International Study of Asthma and Allergies in Childhood

The International Study of Asthma and Allergies in Childhood (ISAAC) was the largest collaborative epidemiological study of children in the world. ISAAC has measured the symptom prevalence of asthma, rhinitis and eczema in almost 2 million children in 105 countries. The aims of the ISAAC programme were to continue to measure symptom prevalence and severity of asthma, rhinitis and eczema in children, especially in developing countries where it had not been documented before; measure time trends in these conditions; identify major risk factors for asthma, rhinitis and eczema in all regions of the world; and to develop interventions to reduce the prevalence, mortality and burden of disease of asthma, rhinitis and eczema.

The ISAAC Programme formally finished in December 2012. A new network to continue ISAAC's work in asthma The Global Asthma Network was founded in 2012 and will extend the work of ISAAC in the asthma field.^[1]

History

The International Study of Asthma and Allergies in Childhood was formed in 1991 to facilitate research into asthma, rhinitis and eczema by promoting a standardised methodology able to be used in diverse locations around the world.

• Asthma causes wheezing, and often cough and breathlessness too, due to airway obstruction with smooth muscle contraction and airway inflammation. In children it is most commonly intermittent, but may be persistent. Asthma affects an estimated 300 million people worldwide, causing an estimated 250,000 deaths annually (all ages). Around 15 million disability adjusted life years (DALYs) are lost annually,^[2] and school absenteeism due to asthma results in reduced educational opportunities, and thus impacts on the economy. Based on studies undertaken in developed countries, asthma has been misinterpreted as a westernized problem based on allergy (atopy). Findings from ISAAC and others have shown that much of it does not have an allergic basis, especially in developing countries^[3][4][5] where its prevalence is increasing (Africa, Latin America and parts of Asia).^[6]
• Rhinitis (also known as rhinoconjunctivitis or hay-fever) gives troublesome nasal symptoms with itchy watery eyes, and is a common reason for medical consultation and use of medicines.^[7] ISAAC has shown that in developing countries these symptoms have little association with allergy and important differences may underlie allergic and non-allergic rhinoconjunctivitis.^[8]
• Eczema (also known as atopic eczema, childhood eczema or atopic dermatitis) is the world’s commonest skin disease in children, and is an itchy inflammatory skin condition which commonly settles in the skin creases such as the folds of the elbows or behind the knees. It is commoner in children whose families also have eczema, asthma and hay fever. Many people with eczema have antibodies in their blood to allergens in the environment such as house dust mite; they are then classified as being “atopic”. This does not necessarily mean they are allergic to those substances though. The excessive skin dryness which is commonly seen in eczema may be due to genetic factors that result in defective production of a protein found on the skin surface called filaggrin, which is important for the integrity of the barrier function of the skin. Eczema results in loss of sleep for the child and parents, time off school and work and social exclusion.^[9] The costs of eczema may be as high as $3.8 billion per year.^[10] ISAAC, the first study of eczema in developing countries has shown that eczema is not only common, but also largely non-allergic^[11] and is increasing in prevalence, especially in younger age groups.^[12]

ISAAC developed from a merging of two multinational collaborative projects each investigating variations in childhood asthma at the population level. These were an initiative from Auckland, New Zealand to conduct an international comparative study of asthma severity, and an initiative from Bochum, Germany to conduct an international study to monitor time trends and determinants of the prevalence of asthma and allergies in children.

ISAAC was a unique project investigating variations in the prevalence of these conditions at the population level and their potential causes. ISAAC attracted significant worldwide interest and large-scale participation, and became the largest worldwide collaborative research project ever undertaken in children resulting in a Guinness World Record.^[13] Since 1991, the ISAAC programme has involved 306 research centres in 105 countries with nearly 2 million children.

Organization

The ISAAC programme is led by an international Steering Committee of 26 scientists including clinicians, some from developing countries, which oversee all aspects of the programme. Many of the Steering Committee members also have positions on or are advisors to other international bodies. The Steering Committee meets yearly and the ISAAC Executive has a monthly telephone conference. As can be seen from the diagram, decisions from the Steering Committee are then passed from the Regional Coordinators to the National Coordinators, and then to the individual research centres. The International Data Centre receives data from the centres, as well as advising at all levels on methodology or other aspects of the programme.

Methodology

The ISAAC Steering Committee developed a standardised core questionnaire to measure symptom prevalence of asthma, rhinitis and eczema.^[14] These questionnaires were tested and validated to ensure they were standardised across populations and age groups, and suitable for international comparisons, in different geographical locations and languages.^[15] Using standardised guidelines, the questionnaires were translated into 53 languages and the correctness evaluated.^[16] ISAAC involved two age groups of children, 13-14 year olds, who self completed the questionnaire, and 6-7 year olds, in which the questionnaire was completed by the parents. Subjects were selected from randomly selected schools within a specified geographical area (or all schools) around each study centre. An asthma symptoms video questionnaire for the adolescents was optional. A sample size of 3000 per age group was used to give sufficient power to detect differences in severity of asthma (90% at a 1% significance level), and a high participation rate was a requirement.

ISAAC also developed tools to assist centers with the methodology,^[17] including manuals and guidelines for fieldworkers. The Phase One and Three manuals detail the development, scientific background, aims and methods of the ISAAC programme. These tools are all available from the International Data Centre, based at The University of Auckland, New Zealand, or from the ISAAC website (http://isaac.auckland.ac.nz).

The collaborative studies were designed to be conducted in three phases.^[14] Phase One used the core questionnaires designed to assess the prevalence and severity of asthma and allergic disease in defined populations. Phase Two involved more intensive studies in a smaller number of selected centres and was designed to investigate the relative importance of hypotheses of interest that arose from the Phase One results. Phase Three was a repetition of Phase One, after at least five years, examining time trends in prevalences.

Phases

Phase One

ISAAC Phase One involved 156 collaborating centers in 56 countries with 721,601 participating children (3000 per age group per centre) and used the methodology described in the previous section. The aims of ISAAC Phase One were:

1. To describe the prevalence and severity of asthma, rhinitis and eczema in children living in different centres and to make comparisons within and between countries;
2. To obtain baseline measures for assessment of future trends in the prevalence and severity of these diseases; and
3. To provide a framework for further aetiological research into lifestyle, environmental, genetic and medical care factors affecting these diseases.

Large variations in the symptom prevalence of asthma, rhinitis and eczema were found throughout the world mostly in hitherto unstudied populations.^{[18][19][20][21][22]} Reasons for these variations were explored with ecological analyses which identified possible protective factors as well as risk factors.^{[23][24][25][26][27][28][29][30][31][32]}

Phase Two

ISAAC Phase Two involved more intensive studies in a smaller number of selected centres. It began in 1998 and involved 30 centres in 22 countries with over 54,000 participating children. Phase Two was designed to investigate the relative importance of hypotheses of interest that arose from the Phase One results. ISAAC Phase Two enabled internationally standardised comparisons of disease and relevant risk factors using the modules developed by ISAAC collaborators (ISAAC Phase Two Modules Manual). These modules include the ISAAC core questionnaires, supplementary questionnaires, including questionnaires on disease management, child contact modules including examination for flexural dermatitis, skin prick tests for atopy, bronchial responsiveness to hypertonic saline, blood sampling and storage for serum IgE and genetic analyses, and a risk factor questionnaire module.
ISAAC Phase Two aims were:

1. To describe the prevalence of 'objective' markers of asthma and allergies in children living in different centres, and to make comparisons within and between centres.
2. To assess the relation between the prevalence of 'objective' markers of asthma and allergies and the prevalence of symptoms of these conditions in children living in different centres.
3. To estimate to what extent the variation in the prevalence and severity of asthma and allergies in children between centres can be explained by differences in known or suspected risk factors or by differences in disease management.

Phase Two has shown little evidence of genetic factors in asthma^[33] and that most asthma, rhinitis and eczema has a non-allergic basis, especially in developing countries.^{[4][8][11][34]}

Phase Three

ISAAC Phase Three included many new centers from developing countries, with a total of 245 centers in 99 countries and 1,187,496 children being involved. ISAAC Phase Three repeated Phase One after at least five years for centres that undertook Phase One (time trends analyses). New centres which did not do Phase One (enlarged worldwide prevalence maps) were included, and an Environmental Questionnaire (EQ) was added. The EQ asked questions about diet, height, weight, heating and cooking fuels, exercise, pets, family size and birth order, socioeconomic status, immigration and tobacco smoke exposure. The specific aims of ISAAC Phase Three were:

1. To examine time trends in the prevalence of asthma, allergic rhinitis atopic eczema in centres and countries which participated in ISAAC Phase One (Phase 3A centres).
2. To describe the prevalence and severity of asthma, allergic rhinitis and atopic eczema in centres and countries which did not participate in Phase One (Phase 3B centres).
3. To examine hypotheses at an individual level which have been suggested by the findings of Phase One, subsequent ecological analyses and recent advances in knowledge.

Phase Three identified major global variations in time trends and prevalence of childhood asthma, rhinitis and eczema. The EQ assessed the relationship between patterns found from the symptom prevalence data and many environmental factors. ISAAC Phase Three showed that in developing countries asthma and allergic disease were increasing,^{[6][12][35][36][37]} and risk factors that may have contributed to these increases are currently being analysed^[38][39] .

Phase Four

ISAAC Phase Four is the development and expansion of the scope of the ISAAC website (http://isaac.auckland.ac.nz) as a resource for ISAAC collaborators especially those in the developing world.

ISAAC was originally designed to have three phases; however, demand from researchers, particularly those in developing countries has indicated that a repeat cycle (Phase Five) is required. Funding is currently being sought to undertake this.

Impact

The ISAAC programme is currently the only global study of pediatric asthma and allergy currently in existence.^[40] Before ISAAC Phase Three, only five centres in the world had previously studied time trends in all three conditions. ISAAC Phase Three has provided time trend data in two age groups from 104 centres in 55 countries. ISAAC has established worldwide networks with organizations concerned with health in developing countries such as the International Union Against Tuberculosis and Lung Disease (IUATLD) and the World Health Organisation (WHO). Keys to ISAAC’s success have included the use of simple standardised questionnaires and rigorous data and methodology checks, to ensure standardised data that allows comparisons across geographic and linguistic boundaries.

ISAAC has demonstrated that asthma and allergies are a global health problem and environmental factors^[41] are key. The scientific value of ISAAC is attested to by the large number of publications produced by ISAAC collaborators, who have published more than 340 articles in over 100 journals including the Lancet, the British Medical Journal, the American Journal of Respiratory and Critical Care Medicine, Thorax and the European Respiratory Journal. The major effect of the findings has been to stimulate debates concerning the causes of the global variations in asthma, rhinitis and eczema, aided by the hypotheses suggested by the findings of the ecological analyses.^[42] ISAAC findings are cited by any organisation involved in monitoring and preventing Chronic Respiratory Diseases (CRD’s) and are used to inform Global Health Initiatives which include WHO, and its NGO (Non Governmental Organisation) the Global Alliance against Chronic Respiratory Diseases (GARD). ISAAC publications are included in the ‘GARD Basket’, a package of information, offered to countries by WHO to assist policy decisions relating to CRD’s.^[43]

In addition, the ISAAC Steering committee has successfully developed a surveillance tool that is able to be replicated in most places in the world, has enhanced research capacity into asthma and allergies throughout the world, and has been acknowledged for these roles by the WHO and the IUATLD – one of the leading bodies for respiratory health in developing countries. The ISAAC methodology has been the subject of positive editorial comment in the International Journal of Tuberculosis and Lung Disease, the official journal of the IUATLD, for its unique role in fostering research and critical thinking.^[44] They state “ISAAC is a model that should be followed by all those of us who are committed to improving public health in low-income countries.” ISAAC uses a simple framework which enables standard measures and comparisons across geographic, cultural and linguistic boundaries which means it can be carried out relatively inexpensively, making it particularly suitable for use in developing countries and allowing “truly global participation”. This inclusive and encouraging approach has resulted in ISAAC becoming the largest study of its kind. As stated by the Commission on Health Research for Development, ‘. . .for the world’s most vulnerable people, the benefits of research offer a potential for change that has gone largely untapped’. Such research is essential to improve public health globally and equitably. A major barrier to achieving this is a lack of confidence of health care workers to involve themselves in research. ISAAC has addressed this obstacle and produced a body of knowledge that informs policy. The World Allergy Organization has reported that “studies such as ISAAC are a major step toward overcoming barriers to the worldwide diagnosis and treatment of asthma”.^[45]

The ISAAC methodology has been adopted by the epidemiological community and is widely used in studies of asthma, rhinitis and eczema throughout the world.^[46]

References

1. ↑ "About Us The Global Asthma Network". 
2. ↑ Masoli M, Fabian D, Holt S, et al. Global Burden of Asthma: Global Initiative for Asthma (GINA); 2004.
3. ↑ Pearce N, Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax. 1999;54(3):268-72.
4. 1 2 Weinmayr G, Weiland S, Björkstén B, et al. Atopic sensitization and the international variation of asthma symptom prevalence in children. Am J Respir Crit Care Med. 2007;176(6):565 - 74.
5. ↑ Simpson JL, Brooks C, Douwes J. Innate immunity in asthma. Paediatr Respir Rev. 2008;9(4):263-70.
6. 1 2 Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368(9537):733-43.
7. ↑ Stempel DA, Woolf R. The cost of treating allergic rhinitis. Curr Allergy Asthma Rep. 2002;2(3):223-30.
8. 1 2 Weinmayr G, Forastiere F, Weiland SK, et al. International variation in prevalence of rhinitis and its relationship with sensitisation to perennial and seasonal allergens. Eur Respir J. 2008;32(5):1250-61.
9. ↑ Kemp AS. Atopic eczema: Its social and financial costs. Journal of Paediatrics and Child Health. 1999;35(3):229-31.
10. ↑ Mancini AJ, Kaulback K, Chamlin SL. The socioeconomic impact of atopic dermatitis in the United States: a systematic review. Pediatr Dermatol. 2008;25(1):1-6.
11. 1 2 Flohr C, Weiland SK, Weinmayr G, et al. The role of atopic sensitization in flexural eczema: findings from the International Study of Asthma and Allergies in Childhood Phase Two. J Allergy Clin Immunol. 2008;121(1):141-7 e4.
12. 1 2 Williams H, Stewart A, von Mutius E, et al. Is eczema really on the increase worldwide? Journal of Allergy & Clinical Immunology. 2008;121(4):947-54.e15.
13. ↑ Anonymous. Guinness World Records. London: Guinness World Records, Ltd; 2004.
14. 1 2 Asher MI, Keil U, Anderson HR, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. European Respiratory Journal. 1995;8(3):483-91.
15. ↑ Jenkins M, Clarke J, Carlin J, et al. Validation of questionnaire and bronchial hyperresponsiveness against respiratory physician assessment in the diagnosis of asthma. International Journal of Epidemiology. 1996;25(3):609-16.
16. ↑ Ellwood P, Williams H, Aït-Khaled N, Björkstén B, Robertson C, ISAAC Phase III Study Group. Translation of questions: The International Study of Asthma and Allergies in Childhood (ISAAC) experience. Int J Tuberc Lung Dis. September 2009; 13(9): 1174-1182
17. ↑ Ellwood P, Asher MI, Beasley R, et al. The international study of asthma and allergies in childhood (ISAAC): Phase Three rationale and methods. International Journal of Tuberculosis & Lung Disease. 2005;9(1):10-6.
18. ↑ Beasley R, Ellwood P, Asher I. International patterns of the prevalence of pediatric asthma the ISAAC programme. Pediatric Clinics of North America. 2003;50(3):539-53.
19. ↑ Strachan D, Sibbald B, Weiland S, et al. Worldwide variations in prevalence of symptoms of allergic rhinitis in children: the International Study of Asthma and Allergies in Childhood (ISAAC). Pediatric Allergy & Immunology. 1997;8(4):161-76.
20. ↑ ISAAC Steering Committee. Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC). European Respiratory Journal. 1998;12(2):315-35.
21. ↑ ISAAC Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema: ISAAC. Lancet. 1998;351(9111):1225-32.
22. ↑ Williams H, Robertson C, Stewart A, et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood. Journal of Allergy & Clinical Immunology. 1999;103(1 Pt 1):125-38.
23. ↑ Anderson HR, Poloniecki JD, Strachan DP, et al. Immunization and symptoms of atopic disease in children: results from the International Study of Asthma and Allergies in Childhood. American Journal of Public Health. 2001;91(7):1126-9.
24. ↑ Burr M, Emberlin J, Treu R, et al. Pollen counts in relation to the prevalence of allergic rhinitis, asthma and atopic eczema in the International Study of Asthma and Allergies in Childhood (ISAAC). Clinical & Experimental Allergy. 2003;33(12):1675-80.
25. ↑ Ellwood P, Asher MI, Björkstén B, et al. Diet and asthma, allergic rhinitis and atopic eczema symptom prevalence: an ecological analysis of the International Study of Asthma and Allergies in Childhood (ISAAC) data. European Respiratory Journal. 2001;17(3):436-43.
26. ↑ Mitchell EA, Stewart AW, the Isaac Phase One Study Group (International Study of Asthma and Allergy in Childhood). The ecological relationship of tobacco smoking to the prevalence of symptoms of asthma and other atopic diseases in children: the International Study of Asthma and Allergies in Childhood (ISAAC). European Journal of Epidemiology. 2001;17(7):667-73.
27. ↑ Newson RB, Shaheen SO, Chinn S, et al. Paracetamol sales and atopic disease in children and adults: an ecological analysis. European Respiratory Journal. 2000;16(5):817-23.
28. ↑ Shirtcliffe P, Weatherall M, Beasley R, et al. An inverse correlation between estimated tuberculosis notification rates and asthma symptoms. Respirology. 2002;7(2):153-5.
29. ↑ Stewart AW, Mitchell EA, Pearce N, et al. The relationship of per capita gross national product to the prevalence of symptoms of asthma and other atopic diseases in children (ISAAC). [see comments.]. International Journal of Epidemiology. 2001;30(1):173-9.
30. ↑ von Mutius E, Pearce N, Beasley R, et al. International patterns of tuberculosis and the prevalence of symptoms of asthma, rhinitis, and eczema [see comments]. Thorax. 2000;55(6):449-53.
31. ↑ Weiland SK, Husing A, Strachan DP, et al. Climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children. Occupational & Environmental Medicine. 2004;61(7):609-15.
32. ↑ Weiland SK, von Mutius E, Husing A, et al. Intake of trans fatty acids and prevalence of childhood asthma and allergies in Europe. ISAAC Steering Committee. Lancet. 1999;353(9169):2040-1.
33. ↑ Genuneit J, Cantelmo JL, Weinmayr G, et al. A multi-centre study of candidate genes for asthma and allergy. The International Study of Asthma and Allergy in Childhood Phase Two. Clin Exp Allergy. 2009;(in press).
34. ↑ Weiland SK, Bjorksten B, Brunekreef B, et al. Phase II of the International Study of Asthma and Allergies in Childhood (ISAAC II): rationale and methods. European Respiratory Journal. 2004;24(3):406-12.
35. ↑ Anderson HR, Gupta R, Kapetanakis V, et al. International correlations between indicators of prevalence, hospital admissions and mortality for asthma in children. International Journal of Epidemiology. 2008;37(3):573-82.
36. ↑ Bjorksten B, Clayton T, Ellwood P, et al. Worldwide time trends for symptoms of rhinitis and conjunctivitis: Phase III of the International Study of Asthma and Allergies in Childhood. Pediatric Allergy & Immunology. 2008;19(2):110-24.
37. ↑ Pearce N, Ait-Khaled N, Beasley R, et al. Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax. 2007;62(9):758-66.
38. ↑ Beasley R, Clayton T, Crane J, et al. Association between paracetamol use in infancy and childhood, and risk of asthma, rhinitis, and eczema in children aged 6-7 years: analysis from Phase Three of the ISAAC programme. Lancet. 2008;372(9643):1039-48.
39. ↑ Brunekreef B, Stewart AW, Anderson HR, Lai CKW, Pearce NE.Self reported truck traffic in street of residence and symptoms of asthma and allergic disease: a global relationship in ISAAC Phase Three. Environ Health Perspect July 2009; Epub ahead of print.
40. ↑ Lewis S. ISAAC--a hypothesis generator for asthma? International Study of Asthma and Allergies in Childhood [comment]. Lancet. 1998;351(9111):1220-1.
41. ↑ Wong GW, Chow CM. Childhood asthma epidemiology: insights from comparative studies of rural and urban populations. Pediatr Pulmonol. 2008;43(2):107-16.
42. ↑ Partridge MR. Has ISAAC told us as much as it can? Where now? Thorax. 2009;64(6):462-3.
43. ↑ World Health Organisation. Global Alliance against chronic respiratory diseases (GARD) basket: a package of information, surveillance tools and guidelines, to be offered as a service to countries. Geneva: World Health Organisation; 2008
44. ↑ Enarson DA. Fostering a spirit of critical thinking: the ISAAC story. International Journal of Tuberculosis & Lung Disease. 2005;9(1):1.
45. ↑ Pawankar R, Baena-Cagnani CE, Bousquet J, et al. State of World Allergy Report 2008: Allergy and Chronic Respiratory Diseases. World Allergy Organisation Journal. 2008;(Supplement 1):s4-s17.
46. ↑ ISAAC Observatory.http://www.respirar.org/eng/isaac/index.htm

External links

• Official website