Identification of eczema clusters and their association with filaggrin and atopic comorbidities: analysis of five birth cohorts

Abstract

Background Longitudinal modelling of the presence/absence of current eczema through childhood has identified similar phenotypes, but their characteristics often differ between studies. Objectives To demonstrate that a more comprehensive description of longitudinal pattern of symptoms may better describe trajectories than binary information on eczema presence. Methods We derived six multidimensional variables of eczema spells from birth to 18 years of age (including duration, temporal sequencing and the extent of persistence/recurrence). Spells were defined as consecutive observations of eczema separated by no eczema across 5 epochs in five birth cohorts: infancy (first year); early childhood (age 2–3 years); preschool/early school age (4–5 years); middle childhood (8–10 years); adolescence (14–18 years). We applied Partitioning 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 FLG mutations. Results Analysis of 7464 participants with complete data identified five clusters: (i) no eczema (51.0%); (ii) early transient eczema (21.6%); (iii) late-onset eczema (LOE; 8.1%); (iv) intermittent eczema (INT; 7.5%); and (v) persistent eczema (PE; 11.8%). There was very-high agreement between the 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 characterized by differences in associations with risk factors (e.g. parental eczema was associated with all clusters apart from LOE; sensitization to inhalant allergens was associated with all clusters, with the highest risk in the PE cluster). All clusters apart from LOE were associated with FLG mutations. Of note, the strongest association was for PE [relative risk ratio (RRR) 2.70, 95% confidence interval (CI) 2.24–3.26; P < 0.001] followed by INT (RRR 2.29, 95% CI 1.82–2.88; P < 0.001). Conclusions Clustering of multidimensional variables identified stable clusters with different genetic architectures. Using multidimensional variables may capture eczema development and derive stable and internally homogeneous clusters. However, deriving homogeneous symptom clusters does not necessarily mean that these are underpinned by completely unique mechanisms.

Understanding the heterogeneity of childhood allergic sensitization and its relationship with asthma

“…Comparable with findings for different phenotypes of wheezing, very similar associations between allergic sensitization and different eczema clusters derived using data-driven methodologies were recently reported [34 ▪ ]. All eczema clusters were associated with allergic sensitization in early-school age (although the risk was highest for persistent eczema).…”

“…Eczema preceded sensitization in the persisting clusters, and at age 1 year, less than 10% of children in the clusters with infantile eczema whose symptoms persisted to adolescence were sensitized; by age 16, approximately half were. In contrast, children with late-onset eczema tended to develop sensitization before the onset of eczema [34 ▪ ].…”

“…To tackle these issues, substantial effort has been devoted over the last 15 years to understanding the heterogeneity of childhood atopic diseases using modern data approaches (reviewed in [23 ▪▪ ,24–27]). These data-driven analyses have revealed hidden/unobservable (latent) structures in the large longitudinal datasets from birth cohort studies; especially noteworthily, the methods have now described different clusters of wheeze/asthma [5,28 ▪ ,29 ▪ ] (reviewed recently in [23 ▪▪ ,30,31]), allergic multimorbidity [32 ▪ ], rhinitis [33], eczema [34 ▪ ,35] and lung function [36,37 ▪ ,38,39 ▪ ]. Important questions which still need to be answered are: (1) whether different clusters of asthma and atopic disease are mechanistically different diseases which are underpinned by different pathophysiological mechanisms [40]; and (2) in the context of this review, whether they differ in their associations with allergic sensitization.…”

Component‐specific clusters for diagnosis and prediction of allergic airway diseases

“…using IgE titre or size of skin test response rather than commonly used cut‐offs to define sensitization) can increase the specificity (both in terms of diagnostic accuracy 9,10 and the capacity to predict the persistence of symptoms 11 ), but the problem of false‐positive test results remains 2,12 . Accurate prediction based on a biologically sound interpretation is further complicated by the heterogeneity of both allergic sensitization 13,14 and allergic diseases 15–18 …”

Neonatal Vitamin D and Associations with Longitudinal Changes of Eczema up to 25 Years of Age

“…Recently, it has been suggested that there are different childhood eczema phenotypes, based on when symptoms occur or concomitant sensitization, which may have different underlying causes [27,28]. Yet there were no existing studies that have examined the associations between neonatal vitamin D and longitudinal eczema or eczema/sensitization phenotypes from infancy to young adulthood.…”