tertile had a nearly 4-fold increased risk for having frequent symptoms persisting into adult life, compared with asthmatic children in the other two CC16 tertiles (meta-analyzed adjOR: 3.72[1.78-7.76];P<0.0001). CONCLUSIONS: Circulating CC16 deficits are associated with the presence of asthma with frequent symptoms from childhood through mid-adult life and predict the persistence of asthma symptoms into adulthood. These findings support a possible protective role of CC16 in asthma and its potential use for risk stratification.
van Breugel M, Fehrmann RSN, Bügel M, et al., 2023, Current state and prospects of artificial intelligence in allergy, Allergy, Vol: 78, Pages: 2623-2643, ISSN: 0105-4538
The field of medicine is witnessing an exponential growth of interest in artificial intelligence (AI), which enables new research questions and the analysis of larger and new types of data. Nevertheless, applications that go beyond proof of concepts and deliver clinical value remain rare, especially in the field of allergy. This narrative review provides a fundamental understanding of the core concepts of AI and critically discusses its limitations and open challenges, such as data availability and bias, along with potential directions to surmount them. We provide a conceptual framework to structure AI applications within this field and discuss forefront case examples. Most of these applications of AI and machine learning in allergy concern supervised learning and unsupervised clustering, with a strong emphasis on diagnosis and subtyping. A perspective is shared on guidelines for good AI practice to guide readers in applying it effectively and safely, along with prospects of field advancement and initiatives to increase clinical impact. We anticipate that AI can further deepen our knowledge of disease mechanisms and contribute to precision medicine in allergy.
Zuberbier T, Abdul Latiff A, Aggelidis X, et al., 2023, A concept for integrated care pathways for atopic dermatitis-A GA2 LEN ADCARE initiative, Clinical and Translational Allergy, Vol: 13, ISSN: 2045-7022
INTRODUCTION: The integrated care pathways for atopic dermatitis (AD-ICPs) aim to bridge the gap between existing AD treatment evidence-based guidelines and expert opinion based on daily practice by offering a structured multidisciplinary plan for patient management of AD. ICPs have the potential to enhance guideline recommendations by combining interventions and aspects from different guidelines, integrating quality assurance, and describing co-ordination of care. Most importantly, patients can enter the ICPs at any level depending on AD severity, resources available in their country, and economic factors such as differences in insurance reimbursement systems. METHODS: The GA2 LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD-ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2 EN ADCARE centres. RESULTS: The AD-ICPs outline the diagnostic procedures, possible co-morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD. CONCLUSION: The AD-ICPs provide a multidisciplinary plan for improved diagnosis, treatment, and patient feedback in AD management, as well as addressing critical unmet needs, including improved access to care, training specialists, implementation of educational programs, assessment on the impact of climate change, and fostering a personalised treatment approach. By focusing on these key areas, the initiative aims to pave the way for a brighter future in the management of AD.
Shamji MH, Ollert M, Adcock IM, et al., 2023, EAACI guidelines on environmental science in allergic diseases and asthma - Leveraging artificial intelligence and machine learning to develop a causality model in exposomics, Allergy, Vol: 78, Pages: 1742-1757, ISSN: 0105-4538
Allergic diseases and asthma are intrinsically linked to the environment we live in and to patterns of exposure. The integrated approach to understanding the effects of exposures on the immune system includes the ongoing collection of large-scale and complex data. This requires sophisticated methods to take full advantage of what this data can offer. Here we discuss the progress and further promise of applying artificial intelligence and machine-learning approaches to help unlock the power of complex environmental data sets toward providing causality models of exposure and intervention. We discuss a range of relevant machine-learning paradigms and models including the way such models are trained and validated together with examples of machine learning applied to allergic disease in the context of specific environmental exposures as well as attempts to tie these environmental data streams to the full representative exposome. We also discuss the promise of artificial intelligence in personalized medicine and the methodological approaches to healthcare with the final AI to improve public health.
Granell R, Curtin JA, Haider S, et al., 2023, A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing, eLife, Vol: 12, Pages: 1-57, ISSN: 2050-084X
BACKGROUND: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. METHODS: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. RESULTS: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. CONCLUSIONS: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. FUNDING: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study.
Custovic A, Bourgoin-Heck M, 2023, Pro-Con Debate Sublingual Immunotherapy, Publisher: WILEY, Pages: S69-S71, ISSN: 8755-6863
Custovic A, Haider S, 2023, Evolution of Eczema, Wheeze and Rhinitis - Predicting Atopic Multi-Morbidities, Publisher: WILEY, Pages: S9-S11, ISSN: 8755-6863
Papadopoulos NG, Mathioudakis AG, Custovic A, et al., 2023, Current and optimal practices in childhood asthma monitoring among multiple international stakeholders., JAMA Network Open, Vol: 6, Pages: 1-15, ISSN: 2574-3805
Importance Childhood asthma control largely depends on rigorous and regular monitoring. Although various clinical parameters, biomarkers, and patient-reported outcomes are helpful for monitoring purposes, there is no consensus on the minimum and/or optimal set of parameters and their relative priority.Objective To assess actual and perceived optimal childhood asthma monitoring practices used globally.Design, Setting, and Participants This international, multistakeholder survey study surveyed health care professionals and clinical academics with a professional interest in and exposure to childhood asthma between April 12 and September 3, 2021, to test for differences between the frequency that different techniques are actually used in practice vs optimal practice, between-group differences, and differences across medical settings and country economies.Main Outcomes and Measures Outcomes were frequency of duration of asthma monitoring visits as well as actual and perceived optimal use and importance of monitoring tools and domains.Results A total of 1319 participants with expertise in childhood asthma from 88 countries completed the survey. Participants included 1228 health care professionals with a balanced distribution across different care settings (305 [22.7%] primary care, 401 [29.9%] secondary, and 522 [38.9%] tertiary care) and 91 researchers. Children with mild to moderate asthma attended regular monitoring visits at a median (IQR) of 5.0 (2.5-8.0) months, with visits lasting a median (IQR) of 25 (15-25) minutes, whereas severe asthma required more frequent visits (median [IQR], 2.5 [1.0-2.5] months; median [IQR] duration, 25 [25-35] minutes). Monitoring of symptoms and control, adherence, comorbidities, lung function, medication adverse effects, and allergy were considered to be very high or high priority by more than 75% of the respondents. Different patterns emerged when assessing differences between actual and perceived optimal use of monitoring tools
Duverdier A, Hurault G, Custovic A, et al., 2023, Personalised predictions of patient-reported atopic dermatitis severity scores using a Bayesian machine learning approach, 1st International Societies for Investigative Dermatology Meeting, Publisher: ELSEVIER SCIENCE INC, Pages: S36-S36, ISSN: 0022-202X
Bousquet J, Melén E, Haahtela T, et al., 2023, Rhinitis associated with asthma is distinct from rhinitis alone: The ARIA-MeDALL hypothesis, Allergy, Vol: 78, Pages: 1169-1203, ISSN: 0105-4538
Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.
Wise SK, Damask C, Roland LT, et al., 2023, International consensus statement on allergy and rhinology: Allergic rhinitis - 2023, International Forum of Allergy and Rhinology, Vol: 13, Pages: 293-859, ISSN: 2042-6976
BACKGROUND: In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR-Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR-Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence-based findings and recommendation from the full document. METHODS: ICAR-Allergic Rhinitis 2023 employed established evidence-based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work. RESULTS: ICAR-Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost. CONCLUSION: The ICAR-Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment.
Patel N, Shreffler WG, Custovic A, et al., 2023, Will oral food challenges still be part of allergy care in 10 years' time?, Journal of Allergy and Clinical Immunology: In Practice, Vol: 11, Pages: 988-996, ISSN: 2213-2198
Oral food challenges (OFCs) are currently the definitive diagnostic procedure in food allergy. Their design has evolved over the decades to maximize safety, optimize convenience, and address several specific clinical questions. However, they are a resource-intensive investigation that carry a risk for severe allergic reaction in which fatal outcomes, although rare, have been reported. In this review, we explore the many roles that OFC fulfil in the clinical and research settings. We also discuss progress that has been made in developing alternative diagnostic tools and how far these have reached in offering a viable replacement to OFC in clinical practice. Finally, we discuss the ongoing importance of research OFC to improve the future diagnostic capabilities of novel diagnostic tools.
Wu J, Bahri R, Tsoumani M, et al., 2023, Progenitor cell-derived basophils: a novel barcoded passive degranulation assay in allergic diseases, Clinical and Experimental Allergy, Vol: 53, Pages: 405-416, ISSN: 0954-7894
BackgroundEffector cells assays provide an overall measure of responsiveness to allergen, but the lack of reliable and high-throughput assays limits the clinical utility. We aimed to develop a high-throughput basophil activation test based on human progenitor cell-derived basophils (PCB) and investigate the role of PCB activation test (PCBAT) in allergic diseases.MethodsProgenitor cell-derived basophils were differentiated from CD34+ progenitor cells and sensitized with sera from subjects sensitized to cat, peanut or atopic controls. Sensitized PCBs were stimulated with increasing concentrations of the corresponding allergens in vitro. Degranulation was assessed by measuring CD63 expression using flow cytometry. The correlations between PCBAT and clinical allergy were assessed.ResultsFollowing passive sensitization of the mature PCBs with serum and allergen stimulation, an allergen specific dose-dependent increase in CD63 expression was observed. Sera from subjects sensitized to cat (n = 35, of which 17 subjects had clinical reactivity quantified using inhaled allergen challenge), peanut allergic (n = 30, of which 15 subjects had clinical reactivity validated using double blind, placebo controlled food challenges [DBPCFC]), peanut-sensitized but tolerant subjects (n = 5) were used to sensitize PCBs. PCBAT area under the curve (AUC) correlated with sIgE (r2 = .49, p = .001) in subjects sensitized to cat (sIgE ≥ 0.35KU/L). The provocation concentration of inhaled cat allergen (PC20) correlated with PCBAT AUC (r2 = .33, p = .016). In subjects sensitized to peanut, PCBAT AUC was highly correlated with sIgE to Ara h 2 (r2 = .59, p < .0001). Peanut threshold cumulative dose during DBPCFC was negatively correlated with PCBAT AUC (r2 = .57, p = .001) and IgE to Ara h1 (r2 = .55, p = .007), but not with sIgE to whole peanut or Ara h2. All peanut-sensitized but tolerant subjects showed no reaction to peanut on PCBAT.ConclusionProgenitor cell-
Dramburg S, Hilger C, Santos AF, et al., 2023, EAACI Molecular Allergology User's Guide 2.0, Pediatric Allergy and Immunology, Vol: 34, ISSN: 0905-6157
Since the discovery of immunoglobulin E (IgE) as a mediator of allergic diseases in 1967, our knowledge about the immunological mechanisms of IgE-mediated allergies has remarkably increased. In addition to understanding the immune response and clinical symptoms, allergy diagnosis and management depend strongly on the precise identification of the elicitors of the IgE-mediated allergic reaction. In the past four decades, innovations in bioscience and technology have facilitated the identification and production of well-defined, highly pure molecules for component-resolved diagnosis (CRD), allowing a personalized diagnosis and management of the allergic disease for individual patients. The first edition of the "EAACI Molecular Allergology User's Guide" (MAUG) in 2016 rapidly became a key reference for clinicians, scientists, and interested readers with a background in allergology, immunology, biology, and medicine. Nevertheless, the field of molecular allergology is moving fast, and after 6 years, a new EAACI Taskforce was established to provide an updated document. The Molecular Allergology User's Guide 2.0 summarizes state-of-the-art information on allergen molecules, their clinical relevance, and their application in diagnostic algorithms for clinical practice. It is designed for both, clinicians and scientists, guiding health care professionals through the overwhelming list of different allergen molecules available for testing. Further, it provides diagnostic algorithms on the clinical relevance of allergenic molecules and gives an overview of their biology, the basic mechanisms of test formats, and the application of tests to measure allergen exposure.
Custovic A, Fontanella S, Haider S, 2023, Reply to Beck et al. and to Owora, American Journal of Respiratory and Critical Care Medicine, Vol: 207, Pages: 634-636, ISSN: 1073-449X
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