4. Scientific background of ISAAC
The prevalence of asthma, rhinoconjunctivitis and eczema has been described by ISAAC Phase One (156 centres from 56 countries, undertaken between 1994 and 1995) and Phase Three (237 centers in 98 countries, undertaken between 2001 and 2003) and has ‘mapped’ the prevalence of these conditions in children and adolescents 8-15 as well as investigating time trends in 104 centres in 55 countries 16-21. All ISAAC publications can be found on the ISAAC website: http://isaac.auckland.ac.nz. ISAAC Phase Two, using child contact modules in 10 year old children, was a more in depth study in a smaller number of centres (30 centres from 22 countries), and began in 1998. Phase Two, was designed to investigate the relative importance of hypotheses of interest that arose from the Phase One results using objective markers 22-33. Standardised questions about cough, the medical care of asthma, rhinitis and eczema and child contact protocols were developed. ISAAC Phase Three, was a repeat of the Phase One core questions with an additional Environmental Questionnaire (EQ) in centres that undertook the Phase One methodology. Additionally, the recruitment of ‘new’ centres was encouraged, to obtain a more comprehensive global map of asthma, rhinoconjunctivitis and eczema, particularly in low and middle income countries. ISAAC Phase Three has been a crucial part of the process by which the extent, nature and causes of the global increases in the prevalence of these conditions are understood. Brief summaries of the ISAAC Phase Three results conducted between 2000 and 2003 are as follows:
The global prevalence and severity of asthma symptoms undertaken in ISAAC Phase Three, involved 798 685 adolescents (13/14 year olds) from 233 centres in 97 countries, and 388 811 children (6/7 year olds) from 144 centres in 61 countries 12. As in ISAAC Phase One, wide variations in prevalence were found around the world. The prevalence of wheeze in the past 12 months in adolescents varied from 32.6% in Wellington (New Zealand) to 0.8% in Tibet (China), and in children from 37.6% in Costa Rica to 2.4% in Jodhpur (India). The prevalence of symptoms of severe asthma (defined as ≥4 attacks of wheeze, or ≥1 night per week sleep disturbance from wheeze, or wheeze affecting speech in the past 12 months) varied from 16% in Costa Rica to 0.1% in Pune (India) in adolescents, and from 20.3% to 0% in the same two centres respectively in children. Ecological economic analyses revealed a significant trend towards a higher prevalence of current wheeze in centres in higher income countries in both age groups, but this trend was reversed for the prevalence of severe symptoms among current wheezers, especially in the older age group. Thus wide variations exist in the symptom prevalence of childhood asthma worldwide. Although asthma symptoms tend to be more prevalent in more affluent countries, they appear to be more severe in less affluent countries.
The global prevalence and severity of rhinitis symptoms in ISAAC Phase Three, involved 670 242 adolescents from 232 centres in 97 countries and 388 811 children from 144 centres in 61 countries 13. The average overall prevalence of current rhinoconjunctivitis symptoms was 14.6% for the adolescents (range 1.0–45%). Variation in the prevalence of severe rhinoconjunctivitis symptoms was observed between centres (range 0.0–5.1%) and regions (range 0.4% in western Europe to 2.3% in Africa), with the highest prevalence being observed mainly in the centres from middle and low income countries, particularly in Africa and Latin America. Co-morbidity with asthma and eczema varied from 1.6% in the Indian sub-continent to 4.7% in North America. For 6/7 year old children, the average prevalence of rhinoconjunctivitis symptoms was 8.5%, and large variations in symptom prevalence were also observed between regions, countries and centres. Thus wide global variations exist in the prevalence of current rhinoconjunctivitis symptoms, being higher in high vs low income countries, but the prevalence of severe symptoms was greater in less affluent countries. Co-morbidity with asthma is high particularly in Africa, North America and Oceania. This global map of symptom prevalence is of clinical importance for health professionals.
The global prevalence and severity of eczema symptoms undertaken in ISAAC Phase Three, involved 663 256 adolescents from 230 centres in 96 countries and 385 853 children from 143 centres in 60 countries 14. Current eczema was defined as an itchy flexural rash in the past 12 months and was considered severe eczema if associated with 1 or more nights per week of sleep disturbance. For adolescents, data showed prevalence values ranging from 0.2% in China to 24.6% in Columbia with the highest values in Africa and Latin America. For the children, data showed that the prevalence of current eczema ranged from 0.9% in India to 22.5% in Ecuador, with new data showing high values in Asia and Latin America. Current eczema was lower for boys than girls (odds ratios [OR] 0.94 and 0.72 for children and adolescents, respectively). Thus ISAAC Phase Three provided comprehensive global data on the prevalence of eczema symptoms that is essential for public health planning. This new data revealed that eczema is a disease of developing as well as developed countries.
4.4 Environmental data
In 6/7 year old children from 73 centres in 31 countries the use of paracetamol for fever in the first year of life was associated with an increased risk of asthma symptoms (OR 1.46 [95% CI 1.36 - 1.56]) 34. Current use of paracetamol was associated with a dose-dependent increased risk of asthma symptoms (OR 1.61 [95% CI 1.46 - 1.77] and OR 3.23 [95% CI 2.91 - 3.60] for medium and high use vs no use, respectively). Use of paracetamol was similarly associated with the risk of severe asthma symptoms, with population-attributable risks between 22% and 38%. Paracetamol use, both in the first year of life and in children aged 6/7 years, was also associated with an increased risk of symptoms of rhinoconjunctivitis and eczema. In the analysis of adolescents from 113 centers in 50 countries the recent use of paracetamol was associated with an exposure-dependent increased risk of current asthma symptoms (OR 1.43 [95% CI 1.33 - 1.53] and OR 2.51 [95% CI 2.33 - 2.70] for medium and high versus no use, respectively) 35.
The use of antibiotics was explored in Phase Three in a total of 71 centers in 29 countries 36. Reported use of antibiotics in the first year of life was associated with an increased risk of current asthma symptoms (wheezing in the previous 12 months) with an OR adjusted for risk factors of 1.70 [95% 1.60 - 1.80] when adjusted for other risk factors for asthma. Similar associations were observed for severe asthma symptoms (OR 1.82 [95% CI 1.67 - 1.98]), and asthma ever (OR, 1.94 [95% CI 1.83 - 2.06]). Use of antibiotics in the first year of life was also associated, but less strongly, with increased risks of current symptoms of rhinoconjunctivitis (OR, 1.56 [95% CI, 1.46 - 1.66]) and eczema (OR 1.58 [95% CI 1.33 - 1.51]).
The frequency of truck traffic on the street of residence was positively associated with the prevalence of symptoms of asthma, rhinoconjunctivitis, and eczema with an exposure - response relationship 37. ORs for “current wheeze” and “almost the whole day” versus “never” truck traffic were 1.35 [95% CI 1.23 - 1.49] for adolescents and OR 1.35 [95% CI 1.22 - 1.48] for children. These findings that higher exposure to self-reported truck traffic on the street of residence is associated with increased reports of symptoms of asthma, rhinitis, and eczema in many locations in the world require further investigation in view of increasing exposure of the world’s children to traffic.
There were 206 453 children from 72 centres in 31 countries that participated 38. Parental reported breast feeding ever was not associated with current wheeze, with an OR (adjusted for gender, region of the world, language, per capita gross national income, and factors encountered in infancy) of 0.99 [95% CI 0.92 - 1.05], current rhinoconjunctivitis (OR 1.00, [95% CI 0.93 - 1.08]), current eczema (OR 1.05 [95% CI 0.97 - 1.12]), or symptoms of severe asthma (OR 0.95 [95% CI 0.87 - 1.05]). Breast feeding was however associated with a reduced risk of severe rhinoconjunctivitis (OR 0.74 [95% CI 0.59 - 0.94]) and severe eczema (OR 0.79 [95% CI 0.66 - 0.95]).
A positive association was found between early exposure to farm animals and the prevalence of symptoms of asthma, rhinoconjunctivitis and eczema, especially in non-affluent countries 39. In these countries, ORs for ‘current wheeze’, ‘farm animal exposure in the first year of life’ and ‘farm animal exposure in pregnancy’ were 1.27 [95% CI 1.12 - 1.44] and 1.38 [95% CI 1.21 - 1.58], respectively. The corresponding ORs for affluent countries were 0.96 [95% CI 0.86 - 1.08] and 0.95 [95% CI 0.84 - 1.08], respectively.
Cats and dogs
Among children, cat exposure in the first year of life was associated with current symptoms of asthma, wheeze, rhinoconjunctivitis, and eczema, especially in less-affluent countries 40. Among adolescents, we found a positive association between exposure to cats or dogs and symptom prevalence in more-affluent and less-affluent countries. The global multivariate ORs for children with complete covariate data were 1.17 [95% CI 1.08 - 1.29] for current symptoms of asthma, 1.13 [95% CI 1.05 - 1.23] for rhinoconjunctivitis, and 1.38 [95% CI 1.26 - 1.52] for eczema. Smaller odds ratios were found for exposure to only dogs. Exposure to only cats was associated with eczema.
For the adolescents (128 centres in 28 countries), the estimated average within-country change in center-level asthma prevalence per 100 children per 10% increase in center-level PM2.5 and NO2 was –0.043 [95% CI 0.139 - 0.053] and 0.017 [95% CI 0.030 - 0.064] respectively 41. For ozone the estimated change in prevalence per parts per billion by volume was –0.116 [95% CI 0.234 - 0.001]. Equivalent results for the children (83 centers in 20 countries), though slightly different, were not significantly positive. For the adolescents, change in center-level asthma prevalence over time per 100 children per 10% increase in PM2.5 from Phase One to Phase Three was –0.139 [95% CI 0.347 - 0.068]. The corresponding association with ozone (per ppbV) was –0.171 [95% CI 0.275 - 0.067].
There were 220 407 children that participated from 75 centres in 32 countries. For the adolescents 350 654 participated from 118 centres in 53 countries 42. Maternal and paternal smoking was associated with an increased risk of symptoms of asthma, eczema and rhinoconjunctivitis in both age groups, although the magnitude of the OR is higher for symptoms of asthma than the other outcomes. Maternal smoking is associated with higher ORs than paternal smoking. For asthma symptoms there is a clear dose relationship (1-9 cigarettes/day, OR 1.27; 10-19 cigarettes/day, OR 1.35; and 20+ cigarettes/day, OR 1.56). When maternal smoking in the child’s first year of life and current maternal smoking are considered, the main effect is due to maternal smoking in the child’s first year of life. There was no interaction between maternal and paternal smoking.
Body mass index
A total of 76 164 children from 29 centres and 17 countries and 201 370 adolescents from 73 centres and 35 countries provided data that met the inclusion criteria 43. There were associations between overweight and obesity, but not underweight, and symptoms of asthma and eczema but not rhinoconjunctivitis. Vigorous physical activity was positively associated with symptoms of asthma, rhinoconjunctivitis and eczema in adolescents, but not children. Viewing television for five or more hours/day was associated with an increased risk of symptoms of asthma, rhinoconjunctivitis and eczema in adolescents and symptoms of asthma in children.
Data from 319 196 adolescents from 107 centres in 51 countries and 181 631 children from 64 centres in 31 countries were included in the ISAAC Phase Three diet analysis 44. For adolescents and children, a potential protective effect on severe asthma was associated with consumption of fruit ≥3 times per week (OR 0.89 [95% CI 0.82 - 0.97]; OR 0.86 [95% CI 0.76 - 0.97], respectively). An increased risk of severe asthma in adolescents and children was associated with the consumption of fast food ≥3 times per week (OR 1.39 [95% CI 1.30 - 1.49]; OR 1.27 ([95% CI 1.13 - 1.42] respectively), as well as an increased risk of severe rhinoconjunctivitis and severe eczema. Similar patterns for both ages were observed for regional analyses, and were consistent with gender and affluence categories and with current symptoms of all three conditions.
There were 198 398 children from 70 centres in 29 countries and 314 309 adolescents from 108 centres in 47 countries in this analysis 45. The use of an open fire for cooking was associated with an increased risk of symptoms of asthma and reported asthma in children for wheeze in the past year (OR 1.78 [95% CI 1.51 - 2.10]) and for adolescents (OR 1.20 [95% CI 1.06 - 1.37]). In the final multivariate analyses, ORs for wheeze in the past year and the use of solely using an open fire for cooking were 2.17 [95% CI 1.64 - 2.87] for children and 1.35 [95% CI 1.11 - 1.64] for adolescents. ORs for wheeze in the past year and the use of open fire in combination with other fuels for cooking were 1.51 [95% CI 1.25 - 1.81] for children and 1.35 [95% CI 1.15 - 1.58] for adolescents. In both age groups, there was no evidence of an association between the use of gas as a cooking fuel and either asthma symptoms or asthma diagnosis. Because a large percentage of the world population uses open fires for cooking, this cooking method might be an important modifiable risk factor if the association is proven to be causal.
In this study 162 324 children from 60 centres in 26 countries participated 46. Low birth weight (<2.5 kg) was associated with an increased risk of symptoms of asthma (current wheeze OR 1.20 [95% CI 1.12 - 1.30]). Low birth weight was associated with a lower risk of eczema ever but not with rhinoconjuncitivitis. Large babies (birth weight ≥4.5kg) were not associated with any of these outcomes. This study confirmed that low birth weight is a risk factor for symptoms of asthma, but not for rhinoconjunctivitis. The findings for eczema were equivocal.
This study included 326 691 adolescents from 11 centres from 48 countries and 208 523 children from 72 centres in 31 countries 47. It was found that immigration was associated with a lower symptom prevalence of asthma, rhinoconjunctivitis and eczema in both age groups than among those born in the country studied, and that this association was mainly confined to high-prevalence countries. This reduced risk was greater in those who had lived fewer years in the host country.
Questionnaire data for 210 200 children from 31 countries and 337 226 adolescents from 52 countries was included in this analysis. In both age groups inverse trends (p<0.0001) were observed for reported ‘hay fever ever’ and ’eczema ever’ with increasing numbers of total siblings, and more specifically older siblings. These inverse associations were significantly (p<0.005) stronger in more affluent countries. In contrast, symptoms of severe asthma and severe eczema were positively associated (p<0.0001) with total sibship size in both age groups 48.
4.5 Methodological issues
Three papers discussing methodological issues in ISAAC and one describing the Phase Three methodology have been published. These provide the rationale for the Global Asthma Network – Global Surveillance: Prevalence, Severity, Management and Risk Factors study.
The International Study of Asthma and Allergies in Childhood (ISAAC): Phase Three Rationale and Methods 49
Translation of questions: The International Study of Asthma and Allergies in Childhood (ISAAC) experience 50
The impact of the method of consent on response rates in the ISAAC time trends study 7
The challenges of replicating the methodology between Phases I and III of the ISAAC programme 21
4.6 Significance of the proposed study
The newly formed Global Asthma Network will use international questionnaires to collect further information on the topics addressed in the Global Asthma Reports 2011 and 2014: including asthma prevalence and severity; address how people are getting diagnosed with asthma; unplanned visits including emergency room visits and hospital admissions; and evaluation of different policies for management of asthma in children and adults. Key components of the written questionnaires are: surveillance; asthma management; confirmation of doctor diagnosed asthma, rhinitis and eczema; socioeconomic status; early life environment; potential risk factors in the environment; home environment; and smoking. The data will provide new information from centres not previously involved with ISAAC and from additional questions that have been added to provide more detail about the participant and the environment and will allow some comparisons of data from existing ISAAC centres.