American Journal of Respiratory and Critical Care Medicine

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 ρ = 0.50, P = 0.006, and ρ = 0.74, P < 0.0001, respectively). In addition, the strength of the association between current wheeze and skin test reactivity, assessed by odds ratios, increased with GNI (ρ = 0.47, P = 0.01).

Conclusions: The link between atopic sensitization and asthma symptoms in children differs strongly between populations and increases with economic development.

Scientific Knowledge on the Subject

The prevalence of asthma symptoms has been shown to vary more than 15-fold among countries worldwide. The international variation in the prevalence of atopic sensitization in children and its relevance for the variation in asthma symptoms is unknown.

What This Study Adds to the Field

Prevalence rates of asthma symptoms and atopic sensitisation in children vary widely among 22 countries worldwide. The link between atopic sensitization and asthma symptoms differs strongly among populations and increases with economic development.

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 (47). 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 (1113).

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 (∼100 in each stratum). All centers obtained approval by local ethics committees and made major efforts to ensure comparable data quality (14).

Skin Test Reactivity

The skin prick tests were performed according to a detailed protocol (14). Extracts of six common aeroallergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat dander, Alternaria tenuis, mixed tree pollen, and mixed grass pollen) produced by ALK (Horsholm, Denmark) were used. The centers were encouraged to add allergens of local relevance. Additional allergens were tested in 18 centers and included the following: olive pollen, Parietaria officinalis, cockroach, dog, mixed molds, horse, mixed weeds (16), Cladosporium, bird epithelium, and Turkish tree mix (16). A positive skin reaction was defined as a wheal size of 3 mm or greater, after subtraction of the negative control.

Serum IgE

Allergen-specific IgE antibodies to a mix of common inhalant allergens (D. pteronyssinus, D. farinae, birch, timothy, mugwort, cat, dog, horse, Cladosporium, olive pollen, and Parietaria) were measured by Phadiatop (Phadia AB, Uppsala, Sweden). For almost all centers (except two German centers), the measurements were done in one central laboratory (14). Elevated levels were defined as those 0.35 allergen-specific kilounits per liter (kUA/L) or higher.

Gross National Income

To assess economic conditions, we used gross national income per capita (GNI) converted into U.S. dollars using the World Bank Atlas method (17).

Statistical Analyses

Prevalence rates were calculated. If centers had studied stratified subsamples, prevalence rates and odds ratios (ORs) were calculated applying appropriate sampling weights (18, 19). Ecological correlations were assessed using Spearman rank order coefficients (ρ). Population attributable fractions (PAFs) were calculated using the formula: PAF = Pec × (OR − 1)/OR, where Pec is the prevalence of exposure among the cases (e.g., atopic sensitization among children with wheeze). Population attributable prevalences (PAPs) were obtained by multiplying the PAF with the prevalence of disease. Combined estimates across several study centers were calculated using random effects meta-analysis models (20).

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 ⩾ $9,200); (2) the remaining centers were combined in a group called “nonaffluent countries.” For the correlation analyses, GNI was used as a continuous variable. The analyses were performed using SAS (version 9.1; SAS Institute, Cary, NC) and SUDAAN (version 9.0; RTI International, Research Triangle Park, NC).

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).



Skin Prick Test

Allergen-specific IgE

Study Period Questionnaire
Characteristic of Study Area
n* (%)
n* (%)
n* (%)
 TiranaFeb–April 1999Urban1,052 (94.9)929 (84.0)113 (52.8)970
 UruguaianaMarch 2003–March 2004Urban1,971 (96.3)1,192§ (96.2)3,900
 BeijingOct 1997–Feb 1998Urban4,214 (92.5)1,044§ (90.8)780
 GuangzhouOct 1997–Feb 1998Urban3,510 (93.3)1,078§ (36.1)780
 Hong KongOct 1997–Feb 1998Urban3,011 (96.7)1,324§ (63.8)25,580
 PichinchaMay 2001–Jan 2002Rural894 (100.0)894 (99.9)1,370
 TallinnDec 1996–Feb 1997Urban971 (83.9)642 (55.5)161 (39.7)3,540
 CréteilJune–Dec 1996Urban1,400 (66.1)24,640
 TbilisiMarch 2001–June 2002Urban1,012 (87.7)173 (75.9)173 (75.9)680
 DresdenSept 1995–June 1996Urban3,023 (82.8)2,259 (61.6)2,084 (56.8)25,740
 MunichSept 1995–Dec 1996Urban3,301 (87.5)2,317 (60.6)1,737 (45.4)25,740
 KintampoFeb 2000–July 2000Rural1,354 (ND)1,322 (ND)380
 AthensOct 2000–Feb 2001Urban985 (85.3)985 (85.3)190 (75.5)11,700
 ThessalonikiSept–Nov 2001Urban1,018 (63.0)1,018 (63.0)207 (54.6)11,700
 ReykjavikMay 2000Urban937 (46.6)633 (38.0)29,920
 Mumbai2000–2001Urban1,658 (ND)1,556 (ND)133 (ND)450
 RomeOct 2000–April 2001Urban1,354 (83.5)1,307 (62.3)93 (24.0)20,170
 RigaMay–Nov 1999Urban908 (87.4)295 (30.8)2,570
The NetherlandsApril 1997–July 1998Urban3,541 (64.7)1,286§ (43.3)1,989 (37.4)25,270
New Zealand
 Hawkes BayFeb–June 2000Urban/rural1,320 (84.3)1,288 (82.2)13,480
 TromsøMarch–June 2000Urban/rural3,669 (81.3)722§ (60.2)155 (64.2)35,660
 AlmeriaMarch 2000–June 2001Urban1,126 (49.9)1,075 (47.7)209 (40.3)14,790
 CartagenaMarch 2000–March 2001Urban1,429 (54.6)1,030 (39.6)188 (26.8)14,790
 MadridFeb 2001–April 2002Urban981 (35.8)653 (23.9)341 (12.5)14,790
 ValenciaDec 2000–Dec 2001Urban1,362 (40.4)1,023 (30.5)539 (16.1)14,790
 LinköpingJan–April 1997Urban907 (81.7)857 (77.0)172 (50.4)28,540
 ÖstersundJan–April 1997Urban/rural1,195 (86.0)991 (71.4)268 (63.0)28,540
 AnkaraOct 1999–April 2000Urban2,976 (87.6)2,747 (81.0)2,800
United Kingdom
 West SussexOct 1998–July 1999Urban/rural1,056 (78.6)898 (66.7)199 (68.9)24,070
West Bank
 RamallahSept 2000Urban/rural2,304 (85.4)221 (65.0)1,750


Definition of abbreviations: GNI = gross national income per capita; ND = no data.

Em dash (—) = not performed.

*Number of children ages 8–12 years old.

Participation rate refers to those who were invited (either full or subsamples).

Stratified subsample.

§Random subsample.

The core standard allergens were not licensed in France (where allergens from Stallergènes were tested in 1,451 children).

Average period between questionnaire and skin prick testing > 180 days: Tbilisi (197 d), Tromso (218 d), Reykjavik (354 d), and Riga (385 d).

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%).


12-mo Prevalence

⩾ 4 Asthma Attacks
Severe Wheeze Limiting Speech
Asthma Ever
Positive Skin Prick Tests*
Allergen-specific IgE (⩾ 0.35 kUA/L)
Atopic Wheeze Past Year
NonatopicWheeze Past Year
AlbaniaTirana4.4 (3.1 to 5.6)0.5 (0.1 to 0.9)0.5 (0.1 to 0.9)2.7 (1.7 to 3.7)15.0§ (12.7 to 17.3)19.5 (11.6 to 27.4)1.2 (0.5 to 1.9)3.1 (2.0 to 4.2)
BrazilUruguaiana25.6 (23.7 to 27.5)6.5 (5.4 to 7.6)5.9 (4.8 to 6.9)12.7 (11.2 to 14.1)13.3 (11.3 to 15.2)5.4 (4.1 to 6.7)20.9 (18.6 to 23.2)
ChinaBeijing3.7 (3.2 to 4.3)0.8 (0.5 to 1.1)0.5 (0.2 to 0.7)6.4 (5.7 to 7.2)23.9§ (21.3 to 26.4)1.6 (0.9 to 2.4)1.7 (0.9 to 2.5)
Guangzhou3.2 (2.6 to 3.8)0.5 (0.3 to 0.7)0.2 (0.1 to 0.4)4.4 (3.7 to 5.0)32.0§ (29.2 to 34.8)7.8 (6.2 to 9.4)0.4 (0.0 to 0.7)
Hong Kong5.5 (4.7 to 6.3)1.3 (0.9 to 1.7)0.5 (0.2 to 0.7)7.9 (6.9 to 8.8)45.3§ (42.6 to 48.0)6.9 (5.6 to 8.3)2.1 (1.3 to 2.9)
EcuadorPichincha0.8 (0.2 to 1.4)0.2 (−0.1 to 0.5)0.2 (−0.1 to 0.5)19.7§ (17.1 to 22.3)0.2 (−0.1 to 0.5)0.6 (0.1 to 1.1)
EstoniaTallinn8.4 (6.7 to 10.2)1.5 (0.7 to 2.2)1.1 (0.5 to 1.8)2.5 (1.5 to 3.5)14.6§ (11.9 to 17.4)16.7 (10.7 to 22.7)2.2 (1.1 to 3.4)6.4 (4.5 to 8.3)
FranceCreteil7.6 (6.2 to 9.0)1.8 (1.1 to 2.4)0.9 (0.4 to 1.5)9.2 (7.6 to 10.7)
GeorgiaTbilisi9.2 (7.4 to 11.1)1.7 (0.9 to 2.6)1.1 (0.5 to 1.8)3.2 (2.1 to 4.3)33.0§ (25.1 to 40.9)30.6 (22.9 to 38.4)3.5 (2.3 to 4.7)5.7 (4.5 to 7.0)
GermanyDresden7.9 (6.9 to 8.8)1.6 (1.2 to 2.1)1.9 (1.4 to 2.4)3.6 (3.0 to 4.3)25.7 (23.9 to 27.5)37.0 (35.0 to 39.1)4.5 (3.6 to 5.3)3.2 (2.5 to 4.0)
Munich8.3 (7.3 to 9.2)2.1 (1.6 to 2.6)2.5 (2.0 to 3.1)4.8 (4.0 to 5.5)22.3 (20.6 to 24.0)37.4 (35.1 to 39.7)4.3 (3.5 to 5.2)4.1 (3.3 to 4.9)
GhanaKintampo6.4 (5.1 to 7.7)2.5 (1.7 to 3.4)2.4 (1.6 to 3.3)15.8 (13.9 to 17.8)1.7 (1.0 to 2.4)0.3 (0.0 to 0.6)6.2 (4.9 to 7.5)
GreeceAthens5.6 (4.2 to 7.1)1.0 (0.4 to 1.7)0.6 (0.1 to 1.1)7.5 (5.9 to 9.2)14.4§ (12.2 to 16.6)33.6 (26.3 to 40.9)1.6 (0.8 to 2.4)4.0 (2.8 to 5.2)
Thessaloniki8.4 (6.7 to 10.1)0.7 (0.2 to 1.2)1.6 (0.8 to 2.3)11.6 (9.6 to 13.5)26.8§ (24.1 to 29.5)32.3 (25.1 to 39.5)3.6 (2.4 to 4.7)4.8 (3.5 to 6.2)
IcelandReykjavik9.23.51.722.923.5 (20.2 to 26.9)3.16.4
IndiaMumbai6.1 (4.9 to 7.3)0.8 (0.4 to 1.2)1.6 (1.0 to 2.2)4.8 (3.8 to 5.8)6.4 (5.2 to 7.6)39.7 (30.2 to 49.2)0.5 (0.2 to 0.9)5.8 (4.6 to 7.0)
ItalyRome7.9 (6.5 to 9.4)1.5 (0.9 to 2.2)1.2 (0.6 to 1.8)14.3 (12.5 to 16.2)28.9§ (26.5 to 31.4)43.1 (31.3 to 54.9)5.2 (4.0 to 6.4)2.5 (1.6 to 3.4)
LatviaRiga6.9 (5.3 to 8.6)1.0 (0.4 to 1.7)0.7 (0.1 to 1.2)3.2 (2.1 to 4.4)19.3 (14.8 to 23.9)6.4 (3.6 to 9.3)3.7 (1.6 to 5.9)
The NetherlandsThe Netherlands8.7 (7.8 to 9.6)2.7 (2.1 to 3.2)1.6 (1.2 to 2.0)7.8 (6.9 to 8.7)30.9§ (28.4 to 33.5)30.1 (28.0 to 32.1)6.5 (5.1 to 7.8)2.8 (1.9 to 3.7)
New ZealandHawkes Bay21.9 (19.7 to 24.1)6.8 (5.5 to 8.2)4.6 (3.5 to 5.8)35.6 (33.0 to 38.2)34.5 (31.9 to 37.2)13.4 (11.6 to 15.3)8.8 (7.2 to 10.3)
NorwayTromsø14.0 (12.9 to −15.2)6.3 (5.5 to 7.1)1.8 (1.3 to 2.2)10.3 (9.3 to 11.3)32.7 (29.3 to 36.1)36.5 (27.0 to 45.9)9.1 (7.0 to 11.3)5.0 (3.4 to 6.7)
SpainAlmeria15.53.52.814.643.0 (40.0 to 45.9)48.5 (40.5 to 56.4)10.34.6
Cartagena11.92.11.610.923.8§ (21.2 to 26.4)40.4 (31.8 to 48.9)6.05.5
Madrid11.63.62.811.434.5§ (30.8 to 38.1)40.1 (34.7 to 45.5)7.66.7
Valencia9.§ (12.1 to 16.4)32.9 (28.9 to 36.9)3.35.7
SwedenLinköping7.9 (6.2 to 9.7)2.3 (1.3 to 3.3)1.0 (0.3 to 1.6)9.6 (7.7 to 11.5)19.8§ (17.2 to 22.5)30.7 (22.7 to 38.6)3.7 (2.4 to 5.0)3.8 (2.5 to 5.2)
Östersund10.2 (8.5 to 12.0)4.4 (3.2 to 5.5)1.5 (0.8 to 2.2)10.9 (9.1 to 12.7)26.5§ (23.8 to 29.3)36.7 (30.1 to 43.3)6.2 (4.7 to 7.7)4.0 (2.7 to 5.2)
TurkeyAnkara10.9 (9.8 to 12.0)2.0 (1.5 to 2.6)2.2 (1.6 to 2.7)24.6§ (23.0 to 26.2)2.6 (2.0 to 3.2)8.6 (7.6 to 9.7)
United KingdomWest Sussex16.2 (13.9 to 18.4)6.5 (5.0 to 8.0)2.4 (1.5 to 3.3)20.3 (17.9 to 22.8)17.5 (15.0 to 20.0)41.8 (34.7 to 49.0)6.5 (4.9 to 8.2)10.0 (8.0 to 12.0)
West Bank
8.8 (7.6 to 9.9)
1.5 (1.0 to 2.0)
2.0 (1.4 to 2.6)
9.4 (8.2 to 10.6)
10.3§ (6.2 to 14.4)

1.9 (0.8 to 3.0)
7.0 (5.9 to 8.2)

Prevalence values are in % with 95% confidence intervals in parentheses. Em dashes (—) = not performed/question not asked.

*Wheal size of ⩾3 mm to at least one of the tested aeroallergens.

Defined as wheeze with skin prick test reactivity (⩾3 mm).

Defined as wheeze without skin prick test reactivity (⩾3 mm).

§Local allergens were tested in addition to standard set of six common allergens.

The reported frequencies should not be interpreted as prevalence estimates because participation was <60% (see Methods).

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).


Skin Prick Test Reactivity

Allergen-specific IgE
Fraction (%)
Prevalence (%)
Fraction (%)
Prevalence (%)
 Hong Kong59.6*3.3*
The Netherlands58.6*5.1*55.84.9
New Zealand
 Hawkes Bay45.810.0
United Kingdom
 West Sussex30.44.951.48.3
Combined affluent40.
West Bank
Combined nonaffluent

— = not performed.

*Additional allergens of local relevance were tested (see Methods).

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 (ρ = 0.39, P = 0.05) and skin test reactivity (ρ = 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 (ρ = 0.60, P = 0.002); rates of nonatopic wheeze were not (ρ = −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 (ρ = 0.74, P ≤ 0.0001 for skin test reactivity, and ρ = 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 (ρ = 0.29, P = 0.25). The determinants of the large international variation in the prevalence of asthma symptoms and atopic sensitization are likely to be numerous and complex (2527). A wide range of different factors, including nutrition, microbial and allergen exposure, housing conditions, exposure to pollutants, and so forth, may have played a role (28). Finally, it should to be kept in mind that we report an ecological correlation. A center-level correlation with GNI does not imply a similar relation at the individual level with personal wealth.

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: ρ = 0.68, P = 0.003 without, and ρ = 0.77, P = 0.0003 with additional allergens. The ISAAC II findings are in line with previous reports of lower prevalence rates of skin test reactivity in less affluent countries (3, 4, 7, 22, 2932). Our data also show large variations in the PAFs and attributable prevalence rates, particularly between centers in affluent and nonaffluent countries. The size of the observed PAFs corroborates and extends the findings by Pearce and colleagues for children (PAFs from 25 to 63%) (3) and by Sunyer and coworkers for adults (PAFs from 4 to 61%) (8).

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, ρ = 0.81, P < 0.0001; PAP, ρ = 0.82, P < 0.0001; OR, ρ = 0.76, P < 0.0001; and for allergen-specific IgE: PAF, ρ = 0.79, P < 0.0001; PAP, ρ = 0.83, P = 0.0008; OR, ρ = 0.33, P = 0.29). Exclusion of Tbilisi from our analyses had very little effect on the observed pattern of our findings. Furthermore, it could be speculated that the observed relations are due to differences in phenotype. Similar relations, however, were seen for reports of asthma-ever and frequent wheezing attacks during the past year (data not shown). In addition, when current wheeze was classified depending on whether it occurred in combination with symptoms of allergic rhinoconjunctivitis (i.e., therefore more likely to be related to atopic sensitization) or not, the relationship with GNI was enhanced for wheeze with rhinoconjunctivitis symptoms (e.g., correlation based on the OR: ρ = 0.58, P = 0.002 for prick test reactivity, and ρ = 0.67, P = 0.002 for allergen-specific IgE) and not present for wheeze without symptoms of allergic rhinitis (data not shown). Finally, GNI at the country level is not a precise measure of economic development in the study areas and the prevalence estimates from the study centers are not representative of the country as a whole. Thus, some misclassification cannot be ruled out. However, economic conditions and prevalence rates of asthma symptoms differ much more between countries than between regions within countries (9, 10). In addition, to explain the observed relations, misclassification would have to be differential—that is, dependent on the association between asthma symptoms and sensitization, which appears to be unlikely.

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 (ρ = 0.31, P = 0.10), not with the prevalence of elevated allergen-specific IgE (ρ = 0.07, P = 0.79), possibly indicating that the relevant factors may affect both the development of skin test reactivity and its link with clinical asthma symptoms.

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 (4345). 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 (, 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, 4850).

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.

1. von Mutius E. Environmental factors influencing the development and progression of pediatric asthma. J Allergy Clin Immunol 2002;109:S525–S532.
2. Custovic A, Simpson A. Environmental allergen exposure, sensitisation and asthma: from whole populations to individuals at risk. Thorax 2004;59:825–827.
3. Pearce N, Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax 1999;54:268–272.
4. Yemaneberhan H, Bekele Z, Venn A, Lewis S, Parry E, Britton J. Prevalence of wheeze and asthma and relation to atopy in urban and rural Ethiopia. Lancet 1997;350:85–90.
5. Scrivener S, Yemaneberhan H, Zebenigus M, Tilahun D, Girma S, Ali S, McElroy P, Custovic A, Woodcock A, Pritchard D, et al. Independent effects of intestinal parasite infection and domestic allergen exposure on risk of wheeze in Ethiopia: a nested case-control study. Lancet 2001;358:1493–1499.
6. Palmer LJ, Celedon JC, Weiss ST, Wang B, Fang Z, Xu X. Ascaris lumbricoides infection is associated with increased risk of childhood asthma and atopy in rural China. Am J Respir Crit Care Med 2002;165:1489–1493.
7. Perzanowski MS, Ng'ang'a LW, Carter MC, Odhiambo J, Ngari P, Vaughan JW, Chapman MD, Kennedy MW, Platts-Mills TA. Atopy, asthma, and antibodies to Ascaris among rural and urban children in Kenya. J Pediatr 2002;140:582–588.
8. Sunyer J, Jarvis D, Pekkanen J, Chinn S, Janson C, Leynaert B, Luczynska C, Garcia-Esteban R, Burney P, Anto JM; European Community Respiratory Health Survey Study Group. Geographic variations in the effect of atopy on asthma in the European Community Respiratory Health Study. J Allergy Clin Immunol 2004;114:1033–1039.
9. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC). Eur Respir J 1998;12:315–335.
10. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998;351:1225–1232.
11. Weinmayr G, Rzehak P, Büchele G, Björkstén B, Brunekreef B, Cookson WOC, von Mutius E, Strachan D, Weiland SK; ISAAC II Study Group. International variations in the prevalence pf asthma in children: phase II of the international study of asthma and allergies in childhood (ISAAC II) [abstract]. Eur Respir J 2004;24(Suppl 48):169s.
12. Weinmayr G, Rzehak P, Büchele G, Björkstén B, Brunekreef B, Cookson WOC, von Mutius E, Strachan DP, Weiland SK; ISAAC II Study Group. Internationale Variation in der Prävalenz von Asthmasymptomen und atopischer Sensibilisierung: Ergebnisse der Phase II der International Study of Asthma and Allergies in Childhood (ISAAC II) [abstract] [in German]. Allergo J 2006;15124–15125.
13. Weiland SK, Weinmayr G, Rzehak P, Büchele G, Björkstén B, Garcia-Marcos L, Brunekreef B, Cookson WOC, von Mutius E, Strachan D; ISAAC II Study Group. International variation in the prevalence of asthma in children: the role of atopic sensitisation and economic development [abstract]. Eur Respir J 2006;28(Suppl 50):835s–836s.
14. Weiland SK, Björkstén B, Brunekreef B, Cookson WOC, von Mutius E, Strachan DP; ISAAC II Study Group. Phase II of the International Study of Asthma and Allergies in Childhood (ISAAC II): rationale and methods. Eur Respir J 2004;24:406–412.
15. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, Mitchell EA, Pearce N, Sibbald B, Stewart AW, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995;8:483–491.
16. Saraçlar Y, Kuyucu S, Tuncer A, Şekerel B, Saçkesen C, Kocabaş C. Prevalence of asthmatic phenotypes and bronchial hyperresponsiveness in Turkish school children: an International Study of Asthma and Allergies in Childhood (ISAAC) phase 2 study. Ann Allergy Asthma Immunol 2003;91:477–484.
17. The World Bank Group. World Bank Atlas Method [Internet] [accessed 2006 Oct 5]. Available from:
18. Chambless LE, Boyle KE. Maximum likelihood methods for complex sample data: logistic regression and discrete proportional hazards models. Communication in Statistics–Theory and Methods 1985;14:1377–1392.
19. Pfeffermann D. The role of sampling weights when modeling survey data. Int Stat Rev 1993;61:317–337.
20. Normand SL. Meta-analysis: formulating, evaluating, combining, and reporting. Stat Med 1999;18:321–359.
21. Mallol J, Sole D, Asher I, Clayton T, Stein R, Soto-Quiroz M. Prevalence of asthma symptoms in Latin America: the International Study of Asthma and Allergies in Childhood (ISAAC). Pediatr Pulmonol 2000;30:439–444.
22. Penny ME, Murad S, Madrid SS, Herrera TS, Pineiro A, Caceres DE, Lanata CF. Respiratory symptoms, asthma, exercise test spirometry, and atopy in schoolchildren from a Lima shanty town. Thorax 2001;56:607–612.
23. Mackenney J, Oyarzun MJ, Diaz PV, Bustos R, Amigo H, Rona RJ. Prevalence of asthma, atopy and bronchial hyperresponsiveness and their interrelation in a semi-rural area of Chile. Int J Tuberc Lung Dis 2005;9:1288–1293.
24. Stewart AW, Mitchell EA, Pearce N, Strachan DP, Weiland SK. The relationship of per capita gross national product to the prevalence of symptoms of asthma and other atopic diseases in children (ISAAC). Int J Epidemiol 2001;30:173–179.
25. Wong GW, von Mutius E, Douwes J, Pearce N. Environmental determinants associated with the development of asthma in childhood. Int J Tuberc Lung Dis 2006;10:242–251.
26. von Mutius E. Influences in allergy: epidemiology and the environment. J Allergy Clin Immunol 2004;113:373–379.
27. Schaub B, Lauener R, von Mutius E. The many faces of the hygiene hypothesis. J Allergy Clin Immunol 2006;117:969–977.
28. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006;355:2226–2235.
29. Cooper PJ, Chico ME, Bland M, Griffin GE, Nutman TB. Allergic symptoms, atopy, and geohelminth infections in a rural area of Ecuador. Am J Respir Crit Care Med 2003;168:313–317.
30. Bråbäck L, Breborowicz A, Dreborg S, Knutsson A, Pieklik H, Björkstén B. Atopic sensitization and respiratory symptoms among Polish and Swedish school children. Clin Exp Allergy 1994;24:826–835.
31. Riikjärv MA, Julge K, Vasar M, Bråbäck L, Knutsson A, Björkstén B. The prevalence of atopic sensitization and respiratory symptoms among Estonian schoolchildren. Clin Exp Allergy 1995;25:1198–1204.
32. von Mutius E, Martinez FD, Fritzsch C, Nicolai T, Roell G, Thiemann HH. Prevalence of asthma and atopy in two areas of West and East Germany. Am J Respir Crit Care Med 1994;149:358–364.
33. Sunyer J, Torregrosa J, Anto JM, Menendez C, Acosta C, Schellenberg D, Alonso PL, Kahigwa E. The association between atopy and asthma in a semirural area of Tanzania (East Africa). Allergy 2000;55:762–766.
34. Julge K, Vasar M, Björkstén B. Development of allergy and IgE antibodies during the first five years of life in Estonian children. Clin Exp Allergy 2001;31:1854–1861.
35. Voor T, Julge K, Bottcher MF, Jenmalm MC, Duchen K, Björkstén B. Atopic sensitization and atopic dermatitis in Estonian and Swedish infants. Clin Exp Allergy 2005;35:153–159.
36. Lynch NR, Palenque M, Hagel I, DiPrisco MC. Clinical improvement of asthma after anthelminthic treatment in a tropical situation. Am J Respir Crit Care Med 1997;156:50–54.
37. van den Biggelaar AH, van Ree R, Rodrigues LC, Lell B, Deelder AM, Kremsner PG, Yazdanbakhsh M. Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet 2000;356:1723–1727.
38. Cooper PJ, Chico ME, Vaca MG, Moncayo AL, Bland JM, Mafla E, Sanchez F, Rodrigues LC, Strachan DP, Griffin GE. Effect of albendazole treatments on the prevalence of atopy in children living in communities endemic for geohelminth parasites: a cluster-randomised trial. Lancet 2006;367:1598–1603.
39. Weiss ST. Obesity: insight into the origins of asthma. Nat Immunol 2005;6:537–539.
40. Calvert J, Burney P. Effect of body mass on exercise-induced bronchospasm and atopy in African children. J Allergy Clin Immunol 2005;116:773–779.
41. Björkstén B. Effects of intestinal microflora and the environment on the development of asthma and allergy. Springer Semin Immunopathol 2004;25:257–270.
42. Sepp E, Julge K, Mikelsaar M, Björkstén B. Intestinal microbiota and immunoglobulin E responses in 5-year-old Estonian children. Clin Exp Allergy 2005;35:1141–1146.
43. Alfvén T, Braun-Fahrländer C, Brunekreef B, von Mutius E, Riedler J, Scheynius A, van Hage M, Wickman M, Benz MR, Budde J, et al. Allergic diseases and atopic sensitization in children related to farming and anthroposophic lifestyle: the PARSIFAL study. Allergy 2006;61:414–421.
44. Braun-Fahrländer C, Riedler J, Herz U, Eder W, Waser M, Grize L, Maisch S, Carr D, Gerlach F, Bufe A, et al.; Allergy and Endotoxin Study Team. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 2002;347:869–877.
45. Flöistrup H, Swartz J, Bergström A, Alm JS, Scheynius A, van Hage M, Waser M, Braun-Fahrländer C, Schram-Bijkerk D, Huber M, et al.; The Parsifal Study Group. Allergic disease and sensitization in Steiner school children. J Allergy Clin Immunol 2006;117:59–66.
46. Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM, Wright AL, Martinez FD. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999;354:541–545.
47. Martinez FD. Development of wheezing disorders and asthma in preschool children. Pediatrics 2002;109:362–367.
48. Rönmark E, Jonsson E, Platts-Mills T, Lundback B. Different pattern of risk factors for atopic and nonatopic asthma among children: report from the Obstructive Lung Disease in Northern Sweden Study. Allergy 1999;54:926–935.
49. Garcia-Marcos L, Castro-Rodriguez JA, Suarez-Varela MM, Garrido JB, Hernandez GG, Gimeno AM, Gonzalez AL, Ruiz TR, Torres AM. A different pattern of risk factors for atopic and non-atopic wheezing in 9–12-year-old children. Pediatr Allergy Immunol 2005;16:471–477.
50. Court CS, Cook DG, Strachan DP. Comparative epidemiology of atopic and non-atopic wheeze and diagnosed asthma in a national sample of English adults. Thorax 2002;57:951–957.
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:


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