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Correspondence to: Eugene R. Bleecker, MD, FCCP, Center for Human Genomics, Wake Forest University, Medical Center Blvd, Winston-Salem, NC 27157; e-mail: ebleeck{at}wfubmc.edu
Dr. Eugene Bleecker (symposium chairman): I would like to thank all the speakers for participating in an interesting and informative symposium today. The first question I’d like to ask is directed to Professor Postma. A number of markers have been used to differentiate COPD from asthma, including any evidence of atopy—skin test atopy, symptomatic atopy, the presence of peripheral blood eosinophilia, or even sputum eosinophilia. Do you think this is a good way to approach differentiating these diseases in clinical practice?
Professor Dirkje Postma: No, I don’t think it’s a good idea, for several reasons. For one, atopy is present in 30% of the population, including people who do not have obstructive airways disease. So why would people who have emphysema not have atopy? Secondly, even people who have COPD and refrain from smoking may have sputum eosinophilia or blood eosinophilia; furthermore, eosinophilia is a risk factor for the development of COPD symptoms. So I think it is a waste of patients and a waste of information that we exclude such a large group of individuals from our clinical studies.
Dr. Bleecker: Dr. Meyers, you’ve talked to us about how we can understand genetic susceptibility to both asthma and COPD. Can you discuss some of the implications of these genetic studies?
Dr. Deborah Meyers: I believe that within the next few years we will be developing genetic tests for asthma, COPD, and other common diseases, in addition to the tests we already have. These tests will fall into three different areas. The first area will be tests for multiple disease susceptibility genes, which will be used to determine a risk profile. For example, you’ll be able to determine which children are at the highest risk for developing asthma and then modify that risk as best you can, possibly by decreasing environmental factors. The second area of genetic testing will address the severity and progression of disease. Such tests will be used to determine which patients who already have the disease in question, for example, COPD, are more likely to have severe disease and rapid progression. In the third area—pharmacogenetics—genetic testing will be used to determine how likely a patient is to respond to a given therapy. Using pharmacogenetic testing we should be able to provide more individualized therapy for each patient.
Dr. Bleecker: Let’s move on to some of the physiologic characteristics of asthma and COPD. Dr. Sciurba, frequently FEV1 is the only measure we use to evaluate both disease severity and response to therapy, especially in patients with COPD. Do you think other measurements of lung volume may be useful? In that vein, do you think we may be able to use some of the new technologies, such as CT scan, to evaluate our patients?
Dr. Frank Sciurba: FEV1 has served us well as a meaningful outcome parameter in clinical trials. However, it has definite deficiencies. What ultimately may become more important is someone’s ability to exhale more completely rather than to exhale rapidly, because this represents more closely what an individual does on a minute-to-minute, day-by-day basis. I tell medical students, if you want to experience the disability of a patient with COPD and emphysema, take a deep breath all the way in to the top and just let out a tea cup of air and try to stay up there. At that point, you experience the respiratory muscle dysfunction and the work of breathing that these patients feel. Furthermore, clinical trials have shown that inspiratory capacity, the ability to take a deep breath—which is directly related to how completely someone exhales—correlates more with symptoms than FEV1 does. So FEV1 is definitely not the whole answer. With respect to CT scan, I think that the technology has advanced enough that at this point the issue is implementation. We need to objectively define some of the characteristics we talked about and use them as entry criteria and stratification criteria in clinical trials.
Dr. Bleecker: In some ways it might be worthwhile to combine these techniques, although maybe not for routine follow-up. While FEV1 measures some of what’s going on in the airways, peripheral airways may not be as well characterized, and it may be possible to monitor regional hyperinflation or regional airway function using some of the new techniques. What do you think?
Dr. Sciurba: I think that’s a superb point. As pulmonologists we don’t necessarily want to talk about that, because eventually pulmonary function may best be observed in the radiology suite.
Dr. Bleecker: Dr. Donohue, you’ve talked about a series of different bronchodilator interventions. I’d like you to hone in on some of the newer anticholinergics, specifically on how the long-acting anticholinergic tiotropium may compare to combination therapy with corticosteroids and long-acting ß-agonists. Please try to talk about it in terms of both asthma and COPD.
Dr. James Donohue: I think we’re lucky; we’re going to have a very good choice here for doctors taking care of patients who suffer with both conditions. I think that both tiotropium and combination therapy—a long-acting ß-agonist plus an inhaled steroid—will be highly effective in our patients, and I bet you that most doctors will use both. Now, the trouble is, we have no studies of tiotropium plus combination therapy, but that’s never a problem for doctors. We have to act, and our patients with COPD always seem to benefit when we combine different drug classes. Tiotropium is maybe a better drug than salmeterol in improving FVC. In the 6-month comparison that we published in CHEST,1 the peak FVC with tiotropium was 600 mL. That’s the best I’ve seen in a clinical trial since we studied the solution of ipratropium, 500 µg, plus albuterol, 2.5 mg. So there may be something there. The combination of fluticasone and salmeterol is also very effective. The trough FEV1 was better than with any other drug we’ve ever had. I anticipate that we’ll see a marked improvement in exacerbations with both agents.
The whole issue of exacerbations is interesting. If you geometrically improve the diameter of the airway with any bronchodilator, the rate of exacerbations is always a little bit reduced. However, the data that Dr. Mapel and Dr. Bleecker showed on exacerbations with inhaled steroids is impressive. So I’m excited that we’re going to have both tiotropium and combination therapy for our patients with COPD. As for asthma, we really haven’t studied tiotropium very well so far. We do know that it lasts 48 h. I think that, extrapolating the data from the studies Dr. Bleecker and I did many years ago, it should work, but not as well as the combination of inhaled steroid and long-acting ß-agonist. It’s also important to remember that tiotropium is slow to work. A lot of times you have to go to day 2 or day 3 before you see the improvement. But down the road it’s a big drug, and I think it will help a lot of patients, particularly older asthmatics and those who smoke.
Dr. Bleecker: Dr Mapel, when we consider some of the guidelines about what constitutes appropriate evidence for recommending an intervention, we often talk about prospective, controlled, comparative clinical trials, which rigidly define who enters the trial and how they’re assessed. You showed us some very interesting evidence, population-based data from your health-maintenance organization and other health-maintenance organizations. What are the advantages of that approach?
Dr. Douglas Mapel: First, you have to look at the strengths and limitations of different study designs. There are obvious limitations to retrospective studies, mostly in that they are susceptible to selection biases. We have no control over which patients were treated and were not treated. On the other hand, because these are population-based studies, they capture the natural history of all patients treated within a geographic group or health system. Looking across all patients, we can see how the treatment behaves.
Randomized clinical trials are also limited, in that they focus on selected populations from the total group—selected interventions—which makes them susceptible to selection biases of their own. Since they are randomized, selection biases will be taken away from the treatment effect, and whatever effect you can see you can attribute to the treatment. But because you have eliminated large proportions of the total population because of your inclusion and exclusion criteria, the response in a randomized prospective trial may not represent the experience you see in the general population. It may underrepresent it or overrepresent it, and important side effects may not be apparent.
The retrospective studies of inhaled corticosteroids have limitations, but the magnitude of effect is very large, and it goes in a direction opposite to what you would expect. We’ve seen in Dr. Postma’s presentation that COPD patients who have more reactive airways will have poorer survival. In a retrospective study, you expect that the selection bias is that those who have that feature are the ones who are going to get the inhaled corticosteroids. So you have a mixed effect: the natural history is that patients are going to do worse over time, but the treatment effect shows that they’re doing better over time. The final answer will come from prospective studies. In fact, the ongoing Towards a Revolution in COPD Health study is specifically designed with mortality as its primary outcome.
Dr. Donohue: Dr. Bleecker, we saw in your presentation that, surprisingly, a number of patients in the study by Malmstrom et al2 didn’t seem to respond very well to beclomethasone. We’ve had a revolution in the inhaled steroids; we know how to synthesize better compounds, and there are better delivery devices. Do you think that the findings of the Malmstrom study are representative of what we can expect with the drugs we have at our disposal today and will have in the future?
Dr. Bleecker: First of all, when we limit ourselves to a very good objective test in asthma, measurement of FEV1, we have people who are relatively selected for similar lung function and have the potential for reversibility. If we have a number of individuals whose lung function is normal or near normal, their reversibility is less. So that can bias some of the responses when we interpret that kind of data.
The investigators from the National Heart, Lung, and Blood Institute Childhood Asthma Management Program study have measured hyperresponsiveness in all the children in their study, and recently they have begun to look at whether there’s a spectrum of response in terms of shifting hyperresponsiveness. They have reported initial results that some children have larger shifts in responsiveness and some have less change. Those individuals are going to be ideal to study, perhaps with different types of inhaled corticosteroids and even with pharmacogenetic testing, to understand better why some people with asthma respond well to inhaled steroids and others do not.
Now to address the broader sense of your question, a number of trials have been done with the older, less potent inhaled corticosteroids. The newer drugs, fluticasone and, for the most part, budesonide, are not only more potent but also more selective. Unfortunately, the studies that have been done with an older version of a steroid, such as the Lung Health Study, will not be repeated with one of the new drugs. But we are lucky that new trials are ongoing to look prospectively at how these drugs will affect disease control.
Dr. Donohue: Is there a genetic explanation for the differences in the response to steroids?
Dr. Bleecker: A number of drugs have been investigated in terms of whether we can explain variation in response by looking at either receptors or enzymes that may be important in pathways related to those compounds. The most interesting proof of concept comes from studying 5-lipoxygenase enzymes. In the promoter gene for the 5-lipoxygenase is a variation that decreases activity of this enzyme, which catalyzes leukotriene production. Presumably, asthmatics with this variation will have decreased leukotriene production and may not respond to the administration of a leukotriene antagonist. Several years ago, Drazen3 showed that, in fact, that’s exactly what happens.
With corticosteroids, the hypothesis is that there is some variation in the glucocorticoid receptor gene or in other aspects of the steroid pathway that may help us determine magnitude of response. There’s been an observation from a Dutch group in Utrecht showing that a certain variation in the receptor gene may make people more sensitive to corticosteroids.4 The researchers weren’t studying asthma patients; they were simply investigating a physiologic metabolic function. What’s interesting is that after they reported on this, they went to a nursing home and found that individuals with the gene variation who had no history of corticosteroid therapy tended to have lower bone density, again implying increased sensitivity.
A lot of us in asthma are interested in drug resistance. In my presentation, I mentioned that a variation around the ninth axon of the glucocorticoid receptor gene produces the ß-isoform, which is inactive as a receptor. So, individuals with a more prominent ß-isoform would be expected to be resistant to corticosteroid therapy. In addition, the gene itself has a large promoter region that extends through the first axon, which regulates activity. Variation in that area, we could hypothesize, may determine how responsive an individual is to corticosteroid therapy, and this may answer, in part, why there is variation in response in both asthma and COPD.
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