The epidemiology of asthma is relatively complex, a reflection of the varied nature of the disorder. The figures from the CDC in the tables below are for prevalence, which is the number of cases in the specific population at a specific time. (The number of "attacks" self-reported during a specific period are lower.) The substantial increase over the last generation has occurred in other Westernized countries too, and more recently in less-developed countries too.
Note also the gender differences. Boys have quite a high incidence, but often outgrow the problems. On the other hand, more girls begin to develop asthma as teenagers or later, so that among the 25 to 35 year old group, asthma in women is more than twice that in men.
|under 18||25 to 35|
Also, there are also substantial differences between racial and ethnic groups. And within such subgroups, there are, of course, the variations in gender and age shown above. There also are substantial variations between rural and urban populations. Obesity also increases the risk about two-fold, although it is not clear if this is because obesity itself increases asthma or because some other factor, such as lack of exercise, increases the risk of both obesity and asthma.
Asthma is a disorder of inflammation, with the inflammation leading to airway hyper-responsiveness. The more centrally placed bronchi tend to be involved, although the problems can extend down into the bronchioles. As you would expect, contraction of the smooth muscle, edema and mucous secretion provide the basic pattern of the disorder. Asthma differs from other obstructive disorders in that symptoms can be, at least to some extent, reversible.
Asthma can be divided into two basic types, which can significantly overlap.
Atopic asthma fits the sequence we discussed in Fall Quarter. A combination of a genetic predisposition and environmental factors causes certain individuals to respond to certain antigens with an atopic response -- that is, a response that is "out of place". It doesn't make sense.
The antigen here is usually called an allergen. The most common are from house dust mites, cockroaches, dogs, cats, rodents, molds and fungi. Following its introduction into the body, the allergen is taken up by dendritic cells. The subsequent activation of B cells and T cells, however, does not lead to a typical response, which would promote phagocytosis and other processes that would help the immune system deal with microbes.
Instead, TH2 cells tend to predominate rather than the TH1, which one might otherwise expect. A different set of cytokines is released and the B cells release IgE, setting in motion the secretion of a set of regulatory molecules that significantly promotes inflammation. If this inflammation occurs in the airways and leads to airway hyper-responsiveness, we have atopic asthma.
Given this situation, then exposure to the allergen and/or another precipitating factor, such as a viral infection, can lead to a serious exacerbation. Many factors can increase the response, such as nitrogen dioxide from cars, tobacco smoke, ozone, some particulate air pollution, etc.
Non-atopic asthma begins with the stimulation of the airways by a non-antigenic factor, which can be fairly non-specific. By definition, IgE is not a factor. One of the most common is the onset of exercise. Other examples are breathing cold air or tobacco smoke.
In the hyper-responsive airways in non-atopic asthma, afferent neurons are stimulated by the stimulus involved. This begins a reflex, which occurs either locally or via the CNS, that leads to contraction of smooth muscle and secretion by submucosal glands. Of course, this can occur along with an atopic response.
There are three phases in asthma.
The first, early phase begins in the first hour. Mast cells release inflammatory paracrines such as histamine and particularly leukotrienes. This causes inflammatory changes you would expect in airways:
The second phase begins in about 4 to 6 hours. Now cytokines play an important role. There is continued inflammation, but now with infiltration of cells, such as mast cells and often eosinophils. Airways become hyper-responsive, a key characteristic of asthma.
Finally, over weeks and months, in addition to the inflammation and infiltration by cells, there is airway remodelling, which produces visible histological changes in the airways:
In the fall, we discussed TH1 cells and TH2 cells. Briefly, a combination of a genetic predisposition and environmental factors causes the immune system to generate TH2 cells in the wrong circumstances. As a result, certain antigens produce inappropriate inflammation. Perhaps, so the thinking goes, the set of antigens the immune system is exposed to in infancy determines whether or not a genetically predetermined individual tends to develop atopic responses.
In what ways do the immune responses orchestrated by TH1 cells and TH2 cells differ?
In the end, what factors lead to a a patient winding up in an emergency room with a severe exacerbation? A number of factors ultimately contribute. Usually the patient has an atopic response to an allergen. This arises due to a combination of genetic predispositions that lead to the immune system making the inappropriate response. But non-atopic factors can contribute. Then, given the presence of asthma, further factors may come into play to create a serious exacerbation. One important factor often is a viral infection. But also an increase in the allergen levels or other factors may be important too.
Note there are three issues involved here. There are the circumstances that create the atopy, there is the presence of allergens, and there are various other factors that trigger exacerbations or make asthma worse. While often confused, these can be three separate issues.
The first, obvious approach is to attempt to remove or reduce exposure to allergens and triggering factors. This can make a difference but, of course, is often difficult.
Essentially all asthma patients use the first drug treatment, which is a inhaled, short-acting beta2 agonist (e.g. albuterol). This is to provide quick relief from symptoms. The action begins in five minutes and persists for 30 to 60 minutes. They are now recommended for use on an "as needed" basis for quick relief of symptoms rather than regular dosing. (Although they might be combined with the corticosteroids discussed next.)
While the above may be sufficient for many patients, if symptoms become more frequent or severe, then the strategy shifts to preventing symptoms or attacks. The current consensus seems to be that this point is reached if a patient uses the short-acting bronchiodilator more than two days per week or more than twice a month following a nighttime awakening. (NEJM, March 5, 2009)
For most patients, the next step is an inhaled corticosteroid (e.g. fluticasone). These drugs suppress inflammation and substantially reduce most of the events discussed above, such as infiltration of cells and mucosal and submucosal changes. (But they don't cure asthma. The inflammation and other changes return in a couple weeks if the drug is stopped.) The dose is increased if the initial dosage is not adequate. At low to moderate doses these drugs are considered safe, even for children. But side effects can be an issue at high doses.
If the above is not adequate, the next step is to add an inhaled, long-acting beta2 agonist (e.g. salmeterol). These have actions similar to the short-acting drugs, but work for 12 hours or so. These long-acting bronchodilators are always given along with the corticosteroid, rather than by themselves, since suppressing inflammation is important for preventing serious exacerbations. The oral drugs in this class are now generally contraindicated, except in certain circumstances.
The next type of drug that can be added is a leukotriene modifier given orally. This can be a leukotriene receptor antagonist (e.g. montelukast) or a blocker of lipoxygenase (e.g. zileuton). These take a few hours to have an effect and reach their maximum action in a couple of days. The use of these drugs depends on many factors. They might be added to an inhaled corticosteroid and an inhaled long-acting beta2 agonist. Or they might replace the beta2 agonist. Or in certain cases they might be used instead of the inhaled corticosteroid for mild asthma. In the latter case, there could be overlapping treatment for rhinoconjunctivitis.
If all the above does not produce adequate control in severe asthma (or produces severe side-effects), then an anti-IgE monoclonal antibody is available (omalizumab). It is given every two or four weeks, and binds to the Fc region of the antibody, preventing it from producing its effects. Of course, it must be injected, since it is a protein. The cost is substantial. Before omalizumab is given, skin tests for allergens and measurement of the serum level of IgE are done in order to be sure that IgE is a sufficiently important factor for the particular patient.