Activity Transcript

William W. Busse, MD: Hello, I'm Dr William Busse, professor of medicine in the Division of Allergy and Pulmonology and Critical Care Medicine at the University of Wisconsin School of Medicine in Public Health, in Madison, Wisconsin. Welcome to this program, Foundations of Asthma: Exploring the Allergic Component of Management. In this segment, which is the first of a 3-part series, we will discuss the role of primary care physicians (PCPs) in evaluating and managing patients with severe allergic asthma, including appropriate situations for referral to specialist care.

In later segments, we'll review the expanding role of biomarkers and asthma management and consideration for the use of biologic therapy in patients with severe asthma. Joining me today is Dr Stuart Stoloff, Clinical Professor of Family and Community Medicine at the University of Nevada School of Medicine, in Reno. Welcome, Stuart.

Stuart Stoloff, MD: Thank you, Dr Busse.

Dr Busse: Let me set the stage on asthma as background and also discuss the disease burden. Asthma affects 25 million people in the United States, including 6 million children who are < 18 years of age. An important component of this fraction of patients with asthma are those who have severe disease, and this encompasses about 5% to 10% of this population. Patients with asthma are characterized by more frequent exacerbations, which lead to an increase in healthcare costs -- emergency room (ER) visits, hospitalizations, and intensive care unit (ICU) stays -- and their disease significantly impacts upon schoolwork, work, and daily activity. And unfortunately, they are many times resistant to usual forms of treatment. Important in our discussion of asthma is the concept that asthma as a disease has evolved; it's not one disease, but many diseases. There's a lot of heterogeneity in individuals with asthma based upon their clinical features, their underlying pathophysiology, and this is particularly apparent in those with severe asthma and is going to reflect how responsive they are to usual forms of treatment.

Dr Busse: Stuart, would you review for us the differences between severe and poorly controlled, or uncontrolled, asthma, and why it's so important to differentiate between these two characteristics of asthma?

Dr Stoloff: Utilizing the European Respiratory Society (ERS) and the American Thoracic Society's (ATS) definitions of severe vs uncontrolled asthma, we can make some distinctions. We consider severe asthma as those individuals who require high doses of inhaled corticosteroids (ICS) plus another controller medication, and/or the use of frequent systemic corticosteroids (CS). Also, asthma that remains uncontrolled, despite CS plus a second controller medication. So, that means in patients who are on very high doses and yet are still symptomatic, they are having more than severe asthma, and that becomes the uncontrolled asthmatic. Those patients have poor symptom control, frequent or severe exacerbations, and that means, by definition, 2 or more courses of systemic CS in a year (at least 3 days each time), hospitalization and/or ventilation, and airflow impairment -- a forced expiratory volume in 1 second (FEV₁) where you see less than 80% predicted.

Now when we consider this, we usually look for common causes, especially in primary care. The first is, are those patients using their inhalers properly -- what is their technique? And in fact, studies have shown that up to 80% of uncontrolled cases throughout the community are, in fact, due to poor inhaler technique. In addition, there's both conscious and, really in a form, unconscious medication adherence. So, these are people who take it when they feel symptomatic but otherwise don't use their medicine as regularly prescribed.

Additionally, there's a group who may, in fact, not have asthma. Their symptoms, which are thought of as asthma are, in fact, due to other events. In many cases, they could be comorbid conditions, such as vocal cord dysfunction, cardiac failure, for which patients may wheeze, or lack of physical fitness. Then we have the whole group that we see frequently in severe asthmatics of the comorbidities and complicating factors. This includes the rhinosinusitis, gastroesophageal reflux, obstructive sleep apnea (OSA), and, a big one, obesity. Then, in many people's cases, they have ongoing exposure to irritant agents or sensitizing agents either due to the workplace or at home.

Now, when we look at this we try to look at the group who are undertreated asthmatics, those who have difficult-to-treat asthma, and those, in spite of the best therapy we have and their adherence to the therapy, have refractory asthma. In undertreated asthma, their symptoms are high. The difficult-to-treat, they're also high. In the severe group, they're also high. In the undertreated, as you'd expect, they're not taking their medicine. In the difficult-to-treat asthmatic, the majority really do take their medicine, and in the severe treatment-refractory asthmatic, obviously they're taking their medicines. What we're looking for is control; control whether it's measured by Global Initiative for Asthma (GINA) standards or by the National Heart, Lung, and Blood Institute (NHLBI) standards written in 2007.

The comorbidities, especially in the difficult-to-treat asthmatic and in the severe treatment-refractory asthmatic, are not managed well. But in the severe treatment refractory patient, we're recognizing it more and we're trying to treat it. What's the recommended management? The minimum is combination therapy; usually it's an ICS with a long-acting bronchodilator. In the severe treatment-refractory asthmatic group, in addition we're trying to give personalized medicine. That means we're looking at the phenotype and we're using targeted therapy, which includes, invariably, combination therapy of an ICS and a long-acting bronchodilator.

Dr Busse: Stuart, how do you assess a patient with asthma who's continued to have symptoms or exacerbations while on treatment? What is the process that you use to take better care of these people?

Dr Stoloff: Well, the first thing I do, Bill, is I will give them a placebo of the device that they are normally taking as their maintenance therapy and I'll observe their technique in the office. Then we'll discuss the improvement necessary; in the overwhelming majority of those individuals, until they can demonstrate proficiency, we'll do that at every visit. We'll discuss what adherence is -- where they take on responsibility -- and then we'll look at confirming the diagnosis additionally. And we do this frequently in my practice; we do spirometry pre- and post-bronchodilator. If we consider challenge testing with methacholine or mannitol, we will go to the appropriate facility to do that. Most importantly, I'm looking at comorbidities, especially obesity and the factors associated with that, such as OSA, as well as the common ones of the allergic condition -- rhinosinusitis, nasal polyps -- and we'll consider treatment step-up, obviously. Now, these discussions take place in a cooperative shared decision-making position with the patient.

Dr Busse: Under what circumstances do you consider referral of your patients to an allergist or an asthma specialist to gain better control?

Dr Stoloff: Well, first of all, if by severity when I'm looking at severe asthmatics: are they well controlled, not well controlled, or very poorly controlled? If there's uncertainty in the diagnosis, if there is additional diagnostic testing, I'll refer them to the appropriate allergist in the community because these are high-risk patients. If the patient is taking oral CS and, unfortunately we all see that group, I realize that the long-term side effects associated with use of systemic CS, they're such that additional therapy is absolutely necessary. I'd be looking at biologics and when I'm looking at biologics, I'm looking for assistance from those specialists, allergists, who have experience and expertise with the biologics.

Dr Busse: Could you briefly discuss how you would determine disease risk in a patient with asthma?

Dr Stoloff: I'd be happy to, Bill. First, we do spirometry. I measure FEV₁, FEV₁ over forced vital capacity (FVC) ratio pre- and post-bronchodilator -- short-acting bronchodilator (4 puffs, 6 puffs) used by an inhaler with a valve-holding chamber. Then I want to look at those results. Additionally, I'm looking at biomarkers in my practice, and they're simple for primary care, at least the majority of them. You can get a complete blood count (CBC), get an eosinophil count in the blood -- that helps determine the levels predicting risk for exacerbations. I get a total, an allergen immunoglobulin (Ig)E. That helps me determine eosinophilic effects and allergic affects. And in my practice, we use exhaled nitric oxide -- FeNO (fractional exhaled nitric oxide) -- and that is the biomarker of inflammation that helps me recognize, in patients who are already on ICS, whether they're using them or not using them or something else is going on.

So let's spend the last several minutes discussing asthma phenotypes and endotypes, which will be important when we look at asthma biomarkers and biologics in the later modules. Bill, what's the difference between a phenotype and an endotype?

Dr Busse: Stuart, this is a very appropriate question and many times these two get mixed up. Phenotypes are the clinical characteristics of patients -- later onset of the asthma, early onset, allergic, non-allergic -- and it's really the result from the interaction between gene-environment interactions. Endotypes, we're really only beginning to understand endotypes. This refers to the underlying molecular mechanism of the disease, and all of this integrates the biologic and the clinical features, so we understand the molecular basis, cellular basis, and the functionality. So, different endotypes may have very different phenotypes or specific phenotype characteristics.

Dr Stoloff: What are the two main endotypes of asthma and what are their clinical correlations? What does it really mean?

Dr Busse: Well, this is early in the stage of our understanding endotypes and we've divided this up into 2 major classifications and it's somewhat arbitrary. We talk about type 2 (T2) asthma. This is a profile that's generated by T-helper (Th) lymphocytes, generating cytokines, and also some non-Th2 cells -- type 2 innate lymphoid cell (ILC2), the innate lymphoid cells. And that's why we call it T2, because it generates a cytokine profile -- 4, 5, and 13. The other one is the non-T2. These are individuals who usually have low T2 cytokines but they have other cytokines present, such as T-helper 17 (Th17) and their cellular markers. In contrast to the T2, which are eosinophils, this tends to be neutrophils or no cells at all; paucigranulocytic.

If we look at this in an expanded fashion, looking at the T2, we divide this up into allergic eosinophilic asthma and non-allergic eosinophilic asthma. They both have asthma, which can be severe, and eosinophils are present. Allergic eosinophilic asthma usually has disease that begins early in life and is found in the majority of children. A characteristic feature is allergic sensitization to environmental allergens. Late-onset asthma usually begins in the third or fourth decade of life. Allergy to environmental allergens is not found, but the profile is the same. You've got Th2 cells that are activated, ILC2 that are activated, and you have a variety of cytokines which are driving this process. This is commonly found in, as I said, adult-onset asthma and, more frequently, these individuals have chronic rhinosinusitis and, in some situations, nasal polyps. This group is difficult to get under control and requires frequent use of systemic CS.

Dr Stoloff: What is the allergic asthma phenotype?

Dr Busse: Stuart, this has been somewhat of a difficult definition to make. In most situations, however, the agreement is on the following: these are individuals who have allergic sensitization to aeroallergens. It can also often be associated with other allergic diseases -- allergic rhinitis, atopic dermatitis, or food allergy. A characteristic in these individuals is the demonstration of IgE-specific antibodies to allergens. We try to correlate the presence of the allergic sensitization to environmental exposures and then the development of symptoms. That doesn't always occur, however. However, we do know that in individuals, for example, who are sensitive to cats or other fur-bearing animals, if they avoid these animals their disease is better controlled. So, in essence, what we're talking about with allergic asthma is IgE sensitization plus the presence of symptoms, usually in response or association with allergen exposure.

Dr Stoloff: Bill, could you mention what's available as far as biologics now? I think it's important for primary care to at least hear what is available.

Dr Busse: Stuart, this has been a very important development in the treatment of severe asthma and that's the availability of biologics. The ones we have available now are primarily for severe T2 asthma and we have 3 classes. We have omalizumab, which is anti-IgE, primarily for allergic asthma. Then we have a group of them we're dealing with IL-5 and this is regulation of eosinophils. We have mepolizumab and reslizumab, which are antibodies against IL-5. Then we have benralizumab, which is directed against the IL-5 receptor. These 3 biologics are most effective in eosinophilic-driven asthma. The last one, and the most recently approved, is dupilumab, and this is a biologic which is directed against the IL-4 receptor and also blocks IL-13. It is also indicated in eosinophilic asthma but has a little broader action. We will be discussing this later, in a subsequent program.

In conclusion, asthma is a heterogeneous disease. There are multiple phenotypes and, as we discussed, there are recent discovery of endotypes which can explain this disease. As Stuart indicated, when assessing a patient, it is critical to determine does this patient have asthma or is it something else? Is it severe asthma, or is it poorly controlled asthma? Key assessment markers include spirometry, the recent advanced use of biomarkers to find out more about asthma, and a prediction of risk for exacerbations. Patients with severe asthma should be considered for referral if they are complex, high risk, poorly controlled, or require further evaluation, particularly if they are needing frequent use of systemic CS. A major recent advance has been the availability of biological therapies and these are available for severe asthma, and they target specific molecular pathways in the disease process. As a consequence, they have been able to convert the nonresponsive to the response form of asthma.

Stuart, I'd like to thank you for joining me in this discussion today and I also want to thank our audience for listening. Please proceed to answer the post-activity questions and complete the evaluation. Thank you.

This transcript has been edited for style and clarity.