Asthma and allergy: a worldwide problem of meanings and management?

Experimental researches on the nature and causes of catarrhus aestivus (hay-fever, or hay-asthma) Chapter I § 1. At no period in the history of medicine has the investigation of the causes of disease been carried out more assiduously than it is at the present day. Such is the magnitude of the work, however, and so great are the difficulties which are inseparable from it, that comparatively little has yet been accomplished, and it is still, practically, one of the widest and also one of the least exhausted fields of inquiry in the whole domain of science. With that challenge, issued in 1873, Charles Blackley began an account of his investigations into the causes of hay fever, and opened the door to the study of allergic disease (1). While much has been accomplished in the intervening 129 years, none of the common allergic diseases have been unambiguously defined, the predisposing causes remain largely unknown, and the increasing prevalence is unexplained. Arguably therefore, allergic diseases do, as then, offer plenty of opportunity for inquiry and resolution. Blackley recognized many of the problems of allergic disease that remain today. He recognized that constitutional, as well as environmental factors, were required to develop disease. He described hay-asthma and recognized that this form posed the greatest risk to health and could occasionally be life threatening. Perhaps most pertinent today, was his recognition that these conditions had a predilection for the educated classes, while those regularly exposed to grass and hay, were largely spared: observations that foreshadowed elements of both the hygiene hypothesis and immunological tolerance. But perhaps the most striking feature of hay fever was that it just appeared for the first time in the mid 19th century (2). This paper will not attempt a comprehensive review of global allergic disease, but rather focus on specific aspects of the geographical and temporal variation in the prevalence of childhood asthma. Population surveys have mostly involved children, and asthma has been the outcome of most interest. At the heart of the rationale for population surveys is the search for causality, initially raising hypotheses and later estimating risk. For this, variation in exposure and in disease frequency is required and hence comparative studies by place and over time are of particular interest. International comparisons of asthma prevalence have only recently been undertaken 3-5). Burr et al. compared symptoms and exercise fall in peak flow, as a marker of airway hyper-responsiveness, in 12-year-old children in Wales, New Zealand, South Africa and Sweden (5) Table 1. Asthma prevalence and a fall in Peak Expirator Flow Rate (PEFR) with exercise was higher in New Zealand than Wales, and a fall in PEFR less prevalent in South Africa and Sweden. Asher and collaborators in ISAAC, used simple written and video questionnaires in the first large-scale study of asthma and allergic disease in children, to measure the prevalence of the self reported, or parentally reported, symptoms and signs of allergic disease (6). Almost 258 000 6–7 year olds, from 91 centres in 38 countries, and 464 000 13–14 year olds from 155 centres in 56 countries took part. There was a 15-fold variation in asthma symptoms between countries, with economically developed countries tending to have higher rates of asthma symptoms than less developed countries. This economic development gradient was apparent within Europe, with Western European countries tending to have higher prevalence than Eastern European countries. Very high rates were found in some, but not all, South American countries, often higher than in Spain or Portugal. The single most striking feature of the ISAAC data, was the uniformly high rates of asthma symptoms reporting by children from the UK, and ex-UK colonies with a history of extensive in-migration of UK citizens, Fig. 1. The highest rates were seen in the UK, New Zealand, Australia and Canada with lower rates in the US and much lower rates in Hong Kong, Singapore and India. In these latter three countries, some or all of the questionnaires were delivered in English, but the respondents were predominantly indigenous, suggesting that it is not the language of enquiry that is the principal determinant of symptom reporting. Furthermore, video questionnaires showing asthma symptoms without any language component showed the same patterns of asthma prevalence, although symptom prevalence measured by the video questionnaire was invariably lower than from written questionnaires. Percent prevalence of self-reported wheezing in the last 12 months amongst 13–14 year olds. (from [ 6 ]). Within Europe, symptom prevalence in France and Germany is less than half that of the UK, and in Southern Europe a third, Figure 2. Table 2 show the prevalence ratios for asthma symptoms in the UK and former colonies, compared with Western and Eastern Europe. For 6–7 year olds, the differences between Western and Eastern European countries are small, compared to the differences between both these regions, and the UK and former colonies. For 13–14 year olds, there are greater differences between Western and Eastern Europe, but once again prevalence is considerably lower than in the UK and the former colonies. The higher of asthma symptom prevalence amongst native English-speaking people (the same was true to a lesser extent for rhinitis and eczema) is striking. The same pattern was found for young adults in the European Community Respiratory Health Survey (7). The reasons are unexplained, but important clues to the causes of asthma and allergic disease might be related to these differences. ISAAC has shown for the first time, that the symptoms of asthma and allergic disease in children are truly global, symptoms were reported from every centre, with considerable international variation and a predilection for English speakers. The history of the changing prevalence of asthma in English-speaking countries over time, is therefore worthy of review. Logan and Cushion reported in 1958 that the prevalence of asthma in England and Wales, was 1.2% for boys and 0.64% for girls aged under 15 years (8). In 1961 Morrison Smith, defining asthma as ‘recurrent wheezing and dyspnoea not known to be of extrapulmonary origin’, reported rates of 1.8% for 5–6 year olds and 10–11 year olds and 1.6% for 13–15 year olds in schoolchildren from Birmingham, UK (9) and confirmed higher prevalence in male subjects up to the age of 15. These rates were similar to those in Norway in 1954, 1.8% in 7 year olds (10), and in Sweden in 1954, 1.4% amongst children aged 7–14 years (11). In these early surveys there was no evidence that prevalence was higher in the UK compared to Scandinavia. But at exactly the same time, Broder et al. reported a prevalence of asthma of 14% in 6–9 year olds in Michigan, some nine-fold higher than in the UK or Scandinavia. Their criterion for asthma, included wheezy bronchitis, or wheezing associated with respiratory infection (12). With the exception of the Michigan survey, these studies considered what we would now regard as the severe end of the spectrum of asthma, as suggested by the definitions involving recurrent wheezing in the absence of infection. When wheezy bronchitis was considered in addition to recurrent wheezing without infection, much higher rates were also recorded in the UK. In 1978, Peckham reported data from a national UK birth cohort of children born in 1958 (13). At the age of 7, 3% of children were reported to have a history of asthma and a further 15% were reported to have a history of one or more attacks of wheezy bronchitis, a total of 18% with a history of any wheezing. By the age of 11, a further 4% had developed asthma or wheezy bronchitis since the age of 7 years, giving a prevalence of any recurrent wheezing illness of 22%. In 1969 Williams and McNicol, in a landmark study, published a detailed account of the prevalence and natural history of wheezy bronchitis and asthma, in 10-year-old Melbourne school children (14). They defined three groups: • mild wheezy bronchitis – < 5 episodes wheezing always with bronchitis or apparent respiratory infection; • wheezy bronchitis – > 5 episodes wheezing always associated with bronchitis or apparent respiratory infection; • asthma – wheezing children where at least one wheezing episode was not associated with bronchitis or apparent respiratory infection. The prevalence of asthma by this definition was 3.7%, while the prevalence of wheezy bronchitis was 15.4%, giving a prevalence of any recurrent wheezing of 19.1%, although only a third of these children, or 6% of the population, experienced wheezing in the last year, Table 3. All of these wheezy children were more likely to be atopic than non wheezy children, even the mild wheezy bronchitis group were four times more likely to be atopic than non wheezers, while 80% of the ‘asthmatic’ children, who wheezed without infection, were atopic and their respiratory symptoms tended to be more severe. The authors considered that all of these wheezy children belonged to a single population who shared a common abnormality that was variably manifest, leading to considerable variation in symptom frequency and severity. These studies of asthma prevalence in young children in the 1960s suggest that a history of wheezing was common; up to 20% in both the UK and Australia, the majority of wheezing occurring in association with respiratory tract infections. Only a small proportion of these children experienced frequent or severe attacks, and the more wheezing they experienced, the more likely they were to be atopic. Early studies of asthma prevalence had in fact only revealed the tip of the wheezing iceberg, by restricting cases to those with frequent wheeze in the absence of respiratory infection. The therapeutic implication of disassociating wheezing from a diagnosis of asthma was first raised in the UK by Speight in 1978. In a series of 34 paediatric asthma referrals from general practice, a failure to make a positive diagnosis led to inappropriate management. In 1983, Speight et al. explored this in more detail in 7-year-old children in the UK (15). Amongst 300 7 year olds, who had wheezed since starting school, only 12% had been diagnosed as having asthma and only a third had ever received a bronchodilator, despite many of them experiencing frequent symptoms. The studies by Speight, and Williams and McNicol had a significant impact on clinical practice, especially in the UK, Australia and New Zealand, increasing the readiness to diagnose childhood wheezing as asthma, which in turn led to more rational treatment with inhaled bronchodilators rather than antibiotics (16). This change may however, have reduced the appreciation of the importance of respiratory infection as a cause of wheezing both in children with and without atopy and has meant that most studies since the early 1980s have not separated wheezing with and without respiratory infection (16). More recently this situation has been addressed with longitudinal studies exploring the etiology of childhood wheezing in relation to lung size, infection and atopy separately (17). In 1982, et al. asthma prevalence in children in a small of New South The prevalence of asthma symptoms in were similar to those found by Williams and McNicol in years as the authors in their Table In the years between these both undertaken in Australia, only reported wheezing in the last 12 months had The prevalence of atopy had later in the was in asthma diagnosed asthma and asthma treatment had in fact the prevalence of symptoms had a diagnosis of asthma had and asthma treatment had Table The prevalence of atopy was The authors also an in to amongst atopic children, however, the used to were in the later study and their may have this prevalence of is for these and in reported frequency of attacks, diagnosed asthma, and asthma they are not related to to it is striking that between the Melbourne study in and the first study in 1982, the prevalence of atopy had but symptoms of asthma had and in atopy was but symptoms of asthma had to high rates of asthma symptom reporting have also been found more recently in Melbourne and to be largely Australia, and as the ISAAC study has the English-speaking (6). In and published a prevalence from over years from to The reported by was in but with differences in and with rather than questionnaires The data was to make it more with the The was again in years and again only 5 years, in both diagnosed asthma, and attacks of of were Table The of for all hay fever, between and is considerably on an than between and comparative studies over time in the UK have revealed less et al. compared asthma prevalence and in in olds between and They a in reported wheezing in the last year, but a in severe attacks, which they to the of inhaled Burr et al. compared asthma prevalence in 12 year olds in between and They reported a in asthma and and diagnosed asthma and a in wheeze in the last year, but no in as measured by a fall in peak rates a and are common in allergic causes from in surveys is In the same that the has led to in respiratory health surveys so the or have led to problems in further rhinitis or the European of and has published a where is defined by the of an is in this as the to both the and often to as these problems of definition most comparative studies have tended to show an in the prevalence of both conditions over time but these have not been as as for asthma. symptom have been for asthma often or a diagnosis for and allergic for surveys have only recently been and a diagnosis in hay fever prevalence were apparent from early For Williams and McNicol a prevalence of hay fever at 7 years of increasing to by age years in Melbourne schoolchildren in (14). they also a prevalence of for or recurrent these conditions were much more common amongst wheezy children and or rhinitis from rhinitis to frequent in young children is There differences in prevalence between studies in the same For the prevalence of hay fever reported by of predominantly year olds in New Zealand, in was In the ISAAC study, a later in the of children in reported a prevalence of hay fever of are apparent in For the prevalence of hay fever in children in New South in was increasing to by In however, in in the ISAAC study amongst 6–7 year olds the prevalence was While some of this variation will be to the small differences in age of the children and the these studies not suggest a in the prevalence of allergic The of allergic rhinitis in general in the UK no between and In the changing prevalence of allergic rhinitis in the English language an in the UK from 12% to amongst year olds in born in 1958 and In the US surveys undertaken between and showed a prevalence between 15 and while a national between and a prevalence of questionnaires for the prevalence of allergic rhinitis in adults and children will over time, and in particular the important between allergic rhinitis and asthma at and their with atopic For the prevalence rates are more in the reported prevalence of in children was in the ISAAC study in it was For in to in while in in the was while in the problems of definition and some studies suggest an in both allergic rhinitis and allergic over the last years, but no evidence of an as for asthma symptoms between the 1980s and the population surveys of over time have been reported an in specific to a of in schoolchildren in to environmental over years in the study, but most of this change was to in-migration in showed a in atopy over an but the in the was lower than in the raising the of Perhaps most striking is the of in the prevalence of atopy in New South Wales, asthma symptom prevalence to For children born in the and at least in the UK, Australia and the wheezing to respiratory tract infection was common but not and was Only a small proportion had recurrent wheezing in the absence of infection, most of these children were and were In the and especially in UK, Australia and New Zealand, the wheezy children were under the asthma it was that their with the of inhaled bronchodilators rather than For children born in the 1980s and in the in some studies in Australia and in and to a lesser extent in Wales, there to have been an in asthma diagnosed asthma and asthma largely by any in or a in atopic patterns from this review of asthma • in prevalence of asthma and atopic disease between the the first population surveys and the • in the prevalence of asthma symptoms from the most in the UK and the former UK colonies. • rates of asthma symptoms in the UK and former UK colonies compared to most countries The in the prevalence of atopic disease has been to the in disease. In and amongst from of in They compared total and the prevalence of atopic disease with from in the same The prevalence of was higher and asthma higher in the compared to the In to this the total was higher in the compared with the In their these authors out what was to be the hygiene hypothesis a prevalence of asthma, and was greater in the than in the and with the prevalence of as well as of and diseases in the is suggested that atopic disease is the by some of the for their from diseases to and In this between infection and atopic disease they as had in and and the that in exposed to more infection and in total was but atopic disease In a between and hay fever in cohort data in the UK He first and the to these suggesting that a greater exposure to infection in early childhood might from with a of studies have prevalence between atopy or atopic disease and specific In which has high rates of infection, a positive has been between the of and positive a between size, the risk of infection and the risk of atopic disease. The were by a immunological hypothesis in which reduced infection and exposure in early life would the from a to in is in this from to that infection and exposure would be to exposure a The of the hygiene hypothesis is that it a between the and the of disease. might to the time and the of hay fever in the mid 19th The in disease and reduced and treatment and in the developed the 19th and led to an with risk of and from disease. The same would the single so for the positive between atopic disease and the Western When this to is with exposure to common environmental and to a greater of the hypothesis even more as an for the in the prevalence of atopic disease. risk for the in asthma prevalence have been While there are no small in study definition may have an important on prevalence as has been seen by the or of children who wheeze with and without infection. The greater of asthma in many and amongst health are likely to have symptom reporting and the of asthma symptoms for childhood wheezing the recognition of significant in the early 1980s will in have the diagnosis of asthma by health and their a to bronchodilators is of the of asthma But it that this could all of the in asthma symptoms seen in Australia or in the is even less likely that these later could be related to in infection or as has the hygiene hypothesis only to disease and asthma is only related to less so in and early childhood than in children or young it is to in hygiene or disease exposure for children up the and in Australia or or that hygiene and infection be so between the UK and for again as has the between exposure and a or change in prevalence, differences in exposure to the risk or a or both at least they further however, to be that the in treatment from the and early and in particular their as treatment rather than as required to might be for some of the in the frequency and of asthma symptoms in the and 1980s New Zealand an of asthma In we reported a study of amongst who had from asthma, and to with asthma but who not and showed that the 2 the risk of a outcome from a severe of asthma In further studies we confirmed these and further was by et al. in Canada The and from the in New Zealand led to a and in asthma of for asthma also in New Zealand suggesting that the risk of by increasing the of asthma. In et al. reported that for asthma was in compared to and that this was not associated with any in More recently et al. has the of and on asthma For no differences in rates were found compared to but both the and of as by were greater treatment with than with as required There is evidence that have a increasing and airway et al. have shown that airway to but not in subjects with allergic rhinitis This evidence that on the airway of asthma. In the of this was to asthma and for asthma in New three studies have the of and have to any significant of these have been of and in mild but a study in a more severe group of has also to show study with found a small but significant in in the but not in the group These studies are with regard to treatment in adults with asthma. most of the increasing asthma prevalence has been amongst children, while the studies of of bronchodilators have been amongst There have been studies in children that have the of asthma on associated asthma the at the end of the and early 1980s all childhood wheezing with regularly by while may have and symptoms more frequent and especially from wheezing. Such an hypothesis would the in asthma symptom frequency for children up in the it would the high prevalence in the UK, Australia and New for as well as asthma was most up in English-speaking countries, with the exception of the US where the of into the 1980s of asthma prevalence in the US have shown lower rates than in the UK or although the now to be symptom reporting was lower in US centres compared to the UK, Australia, New Zealand or Canada Fig. in the ISAAC we have seen from ISAAC, asthma symptom prevalence is much lower in France and Europe compared with the UK. of respiratory carried out in revealed that in and European countries, the was on the of and rather than inhaled as first for asthma for in the natural history of wheezing in early childhood and would aspects of asthma prevalence, the predilection for English-speaking countries, and the in symptoms in some studies in these countries. would also to the recently by in that exposure is common amongst wheezing children least in the UK and former UK and amongst children and could the to in symptom prevalence without an risk. is also that treatment of young wheezy children might have to the considerable in asthma in the UK, New Zealand, and Australia, and to a lesser extent in Canada and the US a in childhood for asthma in the UK between 1958 and much more than in both and children, with the occurring in children aged In a in the was to show that this was not to a in on or an in rates but suggested an in the of children experiencing severe attacks are related to this in the of the would have to with at least in In turn this would suggest that wheezing associated with with might be more likely to to an outcome than wheezing associated with In wheezy bronchitis, and to the importance of and both to the and to treatment in children (16). These in relation to asthma treatment be and The in asthma symptom prevalence and in children, could be a lesser of the of and in and the in asthma prevalence in children, at least in might have a is by a principal and The Asthma by a from the Health of New

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