Jointly provided by Tufts University School of Medicine and DKBmed, LLC

Supported by an educational grant from Sanofi Genzyme

Table of Contents

Intro

Asthma affects about 20 million people in the United States and more than 300 million worldwide. Between 5% and 10% have severe asthma,1 which is refractory to medications that are usually effective for asthma that is not severe. But severe asthma is more than just difficult-to-treat asthma. Severe asthma differs from mild or moderate asthma in its characteristics and complex pathophysiology.

This monograph focuses on diagnosing and treating severe asthma, recognition of phenotypes and endotypes of severe asthma, and new and emerging treatments for severe asthma. Throughout this monograph, a patient case with severe asthma will be used to illustrate these topics. Nicholas S. Hill, MD, professor of medicine at Tufts University School of Medicine and the chief of pulmonary, critical care, and sleep medicine at Tufts Medical Center presented this case at the 2017 annual conference of the American College of Chest Physicians, CHEST, in Toronto.

In the clip below, Dr. Hill describes his first encounter with Michael, his patient, to the audience at CHEST.

Michael - Part 1





We will now go to the TED Talk part of this presentation and I am going to introduce you to Michael who is a patient I first met about four years ago when he was 48 years old and had been referred by his primary care doc who he had seen a couple of days previously complaining of a lot of trouble with his asthma.

He first developed symptoms of asthma only about six months previously. He did not have a history of childhood asthma, and it started with upper respiratory infection-type symptoms and he never kicked it. He had seen his PCP early on who had put him on an antibiotic and gave him a rescue inhaler. He was using his rescue inhaler more and more, he was having symptoms on the job, symptoms at night and said he had used his rescue inhaler as much as 30 to 40 times in a day.

He is a stoic and he didn’t like going to doctors or complaining, so when he showed up a couple of days before we met him with his PCP, he was in pretty tough shape. He was wheezing a lot and dyspneic with minimal exertion. She wanted him to go to the emergency department, but he refused, and so she contacted us and we got him in as soon as we could.

When he came to our office he was still in very tough shape. At rest he was mildly dyspneic but he was obviously laboring to breathe. He was breathing at a rate in the low 20s using accessory muscles, and any exertion was making him short of breath. Surprisingly, he had gone to work the day before, although he had been missing some days from work. We wanted him to go to the emergency department, too, but, again, he refused.

On exam he was wheezing diffusely. We got a spirogram in the office and his FEV1 was 34% predicted with an obstructive pattern. We put him on oral corticosteroids, of course, with a steroid taper. We started him on a combination inhaled corticosteroid/LABA, long-acting beta agonist, combination inhaler and told him to call us in a few days and let us know how he’s doing. We told him if got any worse he absolutely had to go to the hospital.

A few days later he said he felt a lot better. We had him come to the office a month later and his baseline FEV1 was up to 83%. And in response to a bronchodilator at that time he improved another 12%, so that documented his diagnosis of asthma.

He had a few issues that challenged us because he was a smoker, he had smoked since age 13, cigarettes, and he had tried to stop multiple times. Each time he stopped he might go a few days, a few months, I think the longest period he told us was about six months he had successfully stopped but he always relapsed and went back to smoking. In fact, when he came into the office when we first met him, he said, "Oh, yeah, I quit smoking two days ago and when he came in for follow-up he was still abstinent from cigarettes, but started again shortly thereafter, it reminded me of what Mark Twain once said about cigarette smoking - many of you may be familiar with this - which is “Quitting smoking, easiest thing in the world, I’ve done it thousands of times.”

So that was one problem, and the other challenge was his job. This man is a construction worker, who works with explosives, he likes his job, and he gets very well compensated for it because it’s hazard duty. Unfortunately, it’s not a good job to have if you have airways disease because there’s a lot of dust and a lot of potential allergens in the environment where he’s working. Although he tried to use a respirator it was really impossible because there’s a fair amount of heavy labor involved and when he tried to exert himself, a tight respirator like an N95 mask, would interfere with his breathing, and the loser surgical type masks didn’t do anything. So, he wasn’t protecting himself on the job.

Well, over the subsequent couple of years, we struggled with Michael. He had multiple episodes, approximately six, where he needed steroid tapers due to exacerbations. He came to the emergency department on a number of occasions, but we never got his symptoms under particularly good control. He would be having problems at work, he had problems at night. We had him on prolonged courses of corticosteroids on a couple of occasions. We tried more intensive inhaled corticosteroids. We added another ICS to try to control him better, we added montelukast, we tried tiotropium, Macrolides would be another option, we didn’t try them but nothing really got him under good control. Finally, he came into the office with his wife who was very distressed about how much he was suffering with his asthma and said you guys must do something about this.


Definition, Phenotypes, and Endotypes


Defining and Diagnosing Severe Asthma

The American Thoracic Society/European Respiratory Society guidelines define severe asthma as asthma that requires treatment with guidelines-suggested medications for Global Initiative for Asthma (GINA) steps 4 to 5 asthma (high-dose inhaled corticosteroids [ICS] and long-acting β2-agonists [LABA] or leukotriene modifier/theophylline) for the previous year or systemic corticosteroids for ≥50% of the previous year to prevent it from becoming “uncontrolled” or that remains “uncontrolled“ despite this therapy.2 Uncontrolled asthma is defined by ongoing frequent or severe symptoms, frequent or severe exacerbations, or evidence of airflow limitation.

This definition applies to patients who maintain control of the disease or never achieve control. It also applies to patients who received an adequate trial of these therapies but whose treatment was stopped because of lack of response.

While people with severe asthma account for between 5% and 10% of all asthmatics, costs associated with treatment of severe asthma represent 50% of all asthma-related costs. It is estimated that treatment of severe asthma costs $28 billion per year.3


Severe asthma is seen in a subset of patients with difficult-to-control asthma. Referring to the GINA stepwise approach to managing asthma in adults, step 3 is low-dose inhaled corticosteroids combined with a LABA, and step 4 is medium or high-dose inhaled corticosteroids, combined with LABA. Most patients with asthma are controlled with step 2 to step 4 therapy. When the patient reaches step 4 or step 5, the clinician should consider the possibility that the patient has severe asthma.

Before diagnosing severe asthma, however, clinicians must complete a thorough evaluation. The first step is to confirm the diagnosis and rule out other diagnoses. Next, it is important to identify and attempt to eliminate risk factors and exposures, such as smoking, allergens, and occupational exposures. It is also important to recognize comorbidities, such as GERD, obesity, and psychological conditions, that can worsen asthma. The clinician should assess both the patient's inhaler technique, to confirm that the medication is properly delivered, and the patient's adherence to the treatment plan. If patients are not taking medications as prescribed, the clinician should ask questions that will help identify the patient's barriers to adherence so they can be properly addressed.

Finally, if the diagnosis of asthma is confirmed and the patients is adherent to treatment, stepping up treatment based on guidelines may be warranted.




(See Table: Stepwise approach to control asthma symptoms and reduce risk)

Uncontrolled Asthma

Asthma is considered uncontrolled when the patient has consistently poor symptom control; frequent severe exacerbations, requiring at least two bursts of systemic corticosteroids for more than three days each in the previous year; serious exacerbations, such as hospitalization or need for mechanical ventilation or stay in intensive care; or an expiratory airflow limitation as assessed by spirometry (pre-bronchodilator FEV1 <80% predicted and FEV1/FVC below the <lower limit of normal).

Variations in Disease

Standard treatments often fail to work in patients with asthma because asthma is a heterogenous disease. Patients present with different symptoms, have different triggers (eg, exercise, allergens), respond to treatments differently, and experience differing clinical courses.

The presence and type of inflammation also vary. Inflammation can be categorized as eosinophilic, neutrophilic, mixed, or paucigranulocytic. The presence of both eosinophils and neutrophils (ie, mixed) has been reported to be associated with the most severe manifestations of severe asthma.

Even within these categories of inflammation, patients with severe asthma demonstrate wide variability from very high levels of either cell types to none, despite being on high-dose corticosteroids. Both eosinophil and neutrophils sputum numbers vary substantially monthly. However, sputum eosinophilia appears more stable, especially in severe asthma, when examined over year-long periods in adults.

Viral infection is known to contribute to severe asthma, and the role of bacterial infection has recently been explored. 4 Haemophilus and Pseudomonas have been seen in sputum cultures of these patients, even without underlying bronchiectasis. Patients with Chlamydia have shown to have fixed airflow obstruction. Similarly, there has been an association between staph superantigen IgE and asthma severity and sinusitis. The exact role of bacterial infection is not known, but data are available to support the association.

Structural abnormalities, such as thicker epithelium and increased airway smooth muscle, are also seen in patients with severe asthma. These structural alterations affect airway mechanics, with more chronic airflow limitation. Air trapping is more frequent in people with severe asthma, compared with people with non-severe asthma, with the same level of airflow limitation.5

Finally, natural history of severe asthma is poorly understood, as no long-term studies are available to inform whether severe asthma develops early in the course of the disease or whether it develops over time.


The graph below illustrates symptoms on the Y axis and inflammation on the X axis. In most cases, asthma seen in practice is concordant: as inflammation in the airway increases, asthma symptoms appear worse. In these patients, guideline-based and symptom-based therapy generally improve symptoms. As symptoms increase in patients with concordant disease, therapy is stepped up and patients generally improve.

However, most of the patients with severe asthma have discordant disease: severe symptoms without significant inflammation, or mild symptoms with significant inflammation. In these patients, monitoring inflammation permits optimizing use of corticosteroids. In patients with low inflammation, corticosteroids can be decreased, limited side effects, while high-dose corticosteroids can be reserved for patients with significant inflammation, who are more likely to benefit from the corticosteroids.




(See Table: Severe Asthma:Discordant Symptoms and Inflammation)6

Phenotypes

Because of the heterogeneity of severe asthma, phenotyping has emerged to improve understanding the variety of clinical presentations and outcomes of asthma patients. Phenotype has been defined as the "observable characteristics of an organism, resulting from interaction between its genetic makeup and environmental influences.” 7 Classification by phenotype integrates biologic and clinical features, ranging from molecular, cellular, morphologic, and functional to patient characteristics, all with the goal of improving therapy.

Many factors contribute to a patient's specific phenotype, beginning with the expression of genes that affect airway anatomy and lung function. The combination of factors determines the individual patient's symptoms, comorbidities, effect on quality of life, and response to treatment.

While there are no widely accepted definitions of specific phenotypes, several phenotypes have been described and some are better understood than others.




(See Table: Factors That May Contribute to the Ultimate Phenotype of Severe Asthma) 8

Clinical Characteristics

Age of onset and presence or absence of evidence of atopy or allergy are among the primary clinical characteristics used to categorize patients into phenotypes. Childhood-onset atopic asthma, for example is one phenotype; adult-onset nonatopic is another. Aspirin sensitivity may be associated with severe asthma, defining another phenotype. Finally, asthmatic granulomatosis is another clinical phenotype, recently reported by the University of Pittsburgh after patients with severe asthma received, unconventionally, lung biopsies to determine the cause of severity. In these patients, lung biopsies revealed many granulomas. These patients also tend to have a family history of autoimmune disease and be more eosinophilic.

Cellular Characteristics

The cellular inflammatory phenotypes are defined by which type of inflammatory cells are preponderant. Patients with a preponderance of eosinophils have eosinophilic asthma; those will a preponderance of neutrophils have neutrophilic asthma. Patients with relatively number of both inflammatory cells are considered to have mixed inflammation, which is the more severe variety, whereas other patients with low levels of both are considered to have noninflammatory asthma.

The phenotypes are not mutually exclusive and there is considerable overlap among phenotypes.

Finally, some additional characteristics are not necessarily used to categorize into phenotypes, but they are observed in patients seen in clinical practice. Patients may be resistant to oral or inhaled steroids or both, some patients do not have daily symptoms but they have frequent exacerbations, others have symptoms that are associated with exercise or being overweight, and some women may develop asthma after menopause.

Commonly Recognized Phenotypes

The three commonly recognized phenotypes are allergic, eosinophilic, and neutrophilic asthma. 9, 10

Allergic asthma may be considered the "typical" phenotype. Patients with severe asthma tended to develop asthma when they were children, with a strong family history of asthma and allergies, and seasonal variations in symptoms and exacerbations.

Eosinophilic asthma is more common in women and tends to develop late, but it can also develop early with allergies and high immunoglobulin-E levels. People with eosinophilic asthma tend to have comorbidities, such as obesity, nasal polyposis, or aspirin sensitivity, and frequent exacerbations, with high healthcare use. Many require inhaled corticosteroids for maintenance therapy.

Neutrophilic asthma also tends to be late-onset but triggers are more likely to be exposures such as smoking, occupational exposures, infections (viral and bacterial) rather than allergens. People with neutrophilic asthma tend to be less responsive to inhaled corticosteroids than people with allergic and eosinophilic asthma varieties, and they tend to have more mucus and occasional bronchiectasis .



(See Table: Severe Asthma Phenotypes)11

Less Recognized Phenotypes

Less recognized phenotypes include mixed inflammation, paucigranulocytic, fixed obstruction, and hyper-responsive and variable obstruction.

As previously mentioned, the mixed inflammation phenotype tends to be more severe than either eosinophilic or neutrophilic. The paucigranulocytic phenotype, with no inflammation, is associated with airways that tend to have smooth muscle hypertrophy, airway remodeling, and hyperplasia. Patients with paucigranulocytic asthma often present with fixed or variable obstruction. Patients with fixed obstruction have obstructive lung disease on spirometry with little potential of reversing pulmonary function. Fixed obstruction may be caused by smoking, severe childhood asthma, mucus hypersecretion, bronchiectasis, or long-standing untreated asthma. Finally, patients with hyper-responsive or variable obstruction have increased bronchoprovocation.




(See Table: Severe Asthma Phenotypes)

Endotypes

Endotyping combines clinical characteristics with identifiable mechanistic pathways. After the phenotype has been determined, usually as a result of targeted questioning, particular biomarkers may be used to identify the patients' underlying pathobiology, or endotype.12 Biomarkers can help identify patients with a phenotype cluster who are more likely to respond to a given immunomodulation therapy. The ultimate goal of phenotyping and endotyping is to facilitate selection of patients for various treatments.

Key Takeaways

  • Severe asthma is defined as asthma that requires treatment with high-dose inhaled steroids and a second controller agent, with or without systemic steroids, to prevent its becoming uncontrolled or asthma that remains uncontrolled despite this therapy.
  • Asthma is a heterogenous disease, with different symptoms, triggers and responses and clinical courses.
  • Phenotyping allows clinicians to classify asthma for a particular patient based on the observable characteristics. The better recognized phenotypes include allergic, eosinophilic and neutrophilic asthma.
  • Phenotypes can help identify a patient's pathobiology, which can then direct appropriate therapy.

Biologic Treatments

Returning to the patient, Dr. Hill continues describing his encounter with Michael and how he determined his patient's phenotype.


Michael - Part 2








So, we left off with Michael when he came into the office with his wife and she said I’mnot happy with the way things are going and she was even more forceful. What else can we do? Now, the first step is deciding what kind of asthma did Michael really have.How many people in the audience think that Michael fit the diagnosis of severe asthma by raising your hand? So, it looks like most of us do, I would agree.

He had poorly controlled asthma. He had symptoms both during the daytime and at night occurring quite frequently. He had had at least six episodes during the previous two years requiring corticosteroids. He wasn’t hospitalized but he did go to the ED on a number of occasions, you need two or more to fit that diagnosis.

We did check his spirometry most of the time when he came in and it ranged, not surprisingly, sometimes he was as high as 90%, but he was down in the 70s. He never went as low as he did during that initial visit, 34%, but it was quite variable. So I don’t think there is any doubt that he fits that definition.

You could argue about the exposure part of this because ideally you don’t want to diagnose severe asthma unless you’ve had adequate environmental controls. He simply could not stop his smoking and he sure as hell wasn’t going to quit his job. He was a very committed family man, he had three young children and this is what he knew how to do, explosives, he was well compensated and he had very good health insurance, and he said what do you want me to do, work at McDonald’s? because otherwise that’s what he was looking at. I understood that, I could fully identify with him on this.

He was very stressed out and, of course, we’re taught if someone has bad asthma try to minimize their stress, but his boss had been telling him he was losing too much time from work and was thinking about maybe replacing him. His wife was stressed out because he had been so ill and stressed out himself. And he really was in a fix, almost a Catch 22.

Now what about biologics for this man? We had sent off the appropriate tests to phenotype him. His IgE levels were never really in the range. You’re supposed to have over 30 (U / mL) of blood to qualify, and he varied a bit and was over on a couple of occasions but really did not have very elevated IgE. But his eos were quite elevated and ranged from 300 to 1,400 cells/µl over that period of time. He certainly had an eosinophilic type, so he might qualify for a biologic.

And if we try to be hard on him with regard to smoking and his job, he would then probably lose his job and things would be much worse, so we were very interested in considering a biologic - but which one?

We agree that Michael had severe asthma and before you move onto biologics you have to go through an algorithm, a routine to decide that your patient really needs biologics. You want to confirm the diagnosis. Michael didn’t have evidence of allergic bronchopulmonary aspergillosis and his IgE levels were really not that high. Nothing to suggest these other entities.

Adherence. He was very adherent coming to the office, we went over the use of the inhalers and his inhaler technique. He assured us that he was adherent and I believe him. An approach that has been championed by physicians in the UK called single maintenance and rescue therapy or SMART therapy which generally consists of an inhaled corticosteroid with formoterol which is a rapidly onset LABA, you can use the same inhaler for both maintenance and rescue. And they have achieved somewhat better control. We didn’t try that in him but it’s one of the things you might consider.

You seek the triggers. Some of the triggers we’ve talked about we couldn’t control, did the best we could. He did try a number of nonpharmacological therapies, he got his vaccines regularly, we did have an action plan. He was under a lot of stress but the stress was related to the predicament he was in and something that made him better would certainly be great at stress reduction.

And then the non-biologic add-ons like leukotriene modifiers - he was on montelukast. We did try tiotropium. We didn’t try macrolides or theophylline, I’m not really a big fan of theophylline because it’s got that narrow therapeutic index, probably not all that effective. And then oral corticosteroids - yes, we had used them as I mentioned. So, I think we’ve reasonably checked off the boxes here as best we can, and biologics are certainly considerations for him.



The choice of biologic depends on the pathophysiology of asthma. Referring to the figure above, the left side illustrates the mechanisms behind type 2 inflammation, which is atopic or allergic asthma, while the right side illustrates mechanisms behind non-type 2 asthma, which is not allergic. With type 2 asthma, IgE and eosinophils are plentiful, whereas in non-type 2 asthma, the neutrophil appears to be the main inflammatory cell. Each of the cells in this illustration serves as a potential target for biologics.

All the biologics currently approved target type 2 inflammation. Thymic stromal lymphopoietin (TSLP) is one of the early regulatory mediators that stimulates the TH2 lymphocyte to produce interleukins, including IL-4, IL-5, and IL-13. IL-4 and IL-13 promote downstream effects, including effects on B cells, production of IgE, and the mast cell. IL-5 is most important for stimulating and sustaining eosinophils. Elevation of eosinophil levels is related to IL-5 and, of course, the eosinophil is a central cell in the inflammatory response.

The CRTH-2 receptor is also important, both on the TH2 cell and also on eosinophils for release of further cytokines.

The mast cell releases at several different mediators, including leukotrienes, histamine, and interleukins.

Biologic Medications Approved in the United States

Name Mechanism Target Population
Omalizumab Anti IgE IgE> 30 IU/mL; FENO ≥ 20 ppb best
Mepolizumab Anti IL-5 ≥ 2 exacerbations/year; ≥ 300/μL eosinophils
Reslizumab Anti IL-5 ≥ 2 exacerbations/year; ≥ 400/μL eosinophils
Benralizumab Anti α subunit of IL-5 receptor ≥ 2 exacerbations/year; ≥ 300/μL eosinophils

Biologics are FDA approved for specific indications and are to be used as maintenance therapy rather than emergency treatment of acute disease.

Omalizumab, an anti-IgE antibody, was approved by the FDA in 2003 for moderate to severe asthma with a positive allergy skin test, and poor control with inhaled corticosteroids. Dosing depends on weight, IgE level, and age. Omalizumab is approved for IgE levels between 30 and 700 IU and is currently delivered subcutaneously every two to four weeks. When omalizumab was first introduced, it was delivered via intravenous infusion. Anaphylaxis occurred in roughly 0.2% of patients with intravenous delivery, but risk of anaphylaxis appears to be lower with subcutaneous delivery.

A Cochrane systematic review of 25 studies of omaluzumab demonstrated that, on average, exacerbations are reduced by 45%, with the proportion of patients who had annual exacerbations reduced from 26% to 16%.14 Hospitalizations were reduced by more than 80%, from 3% of patients to 0.5%. A slight decrease in inhaled corticosteroids was observed, without a reduction in oral steroids. Adverse events were decreased, but local site reactions, which are common to all biologics, were higher than placebo (9% vs 5%). Local site reactions include itching and redness.

Mepolizumab, which was approved but the FDA in 2015, is an anti-IL-5 agent, so it attacks the eosinophil. Mepolizumab is labeled as an add-on treatment for severe asthma for patients aged 12 years or older with an eosinophilic phenotype (>150/UL for many insurers). The dose is 100 mg, administered subcutaneously every four weeks. The DREAM study demonstrated that at the 100-mg dose, exacerbations are reduced by 50%.15 16 A third randomized controlled trial demonstrated that oral steroids were decreased by 50% with an improved score on the asthma control questionnaire score. 17

Reslizumab, approved by the FDA in 2016, is also an anti-IL-5; however, it is delivered intravenously every four weeks. Reslizumab appears to have the same reduction in exacerbations as mepolizumab, but only with higher levels of eosinophils compared to mepolizumab (>400 IU/μL vs >300 IU/μL). The need for an IV infusion also increases its risk for anaphylaxis; approximately 0.3% 18, 19. On the other hand, the dose is adjusted according to weight and other factors, which may be helpful in cases that are recalcitrant to mepolizumab, which has a fixed dose.

The most recent entry to the biologic market for severe asthma is benralizumab, which was approved by the FDA in late 2017. Benralizumab is an antibody against the alpha subunit of the IL-5 receptor. In phase 3 study, the annual exacerbation rates were 36% and 28% lower for patients treated with benralizumab every four weeks and eight weeks, respectively, compared to the rates for patients treated with placebo.20 Benralizumab is delivered subcutaneously every four weeks.

Emerging Medications

Name Mechanism Target Population
Dupilumab Anti α subunit of IL-4, IL-13 receptor ≥2 exacerbations/year; ≥ 300/μL eosinophils
Fevipiprant Anti-CRTH2, (PGD2 receptor) TH2 phenotype
Lebrikizumab Anti IL-13 Periostin > 50 μg/mL; > 300 μL eosinophils
Tralokinumab Anti IL-13 Inadequate control despite ICS + LABA; periostin
Tezepelumab Anti-TSLP Inadequate control despite ICS; ≥ 2 exacerbations or 1 hospitalization

Dupilumab, which targets the alpha subunit of IL-4 and IL-13, increases eosinophils, perhaps in a compensatory manner. Nonetheless, the effect is significant.

Fevipiprant has a unique action against the CRTH-2 receptor, and is the only medication in the pipeline with oral administration.

Lebrikizumab and tralokinumab target only IL-13 which looks to be a very important interleukin. Study results have been mixed.

Finally, tezepelumab, an anti-thymic stromal lymphopoietin, interferes with downstream actions in the signaling pathways; therefore, it decreases IgE and eosinophils, and reduced frequency of exacerbations by slightly over 60%, with a very good safety profile. Importantly, the effect was similar with eosinophils below and above 250 μL.

With a diagnosis of severe asthma that is not controlled, Dr. Hill’s patient Michael may be eligible for treatment with biologic therapy. The following audio clip picks up as Dr. Hill and his patient consider the options.


Michael - Part 3








So, we get back to Michael. We left off with Michael in the office having a discussion, talking about his severe asthma, that we haven’t achieved adequate control of his asthma, we’ve tried a lot of different things, time has gone on, we’ve tried to get rid of this smoking, we’ve talked about the job. We really are at an impasse what additional non-biological therapy we can provide.

Should we consider giving Michael a biologic, and if so, which one should we recommend? So, show of hands, who would be interested in giving Michael a biologic? All right, we got a number of takers, it’s a pretty expensive thing to do, probably well above $100,000 a year. Fortunately, he has good insurance as long as he hangs onto his job.

If we want to give him a biologic, who would go with omalizumab? How about mepolizumab? Okay, a few hands there. How about reslizumab? A few takers there. I’d be interested to hear your thinking when we get into our Q&A session.

We believe in shared decision making so we provided the information I just gave you in a little less detail. What are the actions, what are the differences in how they’re administered, the potential side effects, and we did decide on mepolizumab. We decided on that because of the strong elevation in eosinophil levels that was repeated over a period of time.

The IgE level I said bounced around a little bit, but most of the time it was under that 30 level. You can see people who have substantial elevations in both lgE and eosinophils, perhaps that’s something we can talk about in the Q&A session. But clearly, he needed an IL-5 antibody because of the eosinophilic phenotype, but then the question became is it mepo or reslizumab, We mutually decided on mepo because of the convenience of the subcutaneous approach. Michael did not want to lose any time from work, and so the subcutaneous once a month was an attractive feature. Reslizumab, remember, has to be given by intravenous infusion and the other differences are that mepo is approved for ages 12 and over, reslizumab 18 and over, and the eosinophil count level is a little bit different, 150 versus 400, neither of those were really important factors, and the cost is similar.



Key Takeaways

  • Biologics are reserved for asthma that is uncontrolled after optimal routine therapy.
  • Four biologics are currently approved.
  • Other biologics appear promising, but agents that solely target IL-13 may not be as effective as agents that simultaneously target IL-4 and IL-13 by blocking.



(See Table: Inflammatory Mechanisms Associated With Granulocytic Inflammation) 13

Treatment Selection

The above figure depicts Type 2 asthma and non-type 2 asthma based on asthma severity and age of onset.21 The intensity of color represents the degree of severity, and the relative size of the subcircles suggest the proportions of affected individuals.

Type 2 Asthma

Type 2 asthma consists of both early- and late-onset asthma, and severity can range from mild to severe. The majority of the early-onset allergy asthma is mild but with increasing complexity of the immune processes, greater severity may develop.

Later-onset eosinophilic asthma without the traditional elements of allergy tends to be severe, while exercise-induced asthma is usually intermittent, type 2 driven, and mild. Thus, even within the type 2 group, significant variation exists.

Allergic asthma accounts for the bulk of type 2 asthma, as does the late-onset eosinophilic asthma. Aspirin-exacerbated respiratory disease and exercise-induced asthma accounts for smaller proportions of type 2 asthma.

Non-type 2 Asthma

Non-type 2 asthma includes very late onset, obesity-associated, smoking-related, and neutrophilic asthma as well as paucigranulocytic, which is predominantly structural disease in the airways and non-inflammatory asthma.




(See Table: Type 2 and Non-type 2 Asthma)

Biomarkers

As discussed earlier, biomarkers are often able to link the phenotype to the patient's underlying endotype, with the ultimate goal of guiding treatment selection. Therefore, assessing particular biomarkers may help identify patients who would benefit from biologic medications.

Eosinophils may be quantified in blood and sputum. Blood eosinophil measurements are used to select patients for anti-IL-5 therapy. However, certain factors, such as fasting, obesity, and adrenal insufficiency, can affect eosinophil counts; these confounding factors must be considered. Further, it may be difficult to taper and discontinue oral corticosteroids for patients with severe asthma before assessing eosinophils, and it is difficult to predict what the eosinophil count would be if the patient were not on prednisone.

Sputum eosinophils accurately predict response to inhaled corticosteroids as the measurement reflects eosinophilia in the airway; however, techniques to quantify sputum eosinophils are cumbersome. Many institutions do not currently have the capability to measure sputum eosinophils.

Fraction of exhaled nitric oxide (FeNO) is easily performed in an office-based setting and generally correlates with sputum and blood eosinophils. However, FeNO-guided algorithms have not outperformed symptom-guided treatment, and ATS/ERS guidelines do not recommend use of FeNO quantification.

Finally, immunoglobulin-E can be used as a surrogate marker for atopy. The IgE measurement is required to determine if a patient is a candidate for omalizumab. However, IgE levels tends to decline with increasing age, which is an important consideration. Also, the IgE level is not predictive of response.

How are biomarkers used to treat type 2 asthma in clinical practice?

Patients with allergic asthma generally have a high IgE level along with evidence of allergen sensitivity, whether that’s an IgE level to an allergen or a skin test. These patients may or may not have eosinophilia and high FeNO levels. Patient with allergic asthma may be considered for treatment with omalizumab.

Patients with eosinophilic asthma have eosinophilia in either their blood or sputum; they may or may not have allergy sensitivity or FeNO. There may also be overlap. Patients with eosinophilic asthma may be considered for treatment with mepolizumab, reslizumab, or benralizumab.




(See Table: Using Biomarkers to Identify and Treat Type 2 Asthma)

Approach to the Patient with Severe Asthma

Spirometry can assess airway function, but the patient must be queried about history. How severe and frequent are the symptoms? When did allergies develop? When did asthma first appear? Is there a family history of asthma? What is the patient's exacerbation history? How many times have they used prednisone or visited an emergency room for asthma in the past year? Has the patient been hospitalized, admitted to the intensive care unit, or intubated for asthma? What are the patient's comorbidities?

After the likely phenotype has been established, assess biomarkers that may be relevant for particular treatment options, as discussed in the previous section.

Patient Cases

Case One:
A 35-year-old nonsmoking female with asthma since age 18 presents for evaluation. She reports over the last year she has had nighttime symptoms three to four times a month, daily daytime symptoms, postnasal drip, nasal congestion, and two emergency room visits, where she was given prednisone, in the last year. Her medications include inhaled corticosteroids, long-acting bronchodilator, a leukotriene antagonist, nasal steroid, and antihistamine. She had an allergy test a long time ago, and subcutaneous immunotherapy has not really helped. Her exam reveals pale mucosa and bilateral expiratory wheezing. FEV1 is 70% predicted. What is the appropriate next step for management of this patient?

  1. Continue current therapy
  2. Check IgE level and eosinophil count
  3. Check FeNo
  4. Initiate omalizumab

The correct answer is 2. In this patient with uncontrolled asthma despite step 4 therapy, it is reasonable to check biomarkers to determine if she will benefit from additional targeted therapy.

Continuing current therapy, option 1, is not appropriate as her asthma currently is not controlled. Option 3, checking FeNO, is not recommended according to ATS/ERS asthma guidelines on severe asthma, which states that clinicians not use FeNO to guide treatment in adults or children with severe asthma. FeNO does not add information to symptom-driven treatment. Finally, option 4 is not correct because although this patient has allergic asthma that is not controlled despite ICS and has demonstrated positive allergy test, an IgE level is indicated before initiating therapy with omalizumab.


Case Two:
A 55-year-old obese female, BMI of 35, is admitted for her third hospitalization for asthma this year. She developed asthma and seasonal allergies in her 40s. The patient has gained 15 pounds in the last few months, which she attributes to prednisone. She is not able to exercise because of cough, wheezing and dyspnea, and she uses nebulized albuterol multiple times a week. The patient does not smoke and her medications include combination of ICS and LABA, leukotriene antagonist, nasal steroid, and a proton pump inhibitor. She has expiratory wheezing with a prolonged expiratory phase. A spirometry done three months ago shows an FEV1 of 70% predicted, and labs show an eosinophil count of 600 cells and an undetectable IgE level. Which of the following is not in line with the current guidelines for treatment for asthma management?

  1. Checking inhaler technique
  2. Check medication adherence
  3. Initiate omalizumab
  4. Initiate mepolizumab

The correct answer is 3, initiate omalizumab. Omalizumab is not indicated in this patients because of her undetectable IgE. IgE levels must be over 30 for omalizumab.

Before beginning biologics in any patient, it is imperative to check inhaler technique and medication adherence, options 1 and 2. Finally, mepolizumab is a good option for this patient, who has adult-onset uncontrolled asthma. With elevated eosinophils, she is eligible for anti-IL-5 therapy, such as mepolizumab.


Case Three:
A 45-year-old male with asthma presents for an evaluation. He is a nonsmoker with no allergies who developed asthma in his 20s. However, two or three times each year, when he develops a cold or sinus infection, he requires prednisone for asthma. He takes high-dose combination therapy, leukotriene antagonist, and tiotropium mist. His exam is normal, FEV1 is 55% predicted, and eosinophils and IgE are normal. Skin test for dust mite sensitivity is negative. Which of the following should be considered for the next step in treatment?

  1. Initiate omalizumab
  2. Initiate reslizumab
  3. Enroll in a clinical trial
  4. Bronchothermoplasty

Options 1 and 2 are not appropriate because the patient's eosinophils and IgE levels are normal. In this patient with adult-onset asthma, infection is the predominant trigger. The phenotype is neutrophilic asthma. Option 4, bronchothermoplasty, involves radiofrequency ablation of the airway smooth muscles, which increases short-term risk of exacerbation. Studies have demonstrated that a large placebo effect of broncothermoplasty, with sham procedures leading to improvement of symptoms. Currently, no biologics are approved for neutrophilic asthma. Therefore, the correct answer is option 3, enrollment in a clinical trial with the hope of testing additional medications neutrophilic asthma.

Key Takeaways

  • Allergic and eosinophilic asthma are two type 2 asthma.
  • Neutrophilic asthma is non-type 2.
  • The biologic targets for type 2 asthma are IgE, IL-4. IL-5, and IL-13.
  • Biomarkers for type 2 are IgE, FeNO and eosinophils, either in blood or sputum.
  • Biomarkers can help direct appropriate treatment for the patient with severe asthma.

In the final audio segment, Dr. Hill concludes his presentation at CHEST by talking about his patient's experience on biologic medication.

So, what has happened subsequently - he started mepolizumab almost a year ago - magic. Almost after his first dose Michael was feeling better. Since then we have not had any ED visits, we have not had to give him any corticosteroids, his symptom control has been very good. To my knowledge he hasn’t missed any days from work. He is very happy, his wife is very happy, the only complaint is that he does have a flu like syndrome after each injection that goes on for maybe a couple of days and then the rest of the month he feels fine. This has been a tremendous win for him, and we’re very pleased. He’s still smoking so maybe we’re smoking enablers but under the circumstances we feel very pleased with this.

I hasten to point out that this is not what we see all the time in these people. I am sure there are people in the audience who have experience with these agents but not everybody has a response that’s so good. And we have had some people who were total failures and don’t seem to have responded at all to these agents.

References

  1. Ray A, Raundhal M, Oriss TB, Ray P, Wenzel SE. Current concepts of severe asthma. J Clin Invest. 2016;126(7):2394-403.
  2. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-73
  3. Ray A, Raundhal M, Oriss TB, Ray P, Wenzel SE. Current concepts of severe asthma. J Clin Invest. 2016;126(7):2394-403
  4. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-73
  5. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-73.
  6. Haldar P et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008; 178(3)
  7. Wenzel SE. Asthma Phenotypes: the evolution from clinical to molecular approaches. Nature Med 2012;18
  8. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-73.
  9. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377:965-976
  10. Opina et al. Phenotype – driven therapeutics and severe asthma. Curr Allergy Asthma Rep 2017;17
  11. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377:965-976
  12. Fitzpatrick, Moore. Severe Asthma Phenotypes – How should they guide evaluation and treatment. J Allergy Clin Immunol Pract 2017;5
  13. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377:965-976.
  14. Normansell R, Walker S, Milan SJ, Walters E, Nair P. Omalizumab for asthma in adults and children. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD003559. DOI: 10.1002/14651858.CD003559.pub4
  15. Pavord I et al, Lancet 2012; 380: 651-9.
  16. Ortega H et al, NEJM 2014; 371:1198
  17. Bel E et al, NEJM 2014; 371:1189-97.
  18. Castro M et al, Lancet Resp Med 2015
  19. Corren J et al, Chest 2016
  20. Fitzgerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388(10056):2128-2141.
  21. Wenzel SE. asthma phenotypes: the evolution from clinical to molecular approaches. Nature Med 2012;18

Jointly provided by Tufts University School of Medicine and DKBmed, LLC

Supported by an educational grant from Sanofi Genzyme

Asthma affects about 20 million people in the United States and more than 300 million worldwide.

Between 5% and 10% have severe asthma, which is refractory to medications that are usually effective for asthma that is not severe. But severe asthma is more than just difficult-to-treat asthma. Severe asthma differs from mild or moderate asthma in its characteristics and complex pathophysiology.

This monograph will:

  • Describe how the phenotypes and endotypes of severe asthma can be used to inform the delivery of effective treatment of this disease.
  • Explain the mechanisms of action for newly introduced or emerging biologic medications that are targeted to the specific pathophysiology of severe asthma.
  • Discuss how clinicians can practice personalized medical care by identifying and assessing biomarkers for severe asthma that guide selection of optimal therapeutic agents.
  • Demonstrate optimal shared decision-making practices with patients for managing severe asthma.
  • Illustrate this topic with a patient case from Nicholas S. Hill, MD, professor of medicine at Tufts University School of Medicine

Start Program

Jointly provided by Tufts University School of Medicine and DKBmed, LLC

Supported by an educational grant from Sanofi Genzyme

Faculty

Nicholas S. Hill, MD - Co-Course Director

Chief, Pulmonary, Critical Care and Sleep Division
Tufts Medical Center
Professor of Medicine
Tufts University School of Medicine
Boston, Massachusetts


Sucharita R. Kher, MD - Co-Course Director

Medical Director Pulmonary Clinic
Pulmonary Attending Physician
Tufts Medical Center
Assistant Professor of Medicine
Tufts University School of Medicine
Boston, Massachusetts

Jointly provided by Tufts University School of Medicine and DKBmed, LLC

Supported by an educational grant from Sanofi Genzyme

CME/CE

Original Release Date: March 1, 2018
Last Review Date: February 28, 2018
Expiration Date: February 28, 2019

Estimated time to complete this activity: 1.25 hours

There is no fee for this activity.

Faculty

Nicholas S. Hill, MD - Co-Course Director & Speaker
Chief, Pulmonary, Critical Care and Sleep Division
Tufts Medical Center
Professor of Medicine
Tufts University School of Medicine
Boston, MA

Sucharita R. Kher, MD - Co-Course Director & Speaker
Medical Director, Pulmonary Clinic
Pulmonary Attending Physician
Tufts Medical Center
Assistant Professor of Medicine
Tufts University School of Medicine
Boston, MA

Dean Beals - Planner
President & CEO
DKBmed, LLC
New York, New York

Stan J. Pogroszewski, JD - Planner
COO/Director Compliance
DKBmed, LLC
New York, New York

Disclosures for Faculty, Course Directors, Planning Committee, and Others in a Position to Control the Content
All faculty, course directors, planning committee members, and others in a position to control the content of an educational activity are required to disclose any relevant financial relationships with a commercial interest.

The following individuals have no relevant financial relationship with a commercial interest to report in the last 12 months:
Nicholas S. Hill, MD, Sucharita R. Kher, MD, Dean Beals, Stan J. Pogroszewski, JD, Carolyn Langer, MD, JD, MPH (reviewer)
Karin Pearson (TUSM OCE Staff), Jennifer Besaw (TUSM OCE Staff) and Mirosleidy Tejeda (TUSM OCE Staff)

Commercial Support Received:

This program is supported by an educational grant from Sanofi Genzyme.

Target Audience:
This activity has been designed to meet the educational needs of clinicians treating patients suffering with severe asthma: pulmonologists, allergists, nurse practitioners, nurses, and pediatric pulmonologists.

Activity Goal:

Educate clinicians on the phenotypes and endotypes of severe asthma; discuss newer therapies, and treatment selection.

Learner Objectives/Outcomes - At the conclusion of the activity, learners will be able to:

  • Describe how the phenotypes and endotypes of severe asthma can be used to inform the delivery of effective treatment of this disease.
  • Explain the mechanisms of action for newly introduced or emerging biologic medications that are targeted to the specific pathophysiology of severe asthma.
  • Discuss how clinicians can practice personalized medical care by identifying and assessing biomarkers for severe asthma that guide selection of optimal therapeutic agents.
  • Demonstrate optimal shared decision-making practices with patients for managing severe asthma.

This activity is designed to address the following ACGME/ABMS competencies:
Patient care and Procedural Skills, Medical/Clinical Knowledge, and Practice-Based Learning and Improvement.

Accreditation Statement

Physicians
This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Tufts University School of Medicine (TUSM) and DKBmed, LLC. TUSM is accredited by the ACCME to provide continuing medical education for physicians.

TUSM designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Requirements for Successful Completion

To receive CE credit, participants must register, view the content, complete the evaluation, and successfully complete the post-test with a minimum score of 70%. Certificates/statements of credit will be available electronically after successful completion of the activity.

ADA/OEO Nondiscrimination Policy

Tufts University School of Medicine (TUSM) considers all applicants and activity participants without regard to race, color, national origin, age, religious creed, sex or sexual orientation. TUSM is an Equal Opportunity Employer. TUSM does not discriminate on the basis of a disability in admissions, access to treatment, or employment in their programs and activities as identified in the American with Disabilities Act.

Policy on Privacy and Confidentiality

To view the privacy policy for TUSM OCE, please see:
http://medicine.tufts.edu/Education/Continuing-Education/Privacy-and-Confidentiality-Policy

CME Questions

Please contact TUSM OCE at med-oce@tufts.edu or 617-636-6579.

Technical Help

Please contact info@dkbmed.com