Asthma under control: A history of management and revolutionary research
McMaster Perspective Extended

Dr Paul O’Byrne, dean and vice-president of the Faculty of Health Sciences at McMaster University, joins Dr Roman Jaeschke to provide an insightful overview of the history of asthma treatment over the past 30 years, highlighting significant advancements and the evolution of therapeutic approaches.

Contents

1. Evolution of asthma management: New medication versus adherence
2. Biologics for severe asthma
3. Is full asthma control possible to achieve?
4. Asthma and comorbidities: Are beta-blockers safe?

Transcript

Roman Jaeschke, MD, MSc, DPharm: Good morning. Welcome to another edition of McMaster Perspective. This is a special extended edition devoted to interviewing people who have shaped the management of common diseases over the years, if not decades. Our goal is to give some sort of historical perspective rather than one shot in time of how things are handled today. We found that it may be of interest to a number of people to know how we got here over the decades.

Professor O’Byrne, the floor is yours. My first question is the history of milestones in asthma treatment and maybe your personal contribution to it.

Paul O’Byrne, MB: Good morning, Roman, and thanks for this opportunity. I’m actually looking forward to discussing this historical perspective on how asthma management has changed, and it has changed extraordinarily, very dramatically, particularly over the past 10 years.

To put some of this into context, I think I’m going to have to start maybe 30 years ago, around the time when I was first getting interested and involved in studies looking at the optimal way to manage patients with asthma. At that time the focus was very much on medications, drugs, that caused bronchodilation, that relaxed airway smooth muscle, opened up the airway, and rapidly improved symptoms. The major class of these drugs were inhaled beta₂-agonists, but another type, although acting pharmacologically quite different, was theophylline, which was given orally. And there was a great deal of emphasis, some work on getting the doses of these medications right, and how to use them properly, and on, and on.

The first really major change in that came about with the recognition of the immense benefit of using low doses of inhaled corticosteroids (ICSs) on a regular basis. I was very fortunate to be part of some of those studies that demonstrated that across a range of asthmatic patients—from those considered to be quite severe, difficult-to-manage asthmatics, right down to patients with rather milder disease, intermittent symptoms, certainly less than every day—that low doses of inhaled steroids provided really quite dramatic benefit in reducing the risk of a severe exacerbation, which for an asthmatic is by far the greatest risk and in my view is the most important treatment target when we’re considering managing asthma, but also improved symptoms, improved the degree of bronchoconstriction, and improved airflow obstruction and quality of life. Everything was very much better when these medications were used.

And so, with inhaled corticosteroids, then the emphasis on managing asthma was not so much on reversing bronchoconstriction but rather achieving what we now call asthma control. And asthma control is having the patient essentially normal, without symptoms, with normal or close to normal lung function, and with the minimal risk of exacerbations—as low as possible—and leading a normal lifestyle, being able to exercise, sleeping through the night without symptoms, and so on. Asthma control became the focus of our attention in relation to clinical trials and it became clearer and clearer that regular low doses of inhaled steroids were by far and away the best option right across the spectrum of asthma.

The next realization, and I think innovation, occurred in the early 1990s with the introduction of inhaled beta₂-agonists, which had a longer duration of action than the previously available drugs. Medications were developed that contained both an inhaled corticosteroid and one of these long-acting inhaled beta₂-agonists. We call them, the acronym is LABAs. So, ICSs and LABAs put together in the same inhaler. The evidence began to accumulate that for patients who were not really well controlled on low doses of inhaled steroids, switching to a combination inhaler was a better choice than continuing to increase the dose of inhaled steroids. There was quite a steep dose response with inhaled steroids, the benefit was occurring at low doses, and there was very little additional benefit seen with higher, and higher, and higher doses, although some side effects became obvious at very high doses. So, the ICS + LABA combinations were then widely accepted as the next step in treatment, but still using the inhaled steroid as the basis of even that combination.

One of the LABAs, a drug called formoterol, serendipitously wasn’t designed to do this but turned out not only to have a very long duration of action but also to have a very rapid onset of action, very much like the previously widely used short-acting beta₂-agonists such as albuterol (salbutamol) or terbutaline. And in the mid- to late 1990s an idea came forward that perhaps this combination, inhaled medication that had a steroid but also had this rapid-onset but long-lasting beta₂-agonist could be used both as a twice-daily maintenance treatment in more moderate to severe asthma, but also as the reliever medication. Now, the thinking behind that was also based on a long history and a large number of studies, which had demonstrated, I think very convincingly, that just using a beta₂-agonist, the bronchodilating medication alone, actually, when used intermittently, probably was okay, but when used regularly and certainly when overused from patients who were getting exacerbations or had more difficult asthma, actually made matters worse rather than better.

My lab provided some evidence to show that in fact, in the right circumstance, regular use of these short-acting beta₂-agonists (SABAs) could actually enhance the airway inflammatory response rather than reduce it, which is what inhaled steroids do. Studies had associated the overuse of SABAs with really bad outcomes such as severe exacerbations and, even more concerningly, with asthma deaths.

Putting all that together, the emphasis began to move quite quickly away from using any monotherapy with a beta₂-agonist to drugs that had the beta₂-agonist, a LABA now, at this point, but with the steroid, and when they’re in the same inhaler, you cannot take one without getting the other. The studies of using the combination were done with a steroid called budesonide and with formoterol, this rapid-onset LABA, and demonstrated that across a range of asthmatic subjects who needed maintenance treatment—moderate to severe patients—using it both as a maintenance as well as a reliever was [associated with] significantly and in fact clinically important differences in relation to exacerbation risk. It reduced the exacerbation risk by somewhere in the range of 30% to 50%, depending on the severity of asthma. That was the next major change in asthma management, to say that if you’re going to use a combination as a maintenance, you probably should also use this particular combination as your reliever medication.

Around that time, in the early 2000s, so, probably >20 years ago, the very first of the biological approaches to treating asthma began to be studied. The first of these was a drug called omalizumab that works by binding to immunoglobulin E (IgE) and was shown to be effective in patients with severe asthma, but who had a history of allergy and had elevated levels of IgE. And it was effective at reducing exacerbation risk by ~50% when compared to placebo. It was approved ~15 years ago, maybe 18 years ago now, as the first of the biologics. And then the era of biologics really started to ramp up. That was followed by an approach to target eosinophilia in asthma, and that was done by directing an attack on the cytokine, the protein that’s really important in eosinophil maturation, development, and survival, which is interleukin 5 (IL-5). An antibody was developed that bound to IL-5. We now have 2 of those on the market that, by binding to IL-5 , stop it [from] engaging with its receptor. And we have an antibody that binds directly to the IL-5 receptor, therefore stopping engagement of the ligand to the receptor.

These went through big clinical trials. In fact, our lab here in Hamilton was really influential in the very first of these, showing benefit in patients with very severe prednisone-dependent asthma. We now have 6 biologics available in Canada and in many parts of the world, which target not only IL-5 IgE, which are the ones I’ve already mentioned, but now target other aspects of what we have come to call T2-high airway inflammation, inflammation driven by cytokines released from T2 cells [editor’s note: patients with this condition have blood and airway eosinophilia]. That’s IL-4 and IL-13, the antibody binds to that receptor. And then, most recently, an antibody that binds to a protein released by the airway epithelium, or thymic stromal lymphopoietin (TSLP) which, again, is upstream of the inflammatory events. There are probably no direct comparisons yet, but it may be the most effective of these antibodies yet developed. And once again, our lab here in Hamilton did the very first study to show any benefit in asthma with that particular antibody.

So, for severe asthma, we now have approaches that suggest the patient should be on a combination inhaler, probably both as a maintenance and a reliever medication. There is benefit in adding an anticholinergic, such as tiotropium, if asthma is not fully controlled. So, triple therapy for asthma, and then a range of biologics that we can potentially use, mostly directed at, as I said, T2-high severe asthma. These are patients with eosinophilia in the blood and in the airway, and we have a range of choices in relation to that, as well as if they have severe allergic asthma: an antibody that binds to IgE.

That would have been the state of play maybe 4 or 5 years ago. The antibodies have come along gradually but now, as I say, we have 6 of these. But I think the biggest single change in my experience and in my time studying asthma has occurred in the past 3 years. That is because of some studies, again, which I was very fortunate to be part of leading, that asked the question whether—in fact, in much milder asthmatic populations, which make up perhaps 70% or maybe 80% of all asthma—whether switching from a SABA, which is still the recommended reliever medication, to a reliever medication that also contains a steroid, would be beneficial. The reason we were focusing on this is due to a very pragmatic issue, which I’m sure you’ve heard about, heard from everybody you’ve interviewed who manages chronic diseases. And that issue is adherence with regular therapy, particularly in diseases where the patient is asymptomatic a lot of the time, such as hypertension and asthma.

Mild asthmatic patients have long stretches of time where they have no symptoms. They are, as a population, still at risk of exacerbations. There’s lots of evidence now to say that the risk of an exacerbation for a very mild asthmatic—with intermittent symptoms maybe a couple of days a week or if they’re out in the cold weather or very hot humid weather, and so on—but the risk in that population is about 20% per year, so ~1 in 5 even very mild asthmatics will get an upper respiratory viral illness, which is the commonest trigger, and get a severe exacerbation.

They are poorly adherent, very poorly adherent with daily inhaled steroids, which reduce the risk of this exacerbation very dramatically. And so we argued, maybe we could, instead of suggesting daily maintenance steroids, which the patients won’t use, rather give the steroid associated with the reliever medication, so every time they take a reliever, they get some steroid. And of course during an exacerbation, these gradually develop over 5, 6, 7 days, thus increasing reliever use during that time, so increasing doses of steroids would be given.

Two studies were conducted, 2 large randomized clinical trials, published in the same issue of the journal, showing that in ~7000 patients randomly allocated to either SABA treatment, which is what the patient does, compared to maintenance steroids with the SABA, which is what we would normally recommend, compared to using this combination of the steroid and formoterol as reliever, and of course, because it was a double-blind study, they all had placebo maintenance treatments if they were just getting a reliever. What we showed was that just switching the reliever from a SABA to an ICS + LABA reduced exacerbation risk by 64%—just that switch—and was as good as—in fact very slightly better than—using the maintenance steroids every day. So now, most of the major guidelines are recommending that for all patients with asthma, from the mildest right through to the most severe, the reliever medication, which asthmatics rely on more than anything else for the treatment, should contain an inhaled steroid.

The final thing I’ll say, and then maybe you’ll ask me another question or we can move on, Roman, is that just a few months ago, there was a study published in the New England Journal of Medicine, from some colleagues in Europe and in the United States, showing that a reliever that contained even a SABA—in this study it was albuterol (salbutamol)—with the steroid budesonide, was significantly better than the albuterol alone in exactly the same way. The magnitude of the effect wasn’t quite as good, but there are no direct head-to-head comparisons yet. But still, there was a ~26% reduction in exacerbation risk just by switching your reliever from one with the SABA only to an ICS + SABA combination.

Roman Jaeschke: That’s quite a tour de force. Some questions did come to my mind; the first one would be the threshold for using biologics. What does it depend on? I presume you are not starting from it, obviously.

Paul O’Byrne: At the present time, the biologics are confined to patients who have severe asthma, and that’s defined mostly as having high exacerbation risk, by having ≥1, and for some of the biologics 2, severe exacerbations in the previous 12 months. The only known risk of subsequent exacerbation is previous exacerbation in asthma, so if they’ve had 1 or 2, they’re at a higher risk of getting another exacerbation. And secondly, we have evidence that there’s still T2-high inflammation in their airways, and that’s mostly measured by increased levels of blood eosinophils. So, if you have recently had severe exacerbations at elevated blood eosinophils, you are eligible to be prescribed a biologic in Canada.

Now, which of the biologics you use is a very challenging and very hot topic at the moment because they all work, the magnitude of the effect is relatively similar, but one of them, for example, has also been demonstrated in well-designed trials to work in other diseases that are comorbid with asthma, such as severe atopic dermatitis, rhinosinusitis, and nasal polyposis. So, if the patient has one of those, then you might choose one of these drugs or dupilumab, which blocks the IL-4 receptor alpha. If patients have a very high blood eosinophil count, which some do, you might consider one of the biologics that is very effective at completely eliminating blood eosinophils, and the best at that is a drug called benralizumab, which binds to IL-5 receptor alpha. The most recently approved drug, tezepelumab, is the only one of these 6 that has been shown, again in well-designed, large clinical trials, to have benefit even in patients who do not have elevated blood eosinophils, so, if you like, T2-low severe asthma.

I think we’re still learning a little bit about just how effective it is in that population, but if patients are having frequent exacerbations but don’t have any evidence of elevated blood eosinophils, it’s at least feasible to consider using tezepelumab in that patient population.

Question becomes, though, would it make any sense to start using these biologics earlier on in the progress of the disease, if you like? Those studies are actually just currently being designed. Hopefully in the next few years we’ll have some much better information about that.

Roman Jaeschke: Is cost the factor here?

Paul O’Byrne: Yes, cost is a very major factor. These drugs are very expensive, in the range of $20,000 to $25,000 per year of treatment. And that is the reason that Health Canada, the funding agencies, and so on, really only limit their use to patients who have had severe exacerbations, because they are very costly, when they occur, particularly when they result in hospital visits or hospital admissions.

Roman Jaeschke: Right. Are there prerequisites in terms of other medications being used before considering those?

Paul O’Byrne: Yes, there are. The patients should have been on what would be previously considered to have been the optimal treatment for severe asthma, which is ICS + LABA combination. I must say many of us will only use them in patients who are on triple therapy, ICS + LABA with the long-acting muscarinic antagonist (LAMA), and still at exacerbation risk or who have poor control and elevated blood eosinophils. The other therapeutic concern, of course, are patients who require oral corticosteroids for asthma control. And if patients are on prednisone, daily or alternate daily, then the biologics are considered as a reasonable option.

Roman Jaeschke: Any room for theophylline or leukotriene inhibitors?

Paul O’Byrne: No, theophylline doesn’t have a place. Well, very, very, very limited place. I mean, there are occasional patients, I’m told, who are started on theophylline with very severe asthma. There’s no evidence that’s of any real benefit in that population.

Leukotriene receptor antagonists are still used reasonably frequently in children with asthma. That is because childhood asthma tends to be more allergic, have a more allergic diathesis than adult asthma. Children get worse symptoms during the pollen season or when exposed to pets and so on. Antileukotrienes are quite effective in reducing symptoms when patients are exposed to allergens. It’s an oral once-a-day medication and it’s not a steroid. And parents are very often anxious about starting their children even on low-dose once-daily inhaled steroids.

Roman Jaeschke: Right. That’s quite an amazing field, which you presented to us. My final question is, is it really possible to achieve full control and normal life for almost all patients with asthma?

Paul O’Byrne: Yes, absolutely. It certainly is. It does require, most importantly, that the patient is adherent with their inhaled medications. And when patients are poorly controlled, in my clinical experience, by far and away the main reason is that patients just are very poorly adherent or they will use the medication only when they start having symptoms, and then don’t use it for long stretches of time, and then symptoms recur.

Inhaled steroids have changed the field completely in asthma management, there’s no question about that. I had an opportunity just recently, actually, at the McMaster International Review Course in Internal Medicine (MIRCIM) meeting in Kraków just earlier this year to speak to a couple of my colleagues in intensive care medicine who work here at McMaster University, because I was speaking at the time about severe exacerbations. And it was my sense that the risk of patients presenting to the intensive care unit with acute severe asthma requiring intubation, mechanical ventilation, or other very invasive approaches to manage them has almost completely disappeared. When I was in training, it was a weekly occurrence. And I think we can say that’s 30 years, but it is extraordinary how the regular use of inhaled steroids has completely changed the field in relation to asthma control. There are patients, no doubt about it, who are adherent and who are not well controlled, and really, they are the patients in whom the biologics should be reserved for.

Roman Jaeschke: I want to congratulate you on your own contribution to it and to this sea change in medicine. I agree, the intubated asthma patients almost disappeared and that’s a major success story.

Professor O’Byrne, I would like to finish by asking a more specific clinical question. Recently, I ran through an article in which people were trying if beta-blockers could be of use, therapeutically or preventively, in patients with chronic obstructive pulmonary disease (COPD). It’s kind of putting on its head everything I’ve learned for the last 40 years. What is your approach to patients who have asthma and who need beta-blockers these days?

Paul O’Byrne: That’s an excellent question. A clinical conundrum that occurs fairly frequently, actually, because of the added value of beta-blockers in so many ways and the fact that asthma is a very common condition, so these 2 things intersect quite frequently.

When I have the discussion with the patient, or very often the patient’s physician, about whether or not beta-blockers should be used, I think what is necessary is, first of all, an understanding that the risk of beta-blockers is that even the most selective beta-blockers used for cardiovascular disease, or tremor, or so forth still have some, albeit small, lack of selectivity for the beta₂ receptor, and the beta₂ receptor is what’s needed for beta₂-agonists to cause bronchodilation in asthma. So, the risk perceived and, I think, occasionally real of the use of beta-blockers is in patients who have very poorly controlled asthma, who are relying on their beta₂-agonist for symptom relief and for bronchodilation, in whom the beta-blocker is preventing at least part of that benefit being achieved. So, before I give advice about the beta-blocker, my first thought is, is this patient’s asthma well controlled? Is their need for a beta₂-agonist essentially minimal or virtually nonexistent? Is their lung function normal? And that’s the majority of asthmatics, quite frankly. If that’s the case, then I talk to the patient and often call the physician and say, I think the beta-blocker can be used, I think it can be used safely, but the patient must understand what the risk is. And the risk is, as I say, you start needing to use frequent beta₂-agonists, but you may not get the full benefit from their use.

The second thing is relating back to a comment I made a little earlier in our discussion, Roman, and that is that the reliever medication should also have a steroid. I will emphasize that to the patient that you do not rely on a SABA alone, that you have a LABA, or even a SABA, but with the steroid from the same inhaler. So far that approach has worked very well. The conundrum really comes about when you have a patient who has very unstable and severe asthma but also unstable coronary artery disease or something else where a beta-blocker would be indicated. And if the asthma is really unstable, the effort I will make of course is to try to improve that, looking at things like adherence, which I’ve mentioned earlier, and the possibility of using a biologic. But in that instance I would speak to the physician and say, is there another option rather than using a beta-blocker to achieve this benefit in hypertension, in cardiovascular disease, or something else? Because I do feel it’s a small risk, but it’s a risk that this patient may go on to develop a severe exacerbation and in that instance, the beta-blocker might be having a deleterious effect.

Roman Jaeschke: All right. As usual it’s not black and white, there’s a little bit of gray, but something that used to be an absolute contraindication, I guess, lost its edge at least a little bit and if needed, there are some options for both asthma control and maybe considering other cardiovascular medication.

Professor O’Byrne, I want to thank you very much for putting us through these few decades of asthma research. Again, congratulations on your contribution and thank you and hope to see you again as a contributor to the McMaster Textbook of Internal Medicine, of which you are one of the chief editors, by the way.

Paul O’Byrne: You are most welcome. Thank you very much, Roman.

Roman Jaeschke: Thank you. Goodbye.