Predisposing Factors

DR. SOPHOCLES: What are the predisposing factors for the development of asthma?
DR. COX: We believe the three main predisposing factors are genetics—and that is genetics and the interaction with environmental influences—atopy, which is the genetic predisposition for the development of IgE, the antibody involved in allergic reactions, and viral respiratory track infections which are the most important cause of asthma exacerbations but they may also contribute to the development of asthma.
DR. SOPHOCLES: How does genetics play a role in asthma?
DR. COX: We think that you’re born with certain genetic phenotype that make you more susceptible to certain environmental exposures. There are a number of different relationships that have recently been discovered that seem to contribute to the development of asthma. And one of the examples that we’ve seen is children that grow up on farms appear to have less incidence of asthma. But when you look a little more carefully, it may be a subset of individuals that carry a certain genetic profile that seem to benefit from growing up on the farm. So gene-by-environment is a combination of that individual’s phenotype and then the environmental exposures that come along after birth.

There is a CD14 polymorphism at the C-159T, which is a promoter gene for endotoxin receptor. One of the reasons for the theory behind the children growing up on farms having less asthma, is that they’re getting a greater amount of endotoxin exposure. The early endotoxin exposure in individuals that have a certain polymorphism for this receptor reduces the incidence of allergic rhinitis and atopy, and what we believe occurs is that the endotoxin shifts the TH2 towards a TH1 which is a non-allergic pathway.

Another polymorphism that’s been identified on the CD14 nucleotide is related to tobacco smoke exposure. And what was found is individuals with GG or GC genotypes and environmental tobacco smoke exposure had lower FEV1’s than individuals who were not exposed to environmental tobacco smoke.

And the third polymorphism that’s been identified that’s linked with asthma development, and again in children growing up on farms, is toll-like receptor 2. Individuals that have a certain polymorphism for toll-like receptor 2 had a decreased incidence of asthma and atopy and current hay fever, compared with children who did not. So in summary, there appears to be different polymorphisms and phenotypes that when interacting with certain environmental exposures, lead to a decrease or increase in asthma and atopy.

One example that probably has received a lot of attention, even outside of the asthma specialty arena, is polymorphism of the beta 2 receptor. Now the beta 2 receptor is a receptor that is required by a betaagonist which asthmatics use as their rescue medication. And it is believed that insertion of Gly at position 16 will alter the way the receptor finds the Beta-Agonist medication in an unfavorable way.

Now there’s a higher incidence of Arg/Arg polymorphism at position 16 in the African-American
population, about one fifth of this population has this polymorphism, where as about one sixth of Caucasians have this polymorphism.

One study was designed to look at the response to regular use of Albuterol versus placebo to see if it did indeed have a harmful effect and they looked at it based on the individual phenotype. So they were divided into the Arg/Arg and the Gly/Gly groups and there was a crossover leg where they received either Albuterol four times a day or placebo four times a day, and then they measured pulmonary function tests, peak flow measurements and their outcome.

And what they found was the group who were Arg/Arg phenotypes, when they were placed on regular Albuterol, they actually had a deterioration in their lung function. So this would suggest for those individuals who have that phenotype, Arg/Arg, that they would not respond well to regular use of Albuterol.

This is an example of gene-by-environment interaction and in particular how it affects response to medication. And there’s also been some studies that have shown that there are certain individuals that do not respond to inhaled corticosteroids and that may also have a genetic basis. This explains some of the information that is coming out about interactions between medications and some individuals responding well and some not responding well and the possible role genetics may play in this.

Maybe in the future what we’ll be seeing is we’ll be phenotyping our patients and selecting a medical regimen based on their particular phenotype — sort of like finger printing. And I really do believe that this is the future, because this is where there’s a lot of interest in asthma research, and I know in other diseases, research is going on. So not all asthma drugs are going to be effective for all asthma patients.

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DR. SOPHOCLES: What is atopy and what role does it play in asthma?
DR. COX: Atopy is a genetically determined state of hypersensitivity to environmental substances that are normally not perceived as harmful. Some atopic conditions are allergic asthma, atopic dermatitis (sometimes referred to as eczema), allergic rhinitis, and food allergies. In the current NHLBI expert panel report, atopy is identified as the strongest predisposing factor for developing asthma.

The key feature of atopy is specific IgE which is designed or developed to react against something, either a food allergen or an airborne allergen. And then with subsequent exposure, the individual then develops allergic symptoms. Depending on where this allergic event takes place, the symptoms could be nasal congestion, if it’s inhaled, or wheezing. There is even recognition that there are gastrointestinal disorders that are linked with food allergens.

The schemata of the allergic immune pathway involves a number of cells. I mentioned earlier the Th2 and the Th1 paradigm. Th2 is the T-cell pathway that is involved primarily in producing the allergic response. Th2 cells produce IL-4 which is a cytokine that stimulates B-cells to produce IgE.

The IgE is then produced and it circulates and then sits on the mast cell in the tissue or the basophils that circulate, and it waits for the allergen which it was designed to react against. If there’s exposure to allergen, there’s cross-linking of the IgE on the surface of the mast cell. A series of messages get sent inside the mast cell and there is immediate release of preformed granules such as histamine and hearin. And then there is formation of new mediators such as prostaglandins and leukotrienes minutes later. And over many hours, there is recruitment of a second wave of inflammatory cells which we refer to as the late phase reaction.

The symptoms that one would have during an immediate allergic reaction would be sneezing, itchy watery eyes, wheezing if one has asthma, or airway hyper-responsiveness. The clinical examples I give to some people to help them visualize the immediate reaction is if they’ve ever seen anybody who’s allergic to a cat, and they walk into a room and within minutes they’ve basically had almost a generalized allergic reaction. Their eyes might start to water, or they might sneeze, or they might start coughing.

It’s been long recognized that IgE seems to be important or linked with asthma. There was a study done many years ago, published in the New England Journal of Medicine in 1989, that looked at IgE levels and the incidence of asthma and found almost a very clear relationship with higher levels of IgE and asthma.

One study that looked at asthmatics that had been in the emergency department with asthma exacerbation in the previous 24 months, found that there was again almost a linear relationship between higher IgE levels and their risk of having airway hyper-responsiveness.

Another study that looked at children from birth and followed them over a number of years found that there was a clear relationship with IgE levels and risk of developing wheezing in the first sixyears of life. So, there have been a number of different studies with different designs that have looked at IgE and risk of developing asthma or having airway hyper-responsiveness, which is a key component of asthma, and they have found a clear relationship.
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DR. SOPHOCLES: Can viral respiratory infections contribute to the development of asthma?
DR. COX: We recognize that viral infections can influence both the development and severity of asthma.
They have been related to the inception of recurrent wheezing illness and asthma in infants and are probably the most frequent cause of exacerbations of established asthma in older children and adults. Using a very sensitive viral detection assay, the rate of viral infections is approximately 80% among hospitalized wheezing children under age three in one study.

In early life, viral infections can either increase or decrease the risk of subsequent asthma. Increased risk appears to be associated with parainfluenza, rhinovirus, and RSV (Respiratory Syncytial Viral) infections. On the other hand, there is a theory, referred to as the hygiene hypothesis, that infection early in life will actually shift that Th2/Th1 paradigm towards Th1, the non-allergic pathway. And some of the infections or the viruses that have been associated with less incidence of asthma are measles and repeated viral infections other than infections that cause lower respiratory track infections.

Respiratory Syncytial Virus has long been thought to have some role in persistent wheezing. RSV bronchiolitis in infancy severe enough to cause hospitalization was highly associated with development of asthma and allergic sensitization up to age seven. The cumulative presence of asthma was 30% in the RSV group versus 3% in the control group. Allergic sensitization was found in 41% of the RSV group versus 22% of the control group, and multivariant evaluation of possible risk factors for all these 140 children in this particular study showed that RSV bronchiolitis was the highest independent risk factor for asthma with an odds ratio of 12.7, and a significantly elevated independent risk ratio for allergic sensitization with an odds ratio of 2.4. So it appears that RSV infections, particularly severe enough to require hospitalization, seem to be a predisposing factor for subsequent development of asthma and possibly allergic sensitization.

A study of 285 children designed to evaluate the relationship between viral respiratory infections during infancy to the development of subsequent wheezing and/or allergic disease in early childhood found the most significant risk factor for preschool childhood wheezing is the occurrence of symptomatic rhinovirus during infancy. First year wheezing with rhinovirus was the strongest predictor of subsequent third year wheezing, with an odds ratio of 6.6.

So, in summary, there’s been a shift in the focus of asthma therapy and theories on asthma pathogenesis. In the 1970s we thought asthma was basically a disease of bronchospasm and treatment was directed at relieving symptoms, in other words, beta-agonists. In the 1990s, we began to recognize that inflammation played an important role in asthma, so in addition to relieving symptoms, we began to use medications to control and prevent inflammation. Now in 2007, we’ve learned even more. We understand there is an interaction between the environment and the individual’s genetic profile. Our treatment emphasis is on asthma control, emphasizing minimizing risk and impairment. So we’re looking at symptoms, we’re looking at exacerbations, we’re looking at the natural history of asthma, and seeing if there are ways we can intervene before it becomes irreversible. We’re looking at objective and subjective measures of asthma control and we’re still looking for the gold standard for how to monitor asthma control in terms of objective testing, and that refers basically to whether we should be doing pulmonary function tests or other types of tests to assess asthma control.
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