Primary care of asthma: new options for severe eosinophilic asthma

Abstract

Objective: Asthma is a common heterogeneous disease characterized by airway inflammation and bronchoconstriction. Current treatment guidelines provide recommendations for categorizing disease severity, asthma control and management. This paper reviews asthma assessment in primary care and describes the pathophysiology, clinical characteristics and new targeted treatments available for patients with severe eosinophilic asthma.

Methods: A non-systematic PubMed literature search was conducted and articles, primarily from the last 5 years, were selected based on relevance to primary care practice, asthma pathophysiology and biologic therapies.

Results: Despite optimal therapy including high-dose inhaled corticosteroids (ICS), long-acting β2-agonists and tiotropium, ∼4–10% of all patients with severe asthma continue to have poor asthma control. These patients have impaired quality of life, frequent exacerbations and are exposed to the side effects of repeated courses of oral steroids. Approximately 50% of patients with severe uncontrolled asthma have eosinophilic asthma, with increased airway expression of type 2 cytokines IL-4, IL-5 and IL-13. Eosinophilic asthma is identified in primary care by having eosinophils ≥150–300 cells/μL on a complete blood count with differential.

Conclusions: A new class of agents is available for patients with moderate to severe eosinophilic asthma. Four biologic therapies – mepolizumab, reslizumab, benralizumab and dupilumab – that interfere with the regulation and activity of eosinophils have been approved by the FDA for patients with moderate to severe asthma with an eosinophilic phenotype. Primary care physicians should be familiar with these medications to explain part of the rationale for referral to specialist care and manage patient expectations for treatment.

Keywords:

• Eosinophils
• asthma
• biologics
• IL-5
• primary health care

Introduction

According to 2015 data, approximately 8% of the total US population has asthma¹. In 2014, asthma was among the 20 most common diagnoses in primary care office visits², with an expected increase worldwide³. Most patients with asthma in the US are managed by primary care physicians^4,5, highlighting the need for primary care physicians to be familiar with identification, classification and therapeutic management.

Severity and control are crucial, but separate, aspects of asthma management. Asthma control is the extent to which a patient’s asthma symptoms can be observed or have been reduced by therapy, while asthma severity refers to the level of treatment required to control symptoms and prevent exacerbations⁶. Frequent exacerbations are also a sign of uncontrolled asthma; patients with frequent exacerbations despite maximal maintenance therapy should be reassessed for control to determine why it was not achieved or was lost⁶. A patient with mild asthma may still have uncontrolled disease, and a patient with severe asthma may have good control of their symptoms. Asthma is a dynamic disease and, as such, the severity of a patient’s asthma may change over time⁶. It is therefore important to regularly assess whether current therapy is appropriate or whether modifications should be made to increase or decrease the level of intervention using structured reviews to ensure treatment optimization. Furthermore, making the correct initial diagnosis is critical: two different studies have estimated that 12% to 33% of patients diagnosed with uncontrolled asthma suffered from non-asthmatic conditions^7,8.

In 2013, the total cost of asthma in the US was estimated to be $82 billion⁹. Four to ten percent of patients with asthma are classified as severe, and they account for a disproportionate amount of health care utilization and costs^10–13. When severe asthma is uncontrolled, patients are at higher risk for serious exacerbations with subsequent decreased lung function, as well as emergency department visits and extended hospitalizations^14–16. Patients with severe uncontrolled asthma are also more likely to miss work or school because of their disease than those with less severe disease, leading to lost productivity and reduced quality of life^17,18. The hospitalization rate for patients with controlled asthma in the US is not different from those without asthma, but patients with uncontrolled asthma were hospitalized 4.5-fold more frequently and visited the emergency department 1.8-fold more often than patients without asthma¹⁹. Socioeconomic factors further complicate asthma control, as lower-income populations often have less access to regular care for chronic diseases^20,21. In addition, the burden of asthma varies country to country; for example, a structured approach to care significantly reduced the morbidity and costs associated with asthma in Finland²².

Patients with asthma have airway inflammation, bronchoconstriction, and symptoms of wheezing and shortness of breath, though the underlying pathophysiology of asthma may vary. A large number of patients with severe asthma that remains uncontrolled despite appropriate therapy with inhaled corticosteroids (ICS) have been found to have high eosinophil counts in their sputum, blood and/or bronchial biopsies^23,24. This eosinophilic phenotype of asthma accounts for approximately 5% of all asthma cases, but occurs in 30% to 50% of all patients with severe asthma^23,25. Eosinophils are a sub-type of white blood cells that migrate to defend against infections, mediate allergic response and contribute to tissue inflammation^25–27. Eosinophils contain cytoplasmic granules which, when activated, lead to the production of proinflammatory cytokines²⁸. Eosinophilic asthma is associated with a higher risk of exacerbation and worse lung function than non-eosinophilic asthma²⁹.

The goal of this paper is to review the pathophysiology, clinical characteristics and new targeted treatments available for patients with severe, uncontrolled eosinophilic asthma. All patients with severe asthma that remains uncontrolled despite appropriate first-line treatment should be referred to a specialist for further evaluation and treatment. Some patients with severe uncontrolled asthma have an eosinophilic phenotype and may be candidates for therapy with one of the new classes of biologic agents.

Methods

We conducted a non-systematic PubMed literature search for articles, primarily published in the last 5 years, relevant to primary care practice, asthma pathophysiology and biologic therapies. Articles focusing on the mechanism of eosinophilic asthma were of particular interest. In cases where more recent data were not available, we extended this search to include studies published within the last 20 years.

Results

Guideline-based identification and treatment of severe asthma

The 2018 Global Initiative for Asthma (GINA) report⁶, consistent with but updated from the 2007 National Asthma Education and Prevention Program (NAEPP) treatment guidelines³⁰, outlines a stepwise process for the treatment of asthma with increasing degrees of intervention for increasing severity of illness (Figure 1)⁶. The 2018 GINA report makes an important distinction between severity and control. Asthma may be considered uncontrolled either because of persistence of symptoms despite appropriate treatment, or due to poor adherence to therapy or use of inhaler devices. Regardless of treatment step, a patient who has experienced three or four of the following characteristics over the past month has asthma that is “uncontrolled” according to GINA: daytime symptoms more than twice per week; reliever medication (e.g. short-acting β₂-agonists) needed more than twice per week; any nighttime awakening due to asthma; any activity limitation due to asthma⁶. The occurrence of multiple exacerbations is an indicator of severe uncontrolled asthma; having ≥2 exacerbations in the previous year has been part of the inclusion criteria for clinical trials, and may be useful in clinical practice as well^31,32. In a patient with a confirmed diagnosis of asthma, asthma severity is based on the level of treatment required to maintain control of asthma symptoms and exacerbations. Patients who require Step 4 or 5 therapy (medium- or high-dose ICS/long-acting β₂-agonist [LABA]), whether or not their asthma symptoms are controlled, are considered to have “severe asthma”. The 2018 GINA report suggests that the level of treatment may need to be adjusted periodically, especially if a patient is not responding to their current treatment⁶. Similar evaluations will be crucial as expensive biologic therapies become more widely used. Furthermore, if a patient appears to have severe asthma on optimal non-biologic therapy and the disease is still uncontrolled, the initial diagnosis of asthma may require re-evaluation³³. It is possible that some patients may have other diseases that are not asthma but present with persistent asthma-like symptoms such as vocal cord dysfunction. Patients should therefore be carefully evaluated for other underlying conditions³⁴. Thus, it is essential to review and confirm an asthma diagnosis in patients with persistently uncontrolled asthma.

Figure 1. GINA stepwise asthma treatment⁶.

Asthma management requires assessment of current symptoms, adjustment of treatment accordingly and review of the response; assessment should be repeated periodically to ensure optimal treatment. GINA asthma treatment is separated into five steps, with increasing step number corresponding to increasing level of intervention.

Abbreviations. FEV₁, Forced expiratory volume in 1 s; GINA, Global Initiative for Asthma; HDM, House dust mite; ICS, Inhaled corticosteroid; IgE, Immunoglobulin-E; IL, Interleukin; LABA, Long-acting β₂-agonist; LTRA, Leukotriene receptor antagonist; OCS, Oral corticosteroid; SABA, Short-acting β₂-agonist; SLIT, Sublingual immunotherapy. *Not for children <12 years. **For children 6 to 11 years, the preferred Step 3 treatment is medium-dose ICS. †Tiotropium by mist inhaler is an add-on treatment for patients with a history of exacerbations; it is not indicated in children <12 years of age.

From Global Initiative for Asthma (GINA), ‘Global Strategy for Asthma Management and Prevention,’ (2017). Reprinted with permission from GINA, http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-prevention/

Most patients can achieve good symptom control with standard treatments including low-dose ICS alone, or combination therapy with low-dose ICS and LABA (ICS/LABA) bronchodilators (GINA Step 2–3; Figure 1)⁶. However, some patients have more severe underlying disease, and their symptoms may remain uncontrolled despite adherence to high-dose ICS and multiple classes of controller medications¹¹. Antimuscarinic agents such as tiotropium are now FDA approved and recommended by GINA for treatment of asthma as add-on therapy for patients aged ≥6  years at GINA Step 4^35–37.

In order to identify a patient with uncontrolled asthma, a number of objective measures of asthma symptoms and control have been developed to quantify a patient’s responsiveness to prescribed therapy. Lung function can be measured by spirometry, giving a forced expiratory volume in 1 s (FEV₁), and this can be done pre-bronchodilation and post-bronchodilation. FEV₁ is compared with predicted values based on the patient’s age, sex, height and ethnicity³⁸. FEV₁ alone does not define asthma and can be normal even when a patient with severe asthma is being assessed, but the 2007 NAEPP guidelines state that, in patients aged ≥12 years, reduced FEV₁ can indicate moderate (60% < FEV₁ < 80% predicted) or severe (FEV₁ < 60% predicted) asthma³⁹. A patient’s symptom control can be assessed by questionnaires such as the Asthma Control Questionnaire (ACQ)⁴⁰ or the Asthma Control Test (ACT)⁴¹, which quantify factors such as frequency of symptoms, frequency of β₂-agonist use and activity limitations⁴².

Challenges in treating patients with severe asthma in primary care

There are numerous challenges in caring for patients with asthma. Patients may be unwilling or unable to make lifestyle changes, such as avoiding triggers or stopping smoking. There may be problems with medication adherence, which contribute to poor control of asthma⁴³. An estimated 50% of patients (both adults and children) have poor adherence to taking their medications⁶. In addition, incorrect inhaler technique can result in the patient receiving an insufficient dose of medication⁴⁴. Regardless of treatment step, prior to stepping up therapy for a patient with uncontrolled asthma, it is important to determine whether lack of control is due to poor adherence, incorrect inhaler technique or easily addressable environmental exposures, and take appropriate steps to address these issues⁴⁵. Providing patients with information about asthma, a personalized asthma action plan and reinforcing proper inhaler technique over the course of multiple visits have been shown to improve control and reduce the risk of exacerbations⁴⁶.

Although GINA Step 4 therapy is effective for a large number of patients, some patients with severe disease have asthma that remains uncontrolled despite appropriate therapy⁶. Chronic or frequent intermittent oral corticosteroid (OCS) use is associated with increased risk of adverse effects, including osteoporosis and diabetes mellitus^47–49. A recent analysis of real-world data illustrates that risk is elevated even at relatively low cumulative exposure to OCS⁵⁰. Once appropriate adherence and technique have been confirmed, it is then helpful to classify asthma by phenotype in order to determine whether referral to an allergist or pulmonologist for consideration of biologics may be useful^6,51.

Immunology of asthma: the role of eosinophils

An understanding of the basic immunology and molecular mechanism contributing to the pathogenesis of asthma is important for appropriate utilization of new biologic therapies approved for the treatment of severe asthma. Type 1 and type 2 immune responses describe different pathways of the immune system that are regulated by CD4 T cells⁵². Type 1 immune responses are directed against intracellular bacteria, protozoa and viruses, and are the primary defense against infection. Type 2 immune responses are typically allergic mediated and are associated with atopic diseases such as allergic rhinitis and asthma. In Type 2 immune responses, Type 2 T helper cells secrete cytokines IL-4, IL-5 and IL-13, and stimulate type 2 immunity. Type 2 immunity is characterized by high antibody titers and eosinophilia. Recently, cells associated with the innate immune system, innate lymphoid cells, have been identified and found to occur in three lineages producing similar cytokines to T helper cells⁵³. The group 2 innate lymphoid cells (ILC2) produce the type 2 cytokines, including IL-4, IL-5 and IL-13⁵⁴.

In many patients with asthma, the molecular response of airway epithelial cells to a stimulant or trigger is through type 2 inflammation. This type of asthma has been called “type 2 high”. These patients have increased airway expression of type 2 cytokines IL-4, IL-5 and IL-13 compared with the levels typically found in a healthy control population^52,55. These cytokines have effects on many different cell types, but two pathways have emerged as particularly relevant to severe asthma. First, IL-4 and IL-13 switch on B cells to produce immunoglobulin E (IgE), which leads to degranulation of mast cells mediating allergic responses⁵⁶. Second, IL-5 promotes eosinophil maturation, differentiation and migration from the bone marrow into the lungs through binding to IL-5 receptors on the eosinophil surface^28,57,58. Thus, eosinophilic asthma is a result of type 2 inflammation^25–27. In the lungs, eosinophils contribute to ongoing inflammation and airway hyperresponsiveness, and may lead to tissue damage and airway remodeling, in patients with asthma⁵⁹. Eosinophils can also be recruited into the lungs by IL-5 and other factors associated with the allergic response to an antigen⁶⁰.

Clinical characteristics associated with eosinophilic asthma

Eosinophilic asthma is associated with increased eosinophil counts in a patient’s sputum, but sputum testing is not widely available^6,23,61. In patients with asthma, there is a correlation between sputum eosinophil counts and the amount of circulating eosinophils in the blood^62,63. Elevated eosinophil count on a peripheral blood smear may serve as a surrogate marker for sputum eosinophilia. In addition, peripheral blood eosinophil counts have been correlated with the severity of asthma exacerbations⁶⁴. Although a standard definition has not emerged, peripheral blood eosinophil counts of ≥150 cells/μL^65–67, ≥300 cells/μL^31,32,68 or ≥400 cells/μL^69,70 have been used in registration trials of biologic agents to describe eosinophilic asthma and can readily be identified in a primary care setting^69–73. Fractional exhaled nitric oxide (FeNO) is another biomarker that can indicate eosinophilic airway inflammation; FeNO >50 ppb is considered elevated in adults, whereas in children the cutoff is >35 ppb⁷⁴.

The clinical characteristics of eosinophilic asthma are shown in Table 1. After verifying adherence to GINA Step 4 or 5 therapy in patients with uncontrolled asthma, evaluating eosinophil count as a biomarker for underlying type 2 inflammation is a straightforward way to identify eosinophilic asthma, in order to determine whether the patient may potentially benefit from new biologic therapies.

Table 1. Clinical profile of late-onset eosinophilic asthma²³.

Adult onset of asthma

Equal distribution between sexes

Few or no allergies to common allergens

Elevated eosinophils in peripheral blood

At risk of severe exacerbations

Normal or moderately elevated IgE level

Low FEV1 and often persistent airflow limitation

Air trapping and dynamic hyperinflation

Chronic rhinosinusitis with nasal polyposis

Aspirin sensitivity

Good response to systemic corticosteroids

Good response to anti-IL-5 treatment

Abbreviations. FEV₁, Forced expiratory volume in 1 s; IgE, Immunoglobulin E; IL, Interleukin.

Reproduced with permission of the ^© ERS 2018. ERJ Open Res 1: 00024-2015; DOI:10.1183/23120541.00024-2015. Published 24 September 2015.

New biologic therapies for severe asthma

Four biologic therapies that interfere with the regulation and activity of eosinophils are currently FDA approved for severe asthma. Three of these therapies rely on the role of IL-5 in eosinophil maturation, migration, proliferation, differentiation and activation⁷⁵. Mepolizumab and reslizumab are humanized monoclonal antibodies against IL-5 that inhibit the binding of IL-5 to the IL-5 receptor that is expressed on the surface of both eosinophils and basophils, thereby disrupting the pathway regulating eosinophil maturation and activation, resulting in a decrease in eosinophil counts. Benralizumab is a humanized, afucosylated, monoclonal antibody against the α subunit of the IL-5 receptor. Benralizumab is unique in that the afucosylation (removal of the fucose [sugar] residue) of the antibody enhances the binding of natural killer cells to that part of the antibody, which leads to the rapid and direct depletion of both eosinophils and basophils via antibody-dependent cell-mediated cytotoxicity (ADCC)^28,75,76. Figure 2 illustrates the mechanistic difference between the anti-IL-5 agents mepolizumab/reslizumab and the anti-eosinophil agent benralizumab⁷⁶. Sputum and blood eosinophil counts are reduced following treatment with benralizumab⁷⁷, mepolizumab⁷⁸ and reslizumab⁷⁹. In a phase 1 study of benralizumab, treatment of patients with mild asthma resulted in near complete reductions in peripheral blood eosinophil counts within 24 h⁸⁰. Furthermore, airway biopsies have shown a decrease in eosinophil counts of 96% with benralizumab⁷⁷; in a separate study, eosinophil counts measured by airway biopsy were reduced by 55% with mepolizumab⁷⁸.

Figure 2. Mechanistic differences between mepolizumab/reslizumab and benralizumab⁷⁶. (A) Mepolizumab and reslizumab are monoclonal antibodies against IL-5 that prevent the binding of IL-5 to the receptor, resulting in eosinophil depletion. (B) Benralizumab is a humanized, afucosylated monoclonal antibody that binds to the α subunit of the IL-5 receptor. The absence of fucose on the Fc domain of benralizumab facilitates binding to FcgRIIIa receptors on NKs, leading to apoptosis of eosinophils (and basophils) through ADCC. The apoptosis of eosinophils does not result in the release of granule content⁹⁵. Abbreviations. ADCC, Antibody-dependent cell-mediated cytotoxicity; FcgRIIIa, Low affinity immunoglobulin-γ Fc region receptor III-α; IL, Interleukin; NK, Natural killer cell.

Republished with permission from Dove Medical Press Limited, from ‘Benralizumab: a unique IL-5 inhibitor for severe asthma,’ by Tan, Bratt, Godor, et al; Journal of Asthma and Allergy, 2016:9 71-81.

Another biologic therapy recently approved for asthma is dupilumab, a fully human monoclonal antibody against the α subunit of the IL-4 receptor that simultaneously inhibits IL-4 and IL-13 signaling⁸¹. IL-4 and IL-13 both promote IgE synthesis and recruitment of eosinophils proximally in the inflammatory cascade, leading to airway inflammation⁸². The receptor for both IL-4 and IL-13 contains an α subunit of the IL-4 receptor; dupilumab thus inhibits the binding of these cytokines to their receptors and the subsequent signaling cascade⁸². Multiple phase 3 trials have been carried out for each of the biologics, the details of which are presented in Figure 3.

Figure 3. Findings from key anti-IL-5 and anti-eosinophil studies. Phase 3 trial top-line results for anti-IL-5 and anti-eosinophil agents are summarized.

Abbreviations. ACQ-5, Asthma Control Questionnaire-5; AHR, Airway hyperresponsiveness; DB, Double-blind; EOS, Eosinophil count; FEV₁, Forced expiratory volume in 1 s; ICS, Inhaled corticosteroid; IL, Interleukin; IV, Intravenous; LABA, Long-acting β₂-agonist; OCS, Oral corticosteroid; PC, Placebo-controlled; PG, Parallel-group; Q2W, Administered every 2 weeks; Q4W, Administered every 4 weeks; Q8W, Administered every 8 weeks; SC, Subcutaneous.

Mepolizumab⁸³ is indicated for add-on maintenance treatment of patients with severe asthma (≥12 years of age) and with an eosinophilic phenotype. The safety and efficacy of mepolizumab was studied in two phase 3 randomized, double-blind, placebo-controlled trials (DREAM, MENSA) that enrolled patients with evidence of eosinophilic inflammation and a history of recurrent severe asthma exacerbations while taking high-dose ICS and another controller medication^66,68. A third phase 3 trial (SIRIUS) evaluated the ability of mepolizumab to reduce maintenance OCS dose while maintaining asthma control in patients with eosinophilic inflammation on high-dose ICS plus additional controller medications and taking maintenance OCS for ≥6 months⁶⁵.

Mepolizumab demonstrated significant reductions in annualized exacerbation rate in patients with severe eosinophilic asthma, and reduction in OCS dose in patients with severe asthma requiring maintenance OCS treatment. For the DREAM and MENSA trials, the percentage reduction in annualized exacerbation rate versus placebo ranged between 32% and 53%^66,68. In the SIRIUS trial that enrolled patients who required maintenance OCS therapy for at least 6 months prior to the study, the median percentage reduction from baseline in maintenance OCS dose was 50% for mepolizumab, compared with 0% for placebo (Figure 3)⁶⁵. Overall, the frequency of adverse events was similar between mepolizumab and placebo in these studies, and the long-term safety profile was similar to that of the initial studies throughout the additional year of mepolizumab treatment with no reports of mepolizumab-related anaphylaxis during the clinical studies⁸⁴.

Reslizumab⁸⁵ is indicated for add-on maintenance treatment of patients with severe asthma ≥18 years of age and with an eosinophilic phenotype. The safety and efficacy of reslizumab was investigated in two identical phase 3 randomized, double-blind, placebo-controlled trials that enrolled patients with evidence of eosinophilic inflammation and a history of exacerbations requiring treatment with an OCS burst while taking medium-dose ICS with or without an additional controller⁶⁹. Another phase 3 trial enrolled patients with eosinophilic asthma taking medium-dose ICS with or without an additional controller⁷⁰, and a different phase 3 trial enrolled patients taking medium-dose ICS with or without an additional controller regardless of eosinophil count⁸⁶.

Reslizumab demonstrated reductions in exacerbation frequency as well as improvements in FEV₁. Among patients with high blood eosinophil counts (≥400 cells/μL), reslizumab treatment resulted in a 54% reduction in exacerbation frequency compared with placebo⁶⁹, and resulted in improvements in FEV₁ ranging from 115 mL to 242 mL compared with placebo^69,70. The effects of reslizumab on the overall population (unselected for eosinophil count) were more modest⁸⁶. Reslizumab was generally well tolerated; rates of common adverse events with reslizumab were similar to or lower than placebo^69,70,86, although two cases of anaphylaxis were reported⁶⁹. Reslizumab was well tolerated in a 2-year extension study, with no new safety signals associated with the prolonged exposure⁸⁷.

Benralizumab⁸⁸ is indicated for the add-on maintenance treatment of patients with severe asthma ≥12 years of age, and with an eosinophilic phenotype. The safety and efficacy of benralizumab have been investigated in two phase 3 randomized, double-blind, placebo-controlled trials (SIROCCO, CALIMA) that enrolled patients with asthma with a history of exacerbations requiring an OCS burst while taking medium- or high-dose ICS and an additional controller for ≥1 year, and FEV₁ <80% predicted (<90% for patients aged 12–17 years)^31,32. A third phase 3 trial (ZONDA) enrolled patients with evidence of eosinophilic inflammation, a history of maintenance OCS use and exacerbations while taking medium- or high-dose ICS with an additional controller for ≥1 year (medium) or ≥6 months (high)⁶⁷.

Benralizumab demonstrated significant reductions in annual exacerbation rates as well as reductions in maintenance OCS dosage while maintaining asthma control. In patients on high-dosage ICS/LABA with blood eosinophil counts ≥300 cells/μL (SIROCCO and CALIMA), the percentage reduction in exacerbation rate relative to placebo ranged from 28% to 51% and lung function significantly increased from baseline by 106–159 mL (pre-bronchodilator FEV₁), compared with placebo^31,32. In patients with blood eosinophil counts ≥150 cells/μL using daily OCS for management of severe asthma (ZONDA), benralizumab resulted in a median reduction from baseline in OCS dose of 75% compared with 25% for placebo⁶⁷. Benralizumab was also associated with reductions in exacerbation rate of 55% to 70% compared with placebo in this same population⁶⁷. Overall, benralizumab was well tolerated, with similar or fewer adverse events than placebo^31,32,67. An analysis of data from the first year of the BORA long-term safety and efficacy extension study (N = 1576; treatment period, 56 weeks) found that the safety and tolerability profile of benralizumab was consistent with that observed in SIROCCO and CALIMA, and the improvements in efficacy outcomes observed with benralizumab in the placebo-controlled studies were maintained⁸⁹.

Dupilumab is indicated for add-on maintenance treatment of patients with moderate to severe asthma aged ≥12 years with an eosinophilic phenotype or OCS-dependent asthma⁹⁰. The safety and efficacy of dupilumab have been investigated in two phase 3 randomized, double-blind, placebo-controlled trials (QUEST, VENTURE). QUEST enrolled patients aged ≥12 years with asthma currently treated with medium- to high-dosage ICS plus up to two additional controllers, pre-bronchodilator FEV₁ <80% predicted (<90% for patients aged 12–17 years), ACQ-5 score ≥1.5, FEV₁ reversibility of ≥12% and 200 mL, and ≥1 exacerbation in the past year resulting in hospitalization, emergency medical care or OCS treatment for ≥3 days⁹¹. VENTURE enrolled patients aged ≥12 years with asthma currently treated with maintenance OCS for 6 months, high-dosage ICS plus a second controller for ≥3 months, pre-bronchodilator FEV₁ <80% predicted (<90% for patients aged 12–17 years), and either documented FEV₁ reversibility of ≥12% and 200 mL or airway hyperresponsiveness in the prior 12 months⁹².

In QUEST, dupilumab 200 mg reduced severe exacerbations by 47.7% compared with placebo, and by 65.8% for patients with baseline eosinophil counts ≥300 cells/μL⁹¹. The increase in FEV₁ at Week 12 was 140 mL greater than with placebo (p < .001). Patients with eosinophil counts ≥300 cells/μL had improvements in FEV₁ of 210 mL more than placebo with dupilumab 200 mg (p < .001)⁹¹. In VENTURE, 80% of patients treated with dupilumab reduced their OCS dosage by at least 50%, and 48% of patients in the dupilumab group completely discontinued OCS therapy compared with 50% and 25% in the placebo group, respectively⁹². The rate of severe exacerbations was 59% lower in the dupilumab group compared with placebo and FEV₁ increased by 220 mL. Across the two studies, dupilumab treatment resulted in transient hypereosinophilia for slightly more patients (4–14%) than placebo (0.6–1%)^91,92.

Considerations for appropriate patient selection for biologic therapy

Biologic therapies are costly, so it is important to ensure they are only prescribed for the patients who will experience the most benefit. Prior to specialist referral for consideration of biologic therapy (GINA Step 5), the diagnosis of severe uncontrolled asthma should first be confirmed (e.g. pre- and post-bronchodilator spirometry)⁶. Patients with confirmed asthma who have frequent exacerbations or persistent symptoms despite compliance with medium- to high-dosage combination therapy, with or without additional therapies of a leukotriene modifier and/or a long-acting muscarinic antagonist, or who require OCS for control of their symptoms may be candidates for biologic therapy⁹³. Patients with severe asthma who have evidence of type 2 inflammation (e.g. elevated blood or sputum eosinophil counts, elevated FeNO and elevated IgE) may be candidates for the new FDA-approved class of biologic anti-interleukin (IL) medications^23,94.

Conclusion

Patients with severe asthma that is uncontrolled on GINA Step 4 treatments (medium- to high-dose combination ICS/LABA therapy, with or without additional therapies of a leukotriene modifier and/or a long-acting muscarinic antagonist) face a higher risk of exacerbations and lower quality of life compared with patients with well controlled asthma. A new class of biologic agents, which includes mepolizumab, reslizumab, benralizumab and dupilumab, has emerged as a helpful advance in therapy for these patients. Proper identification of eosinophilic asthma defines a population of patients with severe asthma who may benefit from referral for consideration of these new biologic therapies.

Transparency

Declaration of funding

Medical writing support was provided by Katie Gersh PhD of MedErgy (Yardley, PA, USA), which was in accordance with Good Publication Practice (GPP3) guidelines and funded by AstraZeneca (Wilmington, DE, USA).

Declaration of financial/other relationships

N.S.S. has disclosed that he has participated on advisory boards for AstraZeneca, Teva, Eli Lilly, Boehringer Ingelheim, Sanofi and Janssen Pharmaceuticals; has served a speaker for AstraZeneca and Boehringer Ingelheim; and has received research support from Sanofi, AstraZeneca and Boehringer Ingelheim. No potential conflict of interest was reported by S.P.C. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Both authors were involved in the analysis and interpretation of the literature search results. Both authors participated in the development and critical review of the manuscript, provided final approval to submit for publication and agree to be accountable for all aspects of the work.

Acknowledgements

Medical writing support was provided by Katie Gersh PhD of MedErgy (Yardley, PA, USA), which was in accordance with Good Publication Practice (GPP3) guidelines and funded by AstraZeneca (Wilmington, DE, USA).