Origins of ISAAC
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. This section of the ISAAC Story collates the recollections of founder members of the consortium about the early development of ISAAC as a global study.
Asthma epidemiology in the 1980s(Michael Burr)
There is a long history of surveys of childhood asthma in various countries. When the findings of these surveys were compared, it was clear that reported asthma prevalence showed considerable geographical variation. Until relatively recently, each survey used its own methods, so that it was unclear whether the reported differences in prevalence could be attributable to variations in aspects of the methodology, e.g. the way children were selected, local diagnostic criteria, the way questionnaires were administered, the wording of the questions, and the conduct of challenge tests. But a comparison of surveys that used fairly similar methods suggested that the prevalence of childhood asthma was higher in New Zealand than in the United Kingdom.
The first survey planned to compare the prevalence in different countries was perhaps the study of Tokelau Islanders in New Zealand and Tokelau. In 1975-1976 surveys of asthma were conducted among Tokelauan children living in New Zealand and Tokelau, using the same methods (questionnaire and physical examination). Asthma, rhinitis and eczema were all substantially more common in New Zealand than in Tokelau; the differences were ascribed to environmental rather than genetic factors in that both groups of children were of predominantly Tokelauan descent.
In the early 1980s there was growing concern about a sudden rise in asthma mortality in New Zealand during the previous decade. This had not occurred in Australia, Canada, USA or England and Wales; furthermore, hospital admissions for asthma and sales per capita of asthma drugs had also increased disproportionately in New Zealand. The question obviously arose as to whether asthma prevalence was also higher in New Zealand. So in 1985 Innes Asher and others conducted a survey in Auckland, NZ, following the same protocol that had been used three years earlier in two areas of Australia. In each country the subjects were mostly 8 or 9 years old, and the survey employed a respiratory questionnaire and bronchial challenge with histamine. The prevalence of respiratory symptoms and bronchial hyperresponsiveness was similar in Auckland and inland New South Wales but lower in coastal New South Wales than in the other two sites.
The Auckland data were also compared with the findings of a survey in Croydon, England, which had been conducted in 1978. The prevalence of wheeze in the last month, the last 12 months and over the whole lifetime was significantly higher in Auckland than in Croydon; some uncertainty about the conclusions was expressed, however, in that neither the procedure nor the questions were identical, and during the 7-year interval between the surveys the prevalence in Croydon might have changed.
In order to compare asthma prevalence in several countries using the same protocol in each case, a survey was conducted in defined areas of Wales, New Zealand, Sweden and South Africa in 1988-1990. A questionnaire was completed by the parents of 12-year-old children asking about a history of asthma and respiratory symptoms, and the children performed a simple exercise challenge test. Asthma prevalence (determined by various criteria) was highest in New Zealand and lowest in Sweden; asthma mortality in children showed a similar pattern. Thus this study strengthened the evidence for real international differences in asthma prevalence, the disease being particularly common in New Zealand.
Interest in possible geographical variations in asthma was not confined to the disease in children. There was less information about asthma prevalence in adults, and valid comparisons between different areas were impossible because of the lack of any standardised methodology. During the 1980s, to rectify this situation, the International Union against Tuberculosis and Lung Disease began to develop standard methods for studying the epidemiology of asthma, including a questionnaire that would be suitable for large-scale surveys. In 1988 the European Commission funded a study that became known as the European Community Respiratory Health Survey (ECRHS), which would use this questionnaire and various tests to investigate asthma prevalence in people aged 20-44 years. The survey was conducted during the early 1990s in many countries; although it was primarily based in Europe, a few other areas participated, including four centres in New Zealand, where asthma prevalence was again found to be particularly high. Subsequent cross-fertilisation between ECRHS and ISAAC has occurred, including the enlisting of centres in one of these surveys leading to recruitment for the other.
Meanwhile, the development of a questionnaire for use in international surveys of children was stimulated by contact between investigators in Auckland and Bochum, Germany. The ensuing discussions led to a survey in New Zealand, Germany, England and Australia in 1991 that used the ISAAC protocol and was the forerunner of the main ISAAC study. Various indices of asthma (including the use of a video questionnaire) showed a higher prevalence in the Australasian centres than in Germany.
Thus New Zealand has played a prominent part throughout the development of international studies of asthma, arising out of concern about asthma mortality and morbidity in that country. It is entirely appropriate that the ISAAC International Data Centre should be located there.
The origins of ISAAC: a German perspective(Ulrich Keil)
At the beginning of 1987 I had started to build up an Institute of Epidemiology and Social Medicine at the Medical Faculty of the University of Bochum. In 1987 the Federal Ministry of Research and Technology (BMBF )in Bonn approached a number of German epidemiologists to develop a manual for the planning and execution of epidemiological studies in the area of asthma and allergic diseases. They reported that a comprehensive research program would soon be announced to shed more light on the aetiology and medical care of asthma and allergies.
In light of the BMBF`s experience with the German Cardiovascular Prevention Study (Deutsche Herzkreislaufpräventionsstudie, DHP) in the 1980’s, which had cost a hundred million Deutsche Mark but had produced only meagre scientific output, the responsible people at the BMBF wanted to make sure that the envisaged nationwide research program for asthma and allergies should perform better. This is why they called on a number of leading epidemiologists in Germany to develop the above mentioned Manual.
Eight epidemiologists gathered in 1987 in Bochum and other sites in Germany and started developing the requested manual, resulting in a paper published in 1988 by "Berger J, Bergmann KE, Greiser E, Keil U, Lehmacher W, Schäfer H, Schwartz FW, Wichmann HE. Manual für die Planung und Durchführung epidemiologischer Studien auf dem Gebiet allergischer Krankheiten" was published in the journal Allergologie (Allergologie 1988;11:479-92). This manual was meant to be adhered to when studies in the field of asthma and allergies were being planned and developed, and research proposals being written.
My involvement in the writing of this manual in the years 1987 to 1988 acquainted me with the field of asthma and allergic disease epidemiology, which I had touched only sporadically, previously. Before, during and after the publication of this manual I had worked in the field of cardiovascular epidemiology and prevention and in the field of occupational epidemiology, and have continued to do so since.
In 1989 Stephan Weiland applied for a job at my institute in Bochum. He was a young physician from Cologne who had just returned from McGill University in Montreal with a Master of Science degree in epidemiology, but no practical experience in epidemiology. He expressed an interest in pediatric epidemiology and this coincided with the BMBF`s official announcement of a comprehensive research program on asthma and allergic diseases and a request for proposals.
Stephan started working at my institute in January 1990 and we decided to apply for a research grant from this BMBF program. As we were rather ignorant about asthma and allergies we decided to travel to London and see Ross Anderson and David Strachan at St George’s Hospital Medical School. We received a warm welcome by Ross and David, who put aside. a full working day for us and informed us about all they knew about asthma and allergic disease epidemiology. (Bonnie Sibbald informed us about the epidemiology of rhinitis). Coming from the German university system we were quite surprised how well we strangers from Germany were treated.
On our return to Bochum we were full of new ideas and had a good feeling that we might be successful in developing a grant proposal. One request of the BMBF program was that we should get together with other research groups in Germany and develop a collaborative research program. Following this line we contacted a number of interested colleagues in Germany but our major interest was to stay in close contact with international groups. From Ross and David we had learned about research initiatives in Auckland, New Zealand, and from my 1986 sabbatical in Chapel Hill, North Carolina, I knew Neil Pearce from Wellington and his interest in asthma research.
In light of my 10 year experience with the World Health organisation`s MONICA (Monitoring trends and determinants in cardiovascular disease) project we planned for an international workshop with the title " Monitoring Trends of Asthma and Allergies". This workshop took place in Bochum on December 2-5, 1990 and was funded by the BMBF. The research groups from London, Auckland, Wellington and Bochum and additional groups from Germany were well represented. Stephan Weiland wrote the minutes of this workshop and they formed the basis for further developing our ideas and planning for the next international workshop with the title " Monitoring Trends of Asthma and Allergies in Childhood" which again took place in Bochum one year later, namely from December 8-11, 1991. This time the Institute of Social Medicine and Epidemiology of the Ruhr Universität Bochum funded the workshop which was instrumental in choosing the target population, namely children and adolescents, discussing the study design and protocol and the data collection instruments, thus laying the foundation for the worldwide International Study of Asthma and Allergies in Childhood (ISAAC).
I have very good memories of those two December workshops in Bochum, not only because of the wining and dining, but also because participants were very open and positive and because there were excellent presentations and a lot of fruitful discussion which helped producing the ISAAC protocol (Manual) with the written and video questionnaires in 1992.
In the same year a pilot study was started, comprising populations of 12-15 year olds in Wellington (New Zealand), Adelaide and Sydney (Australia), West Sussex (England) and Bochum (Germany). The results of this pilot study were published in 1993 in the European Respiratory Journal under the title "Self-reported prevalence of asthma symptoms in children in Australia, England, Germany and New Zealand: An international comparison using the ISAAC written and video questionnaires." Eur Resp J 1993;6:1455-1461. A year later the pilot study data from Bochum served for another paper with the topic "Self-reported wheezing and allergic rhinitis in children and traffic density on street of Residence", published in Ann Epidemiol 1994;4:243-247.
In the beginning of 1993 I moved from the Ruhr Universität Bochum to the University of Münster and again built up an Institute of Epidemiology and Social Medicine. Stephan Weiland followed me to Münster, enabling us to continue our work with ISAAC. For ISAAC Phase One we established two study regions in Germany, one in the city of Münster (northwestern part of Germany) and one in Greifswald, which lies in the northeastern part of the country. The irony of the ISAAC story is that we started out in Bochum to develop a research proposal for the BMBF to receive funding for a collaborative asthma study in Germany. However, our international contacts and the two workshops in Bochum helped to pave the way for the worldwide ISAAC Study; the original intention to start a Verbundprojekt in Germany (Collaborative asthma study in Germany) materialised only in the mid 1990’s, when we established study sites and regions in Dresden and Munich, loosely connected also to the study in Leipzig. The Verbundprojekt targeted 10 year olds and unlike ISAAC Phases I and III incorporated clinical measurements and blood samples, thus helping to create ISAAC Phase II.
The origins of ISAAC: a New Zealand perspective(Innes Asher)
Origins of ISAAC - New Zealand perspectives
New Zealand started focusing on asthma in earnest in 1979 when it became apparent that a new epidemic of asthma deaths had arisen in 1977, affecting New Zealand more than any other country. This stimulated a range of programmes of research exploring the reasons for this epidemic starting with a prospective national asthma mortality study which confirmed the epidemic. A focus on admission to hospital for asthma found that these were increasing dramatically in New Zealand, Australia, The United Kingdom, Canada and USA and the highest rates were in New Zealand children.
Although deaths from asthma among children are relatively uncommon, the escalating admission rate combined with anecdotal reports of increasing severity, awakened a great deal of interest in finding out more about the prevalence and severity of asthma in New Zealand children, and comparisons with other countries. There had been a few previous childhood asthma prevalence studies in New Zealand, and none used identical methods, so comparison between centres and over time were limited. This led to the design of a study of asthma prevalence in children using standardised methods in centres across countries - Auckland, New Zealand and Belmont and Wagga Wagga, New South Wales, Australia - one of the first international comparison of asthma prevalence using standardised methods. The prevalence of current wheezing and bronchial hyper-responsiveness (using an abbreviated histamine challenge) did not differ between Auckland and Wagga Wagga, but the rates were lower in Belmont.
The finding of little difference in prevalence of asthma between New Zealand and Australia, combined with continuing concern about the possibility of a higher prevalence of severe asthma in New Zealand led our interest in developing a study to explore international differences in severity of asthma in children using standardised methods. Hospital admission rates were available for some English -language countries and showed international differences, but that may have reflected variations in provision or use of health services. Both hospital admissions and mortality rates could not be interpreted easily without better information on prevalence and severity.
During 1990 I contacted centres in Australia, Canada and the United Kingdom about collaborating on an international study of the severity of asthma in children. The concept was to use the “core protocol” approach to the asthma questionnaire developed by Ed Mitchell, Colin Robertson and Ross Anderson in London 1988. The concept of simple but standardised tools designed for widespread use (and based on questionnaires, rather than measures such as bronchial hyperactivity) was accepted, and the questionnaire was further developed. By 15 September 1990 investigators in eighteen centres in five countries were committed in principle to the project: Australia: Melbourne, Sydney, Perth; Canada: Gainesville, Seattle, Tucson; New Zealand: Auckland, Christchurch, Dunedin, Hastings, Nelson, Wellington; United Kingdom: Cardiff, Edinburgh, London, Southampton; USA: Hamilton and Saskatoon.
We were awarded a grant from the Health Research Council of New Zealand (HRCNZ) on 29 November 1991 to compare the prevalence and severity of childhood asthma in two age-groups of children both between countries and within New Zealand (by area and ethnic group). This covered fieldwork in Auckland, Wellington and Christchurch, a full-time data manager, and secretarial and computing support. The funding remained conditional upon at least one other centre outside New Zealand obtaining funds for a similar survey in their own centre. (On 1 April 1992 David Strachan of The Department of Public Health Sciences St Georges Hospital wrote confirming they had funding for a centre in southern England). The HRCNZ funding was activated on 1 July 1992 and did not extend to future studies to assess time trends, nor to detailed investigation (by case-control studies) of aetiological and medical care factors (genetic, cigarette smoke, aeroallergens, pollution, infections, drug use, preventive care, management of acute attacks). Some concerns had been expressed by the Health Research Council about the validity of questionnaire-based- measures, including their reproducibility, correlation with BHR and validation between centres, particularly where translation was involved. There were also issues relating to the choice of centres within each country and the statistical effects of cluster sampling by school.
At about the same time Ulrich Keil and Stephan Weiland were developing ideas for epidemiological studies of asthma and allergic disease in Germany, including baseline surveys for future assessment of time trends. During the first Bochum meeting in December 1990, international comparisons were also discussed and a similar conclusion was reached about the desirability of a core protocol. The original Auckland proposal had focused on asthma, whereas the German interest also included allergies. At the same time Julian Crane and Neil Pearce introduced the idea of a video questionnaire to overcome cultural and linguistic barriers in ascertaining the prevalence of respiratory symptoms. In March 1991, the Bochum and Wellington groups met with Innes Asher in Auckland and the two proposals were merged. This was welcomed by all parties.
By the time of the Bochum meeting in December 1991 there were fewer than 30 centres in the world where the prevalence of asthma in children had been studied at all, and most had used different methodology.
The origins of ISAAC: a United Kingdom perspective(Ross Anderson)
During 1990, an informal meeting was held at St George’s Hospital Medical School, London, between ourselves and Colin Robertson. We discussed ideas for developing an asthma questionnaire which would include measures of severity which were relevant in children. Colin’s interest and expertise related to the long standing follow-up study of wheezy children in Melbourne originated by Howard Williams in the 1960s. We drew on ideas from the surveys that had been completed in Croydon, south London, during 1978 and which we planned to repeat in 1991 to obtain information on time trends in our area. Specifically, the question about wheeze that caused difficulty with speaking had been validated in terms of hospital admissions for asthma in Croydon.
Later in 1990, Ulrich Keil and Stephan Weiland contacted us “out of the blue” requesting a meeting. They had made a day trip from Bochum to St George’s and explained that there was a desire by the German Government for research into allergy and Ulrich was seeking expert advice on methods.
Ross had already had some contacts with a number of the Auckland and Wellington investigators. Neil had visited St George’s to talk about the fenoterol studies. Innes had been to the UK with the results of her children’s survey and in 1988 Ross had been a visiting lecturer at the annual Boehringer respiratory symposium. Thus, there was already the basis for collaboration between St George’s and New Zealand.
At the end of 1990 was the first meeting organised by Ulrich at Bochum. Attending from St George’s were Ross Anderson, David Strachan and Bonnie Sibbald. The meeting included several classic dialogues and debates between epidemiologists and clinicians over methods (diagnostic accuracy versus unbiased ascertainment; the need to consider allergic disease not just asthma) and beginnings of understanding that factors affecting prevalence in populations may be different from risk factors within populations. The meeting had difficulty in agreeing on details of questionnaires. Just as the discussion seemed to be going nowhere, David produced from his briefcase the draft questionnaire that had been developed between the St George’s group and Colin earlier in the year. This put something on the table and helped to focus the discussions, at least concerning asthma.
Eventually the epidemiologists “won” on the principle of using symptoms (manifestational criteria) rather than doctor diagnosis for international comparisons. However, at this stage, we had very little independent validation of the specific questions. There was a natural tendency to promote questions that we had used in our own surveys. Examples which were eventually included in ISAAC instruments are the difficulty in speech question (Croydon), the frequency of attacks question (Auckland) and the video questionnaire (Wellington).
In retrospect, we think that one of the greatest mistakes was not to include, as core, some non-asthma respiratory questions such as cough and phlegm. This would have made the questionnaire a general respiratory one, not just an enquiry about asthma symptoms. (Within ISAAC UK Phase One, carried out in 1995, we added questions on cough and phlegm which proved interesting in relation to indoor environmental risk factors.) Indeed, there is still no general respiratory equivalent to the ISAAC asthma questionnaire, as has become apparent recently while Ross has been reviewing the air pollution literature for developing countries. The range of questionnaires used in published studies is considerable, which makes international comparisons and meta-analysis problematic.
The origins of Phase Two surveys in Germany(Erika von Mutius)
At the end of the 1980’s, epidemiological studies were scarce in Germany. The prevalence of asthma and atopy was unknown, and risk factors have not been investigated in German populations. A colleague of mine, Thomas Nicolai and I designed a cross-sectional survey, enrolling all children in primary schools in Munich and the rural area around Munich. Since the potential adverse effects of air pollution were a major theme in these days, we wanted to compare prevalence rates between urban and rural areas. We designed questionnaires according to our clinical history taking approach and asked the children to perform spirometry and cold air challenges as well as to undergo skin prick tests as objective markers of disease. We had started the fieldwork in September 1989.
Then, in November 1989 the Berlin wall fell. Thomas Nicolai and I had always argued that West Germany was just not polluted enough to show adverse effects on asthma but that studies on pollution levels such as those encountered in the GDR would prove that there was indeed an effect. Such studies had been politically impossible until this time. With the sudden opening of the German border we thought that there was an opportunity. Through various contacts that were difficult to establish we found colleagues in East Germany, i.e. Hans-Heinrich Thielemann in Halle and Christian Fritzsch in Leipzig. These were wonderful people full of excitement and optimism for a better future and were willing to conduct the first East/West German study without any funding. We copied questionnaires in Munich, collected all our lung function equipment from the Munich survey and transported it to Leipzig. A colleague from North Germany, Professor Helgo Magnussen sponsored a cold air challenge device, and we instructed the colleagues in Leipzig to perform exactly the same study as in Munich, with the exception of skin prick testing which we could not afford. The statistical team at GSF in Munich entered the data and performed the statistical analyses. We were rather incredulous when we saw the results, which indicated less asthma and hay fever in polluted Leipzig as compared to Munich. In fact, we discussed whether the data needed to be re-entered.
Meanwhile, Stephan Weiland had appeared on my scene. Stephan had trained in epidemiology at McGill and upon his return he had a dream. Like the big cardiovascular MONICA study he wanted to establish a large survey for asthma. Ulrich Keil had contacts with David Strachan and Ross Anderson in London and Neil Pearce in Wellington, New Zealand. Stephan invited them to Bochum for a meeting - the first meeting of what would become ISAAC, the International Study of Asthma and Allergies in Childhood. This meeting on a grey December day in 1990 at the University of Bochum was decisive. ISAAC was born! At this first ISAAC meeting I met Fernando Martinez who had come as a substitute for Ben Burrows from Tucson, Arizona, USA.
Later I showed Stephan our first East/West German findings from Leipzig. He immediately understood the impact and offered to help write the paper as he was fluent in English after his fellowship whereas I was struggling with this foreign language. Stephan also strongly recommended that I should leave for a fellowship to the US or Canada. Given that Fernando was the only American I knew and that he had impressed me at the first ISAAC meeting, I asked him if I could come for a fellowship to work with him. At the second ISAAC meeting one year later he confirmed that I would become his first fellow. Meanwhile, the political landscape in Germany was strongly in favour of collaborative studies between East and West Germany. Stephan and I applied for a second survey in Halle and Leipzig, East Germany, to include skin prick testing to corroborate the questionnaire data. The first ISAAC phase II study was performed in Halle, East Germany, and Munich, West Germany. In the ISAAC phase II study we corroborated the findings of the first study using skin prick tests and hypertonic saline challenges as the ISAAC protocol had recommended. We had also developed a large and comprehensive questionnaire, inquiring about the ISAAC core questions for outcome definitions and a number of environmental exposures. This questionnaire was then used for the further development of the ISAAC Phase II questionnaire.