Signs of Severe Asthma and the Underlying Pathophysiology

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI: Dr Siri, I’m going to turn to you. Would you like to take it further into the pathophysiology of moderate and severe asthma, now that we’re diving into type 2?

Dareen D. Siri, MD, FAAAAI, FACAAI: I would love to take care of that question. The pathophysiology is quite complex. It’s an interaction between genetics, environmental exposures, and immune hyperreactivity. There are certainly a lot of consequences of inflammation that underlie everything. As Dr Chase discussed, it’s mostly type 2 inflammation, which, as she said, is underscored by IL-4, IL-13, IL-5. These rich T cells, cytokines, and eosinophils are involved, and chemokines can direct the immune system into that overresponsive section. It’s characterized by patients who, because they have inflammation, are coughing, wheezing, and have shortness of breath. Of course, in that context of inflammation, we have an airway that is bronchoreactive and hyperresponsive because of this inflammation. When we have this hyperresponsiveness and the immune system is overactive, then you also get these other things that are happening, such as smooth muscle hypertrophy and mucus production in the airway. Those both limit the airway, of course, and restrict it even more. Then we have mucus production, which then has this milieu of enriched cytokines, as she said. Not only does the smooth muscle have reactivity, but it also increases in terms of numbers, and they become really hypertrophied in that sense of the word. So, with this mucus, the smooth muscles, and the inflammation, we then get exacerbations. Because of these reactive species that are created, what happens then is oxidative stress. When you have oxidative stress in the airways, you get what we call airway remodeling. Unfortunately, that includes collagen deposition and fibrosis. Then you get the cycle of increased asthma exacerbation because of restricted airways, which then of course leads to more airway hyperresponsiveness, more inflammation, and this vicious cycle. In general, the pathophysiology is important because patients lose lung function, they get this scarring over time, and they have many worse outcomes because of exacerbations, which then cause them to be exposed to unnecessary and dangerous medications.

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI: Very well said. You’ve described everything that’s going on inside the body that we cannot see, but we have measurements and we have proxies. With that in mind, Dr White, from your perspective, what are the signs of severe asthma that a health care professional should be looking for? Because they’re not going to understand necessarily the viewpoint of the subspecialist as we have on this panel.

Andrew White, MD: That’s a great question. There are 2 ways I would discuss that. One of the signs is going to be the symptoms—the things we can see in front of us with the patient when they come in. They may have dyspnea, elevated respiratory rates, and they may be coughing in front of us…. We also have lung function measurements, spirometry, and exhaled nitric oxide. I’m going to describe that in a second. But I also think it’s important to say that many of these patients with severe asthma may look normal when they come into the office. They may be between exacerbations, and they may look completely fine. Even their lung function may be normal. I think that’s one of the hallmarks of severe asthma that we need to hone in on. These patients are also prone to exacerbations, as Dr Siri was just saying. There may be a big difference between what we see between exacerbations and then when they come in with an exacerbation.

But the signs that we really are going to anchor to for our patients with asthma are going to be lung function. We’re going to look for airway obstruction on spirometry so their FEV1 [forced expiratory volume in 1 second] is diminished out of proportion to their forced vital capacity. That’s something that should be reversible for most asthmatics. So we give them albuterol and it reverses, and we can tell that they’ve got that bronchial hyperreactivity that Dr Siri was just mentioning. Many of our patients who have a lot of type 2 inflammation will have an elevated exhaled nitric oxide, which is a way to measure type 2 inflammation coming off the airway itself. We’ve got some blood tests that can be very helpful in looking at eosinophil count or other measures of type 2 inflammation, such as their IgE level and whether they are atopic. These are all things that can be helpful signs as we are thinking about our patients who potentially have severe asthma.

The last thing I’ll say that I think is an important consideration or a sign for our patients with severe asthma is going back and looking through what’s happening with their exacerbations. Most of these patients will be exacerbation prone, so looking back at their history, have they been in the emergency department in the past year? Have they had systemic steroid bursts in the past year? Did they have any lab testing done during those episodes? That will be a really helpful marker for us as we think about whether this patient is a severe asthmatic and whether they’re controlled or uncontrolled.

Transcript edited for clarity