key: cord-1024226-0tdqsre7
authors: Sigurdardottir, Sigurveig T.; Jonasson, Kristjan; Clausen, Michael; Lilja Bjornsdottir, Kristin; Sigurdardottir, Sigridur Erla; Roberts, Graham; Grimshaw, Kate; Papadopoulos, Nikolaos G.; Xepapadaki, Paraskevi; Fiandor, Ana; Quirce, Santiago; Sprikkelman, Aline B.; Hulshof, Lies; Kowalski, Marek L.; Kurowski, Marcin; Dubakiene, Ruta; Rudzeviciene, Odilija; Bellach, Johanna; Yürek, Songül; Reich, Andreas; Erhard, Sina Maria; Couch, Philip; Rivas, Montserrat Fernandez; van Ree, Ronald; Mills, Clare; Grabenhenrich, Linus; Beyer, Kirsten; Keil, Thomas
title: Prevalence and early‐life risk factors of school‐age allergic multimorbidity: The EuroPrevall‐iFAAM birth cohort
date: 2021-06-08
journal: Allergy
DOI: 10.1111/all.14857
sha: fe9bdd495c0e7f26bbec5ee83f49365ac48cf2b7
doc_id: 1024226
cord_uid: 0tdqsre7

BACKGROUND: Coexistence of childhood asthma, eczema and allergic rhinitis is higher than can be expected by chance, suggesting a common mechanism. Data on allergic multimorbidity from a pan‐European, population‐based birth cohort study have been lacking. This study compares the prevalence and early‐life risk factors of these diseases in European primary school children. METHODS: In the prospective multicentre observational EuroPrevall‐iFAAM birth cohort study, we used standardized questionnaires on sociodemographics, medical history, parental allergies and lifestyle, and environmental exposures at birth, 12 and 24 months. At primary school age, parents answered ISAAC‐based questions on current asthma, rhinitis and eczema. Allergic multimorbidity was defined as the coexistence of at least two of these. RESULTS: From 10,563 children recruited at birth in 8 study centres, we included data from 5,572 children (mean age 8.2 years; 51.8% boys). Prevalence estimates were as follows: asthma, 8.1%; allergic rhinitis, 13.3%; and eczema, 12.0%. Allergic multimorbidity was seen in 7.0% of the whole cohort, ranging from 1.2% (Athens, Greece) to 10.9% (Madrid, Spain). Risk factors for allergic multimorbidity, identified with AICc, included family‐allergy‐score, odds ratio (OR) 1.50 (95% CI 1.32–1.70) per standard deviation; early‐life allergy symptoms, OR 2.72 (2.34–3.16) for each symptom; and caesarean birth, OR 1.35 (1.04–1.76). Female gender, OR 0.72 (0.58–0.90); older siblings, OR 0.79 (0.63–0.99); and day care, OR 0.81 (0.63–1.06) were protective factors. CONCLUSION: Allergic multimorbidity should be regarded as an important chronic childhood disease in Europe. Some of the associated early‐life factors are modifiable and may be considered for prevention strategies.

Interest in multiple coexisting allergic diseases (allergic multimorbidity) has been increasing, and several recent studies address prevalence and risk factors focusing on childhood and adolescence. Allergic multimorbidity is often defined as two or more allergic diseases: asthma, allergic rhinitis and eczema. The German birth cohort Multicentre Allergy Study (MAS) found an allergic multimorbidity prevalence of 2% at age 9 in those with no family history, compared with 11% of those with at least one allergic parent. 1 The Mechanisms of the Development of ALLergy (MeDALL) meta-analysis showed a relatively high occurrence of coexisting asthma, allergic rhinitis and eczema in 4-and 8-year-old children in many European cohorts suggesting a common mechanism. 2 In their combined data analysis, as well as in the Swedish BAMSE birth cohort, 3 allergic multimorbidity prevalence increased with age up to adolescence.

The iFAAM study is a continuation of the EuroPrevall birth cohort study that recruited newborns in 2005-2010 4,5 and completed its last follow-up assessment at 6-10 years in eight European cities. 6 It gives a unique opportunity to estimate the influence of prenatal and postnatal environmental, lifestyle and sociodemographic early-life factors on the prevalence of asthma (allergic and non-allergic), allergic rhinitis, eczema and allergic multimorbidity at primary school age in Europe, which is indeed the aim of the current analysis.

The study design and baseline characteristic of the study population have been described in detail previously. [4] [5] [6] [7] In summary, the prospective multicentre birth cohort study (funded by the European Commission) were children born before 34 weeks, with a 5-min APGAR score <7, and parents with insufficient skills of the local language. 4 During the years 2014-2017, at primary school age, all the study centres except Milan participated in a follow-up assessment, iFAAM (also funded by the European Commission). Parents answered questions online, including questions on symptoms of current allergic diseases. A few parents who were unable or unwilling to access/ complete the questionnaire by themselves were invited to the study centre or questioned via telephone interviews.

Ethical approval was obtained individually for both study periods from the local ethics committee in each participating country.

Informed parental consent was also obtained for each assessment, in written form for the early childhood period, and online at school age.

Allergic multimorbidity (coexistence of asthma, eczema and allergic rhinitis) is common among European children at primary school age, with 7% of study participants affected. Protective factors identified in the study include female sex, having older siblings and attending day care. Risk factors include history of allergic diseases in first-degree family members, early-age symptoms and caesarean birth.

The iFAAM questionnaire was based on stringent epidemiological definitions and validated and widely used questions in populationbased cross-sectional childhood and teenage studies such as the International Study of Asthma and Allergies in Childhood (ISAAC project). [8] [9] [10] [11] Current asthma at school age was defined as present if at least three of the following five parent-reported criteria were fulfilled: (a1) wheezing or whistling, (a2) breathing difficulties, (a3) dry cough at night, (a4) asthma medication, all in the past 12 months and (a5) doctor-diagnosed asthma ever. Asthma was also considered to be present if criteria (a4) and (a5) were both fulfilled without any of the three symptoms (a1-a3), indicating a well-managed disease.

Current allergic rhinitis at school age was defined as present if at least two of the following three criteria were fulfilled: (r1) sneezing, or a runny or blocked nose, without having a cold, (r2) nasal allergy/ hay fever medication, both in the past 12 months, and (r3) doctordiagnosed allergic rhinitis or hay fever ever.

Current eczema at school age was defined as present if both of the following criteria were fulfilled: (e1) an itchy rash, which was intermittently coming and going, and (e2) doctor-diagnosed eczema/ atopic dermatitis ever.

Current allergic multimorbidity at school age was defined as present if at least two of current asthma, allergic rhinitis and eczema were coexisting.

Many of the early-age covariates were simple yes-no questions: sex, caesarean-birth, child's and mother's antibiotics-at-birth, cows-milkin-first-week, pets-at-home (cats/dogs), live-on-a-farm and mould in the house. Other early-age covariates require more explanation.

Mothers-age is a simple continuous variable, parent-education is also continuous, sum of mother's and father's education codes, each of these in the range 1-4 according to education level. Family-allergyscore at baseline is also a continuous variable and computed as previously described (Appendix S1). 12 Breastfeeding is true if the child was breastfed for ≥6 months (possibly along with other feeding).

Breastfeeding for ≥4 months was also evaluated. The continuous variable early-age-symptoms was defined as the sum of three dichotomous variables: symptoms associated with asthma, allergic rhinitis and eczema. The first of these is 1 if the child had wheezing or whistling in the chest between 12 and 24 months of age; otherwise, it is 0. The second is 1 if the child had at least 2 of the following 3 criteria before age 2: (1) sneezing, or a runny or blocked nose, without having a cold, (2) itchy, watery eyes and (3) doctor-diagnosed hay fever. The third is 1 if the child had an itchy rash or eczema that lasted for at least 7 days, in the fold of the elbows, behind the knees, in front of the ankles, on the cheeks or around the neck, ears or eyes, before age 2.

A crucial variable considered was the study centre. This variable was treated as giving a multiplicative centre effect, as described in more detail in the statistics section below.

Finally, the iFAAM study included a question on current heavy traffic, which was the only school-age covariate considered.

Data were processed with Unix and MATLAB (version 9.3; The MathWorks Inc.). To assess the significance of covariates, a logistic regression model was constructed, where centre effect was included as a multiplicative factor: F I G U R E 1 Flow chart of the population-based pan-European birth cohort study showing the EuroPrevall and iFAAM participants up to inclusion in the current analysis. The EuroPrevall study centre Milan did not participate in the iFAAM project. The eight participating cities were as follows: Reykjavík, Iceland; Southampton, UK; Amsterdam, the Netherlands; Berlin, Germany; Lodz, Poland; Vilnius, Lithuania; Madrid, Spain; and Athens, Greece. 'Not in current study' are children whose parents were not reachable or were not interested in participation at school age

The covariates entering the model were selected using the AICc criterion (Akaike information criterion with correction). One advantage of using AICc is that it is independent of (arbitrary) statistical significance levels: it selects the model with the smallest expected mean squared error. 13 Forest plots were used to show 95% confidence intervals.

Note that in the model all individuals weight equally, and therefore, the centres are effectively weighted by the participant count in each one, as in inverse probability weighting. 14 

Of 10,563 recruited children in the eight participating centres, 5572 (52.8%) fulfilled the eligibility criteria listed in Section 2.1 ( Figure 1 ). Table S1 shows a breakdown of the dropout by study centre. The participation in individual centres is shown in Figure 2 . The children were aged between 6 and 10 years when the last parental questionnaire was answered. The allergic outcomes at school age were as follows: asthma, 8.1%; allergic rhinitis, 13.3%; eczema, 12.0%; allergic multimorbidity, 7.0%; and all three diseases, 1.3% (Table 1) . Odds = (center effect) × (effect of covariate 1) × (effect of covariate 2) × …

The eight centres of the population-based EuroPrevall-IFAAM birth cohort study, the number of children who participated in each one at the school-age follow-up assessment (in total 5572 children) and the proportion of these with allergic multimorbidity (overall proportion 7.0% TA B L E 1 Prevalence of individual allergic diseases at primary school age according to study centre (%), and breakdown according to the number and type of coexisting diseases Note: The bolded italic column, headed '2 or 3', shows the prevalence of allergic multimorbidity, that is two or more of asthma, allergic rhinitis and eczema. The section headed 'Single diseases' shows the percentage of children having one specific disease, and the section headed 'Double diseases' shows the percentage having exactly two specific diseases.

The difference between the centres was considerable, with only 

Tables 2 and S1 show a summary of the covariates for the two groups: the 3212 children dropping out in the last step in Figure 1 and the final study population for the current analysis. There were fewer day care children in the dropout group (two-tailed, p < .01), and that group also had fewer children with early-age symptoms of allergic diseases (p = .04). There were more smoking at home, more pregnancy smoking, less breastfeeding, more dogs and more children but fewer mothers receiving antibiotics at birth, parent education level was lower (p < .01 for all), and there was less vitamin D supplementation in the non-participating group (p = .03).

The logistic regression model included six covariates for allergic multimorbidity, selected according to AICc: family-allergy-score, earlyage-symptoms, sex, caesarean-birth, older-siblings and day-care before 18 months of age (Table 2, Figure 3 ). Female sex, older-siblings and 

Odds ratios and 95% confidence intervals for protective factors (green) and risk factors (red) of allergic multimorbidity at school age [of a model selected according to AICc]. Family-allergy-score is standardized to have SD = 1. Early-age-symptoms is in the range 1-3 and counts the number of allergic symptoms (of allergic rhinitis, eczema, asthma) observed before age 2. All the remaining variables are dichotomous. The OR for family-allergy-score shows the multiplicative effect for each standard deviation, and somewhat similarly, the OR for early-age symptoms shows the multiplicative effect of each such symptom that is present. The factors shown are the ones present in a multivariate logistic model that maximizes the AICc model selection criterion Models including only specific early-age symptoms were also considered. AICc selected early symptoms of both allergic rhinitis and eczema as predictors of school-age allergic multimorbidity by themselves, but not wheezing. However, when combined with one or both of the other two symptoms, wheezing increased the estimated risk, and it was also selected as a predictor of school-age asthma (Table S7) .

Current heavy traffic exposure was identified as a risk factor for asthma, but not for the other two diseases (Table S8 ).

To check the consistency of the modelling, multimorbidity models with each covariate as the only variable apart from centre effect

were constructed. Table S2 shows the odds ratios and AICc values for these models and some additional models, including the final 6-variable model of Figure 3 . The results were consistent. To further check the stability of the results, the final model was fitted 8 times, each time leaving out one centre, and again, the results were consistent (Tables S4 and S5) . 

In our study with children aged 6-10 years, allergic rhinitis and eczema were more common than asthma. There was considerable difference between the study centres with allergic multimorbidity (two or more allergic diseases) ranging from 1.2% in Athens to 10.9% in Madrid. We did not see any clear geographical prevalence gradient across the participating European centres, such as from north to south or west to east, as found in a previous population-based cross-sectional evaluation. 15 While other studies that we considered F I G U R E 4 Odds ratios and 95% confidence intervals for covariates that are predictors for one or more of the individual diseases considered in the study (secondary outcomes). Covariates for which the confidence intervals do not contain 1 are coloured green if the factor is protective and red if it poses a risk. Confidence intervals of variables that are not selected into a corresponding model are shown in orange. See also explanations in the caption of Figure 3 defined multimorbidity also as having at least two of asthma, aller- The differences in definitions of the allergic diseases between studies and study settings make it hard to draw conclusions on whether allergic multimorbidity is a waxing problem in Europe.

However, our prevalence estimates ranging up to 11% in Madrid considering only the three most common allergic diseases shows that allergic multimorbidity is a common problem for many primary school-aged children in Europe.

In our assessments in children up to 2.5-year-olds, Athens (Greece) had the second lowest wheezing prevalence and lowest prevalence of confirmed food allergy, [21] [22] [23] and now has the lowest study prevalence of all three single diseases, as well as allergic multimorbidity. It also has, by far, the lowest estimate for school-age food allergy. 6 However, Madrid, also in Mediterranean Europe, has the highest observed prevalence of both allergic multimorbidity and eczema, and high percentage for the other two diseases.

The considerable differences between cities (Section 3.1) evidently cannot be explained by the geographical locations. Genetic susceptibility and/or environmental factors such as diet may play a role. The relatively low prevalence in Reykjavik could be partly due to the widespread supplementation of fish oil to infants, 12 or possibly less pollution.

As expected, family-allergy-score had a large effect not only on single allergic diseases but also on allergic multimorbidity. Interestingly, allergic family history appeared to influence the occurrence of eczema less than respiratory allergy.

Also, as expected, the best predictor for allergic multimorbidity at school age were early-age-symptoms of allergic diseases.

Early-age symptoms are of course not a risk factor, strictly speaking. Multimorbidity models without early-age-symptoms give odds ratios for the other factors that are comparable to those of the full model ( Figure 3 , Table S2 ). The same holds for individual diseases (data not shown). If the aim is to predict school-age allergic diseases, one would use all available data, including the earlyage-symptoms, but if the aim is to study the causal pathway, this variable should be excluded.

Being a girl is protective against allergic multimorbidity, asthma and allergic rhinitis at school age, but carries a risk for eczema. These findings confirm results from MAS, PARIS, and BAMSE. 1, 10, 16, 24 In MAS, boys with eczema had more allergic multimorbidity than girls with eczema. This was confirmed by our study, 40% and 30% for boys and girls, respectively (p = .07; data not shown). The PARIS study also showed boys to be at higher risk of allergic sensitization to aeroallergens and food allergens, and at much higher risk of being multisensitized.

Pregnancy-smoking was not found to affect allergic multimorbidity; however, according to the AICc criterion, it is a risk factor for primary school-age asthma (OR = 1.54, 95% CI = 0.99-2.38). This is in agreement with multiple other studies, where smoking during pregnancy increased the risk for early-life wheezing and schoolage asthma, even more than other tobacco smoke exposure. 25-30 Figure 4 indicates that pregnancy smoking primarily affects nonatopic asthma, 28, 31 and the same applies to caesarean-birth, which is a risk factor for multimorbidity and asthma, but not for allergic rhinitis or eczema. The result for asthma confirms findings of a recent meta-analysis, albeit with considerable statistical heterogeneity, with mainly retrospective and cross-sectional studies, showing an increased asthma risk by caesarean birth. 32 Not included in this meta-analysis were two separate evaluations of long-term prospective population-based birth cohorts, focusing on asthma and allergy, which did not find association between caesarean birth and asthma at age 15 33 and 20 years. 30 In previous studies, having older siblings and day-care attendance were both protective for respiratory allergic diseases at school age. 20, 34, 35 The protective effects of natural birth, older siblings and day care attendance have been explained by the increased exposure to protective bacteria in infancy, 36, 37 whereas the protection by older siblings was also hypothesized of being an in utero immune priming effect. 35 The negative effect of current traffic on asthma is consistent with earlier findings (Table S7 ). 19 We did not have accessible information on traffic at early age.

Several studies show that allergic multimorbidity can be considered as a special disease. 2, 16 This is supported by a genetic study. 38 In our study, asthma concurrent with allergic rhinitis and/or eczema accounted for about half of the asthma cases, 3.9% (2.9% +1.0%; Table 1 ) out of 8.1%, approximately twice as often as would be expected if the diseases were independent. If they were independent, the prevalence of all three being concurrent would be 0.13% (0.081 × 0.133 × 0.120 = 0.0013), whereas the actual cohort prevalence of the triple multimorbidity is ten times higher, 1.3% (Table 1) .

We concentrated on allergic diseases at the age around 8 years;

however, the coexistence of the diseases may have developed in different patterns from infancy. A study using machine learning identified 8 such patterns, leading to different combinations of the diseases at school age. 39 A study on atopic endotypes in childhood identified four patterns of disease development. 40 

The current study involves multiple countries from all climatic regions in Europe, it uses prospectively collected data from birth to school age by the same standardized methods, and it is to date the 

Allergic multimorbidity of asthma, rhinitis and eczema over 20 years in the German birth cohort MAS

Comorbidity of eczema, rhinitis, and asthma in IgE-sensitised and non-IgE-sensitised children in MeDALL: A population-based cohort study

IgE antibodies in relation to prevalence and multimorbidity of eczema, asthma, and rhinitis from birth to adolescence

The multinational birth cohort of EuroPrevall: Background, aims and methods. Allergy: European

The EuroPrevall birth cohort study on food allergy: Baseline characteristics of 12,000 newborns and their families from nine European countries

Frequency of food allergy in school-aged children in eight European countries-The EuroPrevall-iFAAM birth cohort

A new framework for the documentation and interpretation of oral food challenges in population-based and clinical research

The burden of symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema in children and adolescents in six New Zealand centres: ISAAC Phase One

Birth cohorts in asthma and allergic diseases: Report of a NIAID/NHLBI/MeDALL joint workshop

Allergic sensitisation in early childhood: Patterns and related factors in PARIS birth cohort

Multiple atopy phenotypes and their associations with asthma: Similar findings from two birth cohorts

Fish oil in infancy protects against food allergy in Iceland-Results from a birth cohort study

Multimodel inference: Understanding AIC and BIC in model selection

Inverse probability weighting

Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys

Development and comorbidity of eczema, asthma and rhinitis to age 12 -Data from the BAMSE birth cohort

Allergic sensitization and filaggrin variants predispose to the comorbidity of eczema, asthma, and rhinitis: results from the Isle of Wight birth cohort

Dissociating polysensitization and multimorbidity in children and adults from a Polish general population cohort

Air pollution and the development of asthma from birth until young adulthood

Comparison of individuallevel and population-level risk factors for rhinoconjunctivitis, asthma, and eczema in the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three

Incidence and natural history of challenge-proven cow's milk allergy in European children -EuroPrevall birth cohort

Prevalence estimates and risk factors for early childhood wheeze across Europe: The EuroPrevall birth cohort

Incidence and natural history of hen's egg allergy in the first 2 years of life -The EuroPrevall birth cohort study

Early polysensitization is associated with allergic multimorbidity in PARIS birth cohort infants

Maternal smoking increases risk of allergic sensitization and wheezing only in children with allergic predisposition: Longitudinal analysis from birth to 10 years

Exposure to environmental tobacco smoke and sensitisation in children

Linkage between smoking and asthma. Allergy: European

Maternal smoking in pregnancy and asthma in preschool children: A pooled analysis of eight birth cohorts

Early-life home environment and risk of asthma among inner-city children

Early-life determinants of asthma from birth to age 20 years: A German birth cohort study

Parental smoking and childhood asthma: longitudinal and case-control studies

The association between caesarean section and childhood asthma: An updated systematic review and meta-analysis

Caesarean Section has no impact on lung function at the age of 15 years

Siblings, day-care attendance, and the risk of asthma and wheezing during childhood

Siblings Promote a Type 1/Type 17-oriented immune response in the airways of asymptomatic neonates

Immune-mediated diseases and microbial exposure in early life

Relative importance and additive effects of maternal and infant risk factors on childhood asthma

A novel whole blood gene expression signature for asthma, dermatitis, and rhinitis multimorbidity in children and adolescents

Developmental profiles of eczema, wheeze, and rhinitis: two population-based birth cohort studies

Atopic endotype in childhood