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Eczema phenotypes and risk of allergic and respiratory conditions in school age children

Eczema phenotypes and risk of allergic and respiratory conditions in school age children Background: Eczema phenotypes based on eczema onset and persistence might better identify groups prone to allergic and respiratory conditions than a binary definition of eczema. We examined the associations of childhood eczema phenotypes with allergic sensitization, allergy, asthma and lung function at school age. Methods: This study among 4277 children was embedded in a multi-ethnic population-based prospective cohort study. Five eczema phenotypes (never, early transient, mid-transient, late transient, persistent) based on parental- reported physician-diagnosed eczema from age 6 months until 10 years were identified. At age 10 years, allergic sensitization was measured by skin prick tests, physician-diagnosed allergy and asthma by parent-reported question- naires, and lung function by spirometry. Adjusted linear, logistic and multinomial regression models were applied. Results: Compared with never eczema, all eczema phenotypes were associated with increased risks of asthma (odds ratios (OR) range (95% confidence interval): 2.68 (1.58, 4.57) to 11.53 (6.65, 20.01)), food and inhalant allergic sensitiza- tion (1.72 (1.25, 2.36) to 12.64 (7.20, 22.18)), and physician-diagnosed inhalant allergy (1.92 (1.34, 2.74) to 11.91 (7.52, 18.86)). Strongest effect estimates were observed of early and persistent eczema with the risk of physician-diagnosed food allergy (OR 6.95 (3.76, 12.84) and 35.05 (18.33, 70.00), respectively) and combined asthma and physician-diag- nosed allergy (7.11 (4.33, 11.67) and 29.03 (15.27, 55.22), respectively). Eczema phenotypes were not associated with lung function measures. Conclusion: Eczema phenotypes were differentially associated with risks of respiratory and allergic conditions in school-aged children. Children with early transient and persistent eczema might benefit from more intense follow-up for early identification and treatment of asthma and allergies. Keywords: Eczema, Birth cohort, Child, Asthma, Allergy [2]. It has been suggested that children with eczema and Background food allergies in early life develop asthma and allergic Childhood eczema is a chronic disease with variable onset rhinitis in later life, which has been referred to as the and persistence over time. The prevalence of eczema is up atopic march [3]. However, previous results of longitu- to 25% in infancy and diminishes over time [1]. Eczema is dinal cohorts only found a small proportion of children strongly associated with asthma and allergic sensitization with eczema that follow this atopic march [4]. This might partly be explained by the definition of eczema used in *Correspondence: l.duijts@erasmusmc.nl these studies. In recent years, eczema phenotypes have Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands been introduced in epidemiologic research to replace Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Hu et al. Clin Transl Allergy (2020) 10:7 Page 2 of 8 the binary definition of eczema, as they incorporate the parental-reported questionnaires at 10 years of age (‘Has variability in age of onset and persistence of eczema, and your child ever had eczema diagnosed by a doctor?’). therefore allow identification of specific underlying risk factors which can be used to optimize personalized pre- Lung function, asthma and allergy ventative strategies and improve public health [5]. Also, Children visited the research center at a median age of eczema phenotypes could better identify children that 9.7  years (2.5–97.5th percentile range 9.3–10.3  years). may be at risk for developing asthma and allergy. Results Information on lung function was measured by spirom- of previous studies using longitudinal birth cohorts etry and included forced expiratory volume in 1  sec- showed that all identified eczema phenotypes in early ond (FEV ), forced vital capacity (FVC), FEV /FVC, 1 1 life were associated with up to sevenfold increased risks and forced expiratory flow after exhaling 75% of FVC of asthma and allergy in later life, compared to the never (FEF ). Lung function measures were converted into eczema phenotype [6, 7]. The strongest association was sex-, height-, age-, and ethnicity-adjusted z-scores [11, observed for the persistent eczema phenotype in rela- 12]. Information on current asthma, and physician-diag- tion to asthma and allergy. However, the eczema pheno- nosed inhalant and food allergy were adapted from the types are not yet determined in non-Caucasian children, International Study on Asthma and Allergy in Childhood related to lung function or comprehensive allergy out- (ISAAC) [13]. Current asthma (no; yes) was defined as comes in older childhood. ever diagnosis of asthma with wheezing or medication Therefore, we examined in a multi-ethnic population- use in the past 12  months at 10  years of age. Parental based prospective cohort of 4277 children the asso- reported questionnaires were used to define physician- ciations of eczema phenotypes from birth until 10  years diagnosed inhalant allergy (“Was your child ever diag- with lung function, asthma, allergic sensitization, and nosed by a physician with an allergy to pollen (hay fever)/ allergy at school-age. house dust mite/cat/dog?”) (no; yes) and food allergy (“Was your child ever diagnosed by a physician with an Methods allergy to cashew nut/peanut?”) (no; yes) at age 10 years. Design Additionally, information on allergic rhinitis, a more This study was embedded in the Generation R Study, a detailed question on inhalant allergy, was obtained by population-based prospective cohort study from early a parental reported questionnaire (“Did your child had fetal life onwards in Rotterdam, the Netherlands [8]. The any sneezing, running nose or stuffed nose in the last study has been approved by the Medical Ethical Com- 12  months, even though he or she did not have a cold mittee of the Erasmus MC University Medical Centre or flu?” (no; yes). Information on allergic sensitization in Rotterdam. Written informed consent was obtained was collected by skin prick tests using the scanned area from parents or legal guardians. Children were excluded method [14, 15]. We examined the most prevalent food from the current analyses if information was missing on allergens for children at age 10  years at a population- physician-diagnosed eczema for more than 3 time points based level, and therefore allergens for milk and egg were and if information on lung function, asthma and allergic excluded [16, 17]. Inhalant allergens included house dust sensitization were missing. A total of 4277 children were mite, 5-grass mixture, birch, cat, and dog. Food allergens included for the current analyses (Additional file  1: Fig- included hazelnut, cashew nut, peanut and peach. Details ure S1). on the collection of lung function, asthma and allergy measures are provided in the Additional file 1. Eczema phenotypes Information on eczema was obtained from parental- Covariates reported questionnaires at the age of 6 months, and 1, 2, Information on parity, maternal education, and parental 3, 4 and 10 years (‘Was your child diagnosed with eczema history of eczema, allergy or asthma was available from in the last 6 months/last year by a general practitioner or parental questionnaires obtained at enrolment. Child’s physician in the hospital?’) [9]. As previously described, sex was obtained from midwives and hospital records, in children with available data on at least 3 time points and ethnic origin based on the parents’ country of birth between age 6  months to 10  years, latent class growth according to Statistics Netherlands [18]. Postnatal ques- analysis was used to assign children to their latent classes tionnaires provided information on breastfeeding at 2, 6 based on their respective posterior probabilities [10]. Five or 12 months after birth. eczema phenotypes were identified based on the vari - ous eczema trajectories: never, early transient, mid-tran- Statistical analysis sient, late transient and persistent eczema (Additional Linear, logistic and multinomial regression models were file  1: Figure S2). Data on ever eczema was collected by used to examine the association of eczema phenotypes Hu  et al. Clin Transl Allergy (2020) 10:7 Page 3 of 8 with lung function measures, risk of asthma, allergic Table 1 Characteristics of children and their mothers sensitization or physician-diagnosed allergy, and com- Subjects bined allergic outcomes, respectively, using the pack- n = 4277 ages ‘mice’ (version 3.3.0), ‘stats’ (version 3.5.2) and ‘nnet Maternal characteristics (version 7.3–12) in R version 3.5.2 [19–21]. The analyses Age at enrollment, years mean (SD) 31.7 (4.5) were adjusted for potential confounders, selected from Parity, nulliparous % (n) 59 (2526) literature if they were related with both eczema pheno- Maternal education, higher % (n) 59 (2510) types and the outcome and were not in the causal path- History of eczema, allergy and asthma, yes % (n) 61 (2597) way. In order to examine inhalant allergies in detail, we Child characteristics also examined the correlation between physician-diag- Sex, female % (n) 51 (2181) nosed inhalant allergy and allergic rhinitis, and the asso- Gestational age at birth, weeks median (2.5–97.5th 40.1 (35.5–42.3) ciations of eczema phenotypes with allergic rhinitis. To percentile) study the role of ethnicity in more detail, we performed a Birth weight, grams mean (SD) 3443.1 (566.9) sensitivity analysis by stratifying for ethnicity (European Ethnicity, non-European % (n) 24 (1006) or non-European). We only present the results based on Breastfeeding, ever % (n) 93 (3961) imputed data, because the size and direction of effects Eczema, ever % (n) 23 (859) were similar in complete-case-analysis. We did not adjust Eczema phenotypes % (n) for multiple testing, because the respiratory and allergic Never 76 (3229) measures were related to each other, and examined under Early transient 9 (363) the same hypothesis. More information on the statistical Mid-transient 6 (259) analyses is provided in the Additional file  1. All measures Late transient 8 (333) of association are presented as pooled z-score change Persistent 2 (93) or odds ratios (OR) with their corresponding 95% confi - Current asthma, yes % (n) 5 (203) dence intervals (95% CI). Inhalant sensitization, yes % (n) 32 (985) Food sensitization, yes % (n) 7 (209) Physician diagnosed inhalant allergy, yes % (n) 12 (447) Results a Allergic rhinitis, yes % (n) 20.6 (734) Subject characteristics b Physician diagnosed food allergy, yes % (n) 2 (79) Characteristics of children and their mothers are sum- a Lung function, Z-scores mean (SD) marized in Table  1. For each eczema phenotype, the FVC 0.18 (0.91) prevalence of current asthma, physician-diagnosed food FEV 0.13 (0.96) allergy and inhalant allergy are presented in Fig.  1. Co- FEV /FVC − 0.12 (0.95) occurrence of these comorbidities was most prevalent FEF − 0.00 (0.91) in the persistent eczema group (range 1–19%). Main Values are percentages (absolute values), mean (SD) or median (2.5–97.5th results of loss-to-follow-up analysis showed that children a percentile) after imputation. Data was missing and not imputed for gestational age at birth (0.2%), birth weight (0.1%), ever eczema (11.6%), allergic rhinitis not included in the analyses more often had mothers of (26.9%), and lung function (11.5%). Data on the following outcomes were younger age, multiparity, lower education and no history not imputed for the individual analysis and were missing for: current asthma of eczema, allergy or asthma, and more often had lower (9.7%), inhalant (26.9%) and food sensitization (27.1%), physician diagnosed inhalant (10.9%) and food allergy (12.7%). They were imputed for the combined birth weight, a male sex and a non-European ethnicity outcome analysis and values are for current asthma (yes) 6% (n = 237), inhalant mostly of Moroccan, Turkish and Cape Verdean ethnicity sensitization (yes) 33% (n = 1394), food sensitization (yes) 8% (n = 336), physician-diagnosed inhalant allergy (yes) 12% (n = 521) and physician- (Additional file 1: Table S1). diagnosed food allergy (yes) 3% (n = 105) Eczema phenotypes, lung function and current asthma Compared with never eczema, ever eczema was associ- change (95% CI) 0.11 (0.00, 0.21)) (Table 2). All eczema ated with a higher FVC and FEV (Z score change (95% phenotypes were associated with an increased risk of CI): 0.08 (0.01, 0.16) to 0.08 (0.00, 0.16), respectively), current asthma at the age of 10  years with the strong- but not with FEV /FVC and FEF . Ever eczema was 1 75 est effect estimates for early transient and persistent associated with an increased risk of current asthma eczema (OR (95% CI) 4.82 (3.29, 7.08) and 11.53 (6.65, (OR (95% CI): 6.38 (4.61, 8.83) (Table  2). When exam- 20.01)). Similar size and direction of effect estimates ining eczema phenotypes, we observed that compared were observed among children of European and non- with the never eczema phenotype, only late transient European ethnicity (Additional file  1: Tables S2 and S3). eczema was associated with a higher FVC (Z score Hu et al. Clin Transl Allergy (2020) 10:7 Page 4 of 8 Fig. 1 Prevalence of current asthma, physician diagnosed food and inhalant allergy in eczema phenotype. Values are percentages (absolute values) and based on observed data. n = number of participants with information on current asthma or physician diagnosed allergies, and at least 3 eczema measurements Table 2 Associations of eczema phenotypes with lung function and current asthma in children at age 10 years FVC FEV FEV /FVC FEF Current asthma at 10 years 1 1 75 Z-score (95% CI) Z-score (95% CI) Z-score (95% CI) Z-score (95% CI) odds ratio (95% CI) Never eczema Reference Reference Reference Reference Reference Ever eczema 0.08 (0.01, 0.16) 0.08 (0.00, 0.16) 0.00 (− 0.07, 0.08) 0.02 (− 0.05, 0.09) 6.38 (4.61, 8.83) Never Reference Reference Reference Reference Reference Early transient 0.04 (− 0.07, 0.14) 0.00 (− 0.10, 0.11) − 0.02 (− 0.23, 0.19) − 0.05 (− 0.15, 0.05) 4.82 (3.29, 7.08) Mid-transient − 0.07 (− 0.20, 0.05) − 0.08 (− 0.21, 0.05) − 0.04 (− 0.15, 0.07) − 0.03 (− 0.15, 0.09) 2.68 (1.58, 4.57) Late transient 0.11 (0.00, 0.21) 0.05 (− 0.06, 0.16) − 0.11 (− 0.22, 0.00) − 0.03 (− 0.13, 0.08) 3.07 (1.94, 4.87) Persistent 0.04 (− 0.16, 0.24) 0.00 (− 0.21, 0.21) − 0.02 (− 0.23, 0.19) − 0.00 (− 0.20, 0.19) 11.53 (6.65, 20.01) Values are Z-score mean differences for lung function measurements and odds ratios (95% confidence intervals) for current asthma from linear and logistic regression models for never/ever eczema. Values are average Z-score mean differences for lung function measurements and average odds ratios (95% confidence intervals) for current asthma from linear and logistic regression models, respectively, after multiple sampling based on 150 imputed datasets for eczema phenotypes. Lung function outcomes are force expiratory volume in 1 second (FEV ), forced vital capacity (FVC), force expiratory flow at 75% of the exhaled FVC (FEF ). Full models 1 75 were adjusted for parental history of allergy, asthma or eczema, maternal education, parity, child’s sex, ethnicity and breastfeeding. Italic values indicate statistical significance at the α = 0.05 level Hu  et al. Clin Transl Allergy (2020) 10:7 Page 5 of 8 Eczema phenotypes, allergic sensitization physician-diagnosed allergy only (OR (95% CI) 5.83 and physician-diagnosed allergies (3.49, 9.74) and 4.03 (3.17, 5.11)), and most strongly Compared with never eczema, ever eczema was associ- with asthma and physician-diagnosed allergy combined ated with increased risks of allergic sensitization and (8.98 (5.89, 13.69)) (Table  4). Compared with never physician-diagnosed allergies for both inhalant and food eczema phenotypes, early transient and persistent allergens. The strongest association was observed for ever eczema were most strongly associated with asthma only eczema with physician diagnosed food allergy (OR (95% (OR (95% CI) 5.36 (3.07, 9.36) and 5.23 (1.55, 17.63)), CI) 11.89 (6.85, 20.61)) (Table  3). Of the eczema pheno- physician-diagnosed allergy only (3.68 (2.67, 5.08) and types, the early transient and persistent phenotypes were 10.02 (5.92, 16.96)), and asthma and physician-diag- most strongly associated with increased risks of inhalant nosed allergy combined (7.11 (4.33, 11.67) and 29.03 allergic sensitization (OR (95% CI) 2.62 (2.01, 3.42) and (15.27, 55.22)). Effect estimates for eczema pheno - 4.53 (2.65, 7.51)), food allergic sensitization (OR (95% CI) types were in the same direction and higher odds were 5.73 (3.94, 8.31) and 12.64 (7.20, 22.18)), physician-diag- observed when physician-diagnosed food and inhalant nosed inhalant allergy (OR (95% CI) 3.72 (2.78, 4.97) and allergy were combined and when physician-diagnosed 11.91 (7.52, 18.86)) and physician-diagnosed food allergy food and inhalant allergies were combined with asthma (OR (95% CI) 6.95 (3.76, 12.84) and 35.05 (18.33, 70.00)) (Additional file 1 : Table S6). (Table 3). Physician-diagnosed inhalant allergy and aller- gic rhinitis were correlated (Cramer’s  V (Chi square p value) 0.50 (≤ 0.001)). The observed effect estimates of Discussion the associations of eczema phenotypes with allergic rhi- In this multi-ethnic population-based prospective nitis were in the same direction, but less greater, versus cohort study, eczema phenotypes were differentially those of eczema phenotypes with physician-diagnosed associated with the risk of allergic and respiratory con- inhalant allergy (OR range (95% CI) 1.43 (1.02, 2.00) and ditions in school-aged children. The early transient 4.91 (3.14, 7.66) versus 1.92 (1.34, 2.74) and 11.91 (7.52, and persistent eczema phenotypes were most consist- 18.86), respectively) (Additional file  1: Table  S4). Simi- ently associated with asthma, allergic sensitization, lar size and direction of effect estimates were observed and physician-diagnosed allergies, including allergic among children of European and non-European eth- rhinitis. Results were similar for children of European nicity (Additional file  1: Tables S2 and S3). Effect esti - and non-European ethnicity. Stronger effect estimates mates were in the same direction and stronger if a child were observed for early transient and persistent eczema had both allergic sensitization and physician-diagnosed phenotypes with food allergy related measures and allergy (Additional file 1: Table S5). combined asthma and physician-diagnosed allergies. Compared with never eczema, ever eczema was asso- Eczema phenotypes, asthma and physician-diagnosed ciated with higher FVC and FEV , but not with FEV / 1 1 allergy combined FVC. Eczema phenotypes were not associated with any Compared with never eczema, ever eczema was asso- lung function measurement. ciated with increased risks of both asthma only and Table 3 Associations of  eczema phenotypes with  allergic sensitization and  physician-diagnosed allergies in  children at age 10 years Inhalant sensitization Food sensitization Physician-diagnosed Physician-diagnosed odds ratio (95% CI) odds ratio (95% CI) inhalant allergy food allergy odds ratio (95% CI) odds ratio (95% CI) Never eczema Reference Reference Reference Reference Ever eczema 2.91(2.41, 3.52) 4.90 (3.60, 6.67) 4.54 (3.65, 5.63) 11.89 (6.85, 20.61) Never Reference Reference Reference Reference Early transient 2.62 (2.01, 3.42) 5.73 (3.94, 8.31) 3.72 (2.78, 4.97) 6.95 (3.76, 12.84) Mid-transient 1.72 (1.25, 2.36) 2.13 (1.21, 3.76) 2.66 (1.86, 3.80) 1.44 (0.43, 4.80) Late transient 1.77 (1.33, 2.35) 2.52 (1.56, 4.07) 1.92 (1.34, 2.74) 4.50 (2.19, 9.28) Persistent 4.53 (2.65, 7.51) 12.64 (7.20, 22.18) 11.91 (7.52, 18.86) 35.05 (18.33, 70.00) Values are odds ratios (95% confidence intervals) from logistic regression models for never/ever eczema and average odds ratios (95% confidence intervals) from logistic regression models after multiple sampling based on 150 imputed datasets for eczema phenotypes. Full models were adjusted for parental history of allergy, asthma or eczema, maternal education, parity, child’s sex, ethnicity and breastfeeding. Italic values indicate statistical significance at the α = 0.05 level Hu et al. Clin Transl Allergy (2020) 10:7 Page 6 of 8 Table 4 Association of  eczema phenotypes with  combined asthma and  physician-diagnosed allergy groups in  children at age 10 years Asthma, but no allergy Allergy, but no asthma Asthma and allergy n = 97 n = 413 n = 140 Never eczema Reference Reference Reference Ever eczema 5.83 (3.49, 9.74) 4.03 (3.17, 5.11) 8.98 (5.89, 13.69) Never Reference Reference Reference Early transient 5.36 (3.07, 9.36) 3.68 (2.67, 5.08) 7.11 (4.33, 11.67) Mid-transient 1.37 (0.45, 4.19) 2.21 (1.47, 3.32) 4.31 (2.33, 7.99) Late transient 2.94 (1.47, 5.89) 1.76 (1.18, 2.64) 3.48 (1.88, 6.44) Persistent 5.23 (1.55, 17.63) 10.02 (5.92, 16.96) 29.03 (15.27, 55.22) Values are odds ratios (95% confidence intervals) from logistic regression models for never/ever eczema and average odds ratios (95% confidence intervals) from multinomial regression models after multiple sampling based on 150 imputed datasets for eczema phenotypes. Reference group is no asthma and no allergy (n = 3627). n = number of participants with information on at least 3 eczema measurements. Missing data on asthma and physician-diagnosed allergy was imputed. Full models were adjusted for parental history of allergy, asthma or eczema, maternal education, parity, child’s sex, ethnicity and breastfeeding. Italic values indicate statistical significance at the α = 0.05 level Comparison with previous studies These observed differences might be due to differences When comparing results with previous studies, the dif- in number of children included for analysis, food allergy ference in eczema phenotype definition and follow-up prevalence, eczema phenotypes definition and because duration need to be taken into account. Previous cohort our population has a longer follow-up which allowed studies showed that children with early-onset and persis- the identification of more diverse phenotypes. A cohort tent eczema phenotypes have increased risks of asthma at study in children until age 6  years showed that children ages 6 to 13 year [6, 7]. Results for mid- and late transient with early transient and persistent eczema had increased eczema phenotypes and the risk of asthma are inconsist- risks of food allergy and allergic rhinitis [7]. We observed ent. Our observations in a multi-ethnic population are similar results among children until age 10  years with in line with previous findings and support that children allergic sensitization and physician-diagnosed food and with any eczema phenotype, but especially those with inhalant allergies. Many children among the early tran- early onset and persistent eczema have increased risks of sient and persistent eczema phenotype group had both asthma at school-age [22, 23]. While eczema is strongly asthma and multiple allergic conditions, and a large per- related to asthma and therefore hypothetically also with centage of these (31–61%) had at least one diagnosis of altered lung function, the relationship between eczema asthma, food or inhalant allergy. Therefore, our results do and lung function has not been studied. We observed not support the atopic march hypothesis in all children that children with ever eczema had slightly higher FEV with eczema, but does show that in particular children and FVC, but no changes in FEV /FVC. These findings with early transient and persistent eczema are likely to might be incidental, since there were no associations of develop asthma and/or allergies later in childhood. eczema phenotypes with lung function measures. Other mechanisms might underlie the observed associations of Possible mechanisms ever eczema and eczema phenotypes with asthma, such Early transient and especially persistent eczema consist- as inhalant allergies and possible modulating effects of ently showed the strongest associations with asthma and early allergic sensitization and allergic rhinitis [24]. Also allergic conditions. A common trait of both phenotypes all children included in our analysis had higher FEV and is the early onset of eczema, suggesting that the period FVC z-scores, which might be explained by a relatively before the age of 2  years of age was important for the healthy study population or well-controlled asthma. development of asthma and allergic conditions. Matu- Previous studies showed that persistent eczema was ration rates of the skin, lungs and immune system from associated with elevated total Immunoglobulin E levels at birth until 2 years are high and any change or disruption ages 7–8  years, and with an increased risk of sensitiza- of these maturation processes might have long term con- tion to inhalant allergens, but not to food allergens at age sequences [25]. Proposed mechanisms include dysfunc- 6  years [6, 7]. We showed that children with early tran- tion of the epithelial barrier due to microbial and/or sient and persistent eczema phenotypes had both allergic genetic factors and transcutaneous sensitization, lead- sensitization and physician-diagnosed allergies, with the ing to type 2 inflammation, and thereby predisposing to strongest effect estimates for food allergy at age 10 years. asthma and allergic conditions [25–27]. Our recent study Hu  et al. Clin Transl Allergy (2020) 10:7 Page 7 of 8 showed an association of the four most common filag - eczema might benefit from more intense follow-up grin mutations in Europeans with early and late transient for early identification and treatment of asthma and eczema, but not with persistent eczema [10]. Unfortu- allergies. nately, we were not able to study filaggrin mutations as mediators for the association of eczema phenotypes with Supplementary information asthma and allergic conditions due to lack of power. Also Supplementary information accompanies this paper at https ://doi. org/10.1186/s1360 1-020-0310-7. sensitivity analysis in more detailed non-European eth- nic subgroups was not possible due to small sample size. Additional file 1: Table S1. Characteristics of children and their mothers Therefore, future studies with larger sample sizes are of those included and not included in the analyses. Table S2. Associations needed to examine the potential mediating role of filag - of eczema phenotypes with asthma, allergic sensitization and physician- grin mutations on the associations of eczema phenotypes diagnosed allergies in children of European ethnicity at age 10 years. Table S3. Associations of eczema phenotypes with current asthma, with asthma and allergic conditions, and the role of dif- allergic sensitization and physician-diagnosed allergies in children of ferent ethnicities. non-European ethnicity at age 10 years. Table S4. Associations of eczema phenotypes with allergic rhinitis in children at age 10 years. Table S5. Association of eczema phenotypes with combined allergic sensitiza- tion and physician-diagnosed allergy groups in children at age 10 years. Strengths and limitations Table S6. Association of eczema phenotypes with combined asthma, The strengths of this study include the eczema pheno - physician-diagnosed inhalant and food allergy groups in children at types among a multi-ethnic population with detailed age 10 years. Figure S1. Flow chart of participants included for analysis. Figure S2. Previously identified eczema phenotypes trajectories in 5297 information on asthma, lung function, and multiple aller- children from latent class growth analysis. gic conditions. By using multivariate regression models with multiple imputation and sampling we achieved more Abbreviations precise and unbiased effect estimates. However, some ATS: American Thoracic Society; CI: Confidence interval; ERS: European methodological considerations need to be taken into Respiratory Society; FEF : Forced expiratory flow after exhaling 75% of FVC; account. Children not included in the analyses partly had FEV : Forced expiratory volume in 1 second; FVC: Forced vital capacity; ISAAC: International Study of Asthma and Allergies in Childhood; OR: Odds ratio; SPT: less favourable socio-economic factors and more often Skin prick test. parents with no history or eczema, allergy or asthma. Selection bias due to lost to follow-up might have been Acknowledgements The Generation R Study is conducted by the Erasmus Medical Center in close present if the associations of eczema phenotypes with collaboration with the School of Law and Faculty of Social Sciences of the respiratory and allergic conditions were different in chil - Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, dren that were not included in the analyses compared to Rotterdam, the Rotterdam Homecare Foundation, Rotterdam, and the Sticht- ing Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. the children that were included in the analyses. We aimed We gratefully acknowledge the contribution of children and parents, general to minimize bias by imputation methods [20]. Despite practitioners, hospitals, midwives, and pharmacies in Rotterdam. The Genera- validated questions, misclassification of eczema, asthma tion R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam and the Netherlands and physician diagnosed allergies remains possible due Organization for Health Research and Development. to self-response [13, 28]. We included the most relevant allergens for children of age 10 years at population level, Authors’ contributions CH, TN, NE and LD contributed to the conception and design, acquisition and excluded allergens with low sensitization rates at this of data, analyses and interpretation of the data, drafted the article, revised age, such as milk and egg [16, 17]. Residual confounding it critically for important intellectual content, and gave final approval of the might be present since there might be factors not meas- version to be published. EM, CP, NJ, SP and JJ contributed to the conception and design, acquisition of data, revised the drafted manuscript critically for ured or not included in our analysis. For example, there important intellectual content, and gave final approval of the version to be was no information available to determine the severity published. All authors read and approved the final manuscript. of eczema. Furthermore, we were unable to perform our Funding analyses in more detailed ethnic groups due to lack of The Generation R Study is made possible by financial support from the power [29]. Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development. The study received funding from the European Union’s Horizon 2020 research and innovation programme (LIFECYCLE project, Grant Agreement No 733206; Conclusion 2016). The project received funding from Nestlé Skin Health-Galderma R&D Eczema phenotypes were differentially associated with (Grant Agreement No 35195; 2016). Dr Liesbeth Duijts received funding for risks of asthma and allergic conditions among school- projects from the European Union’s Horizon 2020 research and innovation programma (LIFECYCLE, grant agreement No 733206, 2016; EUCAN-Connect, aged children, and were similar in children from Euro- grant agreement No 824989; and ALPHABET, grant agreements No 696295 pean and non-European ethnicity. The strongest and and Zon MW No 529051014; 2017). most consistent associations were found in children Availability of data and materials with early transient and persistent eczema. This sug - Data requests can be made to the secretariat of the Generation R Study. gests that children with early transient and persistent Hu et al. Clin Transl Allergy (2020) 10:7 Page 8 of 8 Ethics approval and consent to participate of early-life respiratory tract infections on school-age lung function and The study has been approved by the Medical Ethical Committee of the Eras- asthma. Thorax. 2018;73(2):167–73. mus MC University Medical Centre in Rotterdam. Written informed consent 12. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi- was obtained from parents or legal guardians. ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324–43. Consent for publication 13. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, et al. Interna- Not applicable. tional Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J. 1995;8(3):483–91. Competing interests 14. Elbert NJ, Duijts L, den Dekker HT, de Jong NW, Nijsten TE, Jaddoe VW, Christophe Piketty is employed by Galderma Research & Development. Other et al. Maternal psychiatric symptoms during pregnancy and risk of child- authors have no potential competing interests to disclose. hood atopic diseases. Clin Exp Allergy. 2017;47(4):509–19. 15. van der Valk JP, Gerth van Wijk R, Hoorn E, Groenendijk L, Groenendijk IM, Author details de Jong NW. Measurement and interpretation of skin prick test results. The Generation R Study Group, Erasmus MC, University Medical Center Rot- Clin Transl Allergy. 2015;6:8. terdam, Rotterdam, The Netherlands. Department of Dermatology, Erasmus 16. Roberts G, Zhang H, Karmaus W, Raza A, Scott M, Matthews S, et al. Trends MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. in cutaneous sensitization in the first 18 years of life: results from the 1989 Department of Pediatrics, Erasmus MC, University Medical Center Rot- Isle of Wight birth cohort study. Clin Exp Allergy. 2012;42(10):1501–9. terdam, Rotterdam, The Netherlands. Department of Biostatistics, Erasmus 17. Venkataraman D, Erlewyn-Lajeunesse M, Kurukulaaratchy RJ, Potter S, MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Roberts G, Matthews S, et al. Prevalence and longitudinal trends of food CUTIS (Clinical Unit for Tests and Imaging of Skin), Evaluation Department, allergy during childhood and adolescence: results of the Isle of Wight Nestlé Skin Health/Galderma Research and Development, Sophia-Antipolis, Birth Cohort study. Clin Exp Allergy. 2018;48(4):394–402. France. Department of Internal Medicine, Division of Allergology & Clinical 18. 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Elbert NJ, van Meel ER, den Dekker HT, de Jong NW, Nijsten TEC, Jaddoe 2016;27(6):627–35. VWV, et al. Duration and exclusiveness of breastfeeding and risk of child- hood atopic diseases. Allergy. 2017;72(12):1936–43. 10. Hu C, Duijts L, Erler NS, Elbert NJ, Piketty C, Bourdes V, et al. Most associa- Publisher’s Note tions of early-life environmental exposures and genetic risk factors poorly Springer Nature remains neutral with regard to jurisdictional claims in pub- differentiate between eczema phenotypes: the Generation R Study. Br J lished maps and institutional affiliations. Dermatol. 2019;181:1190–7. 11. van Meel ER, den Dekker HT, Elbert NJ, Jansen PW, Moll HA, Reiss IK, et al. A population-based prospective cohort study examining the influence http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical and Translational Allergy Springer Journals

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Abstract

Background: Eczema phenotypes based on eczema onset and persistence might better identify groups prone to allergic and respiratory conditions than a binary definition of eczema. We examined the associations of childhood eczema phenotypes with allergic sensitization, allergy, asthma and lung function at school age. Methods: This study among 4277 children was embedded in a multi-ethnic population-based prospective cohort study. Five eczema phenotypes (never, early transient, mid-transient, late transient, persistent) based on parental- reported physician-diagnosed eczema from age 6 months until 10 years were identified. At age 10 years, allergic sensitization was measured by skin prick tests, physician-diagnosed allergy and asthma by parent-reported question- naires, and lung function by spirometry. Adjusted linear, logistic and multinomial regression models were applied. Results: Compared with never eczema, all eczema phenotypes were associated with increased risks of asthma (odds ratios (OR) range (95% confidence interval): 2.68 (1.58, 4.57) to 11.53 (6.65, 20.01)), food and inhalant allergic sensitiza- tion (1.72 (1.25, 2.36) to 12.64 (7.20, 22.18)), and physician-diagnosed inhalant allergy (1.92 (1.34, 2.74) to 11.91 (7.52, 18.86)). Strongest effect estimates were observed of early and persistent eczema with the risk of physician-diagnosed food allergy (OR 6.95 (3.76, 12.84) and 35.05 (18.33, 70.00), respectively) and combined asthma and physician-diag- nosed allergy (7.11 (4.33, 11.67) and 29.03 (15.27, 55.22), respectively). Eczema phenotypes were not associated with lung function measures. Conclusion: Eczema phenotypes were differentially associated with risks of respiratory and allergic conditions in school-aged children. Children with early transient and persistent eczema might benefit from more intense follow-up for early identification and treatment of asthma and allergies. Keywords: Eczema, Birth cohort, Child, Asthma, Allergy [2]. It has been suggested that children with eczema and Background food allergies in early life develop asthma and allergic Childhood eczema is a chronic disease with variable onset rhinitis in later life, which has been referred to as the and persistence over time. The prevalence of eczema is up atopic march [3]. However, previous results of longitu- to 25% in infancy and diminishes over time [1]. Eczema is dinal cohorts only found a small proportion of children strongly associated with asthma and allergic sensitization with eczema that follow this atopic march [4]. This might partly be explained by the definition of eczema used in *Correspondence: l.duijts@erasmusmc.nl these studies. In recent years, eczema phenotypes have Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands been introduced in epidemiologic research to replace Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Hu et al. Clin Transl Allergy (2020) 10:7 Page 2 of 8 the binary definition of eczema, as they incorporate the parental-reported questionnaires at 10 years of age (‘Has variability in age of onset and persistence of eczema, and your child ever had eczema diagnosed by a doctor?’). therefore allow identification of specific underlying risk factors which can be used to optimize personalized pre- Lung function, asthma and allergy ventative strategies and improve public health [5]. Also, Children visited the research center at a median age of eczema phenotypes could better identify children that 9.7  years (2.5–97.5th percentile range 9.3–10.3  years). may be at risk for developing asthma and allergy. Results Information on lung function was measured by spirom- of previous studies using longitudinal birth cohorts etry and included forced expiratory volume in 1  sec- showed that all identified eczema phenotypes in early ond (FEV ), forced vital capacity (FVC), FEV /FVC, 1 1 life were associated with up to sevenfold increased risks and forced expiratory flow after exhaling 75% of FVC of asthma and allergy in later life, compared to the never (FEF ). Lung function measures were converted into eczema phenotype [6, 7]. The strongest association was sex-, height-, age-, and ethnicity-adjusted z-scores [11, observed for the persistent eczema phenotype in rela- 12]. Information on current asthma, and physician-diag- tion to asthma and allergy. However, the eczema pheno- nosed inhalant and food allergy were adapted from the types are not yet determined in non-Caucasian children, International Study on Asthma and Allergy in Childhood related to lung function or comprehensive allergy out- (ISAAC) [13]. Current asthma (no; yes) was defined as comes in older childhood. ever diagnosis of asthma with wheezing or medication Therefore, we examined in a multi-ethnic population- use in the past 12  months at 10  years of age. Parental based prospective cohort of 4277 children the asso- reported questionnaires were used to define physician- ciations of eczema phenotypes from birth until 10  years diagnosed inhalant allergy (“Was your child ever diag- with lung function, asthma, allergic sensitization, and nosed by a physician with an allergy to pollen (hay fever)/ allergy at school-age. house dust mite/cat/dog?”) (no; yes) and food allergy (“Was your child ever diagnosed by a physician with an Methods allergy to cashew nut/peanut?”) (no; yes) at age 10 years. Design Additionally, information on allergic rhinitis, a more This study was embedded in the Generation R Study, a detailed question on inhalant allergy, was obtained by population-based prospective cohort study from early a parental reported questionnaire (“Did your child had fetal life onwards in Rotterdam, the Netherlands [8]. The any sneezing, running nose or stuffed nose in the last study has been approved by the Medical Ethical Com- 12  months, even though he or she did not have a cold mittee of the Erasmus MC University Medical Centre or flu?” (no; yes). Information on allergic sensitization in Rotterdam. Written informed consent was obtained was collected by skin prick tests using the scanned area from parents or legal guardians. Children were excluded method [14, 15]. We examined the most prevalent food from the current analyses if information was missing on allergens for children at age 10  years at a population- physician-diagnosed eczema for more than 3 time points based level, and therefore allergens for milk and egg were and if information on lung function, asthma and allergic excluded [16, 17]. Inhalant allergens included house dust sensitization were missing. A total of 4277 children were mite, 5-grass mixture, birch, cat, and dog. Food allergens included for the current analyses (Additional file  1: Fig- included hazelnut, cashew nut, peanut and peach. Details ure S1). on the collection of lung function, asthma and allergy measures are provided in the Additional file 1. Eczema phenotypes Information on eczema was obtained from parental- Covariates reported questionnaires at the age of 6 months, and 1, 2, Information on parity, maternal education, and parental 3, 4 and 10 years (‘Was your child diagnosed with eczema history of eczema, allergy or asthma was available from in the last 6 months/last year by a general practitioner or parental questionnaires obtained at enrolment. Child’s physician in the hospital?’) [9]. As previously described, sex was obtained from midwives and hospital records, in children with available data on at least 3 time points and ethnic origin based on the parents’ country of birth between age 6  months to 10  years, latent class growth according to Statistics Netherlands [18]. Postnatal ques- analysis was used to assign children to their latent classes tionnaires provided information on breastfeeding at 2, 6 based on their respective posterior probabilities [10]. Five or 12 months after birth. eczema phenotypes were identified based on the vari - ous eczema trajectories: never, early transient, mid-tran- Statistical analysis sient, late transient and persistent eczema (Additional Linear, logistic and multinomial regression models were file  1: Figure S2). Data on ever eczema was collected by used to examine the association of eczema phenotypes Hu  et al. Clin Transl Allergy (2020) 10:7 Page 3 of 8 with lung function measures, risk of asthma, allergic Table 1 Characteristics of children and their mothers sensitization or physician-diagnosed allergy, and com- Subjects bined allergic outcomes, respectively, using the pack- n = 4277 ages ‘mice’ (version 3.3.0), ‘stats’ (version 3.5.2) and ‘nnet Maternal characteristics (version 7.3–12) in R version 3.5.2 [19–21]. The analyses Age at enrollment, years mean (SD) 31.7 (4.5) were adjusted for potential confounders, selected from Parity, nulliparous % (n) 59 (2526) literature if they were related with both eczema pheno- Maternal education, higher % (n) 59 (2510) types and the outcome and were not in the causal path- History of eczema, allergy and asthma, yes % (n) 61 (2597) way. In order to examine inhalant allergies in detail, we Child characteristics also examined the correlation between physician-diag- Sex, female % (n) 51 (2181) nosed inhalant allergy and allergic rhinitis, and the asso- Gestational age at birth, weeks median (2.5–97.5th 40.1 (35.5–42.3) ciations of eczema phenotypes with allergic rhinitis. To percentile) study the role of ethnicity in more detail, we performed a Birth weight, grams mean (SD) 3443.1 (566.9) sensitivity analysis by stratifying for ethnicity (European Ethnicity, non-European % (n) 24 (1006) or non-European). We only present the results based on Breastfeeding, ever % (n) 93 (3961) imputed data, because the size and direction of effects Eczema, ever % (n) 23 (859) were similar in complete-case-analysis. We did not adjust Eczema phenotypes % (n) for multiple testing, because the respiratory and allergic Never 76 (3229) measures were related to each other, and examined under Early transient 9 (363) the same hypothesis. More information on the statistical Mid-transient 6 (259) analyses is provided in the Additional file  1. All measures Late transient 8 (333) of association are presented as pooled z-score change Persistent 2 (93) or odds ratios (OR) with their corresponding 95% confi - Current asthma, yes % (n) 5 (203) dence intervals (95% CI). Inhalant sensitization, yes % (n) 32 (985) Food sensitization, yes % (n) 7 (209) Physician diagnosed inhalant allergy, yes % (n) 12 (447) Results a Allergic rhinitis, yes % (n) 20.6 (734) Subject characteristics b Physician diagnosed food allergy, yes % (n) 2 (79) Characteristics of children and their mothers are sum- a Lung function, Z-scores mean (SD) marized in Table  1. For each eczema phenotype, the FVC 0.18 (0.91) prevalence of current asthma, physician-diagnosed food FEV 0.13 (0.96) allergy and inhalant allergy are presented in Fig.  1. Co- FEV /FVC − 0.12 (0.95) occurrence of these comorbidities was most prevalent FEF − 0.00 (0.91) in the persistent eczema group (range 1–19%). Main Values are percentages (absolute values), mean (SD) or median (2.5–97.5th results of loss-to-follow-up analysis showed that children a percentile) after imputation. Data was missing and not imputed for gestational age at birth (0.2%), birth weight (0.1%), ever eczema (11.6%), allergic rhinitis not included in the analyses more often had mothers of (26.9%), and lung function (11.5%). Data on the following outcomes were younger age, multiparity, lower education and no history not imputed for the individual analysis and were missing for: current asthma of eczema, allergy or asthma, and more often had lower (9.7%), inhalant (26.9%) and food sensitization (27.1%), physician diagnosed inhalant (10.9%) and food allergy (12.7%). They were imputed for the combined birth weight, a male sex and a non-European ethnicity outcome analysis and values are for current asthma (yes) 6% (n = 237), inhalant mostly of Moroccan, Turkish and Cape Verdean ethnicity sensitization (yes) 33% (n = 1394), food sensitization (yes) 8% (n = 336), physician-diagnosed inhalant allergy (yes) 12% (n = 521) and physician- (Additional file 1: Table S1). diagnosed food allergy (yes) 3% (n = 105) Eczema phenotypes, lung function and current asthma Compared with never eczema, ever eczema was associ- change (95% CI) 0.11 (0.00, 0.21)) (Table 2). All eczema ated with a higher FVC and FEV (Z score change (95% phenotypes were associated with an increased risk of CI): 0.08 (0.01, 0.16) to 0.08 (0.00, 0.16), respectively), current asthma at the age of 10  years with the strong- but not with FEV /FVC and FEF . Ever eczema was 1 75 est effect estimates for early transient and persistent associated with an increased risk of current asthma eczema (OR (95% CI) 4.82 (3.29, 7.08) and 11.53 (6.65, (OR (95% CI): 6.38 (4.61, 8.83) (Table  2). When exam- 20.01)). Similar size and direction of effect estimates ining eczema phenotypes, we observed that compared were observed among children of European and non- with the never eczema phenotype, only late transient European ethnicity (Additional file  1: Tables S2 and S3). eczema was associated with a higher FVC (Z score Hu et al. Clin Transl Allergy (2020) 10:7 Page 4 of 8 Fig. 1 Prevalence of current asthma, physician diagnosed food and inhalant allergy in eczema phenotype. Values are percentages (absolute values) and based on observed data. n = number of participants with information on current asthma or physician diagnosed allergies, and at least 3 eczema measurements Table 2 Associations of eczema phenotypes with lung function and current asthma in children at age 10 years FVC FEV FEV /FVC FEF Current asthma at 10 years 1 1 75 Z-score (95% CI) Z-score (95% CI) Z-score (95% CI) Z-score (95% CI) odds ratio (95% CI) Never eczema Reference Reference Reference Reference Reference Ever eczema 0.08 (0.01, 0.16) 0.08 (0.00, 0.16) 0.00 (− 0.07, 0.08) 0.02 (− 0.05, 0.09) 6.38 (4.61, 8.83) Never Reference Reference Reference Reference Reference Early transient 0.04 (− 0.07, 0.14) 0.00 (− 0.10, 0.11) − 0.02 (− 0.23, 0.19) − 0.05 (− 0.15, 0.05) 4.82 (3.29, 7.08) Mid-transient − 0.07 (− 0.20, 0.05) − 0.08 (− 0.21, 0.05) − 0.04 (− 0.15, 0.07) − 0.03 (− 0.15, 0.09) 2.68 (1.58, 4.57) Late transient 0.11 (0.00, 0.21) 0.05 (− 0.06, 0.16) − 0.11 (− 0.22, 0.00) − 0.03 (− 0.13, 0.08) 3.07 (1.94, 4.87) Persistent 0.04 (− 0.16, 0.24) 0.00 (− 0.21, 0.21) − 0.02 (− 0.23, 0.19) − 0.00 (− 0.20, 0.19) 11.53 (6.65, 20.01) Values are Z-score mean differences for lung function measurements and odds ratios (95% confidence intervals) for current asthma from linear and logistic regression models for never/ever eczema. Values are average Z-score mean differences for lung function measurements and average odds ratios (95% confidence intervals) for current asthma from linear and logistic regression models, respectively, after multiple sampling based on 150 imputed datasets for eczema phenotypes. Lung function outcomes are force expiratory volume in 1 second (FEV ), forced vital capacity (FVC), force expiratory flow at 75% of the exhaled FVC (FEF ). Full models 1 75 were adjusted for parental history of allergy, asthma or eczema, maternal education, parity, child’s sex, ethnicity and breastfeeding. Italic values indicate statistical significance at the α = 0.05 level Hu  et al. Clin Transl Allergy (2020) 10:7 Page 5 of 8 Eczema phenotypes, allergic sensitization physician-diagnosed allergy only (OR (95% CI) 5.83 and physician-diagnosed allergies (3.49, 9.74) and 4.03 (3.17, 5.11)), and most strongly Compared with never eczema, ever eczema was associ- with asthma and physician-diagnosed allergy combined ated with increased risks of allergic sensitization and (8.98 (5.89, 13.69)) (Table  4). Compared with never physician-diagnosed allergies for both inhalant and food eczema phenotypes, early transient and persistent allergens. The strongest association was observed for ever eczema were most strongly associated with asthma only eczema with physician diagnosed food allergy (OR (95% (OR (95% CI) 5.36 (3.07, 9.36) and 5.23 (1.55, 17.63)), CI) 11.89 (6.85, 20.61)) (Table  3). Of the eczema pheno- physician-diagnosed allergy only (3.68 (2.67, 5.08) and types, the early transient and persistent phenotypes were 10.02 (5.92, 16.96)), and asthma and physician-diag- most strongly associated with increased risks of inhalant nosed allergy combined (7.11 (4.33, 11.67) and 29.03 allergic sensitization (OR (95% CI) 2.62 (2.01, 3.42) and (15.27, 55.22)). Effect estimates for eczema pheno - 4.53 (2.65, 7.51)), food allergic sensitization (OR (95% CI) types were in the same direction and higher odds were 5.73 (3.94, 8.31) and 12.64 (7.20, 22.18)), physician-diag- observed when physician-diagnosed food and inhalant nosed inhalant allergy (OR (95% CI) 3.72 (2.78, 4.97) and allergy were combined and when physician-diagnosed 11.91 (7.52, 18.86)) and physician-diagnosed food allergy food and inhalant allergies were combined with asthma (OR (95% CI) 6.95 (3.76, 12.84) and 35.05 (18.33, 70.00)) (Additional file 1 : Table S6). (Table 3). Physician-diagnosed inhalant allergy and aller- gic rhinitis were correlated (Cramer’s  V (Chi square p value) 0.50 (≤ 0.001)). The observed effect estimates of Discussion the associations of eczema phenotypes with allergic rhi- In this multi-ethnic population-based prospective nitis were in the same direction, but less greater, versus cohort study, eczema phenotypes were differentially those of eczema phenotypes with physician-diagnosed associated with the risk of allergic and respiratory con- inhalant allergy (OR range (95% CI) 1.43 (1.02, 2.00) and ditions in school-aged children. The early transient 4.91 (3.14, 7.66) versus 1.92 (1.34, 2.74) and 11.91 (7.52, and persistent eczema phenotypes were most consist- 18.86), respectively) (Additional file  1: Table  S4). Simi- ently associated with asthma, allergic sensitization, lar size and direction of effect estimates were observed and physician-diagnosed allergies, including allergic among children of European and non-European eth- rhinitis. Results were similar for children of European nicity (Additional file  1: Tables S2 and S3). Effect esti - and non-European ethnicity. Stronger effect estimates mates were in the same direction and stronger if a child were observed for early transient and persistent eczema had both allergic sensitization and physician-diagnosed phenotypes with food allergy related measures and allergy (Additional file 1: Table S5). combined asthma and physician-diagnosed allergies. Compared with never eczema, ever eczema was asso- Eczema phenotypes, asthma and physician-diagnosed ciated with higher FVC and FEV , but not with FEV / 1 1 allergy combined FVC. Eczema phenotypes were not associated with any Compared with never eczema, ever eczema was asso- lung function measurement. ciated with increased risks of both asthma only and Table 3 Associations of  eczema phenotypes with  allergic sensitization and  physician-diagnosed allergies in  children at age 10 years Inhalant sensitization Food sensitization Physician-diagnosed Physician-diagnosed odds ratio (95% CI) odds ratio (95% CI) inhalant allergy food allergy odds ratio (95% CI) odds ratio (95% CI) Never eczema Reference Reference Reference Reference Ever eczema 2.91(2.41, 3.52) 4.90 (3.60, 6.67) 4.54 (3.65, 5.63) 11.89 (6.85, 20.61) Never Reference Reference Reference Reference Early transient 2.62 (2.01, 3.42) 5.73 (3.94, 8.31) 3.72 (2.78, 4.97) 6.95 (3.76, 12.84) Mid-transient 1.72 (1.25, 2.36) 2.13 (1.21, 3.76) 2.66 (1.86, 3.80) 1.44 (0.43, 4.80) Late transient 1.77 (1.33, 2.35) 2.52 (1.56, 4.07) 1.92 (1.34, 2.74) 4.50 (2.19, 9.28) Persistent 4.53 (2.65, 7.51) 12.64 (7.20, 22.18) 11.91 (7.52, 18.86) 35.05 (18.33, 70.00) Values are odds ratios (95% confidence intervals) from logistic regression models for never/ever eczema and average odds ratios (95% confidence intervals) from logistic regression models after multiple sampling based on 150 imputed datasets for eczema phenotypes. Full models were adjusted for parental history of allergy, asthma or eczema, maternal education, parity, child’s sex, ethnicity and breastfeeding. Italic values indicate statistical significance at the α = 0.05 level Hu et al. Clin Transl Allergy (2020) 10:7 Page 6 of 8 Table 4 Association of  eczema phenotypes with  combined asthma and  physician-diagnosed allergy groups in  children at age 10 years Asthma, but no allergy Allergy, but no asthma Asthma and allergy n = 97 n = 413 n = 140 Never eczema Reference Reference Reference Ever eczema 5.83 (3.49, 9.74) 4.03 (3.17, 5.11) 8.98 (5.89, 13.69) Never Reference Reference Reference Early transient 5.36 (3.07, 9.36) 3.68 (2.67, 5.08) 7.11 (4.33, 11.67) Mid-transient 1.37 (0.45, 4.19) 2.21 (1.47, 3.32) 4.31 (2.33, 7.99) Late transient 2.94 (1.47, 5.89) 1.76 (1.18, 2.64) 3.48 (1.88, 6.44) Persistent 5.23 (1.55, 17.63) 10.02 (5.92, 16.96) 29.03 (15.27, 55.22) Values are odds ratios (95% confidence intervals) from logistic regression models for never/ever eczema and average odds ratios (95% confidence intervals) from multinomial regression models after multiple sampling based on 150 imputed datasets for eczema phenotypes. Reference group is no asthma and no allergy (n = 3627). n = number of participants with information on at least 3 eczema measurements. Missing data on asthma and physician-diagnosed allergy was imputed. Full models were adjusted for parental history of allergy, asthma or eczema, maternal education, parity, child’s sex, ethnicity and breastfeeding. Italic values indicate statistical significance at the α = 0.05 level Comparison with previous studies These observed differences might be due to differences When comparing results with previous studies, the dif- in number of children included for analysis, food allergy ference in eczema phenotype definition and follow-up prevalence, eczema phenotypes definition and because duration need to be taken into account. Previous cohort our population has a longer follow-up which allowed studies showed that children with early-onset and persis- the identification of more diverse phenotypes. A cohort tent eczema phenotypes have increased risks of asthma at study in children until age 6  years showed that children ages 6 to 13 year [6, 7]. Results for mid- and late transient with early transient and persistent eczema had increased eczema phenotypes and the risk of asthma are inconsist- risks of food allergy and allergic rhinitis [7]. We observed ent. Our observations in a multi-ethnic population are similar results among children until age 10  years with in line with previous findings and support that children allergic sensitization and physician-diagnosed food and with any eczema phenotype, but especially those with inhalant allergies. Many children among the early tran- early onset and persistent eczema have increased risks of sient and persistent eczema phenotype group had both asthma at school-age [22, 23]. While eczema is strongly asthma and multiple allergic conditions, and a large per- related to asthma and therefore hypothetically also with centage of these (31–61%) had at least one diagnosis of altered lung function, the relationship between eczema asthma, food or inhalant allergy. Therefore, our results do and lung function has not been studied. We observed not support the atopic march hypothesis in all children that children with ever eczema had slightly higher FEV with eczema, but does show that in particular children and FVC, but no changes in FEV /FVC. These findings with early transient and persistent eczema are likely to might be incidental, since there were no associations of develop asthma and/or allergies later in childhood. eczema phenotypes with lung function measures. Other mechanisms might underlie the observed associations of Possible mechanisms ever eczema and eczema phenotypes with asthma, such Early transient and especially persistent eczema consist- as inhalant allergies and possible modulating effects of ently showed the strongest associations with asthma and early allergic sensitization and allergic rhinitis [24]. Also allergic conditions. A common trait of both phenotypes all children included in our analysis had higher FEV and is the early onset of eczema, suggesting that the period FVC z-scores, which might be explained by a relatively before the age of 2  years of age was important for the healthy study population or well-controlled asthma. development of asthma and allergic conditions. Matu- Previous studies showed that persistent eczema was ration rates of the skin, lungs and immune system from associated with elevated total Immunoglobulin E levels at birth until 2 years are high and any change or disruption ages 7–8  years, and with an increased risk of sensitiza- of these maturation processes might have long term con- tion to inhalant allergens, but not to food allergens at age sequences [25]. Proposed mechanisms include dysfunc- 6  years [6, 7]. We showed that children with early tran- tion of the epithelial barrier due to microbial and/or sient and persistent eczema phenotypes had both allergic genetic factors and transcutaneous sensitization, lead- sensitization and physician-diagnosed allergies, with the ing to type 2 inflammation, and thereby predisposing to strongest effect estimates for food allergy at age 10 years. asthma and allergic conditions [25–27]. Our recent study Hu  et al. Clin Transl Allergy (2020) 10:7 Page 7 of 8 showed an association of the four most common filag - eczema might benefit from more intense follow-up grin mutations in Europeans with early and late transient for early identification and treatment of asthma and eczema, but not with persistent eczema [10]. Unfortu- allergies. nately, we were not able to study filaggrin mutations as mediators for the association of eczema phenotypes with Supplementary information asthma and allergic conditions due to lack of power. Also Supplementary information accompanies this paper at https ://doi. org/10.1186/s1360 1-020-0310-7. sensitivity analysis in more detailed non-European eth- nic subgroups was not possible due to small sample size. Additional file 1: Table S1. Characteristics of children and their mothers Therefore, future studies with larger sample sizes are of those included and not included in the analyses. Table S2. Associations needed to examine the potential mediating role of filag - of eczema phenotypes with asthma, allergic sensitization and physician- grin mutations on the associations of eczema phenotypes diagnosed allergies in children of European ethnicity at age 10 years. Table S3. Associations of eczema phenotypes with current asthma, with asthma and allergic conditions, and the role of dif- allergic sensitization and physician-diagnosed allergies in children of ferent ethnicities. non-European ethnicity at age 10 years. Table S4. Associations of eczema phenotypes with allergic rhinitis in children at age 10 years. Table S5. Association of eczema phenotypes with combined allergic sensitiza- tion and physician-diagnosed allergy groups in children at age 10 years. Strengths and limitations Table S6. Association of eczema phenotypes with combined asthma, The strengths of this study include the eczema pheno - physician-diagnosed inhalant and food allergy groups in children at types among a multi-ethnic population with detailed age 10 years. Figure S1. Flow chart of participants included for analysis. Figure S2. Previously identified eczema phenotypes trajectories in 5297 information on asthma, lung function, and multiple aller- children from latent class growth analysis. gic conditions. By using multivariate regression models with multiple imputation and sampling we achieved more Abbreviations precise and unbiased effect estimates. However, some ATS: American Thoracic Society; CI: Confidence interval; ERS: European methodological considerations need to be taken into Respiratory Society; FEF : Forced expiratory flow after exhaling 75% of FVC; account. Children not included in the analyses partly had FEV : Forced expiratory volume in 1 second; FVC: Forced vital capacity; ISAAC: International Study of Asthma and Allergies in Childhood; OR: Odds ratio; SPT: less favourable socio-economic factors and more often Skin prick test. parents with no history or eczema, allergy or asthma. Selection bias due to lost to follow-up might have been Acknowledgements The Generation R Study is conducted by the Erasmus Medical Center in close present if the associations of eczema phenotypes with collaboration with the School of Law and Faculty of Social Sciences of the respiratory and allergic conditions were different in chil - Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, dren that were not included in the analyses compared to Rotterdam, the Rotterdam Homecare Foundation, Rotterdam, and the Sticht- ing Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. the children that were included in the analyses. We aimed We gratefully acknowledge the contribution of children and parents, general to minimize bias by imputation methods [20]. Despite practitioners, hospitals, midwives, and pharmacies in Rotterdam. The Genera- validated questions, misclassification of eczema, asthma tion R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam and the Netherlands and physician diagnosed allergies remains possible due Organization for Health Research and Development. to self-response [13, 28]. We included the most relevant allergens for children of age 10 years at population level, Authors’ contributions CH, TN, NE and LD contributed to the conception and design, acquisition and excluded allergens with low sensitization rates at this of data, analyses and interpretation of the data, drafted the article, revised age, such as milk and egg [16, 17]. Residual confounding it critically for important intellectual content, and gave final approval of the might be present since there might be factors not meas- version to be published. EM, CP, NJ, SP and JJ contributed to the conception and design, acquisition of data, revised the drafted manuscript critically for ured or not included in our analysis. For example, there important intellectual content, and gave final approval of the version to be was no information available to determine the severity published. All authors read and approved the final manuscript. of eczema. Furthermore, we were unable to perform our Funding analyses in more detailed ethnic groups due to lack of The Generation R Study is made possible by financial support from the power [29]. Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development. The study received funding from the European Union’s Horizon 2020 research and innovation programme (LIFECYCLE project, Grant Agreement No 733206; Conclusion 2016). The project received funding from Nestlé Skin Health-Galderma R&D Eczema phenotypes were differentially associated with (Grant Agreement No 35195; 2016). Dr Liesbeth Duijts received funding for risks of asthma and allergic conditions among school- projects from the European Union’s Horizon 2020 research and innovation programma (LIFECYCLE, grant agreement No 733206, 2016; EUCAN-Connect, aged children, and were similar in children from Euro- grant agreement No 824989; and ALPHABET, grant agreements No 696295 pean and non-European ethnicity. The strongest and and Zon MW No 529051014; 2017). most consistent associations were found in children Availability of data and materials with early transient and persistent eczema. This sug - Data requests can be made to the secretariat of the Generation R Study. gests that children with early transient and persistent Hu et al. Clin Transl Allergy (2020) 10:7 Page 8 of 8 Ethics approval and consent to participate of early-life respiratory tract infections on school-age lung function and The study has been approved by the Medical Ethical Committee of the Eras- asthma. Thorax. 2018;73(2):167–73. mus MC University Medical Centre in Rotterdam. Written informed consent 12. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi- was obtained from parents or legal guardians. ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324–43. Consent for publication 13. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, et al. Interna- Not applicable. tional Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J. 1995;8(3):483–91. 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