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Lessons from the Developing World: There is more to asthma than atopy
Oral Presentations / Paediatric Respiratory Reviews 11S1 (2010) S1–S78
O.18.2 Lessons from the Developing World: There is more to asthma than atopy R. Stein. School of Medicine – Pontif´ıc6ia Universidade Cat´ o®lica, RGS, Porto Alegre, RS, Brazil Correspondence: Renato Stein. Head, Pediatric Respirology, School of Medicine – Pontif´ıcia Universidade Cato®lica, ´ RGS, Porto Alegre, RS, Brazil. E-mail: [email protected]
Atopic asthma is the most common chronic disease in childhood with high prevalence in many industrialized countries. Recent studies have shown that, in contrast, among non-affluent populations the association between asthma and markers of atopy are not as significant as those observed in most Western countries. However, overall asthma prevalence in Latin America has been shown to be higher than expected. This finding may be in line with the concept of the ‘hygiene hypothesis’, in which a lower risk of asthma and allergy development may be associated with early life exposures to a high burden of infections (bacteria, viruses and parasites). On the basis of this hypothesis, a strong Th1-immune stimulation by microbial exposition and its products in early childhood may inhibit skewing towards Th2 immunity in atopic predisposed children. Consequently, other asthma phenotypes may emerge in different environmental settings, especially among nonaffluent populations. A fact that has been noticed is that the impact of hygiene seems to be mostly associated with markers of atopy instead of asthma-like symptoms. There is no consensus on why there is a greater prevalence for non-atopic asthma in non-affluent countries, but one possible explanation is that the role of crowding in poor urban environments as well as the early introduction of nursery care for children in the first years of life may facilitate an early and aggressive milieu mediated by respiratory viruses and environmental pollutants. A series of prospective longitudinal studies suggest that there is a significant association between early life bronchiolitis and persistent respiratory symptoms/asthma. These studies and other recent data, mostly experimental, suggest that some viruses, especially RSV and RV, may affect the airways, initiating a cascade of events (inflammatory or not) that seem to facilitate the persistence of symptoms. The evaluation of post-viral or even premorbid/predisposing effects associated with airway hyper-responsiveness or with lung function development seem to in part explain the persistence of respiratory symptoms in a complex model aiming to detect mechanisms associated with asthma, independent of atopy. It is well known that atopy is a main driving force in this explanatory model that leads to asthma, and these children are at greater risk of developing childhood asthma than non-atopic subjects who wheeze. Yet the morbidity associated with non-atopic/non-eosinophilic asthma and the size of the population possibly affected by this phenotype is beginning to be recognized as very important for understanding mechanisms of disease. Possible future asthma preventing strategies for affluent or nonaffluent populations depend on a better understanding of these phenotypes, that are far from exclusive, since they express a balancing act of environmental impact on the airways, and how the response is affected by predisposing genetic factors. O.18.3 Lessons from the intervention studies A. Custovic, A. Simpson. University of Manchester, UK The optimum study design to investigate asthma and allergic disorders is the population based prospective birth cohort; this approach overcomes problems of recall bias (due to retrospective data collection) and permits careful longitudinal phenotyping of subjects. Several long-term birth cohort studies (e.g. the Tucson Children’s Respiratory Study the German Multicentre Atopy Study) have unequivocally demonstrated that asthma and allergic diseases
S47
start early in life; in addition, these phenotypes have been shown to be unstable (i.e. they may progress or remit over time). Other long-term observational studies (e.g. in Australia and New Zealand) have shown that asthmatics with significant airway obstruction in mid-adult life already have reduced lung function in childhood. These data suggest that intervention studies aiming at prevention of asthma and allergic diseases need to be started in early life. Another important point relevant to the primary prevention of asthma is that wheeze in pre-school children may result from a number of different conditions [1]. Around half of the children who wheeze early in life become asymptomatic by school age irrespective of any therapeutic intervention. Lung function in these children tends to be diminished in infancy, and improved by age six years. Thus, one of the major problems in the design of intervention studies in early childhood asthma is phenotypic heterogeneity and the difficulties with precise phenotype definition of the primary outcome measures. Early intervention with inhaled corticosteroids: It has been suggested that amongst children who go on to develop asthma, the chronic inflammatory process in the airways starts early in life and is associated with airway changes which may result in a loss of lung function by early childhood; the diminished lung function may then tracks into adulthood. This notion has been the basis of the hypothesis that intervention with anti-inflammatory treatment (e.g. by using inhaled corticosteroids) early in the natural history of childhood asthma may be associated with favourable long-term outcomes. However, three important early intervention studies (PEAK, PAC and IFWIN – reviewed in [2]) have conclusively shown that the early use of inhaled corticosteroids as an antiinflammatory treatment in young preschool children for wheezing had no effect on the natural history of asthma/wheeze later in childhood [2]. In addition, this intervention had no long-term beneficial effect on lung function or airway reactivity. The results of these studies should be used to inform current clinical practice, in that paediatricians and primary care physicians should not rush into the treatment of intermittent infantile wheeze (i.e. wheezing in children less than 12 months of age) with inhaled corticosteroids. The treatment should be commenced when a clear phenotype of early childhood asthma is established, using the following criteria [3]: • Three or more wheezy episodes in previous 12 months (at least one physician confirmed) • Plus either 1 major or 2 minor criteria – major – eczema, sensitisation to an aerollergen or parental asthma – minor – eosinophils >4%, wheeze without colds, sensitisation to eggs, milk or peanuts Early intervention using environmental control: The consistent findings of an association between allergic sensitization and childhood asthma, together with a mounting body of evidence that increased high allergen exposure early in life appears to contribute to the chronicity of asthma and diminished lung function [4], raises the question as to whether environmental control which results in a major reduction in exposure to allergens early in life may reduce the risk of subsequent development of sensitization and/or symptoms of asthma. This question is being addressed by several primary prevention studies which used environmental control as an intervention strategy, either alone or in combination with other measures (e.g. dietary; for detailed review see reference [5]). It is of note that all these primary prevention studies have focussed on children at high risk of developing asthma and allergic sensitisation (in order to increase the power and reduce sample size). The other important point is that all of the studies used different environmental control approaches and were of a different design, using different definitions of primary outcomes, often at different ages – as a consequence, the results between the studies are not directly comparable [5], and any meta-analysis of the data would be difficult, if not impossible.
O.18.2 Lessons from the Developing World: There is more to asthma than atopy R. Stein. School of Medicine – Pontif´ıc6ia Universidade Cat´ o®lica, RGS, Porto Alegre, RS, Brazil Correspondence: Renato Stein. Head, Pediatric Respirology, School of Medicine – Pontif´ıcia Universidade Cato®lica, ´ RGS, Porto Alegre, RS, Brazil. E-mail: [email protected]
Atopic asthma is the most common chronic disease in childhood with high prevalence in many industrialized countries. Recent studies have shown that, in contrast, among non-affluent populations the association between asthma and markers of atopy are not as significant as those observed in most Western countries. However, overall asthma prevalence in Latin America has been shown to be higher than expected. This finding may be in line with the concept of the ‘hygiene hypothesis’, in which a lower risk of asthma and allergy development may be associated with early life exposures to a high burden of infections (bacteria, viruses and parasites). On the basis of this hypothesis, a strong Th1-immune stimulation by microbial exposition and its products in early childhood may inhibit skewing towards Th2 immunity in atopic predisposed children. Consequently, other asthma phenotypes may emerge in different environmental settings, especially among nonaffluent populations. A fact that has been noticed is that the impact of hygiene seems to be mostly associated with markers of atopy instead of asthma-like symptoms. There is no consensus on why there is a greater prevalence for non-atopic asthma in non-affluent countries, but one possible explanation is that the role of crowding in poor urban environments as well as the early introduction of nursery care for children in the first years of life may facilitate an early and aggressive milieu mediated by respiratory viruses and environmental pollutants. A series of prospective longitudinal studies suggest that there is a significant association between early life bronchiolitis and persistent respiratory symptoms/asthma. These studies and other recent data, mostly experimental, suggest that some viruses, especially RSV and RV, may affect the airways, initiating a cascade of events (inflammatory or not) that seem to facilitate the persistence of symptoms. The evaluation of post-viral or even premorbid/predisposing effects associated with airway hyper-responsiveness or with lung function development seem to in part explain the persistence of respiratory symptoms in a complex model aiming to detect mechanisms associated with asthma, independent of atopy. It is well known that atopy is a main driving force in this explanatory model that leads to asthma, and these children are at greater risk of developing childhood asthma than non-atopic subjects who wheeze. Yet the morbidity associated with non-atopic/non-eosinophilic asthma and the size of the population possibly affected by this phenotype is beginning to be recognized as very important for understanding mechanisms of disease. Possible future asthma preventing strategies for affluent or nonaffluent populations depend on a better understanding of these phenotypes, that are far from exclusive, since they express a balancing act of environmental impact on the airways, and how the response is affected by predisposing genetic factors. O.18.3 Lessons from the intervention studies A. Custovic, A. Simpson. University of Manchester, UK The optimum study design to investigate asthma and allergic disorders is the population based prospective birth cohort; this approach overcomes problems of recall bias (due to retrospective data collection) and permits careful longitudinal phenotyping of subjects. Several long-term birth cohort studies (e.g. the Tucson Children’s Respiratory Study the German Multicentre Atopy Study) have unequivocally demonstrated that asthma and allergic diseases
S47
start early in life; in addition, these phenotypes have been shown to be unstable (i.e. they may progress or remit over time). Other long-term observational studies (e.g. in Australia and New Zealand) have shown that asthmatics with significant airway obstruction in mid-adult life already have reduced lung function in childhood. These data suggest that intervention studies aiming at prevention of asthma and allergic diseases need to be started in early life. Another important point relevant to the primary prevention of asthma is that wheeze in pre-school children may result from a number of different conditions [1]. Around half of the children who wheeze early in life become asymptomatic by school age irrespective of any therapeutic intervention. Lung function in these children tends to be diminished in infancy, and improved by age six years. Thus, one of the major problems in the design of intervention studies in early childhood asthma is phenotypic heterogeneity and the difficulties with precise phenotype definition of the primary outcome measures. Early intervention with inhaled corticosteroids: It has been suggested that amongst children who go on to develop asthma, the chronic inflammatory process in the airways starts early in life and is associated with airway changes which may result in a loss of lung function by early childhood; the diminished lung function may then tracks into adulthood. This notion has been the basis of the hypothesis that intervention with anti-inflammatory treatment (e.g. by using inhaled corticosteroids) early in the natural history of childhood asthma may be associated with favourable long-term outcomes. However, three important early intervention studies (PEAK, PAC and IFWIN – reviewed in [2]) have conclusively shown that the early use of inhaled corticosteroids as an antiinflammatory treatment in young preschool children for wheezing had no effect on the natural history of asthma/wheeze later in childhood [2]. In addition, this intervention had no long-term beneficial effect on lung function or airway reactivity. The results of these studies should be used to inform current clinical practice, in that paediatricians and primary care physicians should not rush into the treatment of intermittent infantile wheeze (i.e. wheezing in children less than 12 months of age) with inhaled corticosteroids. The treatment should be commenced when a clear phenotype of early childhood asthma is established, using the following criteria [3]: • Three or more wheezy episodes in previous 12 months (at least one physician confirmed) • Plus either 1 major or 2 minor criteria – major – eczema, sensitisation to an aerollergen or parental asthma – minor – eosinophils >4%, wheeze without colds, sensitisation to eggs, milk or peanuts Early intervention using environmental control: The consistent findings of an association between allergic sensitization and childhood asthma, together with a mounting body of evidence that increased high allergen exposure early in life appears to contribute to the chronicity of asthma and diminished lung function [4], raises the question as to whether environmental control which results in a major reduction in exposure to allergens early in life may reduce the risk of subsequent development of sensitization and/or symptoms of asthma. This question is being addressed by several primary prevention studies which used environmental control as an intervention strategy, either alone or in combination with other measures (e.g. dietary; for detailed review see reference [5]). It is of note that all these primary prevention studies have focussed on children at high risk of developing asthma and allergic sensitisation (in order to increase the power and reduce sample size). The other important point is that all of the studies used different environmental control approaches and were of a different design, using different definitions of primary outcomes, often at different ages – as a consequence, the results between the studies are not directly comparable [5], and any meta-analysis of the data would be difficult, if not impossible.