Published ahead of print on June 15, 2007, doi:10.1164/rccm.200607-994OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200607-994OC
Atopic Sensitization and the International Variation of Asthma Symptom Prevalence in Children 1 Institute of Epidemiology, Ulm University, Ulm, Germany; 2 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 3 Institute for Risk Assessment Sciences, University of Utrecht, and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; 4 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; 5 University of Murcia, Murcia, Spain; 6 Center of Allergy and Immunology, Tbilisi, Georgia; 7 Medical School, Athens University, Evgenidio Hospital, Athens, Greece; 8 Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden; 9 Dr. von Haunersches University Children's Hospital, Ludwig-Maximilians-University, Munich, Germany; 10 Tallinn Children's Hospital, Tallinn, Estonia; 11 Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, RS, Brazil; 12 St. George's, University of London, London, United Kingdom; 13 Paediatric Respiratory Unit, Hippokration Hospital, Thessaloniki, Greece; 14 Wellington Asthma Research Group, Wellington School of Medicine and Health Sciences, Wellington, New Zealand; and 15 Department of Paediatrics, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, NT, Hong Kong, SAR China Correspondence and requests for reprints should be addressed to Dr. Gudrun Weinmayr, Ph.D., Institute of Epidemiology, Ulm University, Helmholtzstrasse 22, D-89075 Ulm, Germany. E-mail: gudrun.weinmayr{at}uni-ulm.de
Rationale: Atopic sensitization has long been known to be related to asthma in children, but its role in determining asthma prevalence remains to be elucidated further. Objectives: To investigate the role of atopic sensitization in the large international variation in the prevalence of childhood asthma. Methods: Cross-sectional studies of random samples of 8- to 12-year-old children (n = 1,000 per center) were performed according to the standardized methodology of Phase Two of the International Study of Asthma and Allergy in Childhood (ISAAC). Thirty study centers in 22 countries worldwide participated and reflect a wide range of living conditions, from rural Africa to urban Europe. Data were collected by parental questionnaires (n = 54,439), skin prick tests (n = 31,759), and measurements of allergen-specific IgE levels in serum (n = 8,951). Economic development was assessed by gross national income per capita (GNI).
Measurements and Main Results: The prevalence of current wheeze (i.e., during the past year) ranged from 0.8% in Pichincha (Ecuador) to 25.6% in Uruguaiana (Brazil). The fraction of current wheeze attributable to atopic sensitization ranged from 0% in Ankara (Turkey) to 93.8% in Guangzhou (China). There were no correlations between prevalence rates of current wheeze and atopic sensitization, and only weak correlations of both with GNI. However, the fractions and prevalence rates of wheeze attributable to skin test reactivity correlated strongly with GNI (Spearman rank-order coefficient Conclusions: The link between atopic sensitization and asthma symptoms in children differs strongly between populations and increases with economic development.
Key Words: wheeze • ISAAC Phase Two • IgE • population attributable risk • gross national income per capita
Atopic sensitization has long been known to be related to childhood asthma (1, 2). However, Pearce and colleagues, in a systematic review, concluded that its role may have been overemphasized (3). The available evidence at the time suggested that usually only less than half of the asthma cases were attributable to atopic sensitization. In addition, studies showing a strong relation between asthma and atopy come mainly from affluent Western countries. Results from studies in less affluent countries provide a more heterogeneous picture (4–7). Thus, it may be that the link between asthma and atopic sensitization differs between countries. The European Community Respiratory Health Survey, involving approximately 13,500 adults, aged 20 to 44 years, in 36 study centers in 16 countries, recently showed that the overall attributable fraction (AF) of asthma symptoms caused by atopy in adults was 30% (8). Between centers, the AF varied widely, ranging from 4 to 61%. Phase One of the International Study of Asthma and Allergies in Childhood (ISAAC I) found that the prevalence of symptoms of asthma, allergic rhinitis and atopic eczema in children aged 6 to 7 years and in those aged 13 to 14 years, assessed by standardized questionnaires, differed more than 20-fold between the 155 study centers around the world (9, 10). Phase Two of ISAAC (ISAAC II) aims to identify determinants of these differences by studying informative populations. The participating study centers reflect the full range in asthma prevalence observed in ISAAC I and include additional study centers with particular living conditions (e.g., rural areas in Ghana and Ecuador). The current article is the first report of ISAAC II findings relating to asthma and atopy. It investigates the role of atopic sensitization in the international variation in prevalence rates of asthma symptoms, with a focus on a potential interaction with economic development in the study areas. Some results of this study have been previously reported in the form of abstracts (11–13).
Study Populations and Field Work The study methods of ISAAC II have been described in detail elsewhere (14), and additional information is given in the online supplement. Briefly, random samples of schools (  10) from defined geographical areas were chosen and children (n 1,000 per center) attending classes with a majority of 9- to 11-year-olds were invited to participate. Standardized parental questionnaires on asthma symptoms were used (15). In four countries, the questions were posed by trained interviewers because illiteracy was a problem.
The ISAAC II methodology allowed objective measurements to be performed either in the full sample (option A) or in random subsamples (option B) of children (14). Most centers invited all children to participate in the skin prick testing, whereas blood samples were collected mostly in stratified random subsamples of children with and without reports of wheeze in the past year (
Skin Test Reactivity
Serum IgE
Gross National Income
Statistical Analyses
Two strata were defined for the initial analyses relating to GNI: (1) centers classified by the World Bank as "high income countries" (i.e., GNI per capita per year
A total of 54,439 children, ages 8 to 12 years old, had completed parental questionnaires, 31,759 underwent skin prick tests, and 8,951 participated in the measurement of IgE antibodies. Participation rates ranged from 36 to 100% for the questionnaire, from 24 to 99% for skin prick tests, and from 12.5 to 76% for IgE measurements (Table 1).
Prevalence Rates of Asthma Symptoms and Atopic Sensitization The prevalence rates of asthma-related symptoms varied widely between study centers (Table 2). Current wheeze (i.e., wheeze during the last year) ranged from 0.8% in Pichincha Province, rural Ecuador, to 25.6% in Uruguaiana, Brazil. Similar variation was observed in the prevalence of severe asthma symptoms. The prevalence of skin prick test reactivity was lowest in Kintampo, rural Ghana (1.7%), and highest in Hong Kong, China (45.3%). Elevated levels of allergen-specific IgE were least common in Tallinn, Estonia (16.7%), and most common in Almeria, Spain (48.5%). The prevalence of atopic wheeze (defined as current wheeze plus skin prick test reactivity) and nonatopic wheeze also varied widely between centers. Atopic wheeze was least prevalent in Pichincha, Ecuador (0.2%), and most prevalent in Hawkes Bay, New Zealand (13.4%). The prevalence of nonatopic wheeze was lowest in Guangzhou, China (0.4%), and highest in Uruguaiana, Brazil (20.9%).
Association between Asthma Symptoms and Atopic Sensitization The association between current wheeze and skin prick test reactivity was statistically significant in all centers in affluent countries, except for Reykjavik, Iceland, where the association did not reach formal statistical significance (Figure 1). The combined odds ratio (OR) for the affluent countries was 4.0 (95% confidence interval [CI], 3.5–4.6). The observed associations were substantially weaker in nonaffluent countries (combined OR, 2.2; 95% CI, 1.5–3.3). Guangzhou, China, was not included in the calculation of this estimate because the OR for this area was an extreme outlier (OR, 58.9) due to the virtual absence of nonatopic wheeze in the sample (Table 2). There was no significant evidence for heterogeneity among centers in affluent countries estimated from random effects meta-analysis (P = 0.21). There was a suggestion of heterogeneity among centers in nonaffluent countries only when the OR of Guangzhou was included in the meta-analysis (P = 0.052). A similar pattern emerged for elevated allergen-specific IgE levels where estimates for the combined OR were 3.5 (95% CI, 2.9–4.2) for centers in affluent countries and 1.9 (95% CI, 1.0–3.9) for centers in nonaffluent countries. Again, there was no apparent heterogeneity (P = 0.26 for affluent and P = 0.43 for nonaffluent countries).
Population Attributable Risks Table 3 shows that the highest fractions of current wheeze that were attributable to skin prick test reactivity (PAFs) were observed in Guangzhou (93.8%), Hong Kong (59.6%), and the Netherlands (58.6%). The very high PAF in Guangzhou was again due to the low number of nonatopic children with wheeze in this center. The lowest PAFs were found in Ankara, Turkey (0%, OR < 1), and Mumbai, India (2%). Overall, the combined PAFs were substantially higher in affluent countries (40.7%) than in nonaffluent countries (20.3%). A similar pattern was observed for IgE antibodies with a combined PAF of 45.6% for the centers in affluent countries and of 18.3% for the centers in nonaffluent countries. The combined estimate for the PAP based on skin prick test reactivity was 4.1% for centers in affluent countries and 1.2% for centers in nonaffluent countries. Again, the results were very similar for allergen-specific IgE (i.e., 4.6 and 1.1%, respectively).
Correlations at the Center Level The prevalence of current wheeze was not correlated with the prevalence of skin prick test reactivity or elevated allergen-specific IgE (Figure 2). Prevalence rates of current wheeze (  = 0.39, P = 0.05) and skin test reactivity ( = 0.37, P = 0.05) were only weakly correlated with GNI (Figure 2). The prevalence of atopic wheeze (i.e., current wheeze in combination with a positive skin prick test) was strongly associated with GNI ( = 0.60, P = 0.002); rates of nonatopic wheeze were not ( = –0.02, P = 0.92; not shown in Figure 2). The PAFs, based on skin prick test reactivity and elevated IgE antibody levels, were both significantly correlated with GNI (Figure 3). The correlations between PAPs and GNI were even stronger ( = 0.74, P  0.0001 for skin test reactivity, and = 0.74, P = 0.003, for IgE antibodies). Finally, the strength of the association between skin prick test reactivity and current wheeze (assessed by OR) also increased significantly with GNI. There was a suggestion for a similar correlation with IgE, but this correlation did not reach statistical significance.
ISAAC II is the first large international study on children that can rely on methodologically comparable prevalence rates of skin prick test reactivity and elevated allergen-specific IgE levels in addition to questionnaire-based reports of asthma symptoms. We observed large variations in the prevalence of asthma symptoms and of atopic sensitization among populations. An intriguing finding is that the link between atopic sensitization and asthma symptoms increased with economic development. Our findings confirm the wide international variation in the prevalence and severity of asthma symptoms in children observed during ISAAC I (9, 10). Study centers that had ranked high (e.g., New Zealand, United Kingdom) or low (e.g., Albania, India) showed similar rankings in ISAAC II. The high prevalence of wheeze in the Brazilian center corroborates previous ISAAC observations of high asthma rates in urban centers in Latin America (9, 21). The ISAAC II data show that this high prevalence is mostly due to nonatopic wheeze, supporting similar findings from other areas in South America (22, 23).
The large variation in prevalence rates of current wheeze could not be explained by prevalence rates of skin test reactivity or elevated allergen-specific IgE levels as shown by the lack of correlation (Figures 2a and 2b). The prevalence of wheeze during the last year, however, increased with GNI, confirming previous analyses of the ISAAC I data (24). We also observed a significant correlation between the prevalence of skin test reactivity in children and GNI, a finding that has not been reported previously. The correlation between GNI and the prevalence of elevated allergen-specific IgE levels did not reach statistical significance, possibly due to the smaller number of centers. When restricting the skin test reactivity analysis to centers with data on IgE, there was also no correlation (
There was a wide variation in the prevalence of atopic sensitization across study centers. The variation was more pronounced for skin test reactivity than for elevated IgE antibodies, which could be partly due to the smaller number of centers with IgE data. Several study centers had tested additional allergens of local relevance, thereby enhancing the validity of findings on skin test reactivity. Inclusion of these additional allergens in the analyses, however, had only small effects on the parameters under investigation and mostly affected prevalence estimates (e.g., among centers that used additional allergens, the range of prevalence rates increased from 7.1 to 42.8% [using the six standard allergens] to 10.3 to 45.3%). For the same centers, the combined ORs for the association between wheezing and skin prick test reactivity changed from OR = 3.95 to OR = 4.06 in affluent countries and from OR = 2.62 to OR = 2.82 in nonaffluent countries after inclusion of the additional allergens. The correlation between GNI and ORs for the association between current wheeze and skin test reactivity became enhanced when additional allergens were included:
We observed a strong correlation of the link between wheeze and atopic sensitization (measured by OR, PAF, and PAP) and GNI of the respective countries. Before discussion of potential interpretations, methodologic aspects need to be addressed. First, participation rates were low in some centers (e.g., <60% for questionnaires and <40% for skin prick or IgE measurements), raising concern about selective participation. In general, allergic symptoms (rhinoconjunctivitis and eczema) and parental allergies were slightly more often reported among participants with measurements of skin test reactivity or serum IgE than among children with completed questionnaires. For skin prick tests, statistically significant differences were only seen in one center (Tbilisi). For IgE measurements, significant differences (i.e., higher rates among those with IgE data) were observed for hay fever symptoms in Cartagena and Tbilisi, and for parental allergies in West Sussex and Tbilisi. However, although potential selection of children may have had some effect on prevalence estimates, it is less likely to introduce systematic bias for the assessment of associations within study centers (e.g., calculation of OR). When centers with low participation were excluded (i.e., <60% for questionnaires and <40% for skin prick or IgE measurements), most associations became substantially stronger (for skin prick test: PAF,
A possible explanation for an increasing link between asthma and atopic sensitization with economic development could be that factors that protect children with atopic sensitization against the development of manifest disease get attenuated or lost in more affluent settings. Differences in the association of wheeze with atopy between populations have been found before, with weaker associations seen mainly in rural or semirural nonaffluent locations (4, 6, 33). In these cases, it is difficult to tease apart the effects of rural/urban versus affluent/nonaffluent, because rural is generally equivalent to less affluent. However, a lack of association was also observed in a deprived but urban environment in Lima, Peru (22). Others reported attenuated associations of circulating IgE antibodies with positive skin prick tests and allergic disease in former socialist countries (34, 35). In our data, ORs for the relation of wheeze with skin prick test reactivity tended to increase with the prevalence of skin test reactivity ( Few studies have specifically investigated the factors that may influence the relation between allergen-specific IgE, skin prick test reactivity, and manifest atopic disease, and most of those relate to helminth infections (36, 37). There is evidence that increased production of IL-10 concomitant with helminth infections down-regulates allergic inflammatory responses (37). However, a cluster-randomized trial of geohelminth treatment in an endemic area showed no increase in atopic sensitization 1 year after the start of treatment (38). Other conditions that may modify the relation between atopic sensitization and asthma symptoms include overweight and obesity (39). A study in urban and rural South Africa observed that increasing body mass index was associated with a greater strength of association between allergen-specific IgE and the corresponding skin test (40). It has also been hypothesized that commensal bacteria acquired very early in life play an important role in the induction of tolerance (41). Less or an altered microbial exposure (e.g., an altered gut flora) could therefore weaken normal immune regulatory function and tolerance. Differences in the gut flora have been reported between children with and without allergic disease (41) and between countries with different prevalence rates of allergic disease (41) (e.g., between Estonia and Sweden) (41, 42). Within affluent countries, special subgroups of children—for example, those living on farms or having an anthroposophic lifestyle—have been found to be at lower risk for asthma and allergies (43–45). The degree of urbanization is one factor that increases with higher GNI. In our study, using national data provided by the Food and Agriculture Organization of the United Nations (http://faostat.fao.org), urbanization was in fact correlated with the prevalence of wheeze attributable to skin test reactivity. However, after adjustment for economic development, only GNI remained significant in the model (see also the online supplement). Our findings show that, at age 8 to 12 years, nonatopic wheeze represents a frequent form of wheeze. In many countries, it comprised the majority of cases, particularly in centers in nonaffluent countries. Studies from affluent settings described a phenotype of asthma that is linked to respiratory infections in early life and outgrown during later childhood (46, 47). The relatively high prevalence of nonatopic wheeze in some of our study centers may be related to increased susceptibility and/or high exposure to infections. The age at which the wheezing episodes are outgrown may also differ among countries, particularly between affluent and nonaffluent settings. The substantial proportion of nonatopic wheeze in many populations warrants further investigation of the determining factors. Several studies have shown that the patterns of risk factors for atopic versus nonatopic wheeze may differ (44, 48–50). In conclusion, our study shows that prevalence rates of asthma symptoms and of atopic sensitization vary widely in 8- to 12-year-old children living under very different conditions worldwide. The fractions and prevalences of wheeze that were attributable to atopic sensitization, as well as the strength of the associations between wheeze and atopic sensitization, increased with economic development.
The authors thank all children, parents, teachers, field workers, and lab workers for their enormous contributions to this collaborative study. ALK generously provided reagents for field work in several low-income countries without charge.
Coordination and central laboratory analyses of the European centers were funded by the Fifth Framework Program of European Commission, (QLK4-CT-1999-01288).
* ISAAC study group members are listed before the REFERENCES.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200607-994OC on June 15, 2007 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. The ISAAC Phase Two Study Group consists of the following members: ISAAC Phase Two Steering Group: B. Björkstén (Stockholm, Sweden), B. Brunekreef (Utrecht, The Netherlands), W. Cookson (Oxford, UK), E. von Mutius (Munich, Germany), D. Strachan (London, UK), S. K. Weiland, ISAAC Phase Two Coordinator (Ulm, Germany). ISAAC Phase Two Coordinating and Data Centre (Institute of Epidemiology, Ulm University, Germany): G. Büchele, C. Dentler, A. Kleiner, P. Rzehak, G. Weinmayr, S. K. Weiland (Director).
Principal Investigators and Scientific Team: Tirana, Albania: A. Priftanji, A. Shkurti, J. Simenati, E. Grabocka, K. Shyti, S. Agolli, A. Gurakuqi; Uruguaiana, Brazil: R. T. Stein, M. Urrutia de Pereira, M. H. Jones, P. M. Pitrez; Pichincha Province, Ecuador: P. J. Cooper, M. Chico; Beijing, China: Y. Z. Chen; Guangzhou, China: N. S. Zhong; Hong Kong, China: C. Lai (National Coordinator), G. Wong; Tallinn, Estonia: M.-A. Riikjärv, T. Annus; Créteil, France: I. Annesi-Maesano; Tblisi, Georgia: M. Gotua, M. Rukhadze, T. Abramidze, I. Kvachadze, L. Karsanidze, M. Kiladze, N. Dolidze; Dresden, Germany: W. Leupold, U. Keil, E. von Mutius, S. Weiland; Munich, Germany: E. von Mutius, U. Keil, S. Weiland; Kintampo, Ghana: P. Arthur (deceased), E. Addo-Yobo; Athens, Greece: C. Gratziou (National Coordinator), C. Priftis, A. Papadopoulou, C. Katsardis; Thessaloniki, Greece: J. Tsanakas, E. Hatziagorou, F. Kirvassilis; Reykjavik, Iceland: M. Clausen; Mumbai, India: J. R. Shah, R. S. Mathur, R. P. Khubchandani, S. Mantri; Rome, Italy: F. Forastiere, R. Di Domenicantonio, M. De Sario, S. Sammarro, R. Pistelli, M. G. Serra, G. Corbo, C. A. Perucci; Riga, Latvia: V. Svabe, D. Sebre, G. Casno, I. Novikova, L. Bagrade; Utrecht, The Netherlands: B. Brunekreef, D. Schram, G. Doekes, P. H. N. Jansen-van Vliet, N. A. H. Janssen, F. J. H. Aarts, G. de Meer; Hawkes Bay, New Zealand: J. Crane, K. Wickens, D. Barry; Tromsø, Norway: W. Nystad, R. Bolle, E. Lund; Almeria, Spain: J. Batlles Garrido, T. Rubi Ruiz, A. Bonillo Perales, Y.Gonzalez Jiménez, J. Aguirre Rodriguez, J. Momblan de Cabo, A. Losilla Maldonado, M. Daza Torres; Cartagena, Spain: L. García-Marcos (National Coordinator), A. Martinez Torres, J. J. Guillén Pérez, A. Piñana López, S. Castejon Robles; Madrid, Spain: G. García Hernandez, A. Martinez Gimeno, A. L. Moro Rodríguez, C. Luna Paredes, I. Gonzalez Gil; Valencia, Spain: M. M. Morales Suarez-Varela, A. Llopis González, A. Escribano Montaner, M. Tallon Guerola; Linköping, Sweden: L. Bråbäck (National Coordinator), M. Kjellman, L. Nilsson, X.-M. Mai; Östersund, Sweden: L. Bråbäck, A. Sandin; Ankara, Turkey: Y. Saraçlar, S. Kuyucu, A. Tuncer, C. Saçkesen, V. Sumbulo Laboratories: Serum IgE levels were measured at the Karolinska Institute, Stockholm (B. Björkstén, M. van Hage). ISAAC Steering Committee: N. Aït-Khaled (Paris, France), H. R. Anderson (London, UK), I. Asher (Auckland, NZ), R. Beasley (Wellington, NZ), B. Björkstén (Stockholm, Sweden), B. Brunekreef (Utrecht, The Netherlands), W. Cookson (Oxford, UK), J. Crane (Wellington, NZ), P. Ellwood (Auckland, NZ), S. Foliaki (Wellington, NZ), U. Keil (Münster, Germany), C. Lai (Hong Kong), J. Mallol (Santiago, Chile), E. Mitchell (Auckland, NZ), S. Montefort (Malta), E. von Mutius (Munich, Germany), J. Odhiambo (Nairobi, Kenya), N. Pearce (Wellington, NZ), C. Robertson (Parkville, Australia), J. Shah (Mumbai, India), A. Stewart (Auckland, NZ), D. P. Strachan (London, UK), S. K. Weiland (Ulm, Germany), H. Williams (Nottingham, UK). The agencies that funded the field work are listed elsewhere (14). Received in original form July 21, 2006; accepted in final form June 15, 2007
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ABSTRACT
AT A GLANCE COMMENTARY
100 in each stratum). All centers obtained approval by local ethics committees and made major efforts to ensure comparable data quality (
The authors regret to announce that Stephan Weiland, University Professor and Director of the Institute of Epidemiology in Ulm, died suddenly and unexpectedly on March 19, 2007, shortly after this paper was accepted for publication. As a founding member of the International Study of Asthma and Allergies in Childhood and the coordinator of ISAAC Phase Two, he played a leading role in international studies of asthma and allergy and the crucial part in the conception of all work leading to this manuscript. He was a teacher and researcher of great warmth, wisdom, and good humor, and this paper is dedicated to his memory. 
lu, P. Geyik, C. Kocaba
; West Sussex, UK: D. P. Strachan, B. Kaur; Ramallah, West Bank: N. El-Sharif, B. Nemery, F. Barghuthy, S. Abu Huij, M. Qlebo. 
ekerel B, Saçkesen C, Kocaba
