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Con debate: atopy is important in asthma – Pro
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Oral Presentations / Paediatric Respiratory Reviews 11S1 (2010) S1–S78
O.11.2 Pro/Con debate: atopy is important in asthma – Pro A. Custovic, A. Simpson. University of Manchester, UK Allergic sensitization has long been recognized as a major risk factor for asthma. However, it is important to emphasize that the presence of IgE antibodies reflects a systemic immune response which may or may not be associated with the symptomatic allergic disease. Consequently, within any population a proportion of “sensitized” individuals have no symptoms of allergic disease (e.g. asthma). On the other hand, in a proportion of “atopic” asthmatics, IgE-mediated sensitization is just a chance finding which is not contributing to either presence or severity of their symptoms. Defining allergic sensitization: The cut-off value to define the presence of allergic sensitization for IgE antibody level and the size of the wheal on skin testing has been a matter of considerable debate (e.g. >0.35 kU/l or >0.7 kU/l for specific IgE antibody levels; >0 or >3mm in relation to negative control for a wheal diameter on skin prick testing). However, we propose that labeling subjects as “atopic” or “non-atopic” based on an arbitrary cut-offs is a gross oversimplification of a trait that is not dichotomous in its relationship to either presence or severity of asthma symptoms. We have recently shown that the probability of asthma in preschool children increases markedly with the increasing summated mite, dog and cat IgE antibody level, suggesting that IgE-antibody quantitation may improve confidence that sensitization has a role in the expression of symptoms in comparison to a simple information on the presence or absence of IgE antibody [1]. We observed similar quantitative relationship between the risk of allergic rhinitis and the level of IgE antibodies to pollen [2]. The other important question is the nature of the association between sensitization and the severity of symptoms. The clinical course of asthma is characterized by a degree of the control of symptoms interrupted by exacerbations which are mostly unpredictable and difficult to prevent and treat. In order to improve treatment, it is essential to understand the factors which cause exacerbations. Allergen sensitization, exposure and asthma exacerbations: We have demonstrated that sensitization per se in the absence of exposure to sensitizing allergen has little effect on lung function in pre-school children. However, sensitization had a major effect on lung function within the context of specific exposure [3]. High allergen exposure is a risk factor for exacerbations in sensitized individuals with asthma. Thus, allergic sensitization in the absence of exposure to specific sensitizing allergen or exposure to high allergen levels in individuals not sensitized to that allergen probably have little effect on symptoms of allergic disease. However, the combination of allergen sensitization and exposure to sensitizing allergen may be associated with poorer outcomes (reviewed in reference [4]). Respiratory virus infections, allergic sensitization and allergen exposure: effect on asthma exacerbations: The association between virus infections and worsening asthma in children was demonstrated using culture and serological methods more than 30 years ago, and this finding was subsequently confirmed in studies using sensitive techniques for virus detection (RT-PCR assays). The most commonly identified virus is rhinovirus. Several mechanisms for rhinovirus inducing asthma exacerbations have been postulated, including direct infection of the lower respiratory tract, reduction in lung function, increasing bronchial reactivity and up-regulation of surface ICAM-1 expression in airway epithelium. However, the question remains as to whether in a reallife situation respiratory virus infection alone (or natural exposure to high levels of sensitizing allergen per se) are sufficient to cause a severe asthma exacerbation (e.g. resulting in admission to hospital). We have recently reported that the risk of admission to hospital with acute asthma in both adults and children was markedly
increased with the combination of sensitisation and current exposure to high levels of sensitising allergens and the presence of virus infection (for review see reference [4]). Allergen sensitization, high exposure to allergen or respiratory virus infection alone were not independent risk factors for exacerbation. This indicates that there may be a synergism between allergen sensitisation, exposure to high level of sensitising allergen and virus infection in inducing asthma exacerbation requiring hospital admission. Whilst precise mechanisms of the synergism require further investigation, we hypothesise that the acquisition of rhinovirus infection in patients sensitized and exposed to high level of sensitizing allergen results in a synergistic augmentation of the pro-inflammatory pathways in the airway resulting in augmented bronchial inflammation. In a real-life situation, numerous factors are associated with asthma exacerbations (e.g. allergen exposure, virus infection, indoor and outdoor air pollution etc.). Each of these factors in isolation is unlikely to have a major effect on symptoms, but is probably inducing subtle changes in inflammatory process in the airways. In sensitized asthmatics (particularly those with high specific IgE antibody levels), there may be a synergism between virus infection, exposure to high level of specific allergen and a number of other environmental factors (e.g. tobacco smoke exposure, air pollution, endotoxin) in inducing more severe exacerbations. Beyond atopy: multiple patterns of sensitization in relation to asthma: We have recently proposed that the presence of a positive ‘allergy test’ (either sIgE or skin prick test) does not equate to the atopic phenotype associated with symptomatic asthma [5]. Using machine learning techniques to redefine atopy, we have demonstrated that IgE antibody responses do not reflect a single phenotype of atopy, but several distinct atopic vulnerabilities which differ in their relationship with asthma [5]. Only one of these atopic vulnerability classes, comprising approximately one quarter of children who would be considered atopic using conventional definition, predicted not only the presence, but also persistence and severity of childhood asthma [5]. Conclusions: We have previously extended the observation that allergic sensitization is a risk factor for asthma by demonstrating that the level of specific IgE antibodies offers more information than just the presence of IgE [1]. We now introduce the concept of different atopic vulnerabilities with distinct characteristics in terms of their association with symptomatic asthma [5]. Thus, whilst atopy is important in asthma, the atopic phenotype needs to be redefined beyond the mere presence or the level of allergen-specific IgE antibodies. Reference(s) [1] Simpson A, Soderstrom L, Ahlstedt S, Murray CS, Woodcock A, Custovic A. IgE antibody quantification and the probability of wheeze in preschool children. J Allergy Clin Immunol 2005; 116:744–9. [2] Marinho S, Simpson A, Soderstrom L, Woodcock A, Ahlstedt S, Custovic A. Quantification of atopy and the probability of rhinitis in preschool children: a population-based birth cohort study. Allergy 2007; 62:1379–86. [3] Lowe LA, Woodcock A, Murray CS, Morris J, Simpson A, Custovic A. Lung function at age 3 years: effect of pet ownership and exposure to indoor allergens. Arch Pediatr Adolesc Med 2004; 158:996–1001. [4] Custovic A, Murray C, Simpson A. Allergy and infection: understanding their relationship. Allergy 2005; 60 Suppl 79:10–3. [5] Simpson A, Tan VY, Winn J, Svensen M, Bishop CM, Heckerman DE, et al. Beyond Atopy: Multiple Patterns of Sensitization in Relation to Asthma in a Birth Cohort Study. Am J Respir Crit Care Med.
Oral Presentations / Paediatric Respiratory Reviews 11S1 (2010) S1–S78
O.11.2 Pro/Con debate: atopy is important in asthma – Pro A. Custovic, A. Simpson. University of Manchester, UK Allergic sensitization has long been recognized as a major risk factor for asthma. However, it is important to emphasize that the presence of IgE antibodies reflects a systemic immune response which may or may not be associated with the symptomatic allergic disease. Consequently, within any population a proportion of “sensitized” individuals have no symptoms of allergic disease (e.g. asthma). On the other hand, in a proportion of “atopic” asthmatics, IgE-mediated sensitization is just a chance finding which is not contributing to either presence or severity of their symptoms. Defining allergic sensitization: The cut-off value to define the presence of allergic sensitization for IgE antibody level and the size of the wheal on skin testing has been a matter of considerable debate (e.g. >0.35 kU/l or >0.7 kU/l for specific IgE antibody levels; >0 or >3mm in relation to negative control for a wheal diameter on skin prick testing). However, we propose that labeling subjects as “atopic” or “non-atopic” based on an arbitrary cut-offs is a gross oversimplification of a trait that is not dichotomous in its relationship to either presence or severity of asthma symptoms. We have recently shown that the probability of asthma in preschool children increases markedly with the increasing summated mite, dog and cat IgE antibody level, suggesting that IgE-antibody quantitation may improve confidence that sensitization has a role in the expression of symptoms in comparison to a simple information on the presence or absence of IgE antibody [1]. We observed similar quantitative relationship between the risk of allergic rhinitis and the level of IgE antibodies to pollen [2]. The other important question is the nature of the association between sensitization and the severity of symptoms. The clinical course of asthma is characterized by a degree of the control of symptoms interrupted by exacerbations which are mostly unpredictable and difficult to prevent and treat. In order to improve treatment, it is essential to understand the factors which cause exacerbations. Allergen sensitization, exposure and asthma exacerbations: We have demonstrated that sensitization per se in the absence of exposure to sensitizing allergen has little effect on lung function in pre-school children. However, sensitization had a major effect on lung function within the context of specific exposure [3]. High allergen exposure is a risk factor for exacerbations in sensitized individuals with asthma. Thus, allergic sensitization in the absence of exposure to specific sensitizing allergen or exposure to high allergen levels in individuals not sensitized to that allergen probably have little effect on symptoms of allergic disease. However, the combination of allergen sensitization and exposure to sensitizing allergen may be associated with poorer outcomes (reviewed in reference [4]). Respiratory virus infections, allergic sensitization and allergen exposure: effect on asthma exacerbations: The association between virus infections and worsening asthma in children was demonstrated using culture and serological methods more than 30 years ago, and this finding was subsequently confirmed in studies using sensitive techniques for virus detection (RT-PCR assays). The most commonly identified virus is rhinovirus. Several mechanisms for rhinovirus inducing asthma exacerbations have been postulated, including direct infection of the lower respiratory tract, reduction in lung function, increasing bronchial reactivity and up-regulation of surface ICAM-1 expression in airway epithelium. However, the question remains as to whether in a reallife situation respiratory virus infection alone (or natural exposure to high levels of sensitizing allergen per se) are sufficient to cause a severe asthma exacerbation (e.g. resulting in admission to hospital). We have recently reported that the risk of admission to hospital with acute asthma in both adults and children was markedly
increased with the combination of sensitisation and current exposure to high levels of sensitising allergens and the presence of virus infection (for review see reference [4]). Allergen sensitization, high exposure to allergen or respiratory virus infection alone were not independent risk factors for exacerbation. This indicates that there may be a synergism between allergen sensitisation, exposure to high level of sensitising allergen and virus infection in inducing asthma exacerbation requiring hospital admission. Whilst precise mechanisms of the synergism require further investigation, we hypothesise that the acquisition of rhinovirus infection in patients sensitized and exposed to high level of sensitizing allergen results in a synergistic augmentation of the pro-inflammatory pathways in the airway resulting in augmented bronchial inflammation. In a real-life situation, numerous factors are associated with asthma exacerbations (e.g. allergen exposure, virus infection, indoor and outdoor air pollution etc.). Each of these factors in isolation is unlikely to have a major effect on symptoms, but is probably inducing subtle changes in inflammatory process in the airways. In sensitized asthmatics (particularly those with high specific IgE antibody levels), there may be a synergism between virus infection, exposure to high level of specific allergen and a number of other environmental factors (e.g. tobacco smoke exposure, air pollution, endotoxin) in inducing more severe exacerbations. Beyond atopy: multiple patterns of sensitization in relation to asthma: We have recently proposed that the presence of a positive ‘allergy test’ (either sIgE or skin prick test) does not equate to the atopic phenotype associated with symptomatic asthma [5]. Using machine learning techniques to redefine atopy, we have demonstrated that IgE antibody responses do not reflect a single phenotype of atopy, but several distinct atopic vulnerabilities which differ in their relationship with asthma [5]. Only one of these atopic vulnerability classes, comprising approximately one quarter of children who would be considered atopic using conventional definition, predicted not only the presence, but also persistence and severity of childhood asthma [5]. Conclusions: We have previously extended the observation that allergic sensitization is a risk factor for asthma by demonstrating that the level of specific IgE antibodies offers more information than just the presence of IgE [1]. We now introduce the concept of different atopic vulnerabilities with distinct characteristics in terms of their association with symptomatic asthma [5]. Thus, whilst atopy is important in asthma, the atopic phenotype needs to be redefined beyond the mere presence or the level of allergen-specific IgE antibodies. Reference(s) [1] Simpson A, Soderstrom L, Ahlstedt S, Murray CS, Woodcock A, Custovic A. IgE antibody quantification and the probability of wheeze in preschool children. J Allergy Clin Immunol 2005; 116:744–9. [2] Marinho S, Simpson A, Soderstrom L, Woodcock A, Ahlstedt S, Custovic A. Quantification of atopy and the probability of rhinitis in preschool children: a population-based birth cohort study. Allergy 2007; 62:1379–86. [3] Lowe LA, Woodcock A, Murray CS, Morris J, Simpson A, Custovic A. Lung function at age 3 years: effect of pet ownership and exposure to indoor allergens. Arch Pediatr Adolesc Med 2004; 158:996–1001. [4] Custovic A, Murray C, Simpson A. Allergy and infection: understanding their relationship. Allergy 2005; 60 Suppl 79:10–3. [5] Simpson A, Tan VY, Winn J, Svensen M, Bishop CM, Heckerman DE, et al. Beyond Atopy: Multiple Patterns of Sensitization in Relation to Asthma in a Birth Cohort Study. Am J Respir Crit Care Med.