Interrelationships between Atopic Disorders in Children: A Meta-Analysis Based on ISAAC Questionnaires
Interrelationships between Atopic Disorders in Children: A Meta-Analysis Based on ISAAC Questionnaires
David H. J. Pols 0 1
Jorien B. Wartna 0 1
Elvira I. van Alphen 0 1
Heleen Moed 0 1
Nadine Rasenberg 0 1
Patrick J. E. Bindels 0 1
Arthur M. Bohnen 0 1
0 Editor: Tesfaye Mersha Baye, Cincinnati Children's Hospital Medical center, UNITED STATES
1 Department of General Practice, Erasmus MC, University Medical Center Rotterdam , Rotterdam , The Netherlands
Only a minority of children suffers from all three atopic disorders, however this co-occurrence
is significantly higher than could be expected by chance and supports a close relationship of
these disorders in children. The data of this meta-analysis supports the hypothesis that there
could be a fourth distinct group of children with all three disorders. Researchers and clinicians
might need to consider these children as a separate group with distinct characteristics
regarding severity, causes, treatment or prognosis.
Eczema, asthma and allergic rhinitis are common atopic disorders among children, making it
an important public health problem worldwide. The prevalences of these three disorders show
variability at regional and even at country level [1–4]. Despite this variability, there seems to be
a close relationship between these disorders. In a triad of events that include eczema, asthma
and allergic rhinitis, eczema is often the first disorder to evolve. A biologically plausible
pathway to explain this cascade was proposed by Burgess et al . As a result of a defective skin
barrier in children with eczema, an epicutaneous sensitization to an allergen can take place
resulting in T-helper type 2 memory cells; these cells can migrate to nasal and bronchial
lymphoid tissue. When the airways become exposed to the same allergen, this might cause asthma
and/or allergic rhinitis symptoms to evolve. However, in practice, the number of patients
following this classic ‘atopic march’ seems to vary considerably [6, 7], only partially explaining
The International Study of Asthma and Allergies in Childhood (ISAAC) was established in
1991 and formally closed in December 2012. The ISAAC study was divided into three phases.
The purpose was to assess the worldwide prevalence of asthma, allergic rhinitis and eczema in
children in the open population and to obtain possible risk factors that could influence these
three disorders using a standardized questionnaire [8–10]. This makes ISAAC a reliable data
source to use when studying the interrelationship of atopic diseases in children aged 6–7 and
13–14 years. Although non-ISAAC research groups (i.e. non-official ISAAC studies) also
published data using ISAAC questionnaires, the official ISAAC reviews do not include these latter
data in their analyses.
The primary aim of this review is to calculate the worldwide prevalence in children of
asthma, allergic rhinitis, eczema, and of having all three disorders, using data obtained with
ISAAC questionnaires and to examine interrelationships between these disorders using risk
ratios. Risk ratios will describe the risk of having two different atopic disorders when the child
is known with one disorder. A secondary aim is to analyze whether these risk ratios and
prevalences are influenced by potential confounders such as study period, age, sex, continent, and
use of the original English-language ISAAC questionnaire.
The protocol of this review is described below.
An extensive literature search was performed in Medline (OvidSP), Pubmed Publisher,
EMBASE, Google Scholar and the Cochrane Controlled Clinical Trials Register. Two
complementary search strategies were used for optimal article retrieval. The first strategy, focusing on
the three atopic disorders, combined the following items: “Child” AND “Epidemiology” AND
“Asthma” AND “Allergic rhinitis” AND “Eczema”. The second strategy, focusing on ISAAC
studies, used additional items and different Boolean operators: “Child” AND “Epidemiology”
AND (“Asthma” OR “Allergic rhinitis” OR “Eczema”) AND (“ISAAC” OR “International
Study of Asthma and Allergies”).
The full search strategies can be found in S1 Appendix. Since ISAAC started in 1991, only
full-text articles published after 1991 were considered; there was no language restriction. The
search was completed on February 2, 2015. A reference check was made on all articles finally
Studies (n>100) with a cross-sectional or cohort design, including youngsters aged 0–18
years, recruited in the open population (e.g. schools) were included. Studies using the ISAAC
questionnaire, performed by both official and non-official ISAAC research groups, were
included if the studies presented data on the prevalence of all three atopic diseases and their
One reviewer (EA) commenced the selection of studies, initially based on title and abstract.
To check for any missed inclusions by the first reviewer, a random selection of 50% of the
articles was independently checked by second reviewers (DP, JW, AB, NR, HM). This check
showed that the first reviewer did not exclude any potentially relevant articles.
Of the abstracts selected, the full-text articles were retrieved. Two reviewers (EA and NR)
independently performed the full-text selection using a standardized form based on the
abovementioned inclusion criteria. Studies were excluded if they only presented aggregated
worldwide data, or when double inclusion of the data could not be ruled out. Disagreement was
resolved in a consensus meeting or with the help of a third independent reviewer (DP).
Authors of the studies were contacted regarding missing data.
To minimize the risk of information bias, the quality of the included studies was assessed by
two independent reviewers (DP and AB). Disagreement was resolved in a consensus meeting.
ISAAC used the same standardized method in ISAAC phase 1 and 3. Methodological
differences between these phases were studied  and it was concluded that the ISAAC
methodology was replicated to a high degree by the majority of the study centers. This showed that the
ISAAC protocol is robust and that working in accordance with this protocol implied
substantial generalizability. Any important violations of this protocol were, therefore, identified in
order to assess quality (Table 1).
The present review includes only those articles that used the ISAAC questionnaires. This
questionnaire has been translated into various languages by regional coordinators of ISAAC,
using a consistent protocol that was evaluated by Ellwood et al. . Use of a validated
questionnaire was also considered an important quality item and was part of the quality assessment
The above mentioned violations and the use of the original questionnaire or not could
potentially influence the comparability of ISAAC and non-ISAAC studies. For this reason we
performed a meta-regression analyses in order to evaluate if these violation would influence
our outcomes (prevalence and RR).
Two reviewers (EA/JW and DP) independently extracted data from the included studies. A
standardized digital form was used to record study design, participants, official ISAAC study
or not, and outcome measures. In view of the outcome measures, the total number of
participants and the number of participants with asthma (As), eczema (Ec), allergic rhinitis (AR) and
of As+Ec, As+AR, Ec+ AR and As+Ec+AR were extracted. These numbers were then entered
in the Review Manager (RevMan) Computer program (Version 5.1. Copenhagen: The Nordic
Lamnisos 2013 
Manning 1997 
Marinho 2007 
Robertson 1998  Yes
* Number of patients available for analysis
† 1) Recruitment at schools; 2) All schools or randomly selected; 3) Age groups 6–7 and 13–14 years; 4) Use of validated questionnaires; 5)
questionnaires completed by parents (< 12 years old) or by adolescents themselves ( 12 years old); 6) Participation >90%; 7) N 3000
‡ Only two centers were included (Benslimane, Morocco; Conakry, Guinea.
Cochrane Centre, The Cochrane Collaboration, 2011). This program provides risk ratios, 95%
confidence intervals (CI) (using the Mantel-Haenszel test and random effects models) and
the weight of every study. The extraction was limited to current symptoms (past 12 months)
and data collected by written questionnaires. Study characteristics regarding gender, age,
continent, validated (English) questionnaires, ISAAC/non-ISAAC study, number of participants,
response rate, study period and ISAAC protocol violations were also collected. Data entry was
additionally checked by two independent reviewers (AB, JW).
In order to calculate the mean prevalences, the studies were weighted for their number of
participants. Risk ratios (RR) calculated by RevMan describe the risk of having two different atopic
disorders when a child is known with one disorder. For example, if the RR for asthma is four,
this would mean that a child with asthma has a fourfold risk of reporting eczema and allergic
rhinitis in contrast to a child without asthma. Heterogeneity (I2) was assessed using a random
For the study characteristics of this meta-analysis, a mixed-effects model was used for
natural logarithm of the calculated RR for asthma, eczema and allergic rhinitis and for the
prevalence of asthma, eczema, allergic rhinitis and having all three disorders. Initial models for these
seven responses contained all covariates of interest as fixed effects: percentage of males, age,
continent, ISAAC/non-ISAAC, number of participants, response rate, study period and the use
of validated English questionnaires. The latter was chosen to explore the influence of using
translations on the RR. Since not all studies provided data on the percentage of male
participants and the response rate, and both variables did not have significant parameters in the
complete case analysis, both variables were excluded from the models in order to be able to use all
57 studies for the meta regression. Some influential centers were removed from initial and final
models using traditional measures: standardized residuals, DFFITS values, Cook's distance and
hat values. All calculations were conducted in R with the metafor package (Wolfgang
Viechtbauer (2010)). A p value of 0.01 was considered the limit of significance because of multiple
testing (Bonferroni correction).
The combined search strategies resulted in 5,178 original abstracts. No articles were excluded
because of language barriers but the majority (n = 3,607; 69.7%) did not meet the inclusion
criteria, mainly because these articles did not present data on all three disorders or because
ISAAC questionnaires were not used. We retrieved 1,571 full-text articles for detailed
evaluation. Of these, another 1,533 studies were not included, mainly because the studies did not use
ISAAC questionnaires or because these articles did not present data on all three disorders.
Finally 38 studies were initially included in this review for further analysis [2, 13–49] (Fig 1).
Description and final selection of studies
The ISAAC Phase 3 synthesis presented by Mallol et al.  covers a large number of surveyed
children (n = 1,184,821). Four of the included ISAAC studies [45–48] were excluded because it
is assumed that the data from these studies were already included by Mallol et al. . The data
presented by Song et al.  showed internal inconsistency and was therefore excluded.
Furthermore, articles that only presented worldwide data (n = 2) [44, 50] were not used for the
Finally, data from 31 studies were used, covering a large number of surveyed children
(n = 1,430,329) in 102 different countries. Table 1 presents descriptive characteristics of the
studies, including the results of the quality assessment. All officially acknowledged ISAAC
studies, with the exception of one , used the same definition for asthma, eczema and
allergic rhinitis. Non-ISAAC studies varied considerably in the definitions they used for the
Overall and regional difference in prevalence of atopic manifestations
The calculated worldwide prevalence for asthma, eczema and allergic rhinitis for children in
the open population is 12.00% (95% CI: 11.99–12.00), 7.89% (95% CI: 7.88–7.89) and 12.66%
(95% CI: 12.65–12.67), respectively. Fig 2 shows the prevalence per continent. None of the
continents significantly influenced the worldwide prevalence of any one of the atopic disorders,
neither did percentage of males, ISAAC/non-ISAAC, number of participants and the use of
validated English questionnaires. There were significant negative associations between age and
prevalence of eczema and between study period and prevalence of asthma. The worldwide
observed prevalence of having all three diseases is 1.17% (95% CI: 1.17–1.17) and was not
influenced by the above mentioned factors. If there would be no interrelationship at all between the
three disorders, the expected worldwide prevalence of having all three disorders is only 0.12%
(12.00% 7.89% 12.66%)). In the present review, the observed prevalence is 9.8 times higher
than could be expected by chance, suggesting a close relationship between these disorders in
children. It is remarkable that the prevalence of ‘all three expected’ is relatively consistent
between the six continents (Fig 2).
Interrelationship between the atopic manifestations
Calculated RR for children with asthma, eczema and allergic rhinitis are presented in the Forest
plots (Figs 3–5). If possible, the Forest plots provide a subdivision per article by continent and
age. The overall RR for patients having asthma to also suffer from eczema and rhinitis is 5.41
(95% CI:4.76–6.16). For patients with eczema the RR is 4.24 (95% CI: 3.75–4.79) and for
allergic rhinitis the RR is 6.20 (95% CI: 5.30–7.27). These risk ratios show a clear relationship of the
three disorders. Additional analyses to examine whether RRs were influenced by covariates
(percentage of males, age, continent, official ISAAC/non-ISAAC study, number of participants,
response rate, study period and the use of validated English questionnaires) showed no
significant effect on the calculated RR.
There is substantial heterogeneity (I2 = 97–98%) between these studies. Subanalyses
performed for different subgroups (percentage of males, age, continent, ISAAC/non-ISAAC,
number of participants, response rate, study period) showed no major change in heterogeneity.
Fig 1. Flow diagram for selection of studies identified in the systematic review.
A comprehensive literature search retrieved data from 102 different countries, making this one
of the largest meta-analysis of asthma, eczema and allergic rhinitis ever conducted. The
calculated worldwide prevalence for asthma, eczema and allergic rhinitis for children in the open
population is 12.0%, 7.9% and 12.7%, respectively. Overall this prevalence is higher than that
presented earlier by Mallol et al . None of the individual continents had a significant
influenced on the worldwide prevalence of one of the atopic disorders.
Fig 2. Prevalence (%) of the atopic disorders per continent.
In this review, the observed prevalence of having all three disorders is 1.17% (95% CI: 1.17–
1.18). This co-occurrence is substantially higher than could be expected by chance, based on
the individual prevalence of each disorder (0.12%). This supports the hypothesis that there
could be a fourth distinct group of children with all three disorders. A new and different way
of looking at the interrelationships is by calculating RRs; the RRs presented in this review,
describe the risk of having the other two atopic disorders when a child is known with one
disorder. The RRs ranged from 4.24–6.20 and were not significantly influenced by any of the
confounders investigated. Since all RR were > 1, this implies that the observed co-occurrence is
not based on chance, but suggest a clear relationship between the disorders. Remarkably, the
RR of eczema is low compared with the other two disorders; this might be because we used
prevalence data based on having complaints in the past 12 months and not on lifetime
prevalences. On average, eczema is seen in children at a younger age than those studied in this
review, thereby resulting in a lower RR. This study also showed a significant decline in the
prevalence of asthma when a child becomes older.
The wide variation in the prevalence of atopic diseases [1–4] has received considerable
attention. Possible causes of these variations include (amongst others): genetics, use of
paracetamol, use of antibiotics, breastfeeding, diet, body mass index, living in a rural area, and air
pollution. However, none of these proposed factors fully explains this wide variation.
Remarkably, when looking at the prevalence of having all three disorders, this wide variation does not
occur to the same extent. In the present study, the limited degree of overlap between the three
conditions (1.17%) was very similar to that reported by others [30, 50]. Asher et al.  even
showed that this overlap has been relatively consistent over a period of seven years; for 6–7
year olds this overlap increased from 0.8% to 1.0% and for the 13–14 year olds the overlap
increased from 1.1% to 1.3%. This consistency in prevalence also suggests that a fourth group
of children with atopic disorders might exist. In addition to the three regularly described
Fig 3. Forest plot of risk ratios for asthma.
Fig 4. Forest plot of risk ratios for eczema.
Fig 5. Forest plot of risk ratios for allergic rhinitis.
groups of children with asthma, eczema or allergic rhinitis, there seems to be a fourth distinct
group of children with all three disorders, that may show distinct characteristics regarding
severity, causes, treatment or prognosis.
We suggest to add another chapter to the already impressive ISAAC study, focusing on this
potentially distinct fourth group of children with all three manifestations. Is this group
distinctive due to severity of symptoms? Does this group have a different genotype? Does this group
need a different pharmacological approach? Does this group have a different prognosis? Which
factors influence this group?
This meta-analysis has some limitations. First, one reviewer selected the studies based on
title and abstract. Despite a random check of 50% of the retrieved articles showing
concordance, we assumed that no relevant articles were missed. However, the full-text selection was
done by two independent reviewers. In our review there was no limitation for any language
and (where possible) authors were contacted for missing data.
When conducting a large multicenter international cross-sectional study, there is always a
risk of potential limitations. Clear examples include language problems, cultural differences,
environmental aspects, different healthcare systems, etc. Either an overestimation or an
underestimation might be found. Another concern is the possible overestimation of the prevalence of
the three atopic diseases. Although the questionnaires asked about symptoms, the symptoms
could well be attributable to other diseases; this concern is shared by others [28, 46, 48, 51].
Furthermore, Cane et al. showed that the conceptual understanding of ‘wheeze’ differs
between reporting parents and epidemiology definitions. Finally, different research groups
used different definitions for the atopic disorders; this could have influenced our results.
The high level of heterogeneity that we found suggests that the included studies differ
significantly from each other. However, this can be explained by the large number of participants in
each study. Because the studies have such large populations, the CIs will be very small. Even
small differences will result in statistical heterogeneity, but not in clinical heterogeneity.
This meta analyses supports the hypothesis that these three atopic disorders are clearly
related. A biological plausible pathway for these relationships can be found in the atopic march
theory. However, the obtained data in this meta-analysis does not allow to quantify the effect
of this atopic march theory. This is due to two limitations. The first limitation relates to the
cross sectional methods used. We have no follow-up data available for an individual child. The
second one is that we limited our data inclusion to symptoms within the previous year (year
prevalence). Using year-prevalences instead of life-time prevalences could result in an
underestimation of the prevalences. Atopic dermatitis often goes into a clinical remission, but the
atopic phenotype persists. The same applies to asthma. For example, when establishing the
prevalence at the age of e.g. 12 years, the child may answer no, but in fact might still have an
We studied the prevalence and interrelationships between asthma, allergic rhinitis and eczema
in children using data obtained from ISAAC questionnaires. The interrelationships were
studied using risk ratios, adjusted for potential confounders. Our meta-analysis has shown that the
prevalence of children with a co-occurrence of asthma, eczema and allergic rhinitis was low,
but significantly higher than could be expected by chance. The prevalence of having all three
atopic disorders was remarkably consistent in all continents. This study supports the
hypothesis that there might be a forth distinct group of children with all three disorders, in contrast to
the traditional classification of children with asthma or allergic rhinitis or atopic eczema.
Researchers and clinicians might need to consider this forth group as a separate group of
children with their own characteristics.
The authors thank Wichor Bramer (biomedical information specialist, Erasmus MC), for help
with the literature search. We also thank Magdalena Murawska and Nicole Erler (Department
of Biostatistics, Erasmus MC) for help with the statistical analyses.
Conceived and designed the experiments: DP HM PB AB. Performed the experiments: DP JW
EA HM NR AB. Analyzed the data: DP AB. Contributed reagents/materials/analysis tools: DP
AB. Wrote the paper: DP JW NR EA PB AB. Article selection: DP JW EA NR.
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