Atopy Is Important in Asthma
Adnan Custovic MD, PhD, FRCP and Angela Simpson, MD, PhD
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 pre-school 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 antibody1. We observed similar
quantitative relationship between the risk of allergic rhinitis and the level of IgE
antibodies to pollen2.
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
exposure3. 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
real-life 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 proinflammatory 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 asthma5. 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
asthma5. 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
asthma5.
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 IgE1. We now introduce the concept of
different atopic vulnerabilities with distinct characteristics in terms of their association
with symptomatic asthma5. Thus, whilst atopy is important in asthma, the atopic
phenotype needs to be redefined beyond the mere presence or the level of allergenspecific IgE antibodies.
REFERENCES
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.