Identifying the Biomarkers for the Treatment of Severe Asthma - Episode 6
Neal Jain, MD, FAAP, FAAAAI, FACAAI: So we’ve talked a lot about severe asthma and some of the therapies that are emerging and coming down the pipeline, or have alluded to those at least. We have someone for whom we’ve identified that we suspect has asthma. What are the traditional pharmacological therapies that we have available to help manage those patients, Nic?
Nicola A. Hanania, MD, MS: Well, the traditional way of approaching asthma pharmacologically: Whether you look at the NAEPP [National Asthma Education and Prevention Program] guidelines or the GINA [Global Initiative for Asthma] strategy, they talk about controller therapies and rescue medication. Of course, the rescue medication includes the short-acting bronchodilators, but also systemic steroids should be thought of as a rescue therapy because we don’t like to keep people on oral steroids forever. So these are short courses. And as controller therapy, the enhanced steroid is still the main play in treating asthma at all stages, at least persistent asthma. There are different doses. Increasing the dose of an inhaled steroid is a strategy we’ve taken, and others have too. But also adding other controllers, like long-acting beta agonists, combination therapies, or long-acting anticholinergics.
Tiotropium has been approved now for step 4 asthma as an add-on to ICS [inhaled corticosteroids and] LABA [long-acting beta-agonist inhalers]. And then we have the leukotriene modifiers. These are oral agents, but they still have some utility in some subtypes of asthma, particularly in patients with upper-airway symptoms, although less potent than inhaled corticosteroids. And of course, we have the biologics, which we’ll talk about later on. The way to use these drugs is in a step-up approach. But many of my colleagues forget the step-down approach too. We need to keep that in mind. We don’t want to keep people on a high dose on an inhaled steroid. We forget about that.
Bradley Chipps, MD: In my practice, just getting started after 39 years, long-acting beta agonists have been the biggest factor in terms of keeping people out of the hospital. I’m interested in your thoughts about that.
Aidan A. Long, MD: Absolutely.
Nicola A. Hanania, MD, MS: Yeah.
Aidan A. Long, MD: When in combination with an inhaled steroid.
Bradley Chipps, MD: Of course, absolutely.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: I’m actually also a pediatrician by training. When do we worry about these traditional therapies, especially with traditional inhaled corticosteroids and dosing? At what point do you sort of say, “OK, we need to start to think about other therapies”? Do we just say, “Just keep pushing up”? How do we approach that question?
Nicola A. Hanania, MD, MS: Brad brought up a very important point that we should not forget when we deal with pharmacotherapy. We assume the patient is taking the inhaler. We assume they’re taking it correctly. These are assumptions. But there is no question that there is a plateau for the dose.
Bradley Chipps, MD: The dose-response curve flattens out.
Nicola A. Hanania, MD, MS: So there are really no good data to show that if you just keep going up with an inhaled steroid you get better.
Bradley Chipps, MD: For fluticasone propionate, it flattens out at 250.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: In thinking about that, it depends on what your outcome is also, right? If you’re looking at something like lung function, there is clearly a plateau. There are, however, patients, and I think this gets into this discussion about biologics, for whom you don’t see, even with higher doses of inhaled steroids, that there’s control of that inflammatory pathway. That ongoing inflammation is what has led to us needing to look at these other therapies, because they continue to have this altered type 2-high or persistent type 2-high inflammation that seems to be somewhat steroid unresponsive.
Nicola A. Hanania, MD, MS: What also adds to this is the story of the terminal airway inflammation, where the usual particle size that we use for an inhaled corticosteroid may not target that airway. And there are some data that suggest that maybe using a small-size particle inhaled steroid may help. I rarely do that, but every now and then I do.
Bradley Chipps, MD: I routinely do that. I will add, to a medium dose of a standard inhaled steroid, an ICS combination, LABA/ICS, 1 of the 2 small particles. I prefer 1 that has less systemic activity to try to decrease the eosinophilic signal of the airway if that is consistently present.
Aidan A. Long, MD: I think 2 hugely important points just came out in the last couple of minutes. One is adherence to therapy. Clearly you might imagine a disease that is symptomatic, such as asthma, in contrast to an asymptomatic disease, such as hypertension or hyperlipidemia, all of which require chronic therapy. You might think the symptomatic disease would have a higher rate of adherence. It turns out not to be the case. Many of these patients feel that once their symptoms are controlled, “Well, I don’t need that medication anymore.”
Bradley Chipps, MD: And that’s the biggest problem in primary care. Asthma is viewed as an episodic disease.
Aidan A. Long, MD: Right. And so, defining the magnitude of that issue, of the nonadherence issue, is hugely important. Then Neal brought up a point. There clearly are some patients who apparently, despite significant steroid exposure and adherence, still have ongoing inflammation. How big is that group? I think the former group is very substantial, and the latter group is very small.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: Yeah.
Aidan A. Long, MD: The number of patients who really can’t be controlled with what we’ve just discussed as conventional nonbiological therapy is probably quite small.
Bradley Chipps, MD: About 5% or 10% of the patients.
Aidan A. Long, MD: Right.
Nicola A. Hanania, MD, MS: And that’s where a biomarker may be helpful—having some biomarkers for detecting those patients, like exhaled nitric oxide. If it’s high, it usually reflects nonadherence to an inhaled steroid. It may reflect those patients who may not respond, but that’s a smaller group. But also, you mentioned, Brad, bronchodilator responsiveness. I feel it is a very ominous sign when you see a 35%, 40% response to albuterol in your spirometry on these patients. Most of the time it reflects poor adherence to an inhaled steroid, and it is a prediction of high response.
Bradley Chipps, MD: It’s a marker of adverse outcomes for sure.
Nicola A. Hanania, MD, MS: I usually go through my patients’ pharmacy records. I track the refills. We know that nationwide, the refills for inhaled steroids, on average, happen 3 to 4 times a year.
Neal Jain, MD, FAAP, FAAAAI, FACAAI: In a year, if we’re lucky.
Nicola A. Hanania, MD, MS: Twelve is not going to happen.
Transcript edited for clarity.