Treatment of severe asthma in adolescents and adults

INTRODUCTION — 

The classification of "severe asthma," according to European Respiratory Society (ERS)/American Thoracic Society (ATS) criteria, refers to patients who require high-dose inhaled glucocorticoid (GC) plus a second controller or continuous or near continuous oral GC treatment to maintain asthma control and those who never achieve control despite that treatment (table 1) [1,2].

The evaluation of patients with severe asthma symptoms, phenotypes of severe asthma, a general overview of asthma management, and a review of nonpharmacologic management are presented separately.

●(See "Evaluation of severe asthma in adolescents and adults".)

●(See "Characterizing severe asthma phenotypes".)

●(See "An overview of asthma management in children and adults".)

●(See "Trigger control to enhance asthma management".)

Treatment issues that pertain to adolescents and adults with severe asthma are covered here. Initiating treatment for patients with asthma, regardless of initial symptom severity, and ongoing monitoring and titration of asthma therapies for those with nonsevere disease are covered separately.

●(See "Initiating asthma therapy and monitoring in adolescents and adults".)

●(See "Ongoing monitoring and titration of asthma therapies in adolescents and adults".)

●(See "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control".)

●(See "Asthma in children younger than 12 years: Management of persistent asthma with controller therapies".)

GENERAL TREATMENT PRINCIPLES — 

Treatment of severe asthma frequently requires a multidisciplinary approach to address patient education needs, remediate irritant and allergic triggers, treat comorbidities, and design an optimal medication regimen.

Triage — For patients with difficult-to-control or severe asthma, referral to specialist centers for further assessment leads to improved asthma control, reduced exacerbations, and decreased oral corticosteroid use [3-6]. Nevertheless, a substantial proportion of patients with uncontrolled severe asthma do not receive specialist visits or medication escalation after significant exacerbations [7]. The benefits of specialist evaluation have likely only increased in recent years with the expansion of biologic treatment options.

Patient education — A written asthma action plan is recommended for all patients with severe asthma (form 1) [8]. Either a symptom-based or peak flow-based plan may be used; although evidence shows similar benefits, patients who are poor perceivers of dyspnea may benefit from a plan based on objective measures of airflow limitation. A prescription for a short course of oral prednisone (eg, 40 mg daily for five days) can be prescribed for patients to keep on hand and to start based on specific criteria in their action plan. (See "Asthma education and self-management".)

Patients may still need to learn how to use their inhalers correctly despite a long history of asthma; each patient's technique should be observed, and the correct method should be carefully demonstrated for each type of inhaler used. The importance of adherence to inhaled medications should also be emphasized. (See "The use of inhaler devices in adults" and "Delivery of inhaled medication in adults".)

Assessing and mitigating contributing factors — Patients with difficult-to-control asthma should undergo careful assessment for treatable factors that might contribute to poor control, including environmental or pharmacologic triggers, poor medication adherence, and other medical comorbidities. This approach is similar to that used for other asthma patients with poor symptom control. (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Assessing and mitigating contributing factors'.)

●Controlling asthma triggers – Because ongoing exposure to asthma triggers is a significant cause of poor asthma control in some patients, those with uncontrolled symptoms should undergo careful assessment for potential triggers of worsening asthma, including exposure to allergens, irritants, and medications. For patients with severe asthma who have no allergic component to their disease, allergen control measures will have little to no effect. Potential triggers that are identified during evaluation (eg, pets, dust mites, workplace exposures, tobacco smoke) need renewed strategies for control (table 2). (See "Trigger control to enhance asthma management" and "Allergen avoidance in the treatment of asthma and allergic rhinitis" and "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Controlling asthma triggers'.)

●Medication adherence – Adherence to medications should be addressed at each visit in partnership with the patient [9]. There are many reasons for nonadherence. Strategies to maintain adherence can be discussed while developing the action plan. If a medication is not subjectively or objectively improving the patient's symptoms or respiratory function after a three-month trial, it should be stopped, and other options should be assessed. (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Medication adherence' and "Enhancing patient adherence to asthma therapy".)

●Treatment of comorbidities – If comorbid conditions that may influence a patient's response to asthma treatment are identified, every effort should be made to control their impact. Common comorbidities that may impact asthma include obesity, smoking or vaping, obstructive sleep apnea, allergic rhinitis, chronic sinusitis, and gastroesophageal reflux disease [10]. Ongoing smoking is a risk factor for fatal asthma. (See "Evaluation of severe asthma in adolescents and adults", section on 'Assessing comorbid conditions' and "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Comorbidities' and "Identifying patients at risk for fatal asthma", section on 'Identifying high-risk patients'.)

Alternative diagnoses and type 2 inflammatory comorbidities — Because of its high prevalence, asthma is frequently diagnosed empirically based on cough, wheezing, shortness of breath, and chest tightness without establishing evidence of reversible airway obstruction or hyperresponsiveness. For patients with highly difficult-to-control symptoms, it is imperative to reconsider whether alternative diagnoses may be the primary drivers of symptoms. (See "Evaluation of severe asthma in adolescents and adults" and "Evaluation of severe asthma in adolescents and adults", section on 'Assessing conditions that mimic asthma'.)

In addition, patients should be evaluated for other diseases associated with type 2 inflammation, as comanagement of these diseases may impact the choice of asthma treatments. These include severe atopic dermatitis, chronic rhinosinusitis with nasal polyposis, aspirin-exacerbated respiratory disease, allergic bronchopulmonary aspergillosis, eosinophilic granulomatosis with polyangiitis, and chronic eosinophilic pneumonia. For many of these conditions, improved management of extrapulmonary disease may have a salutary impact on asthma control [11].

●(See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

●(See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)

●(See "Aspirin-exacerbated respiratory disease".)

●(See "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis".)

●(See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA)".)

●(See "Chronic eosinophilic pneumonia".)

Monitoring — Once a regimen has been developed, we usually request that patients with severe asthma return for frequent follow-up visits until they are better controlled and then personalize their interval follow-up based on symptoms and exacerbation frequency. We evaluate control using standardized questions, either the Asthma Control Questionnaire (ACQ) or the Asthma Control Test (ACT) (form 2) [12-14]. Objective measures of airflow limitation (eg, peak expiratory flow [PEF], spirometry) are important; spirometry may need to be performed more frequently than in patients with milder asthma. In particular, we perform spirometry when there is a significant change in clinical status and to confirm that a step-down in medication has not caused a clinically silent decline in lung function. Spirometry may also be helpful in comparing the efficacy of various add-on controller agents. For patients with elevated type 2 inflammatory markers (blood or sputum eosinophilia, elevated fraction of exhaled nitric oxide), we typically reassess these markers after major treatment changes or if there is no improvement with therapy.

OPTIMIZING STANDARD CONTROLLER THERAPY — 

Patients with severe asthma should already be receiving controller therapy with medium- or high-dose inhaled glucocorticoids (inhaled GCs; aka, inhaled corticosteroids [ICS]) and a long-acting beta-agonist (LABA). They have also usually received a trial of long-acting muscarinic antagonists or antileukotriene agents in accordance with standard step-up therapy advised by national and international guidelines (table 3 and table 4) [8,15]. (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Patients using medium-dose ICS-LABA (Step 4)' and "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Poor control despite three maintenance agents (Step 5)'.)

Explanations for persistent symptoms despite high-dose combination therapy include residual inflammation that is relatively GC resistant, remodeling (not inflammation) resulting in airflow limitation, and inflammation in the distal airways that is not reached by the inhaled GCs. At this point, we consider the following choices in adjusting standard controller therapies:

●Escalation of inhaled glucocorticoids – Inhaled GCs have broad anti-inflammatory effects in asthma and are effective in many patients with severe asthma [8,15-17]. They have been shown to reduce asthma symptoms; improve peak expiratory flow (PEF), spirometry, and quality of life; diminish airway hyperresponsiveness; and prevent or reduce the frequency of exacerbations. In those who have not had a good trial of medium-dose ICS-formoterol as maintenance and reliever therapy (MART) (table 5), we try this first as it is highly effective in most patients. (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Patients using low-dose ICS-LABA or medium-dose ICS maintenance (Step 3)' and "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Anti-inflammatory reliever therapy (AIR) to reduce exacerbations'.)

For those who require additional escalation, we support a trial of a high-potency high-dose inhaled GC when available, as fewer puffs may improve adherence. This should be accompanied by a LABA and an anti-inflammatory reliever, ideally together as MART, if available (table 5 and table 6). (See "Delivery of inhaled medication in adults".)

When asthma is not well controlled on high-dose inhaled GCs (table 6), but appears to be GC responsive, we consider a further increase in dose or use of an inhaled GC with a smaller particle size (table 7). The evidence for increasing the dose of inhaled GC above the equivalent of fluticasone 1000 mcg per day is limited; not all patients will improve with higher inhaled GC doses. As an example, a double-blind, parallel-group study of 671 patients with severe asthma demonstrated slightly greater efficacy with fluticasone 2 mg per day compared with fluticasone 1 mg per day or budesonide 1.6 mg per day [18]. Outcome measures were morning peak flow, rescue medication, daily symptom scores, and diurnal peak flow variation. However, systemic GC side effects will likely occur in this dose range.

Monitoring for GC-related side effects is appropriate for any patient receiving chronic high-dose inhaled GCs. (See "Major side effects of inhaled glucocorticoids".)

●Substituting a third controller agent or adding a fourth controller agent – Evidence in favor of tiotropium or antileukotriene therapies as add-on therapy for patients poorly controlled despite medium-dose ICS-LABA is covered in detail separately. Clinical trials have not assessed the use of either agent as an add-on to three-medicine background therapy. (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Patients using medium-dose ICS-LABA (Step 4)'.)

Evidence for the efficacy of leukotriene modifying agents (LTMAs) as add-on therapy in severe asthma is limited [19-22]. Based on clinical experience, antileukotrienes are most likely to be helpful in patients with aspirin-exacerbated respiratory disease or those with comorbid allergic rhinitis or other manifestations of seasonal allergies. Dosing (table 8), adverse effects, and efficacy of leukotrienes in asthma are discussed in more detail elsewhere. (See "Antileukotriene agents in the management of asthma".)

Clinical trials of add-on tiotropium in patients with poorly controlled asthma despite ICS-LABA therapies have shown minimal effects on exacerbations, modest effects on asthma control and quality of life, and significant improvements in lung function. (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Patients using medium-dose ICS-LABA (Step 4)'.)

Although only a small percentage of patients with severe asthma respond to these adjustments, it can spare this group the cost and adverse effects of alternative therapies.

MINIMIZATION OF SYSTEMIC GLUCOCORTICOIDS — 

Oral glucocorticoids (GCs) are potent and effective at controlling asthma but have substantial side effects when used for months to years [8,15,23]. When possible, we avoid maintenance oral GC therapy in favor of biologic agents.

Systemic GCs are most frequently used in the context of asthma exacerbations. However, even recurrent intermittent use of systemic GCs is associated with the development of osteoporosis, pneumonia, cardiovascular disease, cataracts, and type 2 diabetes in a dose-dependent manner [24]. Because of these and other side effects, we always try to use the lowest dose of oral GCs for the shortest duration possible. High-dose inhaled GC, long-acting beta-agonist (LABA), and other controller medications ideally form the backbone of asthma control and facilitate tapering of oral GC after exacerbations. For patients with chronic airflow limitation, a two-week trial of oral GCs may help determine the potential for reversibility and define a goal for future adjustments in inhaled GCs.

Patients with severe asthma often end up taking systemic GCs nearly every day due to frequent exacerbations and long tapers in the setting of poor asthma control. Traditionally, daily low-dose oral GCs (5 to 10 mg/day) have been used when bursts of oral GCs are required every two to three months despite high-dose inhaled GC, long-acting inhaled beta-agonist, and trials of other controller agents. However, even low doses of oral corticosteroids are associated with increased risk of comorbidities, hospitalizations, and mortality in patients with asthma [25]. This use of systemic GCs has been supplanted in many eligible patients by asthma biologics. However, cost, insurance issues, and drug availability still limit the use of these agents, and some patients may require oral GCs for slow or inadequate response to biologic therapy. Patients on chronic oral GCs need to be monitored for GC side effects. (See "Major adverse effects of systemic glucocorticoids".)

For patients already using maintenance systemic GCs, certain biologics (anti-interleukin [IL]-5/5R and anti-IL-4R) are associated in clinical trials with better systemic GC-sparing effects (algorithm 1).

When a patient has frequent exacerbations despite high doses of inhaled GCs, it is occasionally helpful to determine whether the patient's asthma is actually responsive to GCs. This can be accomplished by injecting a long-acting GC, such as triamcinolone [26]. With this approach, adherence/compliance is no longer an issue. In a randomized trial, patients with a high level of lung eosinophils, despite high-dose inhaled (and even oral) GCs, responded to 3 mL (40 mg/mL) of intramuscular triamcinolone acetonide with improved forced expiratory volume in one second (FEV₁), reduced rescue medication, and decreased lung eosinophils when assessed two weeks later [27]. Patients who respond to triamcinolone are not GC-resistant, but they are often poorly adherent or poorly steroid responsive, requiring very high doses of GCs that may be associated with substantial side effects. After intramuscular triamcinolone, the anti-inflammatory effect and hypothalamic-pituitary-adrenal suppression last about two to six weeks. It is reasonable to reassess symptom control and spirometry in three to four weeks.

Patients who fail to respond to systemic GCs may rarely have GC-resistant asthma. For clinical purposes, this is defined by an FEV₁ that is less than 75 percent of predicted and fails to improve by 15 percent after a two-week trial of oral GCs (eg, prednisone 40 mg per day). (See "Glucocorticoid resistance in asthma".)

PERSISTENTLY UNCONTROLLED SEVERE ASTHMA — 

Some patients have persistently uncontrolled asthma despite high-dose inhaled glucocorticoids (GCs) and additional controller medications. Biologic therapies targeting the underlying airway inflammation have revolutionized treatment for this group of patients. In longitudinal cohorts, approximately 80 percent of patients experience a ≥50 percent reduction in exacerbations and/or maintenance oral GCs following initiation of biologic therapy [28,29]. In one cohort, nearly one-quarter of patients achieved normal lung function, no exacerbations over 12 months, and cessation of maintenance oral GCs [28]. Nevertheless, nearly 50 percent of patients continue to experience partially uncontrolled disease after biologic initiation [29], so these medications should not be introduced as a panacea for severe disease.

Selecting among available biologic agents (anti-immunoglobulin E [anti-IgE] therapy, anti-IL-5, anti-IL-5R, anti-IL-4R, or anti-thymic stromal lymphopoietin [TSLP] treatments) depends on several clinical factors including age, serum IgE level, and type-2 asthma phenotype, as described in the following sections (table 9 and algorithm 1 and algorithm 2) [2,30-32].

For patients who cannot obtain or have not responded to biologic agents, a trial of azithromycin therapy may provide modest benefit in reduction of asthma exacerbations independent of eosinophil level. Bronchial thermoplasty (BT) may be an option for those who meet other specific criteria described below and are willing to accept the risks of the procedure. (See 'Options for those not able to receive biologics' below.)

Selecting among biologic agents — The biologic agents for severe asthma have not been compared in head-to-head trials, and indirect comparisons have shown variable results [28,33-37]. Each agent has particular indications, dosing, and side effect profiles based on clinical trials (table 9). As examples, only patients with an IgE level ≥30 international units/mL and objective evidence of atopy are candidates for omalizumab; only patients with an elevated eosinophil count (>150 cells/mL) are candidates for anti-IL-4R, anti-IL-5 or anti-IL-5R therapies; and only adults are eligible for some agents.

Beyond meeting required indications, characterizing the underlying type of inflammation or asthma phenotype helps guide the selection of therapy (algorithm 2). As an example, patients in the pivotal trials of omalizumab, dupilumab, and tezepelumab who also had an elevated fractional exhaled nitric oxide (FeNO) ≥25 ppb showed more robust responses to these agents compared with other patients in these trials [38-40]. For patients with severe asthma but without elevated FeNO or allergen-driven symptoms, tezepelumab still demonstrates efficacy [40]. Further description and characterization of severe asthma phenotypes are presented separately. (See "Characterizing severe asthma phenotypes".)

Some patients will meet criteria for more than one medication, and there is only indirect evidence to guide which agent will generate the best response. Indirect analysis of clinical trial data suggests a similar degree of effect of dupilumab and the anti-IL-5/5R agents [33]. In general, indirect comparison studies using large databases have somewhat favored dupilumab over omalizumab and anti-IL-5/5R agents in terms of exacerbation reduction [35-37,41]; however, these studies are limited in the data available for adjustment/matching and likely have residual confounding. One study also found differing results (favoring anti-IL-5 agents) for severe exacerbations compared with overall exacerbations [37]. Tezepelumab has not been in widespread use for long enough to be included in these indirect comparison studies. The choice between biologic agents is also impacted by discussions with patients regarding side effect profiles and the timing of injections (table 9).

●Work-up for biologic initiation – To help guide biologic selection, we typically perform the following work-up:

•Assess history of childhood- versus adult-onset asthma (we use onset at age >12 years to define adult onset)

•Assess sensitivity to inhaled perennial allergens by history and either skin-prick or allergen-specific blood IgE testing

•Obtain peripheral blood eosinophil count (BEC), total IgE levels, and FeNO

Repeated measurements of FeNO, BEC, or IgE may be helpful in those with low levels on a single test, as patients with intermittently elevated levels of type 2 biomarkers are common and appear to have similar exacerbation patterns as those with persistent elevations [42-45]. We also test for geographic- and travel-appropriate chronic helminthic infection, as this can complicate biologic therapy.

For patients who are already maintained on chronic oral GCs, certain biologics are more effective at reducing GC dependence over time than others (algorithm 1) [46]. Verifying the diagnosis of asthma and characterizing asthma phenotype in these patients may require discontinuing or decreasing oral GCs to unmask underlying disease features. This can be avoided if historical data prior to oral GC use are available. Some patients may also demonstrate elevated peripheral eosinophils or FeNO despite systemic GC therapy. For patients without current elevations in type 2 markers or prior phenotyping who have been on long-term systemic GCs for more than 24 months, one option is to stop or taper low-dose (5 to 10 mg) oral GCs with a plan to reevaluate as soon as symptoms significantly worsen. This can be particularly helpful if the underlying diagnosis of asthma is uncertain. Typical testing after taper includes assessment of peripheral eosinophils, FeNO, spirometry with bronchodilator reversibility, lung volumes (to assess hyperinflation and air-trapping), and (if spirometry is normal) methacholine challenge. Patients without evidence of bronchodilator reversibility or response to methacholine challenge should not receive biologic agents and should be reevaluated for alternative diagnoses.

Following this work-up, we proceed with the initial choice of biologic using the approach outlined in the algorithms and below (algorithm 2 and algorithm 1):

●Verification of persistently uncontrolled asthma – Biologic agents are indicated only for patients whose disease cannot be controlled with adherence to maximized inhaled controller therapies. In one database analysis from the United States, less than half of patients escalated to biologics met criteria for uncontrolled asthma, and over half had evidence of suboptimal maintenance medication adherence [47]. Additionally, nearly half of patients were only using the equivalent of step 2 or step 3 Global Initiative for Asthma (GINA) therapy (table 10). The risks and costs of biologic treatments do not support their use in these patients, who are highly likely to benefit from increased adherence to or intensification of inhaled therapies. We also optimize treatment interventions for comorbid conditions, such as obesity and gastroesophageal reflux disease, as these conditions worsen or mimic asthma symptom severity. (See 'General treatment principles' above and 'Optimizing standard controller therapy' above.)

●Focused therapies for those with other type 2 inflammatory comorbid diseases – Several comorbid type 2 inflammatory conditions are common in patients with asthma and may be cotreated with specific biologic agents. Biologic agents have also been found to be particularly effective for treating asthma in those with specific type 2 comorbidities (chronic rhinosinusitis and/or nasal polyposis) [48]. Assuring optimal treatment of both diseases may significantly impact biologic agent selection. Specific examples are provided below:

•Eosinophilic granulomatosis with polyangiitis (EGPA) – For patients with nonsevere EGPA, mepolizumab or benralizumab are preferred therapies in conjunction with systemic GCs. The dosing of mepolizumab for this indication is higher than for asthma alone (300 rather than 100 mg every four weeks), but it is generally well tolerated. Benralizumab is dosed every four weeks when used for EGPA. (See "Eosinophilic granulomatosis with polyangiitis: Treatment and prognosis", section on 'Nonsevere disease' and "Eosinophilic granulomatosis with polyangiitis: Treatment and prognosis", section on 'Anti-IL-5 and anti-IL-5 receptor therapies'.)

•Allergic bronchopulmonary aspergillosis (ABPA) – Asthma biologics are indicated in patients with ABPA who have recurrent exacerbations or inability to taper off oral GCs. Anti-IL-5/5R, anti-IL-4, and anti-IgE agent use have all been described in small case series. Our authors prefer to use mepolizumab or benralizumab in those with a BEC ≥300 cells/microL and omalizumab in those with lower eosinophil levels. Further study is needed to determine the appropriate role for these biologics in ABPA and whether any of these agents interrupt the progression of bronchiectasis. (See "Treatment of allergic bronchopulmonary aspergillosis", section on 'Use of biologic agents in ABPA'.)

•Atopic dermatitis (AD) – Because the anti-IL4Ra antibody dupilumab is a first-line systemic therapy for atopic dermatitis, we strongly prefer dupilumab in any patients with severe asthma who require systemic AD treatment. Other asthma biologics are not helpful in the management of AD. (See "Treatment of atopic dermatitis (eczema)", section on 'Biologic agents' and "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults", section on 'First-line therapies'.)

•Chronic rhinosinusitis with nasal polyposis (CRS with NP) – CRS with NP is a frequent asthma comorbidity that can also be treated with biologic agents if control cannot be maintained following a course of systemic corticosteroids or sinus surgery and topical corticosteroid maintenance. When using biologic agents to treat patients with asthma and comorbid refractory CRS with NP, we typically choose dupilumab due to evidence of increased efficacy against NP. Omalizumab and mepolizumab are reasonable alternatives that have also been approved for refractory CRS with NP. Benralizumab does not improve long-term symptom scores, time to surgery, or chronic corticosteroid use in the treatment of NP [49]. Although biologic agents have not been compared directly, systematic reviews of randomized trials in patients with CRS and NP suggest that dupilumab treatment leads to the largest improvements in both patient-reported and objective measures of disease. (See "Chronic rhinosinusitis with nasal polyposis: Management and prognosis", section on 'Biologic therapies'.)

●Patients with childhood-onset asthma – For patients with persistently uncontrolled childhood-onset asthma, several studies suggest that anti-IL-5/5R therapies are less effective as a class, even in patients with elevated eosinophils [50-55]. Dupilumab demonstrates efficacy in this subgroup, although its effects are more robust in those with later onset [56]. In a post hoc analysis of tezepelumab trials, tezepelumab also demonstrated an approximately 50 percent reduction in exacerbations in participants with childhood-onset asthma [57]. Therefore, dupilumab, tezepelumab, and omalizumab are all reasonable options for these patients, with the optimal choice between them uncertain due to a lack of head-to-head comparisons.

Based on post hoc analyses, omalizumab, dupilumab, and tezepelumab have shown increased impact in patients with elevated eosinophils (≥260, ≥150, and ≥300 cells/microL, respectively) or elevated FeNO (≥19.5 or ≥25 ppb, respectively) [38,39,58,59]. In one trial, tezepelumab also showed increased efficacy in patients with higher type 2 markers (FeNO ≥25 ppb or eosinophils >450 cells/microL), but there was no differential effect based on antigen sensitivity [40]. We typically use dupilumab in patients with elevations in both markers due to its striking efficacy (approximately 70 percent reduction in exacerbation risk) in this group in the pivotal trials [39]. For patients without elevations in either marker, tezepelumab may be particularly helpful [59], even if they otherwise qualify for omalizumab. Omalizumab is also a reasonable alternative for those with established allergen-driven symptoms.

●Patients with adult-onset asthma without peripheral eosinophilia – For patients without eosinophilia who have an elevated FeNO or significant allergy-driven symptoms to suggest type 2 inflammation, tezepelumab [40] or omalizumab are reasonable options. Although off-label (in the United States), there is evidence that dupilumab may be effective in those with elevated FeNO but without eosinophilia [60].

For those without eosinophils due to chronic use of oral GCs, we often reassess after temporary tapering or discontinuation of corticosteroids, as described above, however dupilumab may be used for oral corticosteroid-dependent asthma irrespective of eosinophil level [61]. Both anti-IL4R and anti-IL-5/5R agents have shown efficacy in dose-reducing or eliminating oral GCs in those with type 2 inflammation and systemic GC-dependent disease (algorithm 1). (See 'Anti-IL-5/5R antibodies' below and 'Anti-IL-4 receptor alpha subunit antibody (dupilumab)' below.)

Among the biologic agents, tezepelumab is the only agent shown to reduce exacerbation rates in patients without either peripheral eosinophilia or allergen-driven symptoms. We use this agent preferentially in patients without signs of type 2 inflammation or for those without peripheral eosinophilia who do not qualify for omalizumab. Tezepelumab also has demonstrated efficacy in those with peripheral eosinophilia and allergen-driven disease [40,57] and is an effective agent in these settings (algorithm 2). Comparative efficacy data would be invaluable to allow more definitive guidance for the optimal use of this agent. (See 'Anti-thymic stromal lymphopoietin (tezepelumab)' below.)

●Patients with modest elevations in peripheral eosinophils (150 to 300 cells/microL) – Dupilumab is highly effective in patients with elevated eosinophils between 150 and 300 cells/microL, particularly those with an elevated FeNO [39]. In these patients with lower elevations in eosinophils, post hoc analyses demonstrated a 40 percent reduction in exacerbation risk with dupilumab treatment [33,39,62]. Patients who also have a FeNO ≥25 ppb are even more likely to benefit. Tezepelumab has also demonstrated an approximately 40 percent reduction in exacerbation risk in this patient population in one clinical trial [40]. In contrast, the positive data for IL-5/IL-5R agents are more convincing in patients with higher peripheral eosinophils (≥300 eosinophils/microL); reslizumab requires even higher levels (>400 cells/microL). We therefore typically use dupilumab or tezepelumab as first-line agents in this group, with IL-5/IL-5R agents reserved for patients with adult-onset asthma and multiple treatment failures. For patients with evidence of allergen sensitization, omalizumab may also be used. (See 'Anti-IL-4 receptor alpha subunit antibody (dupilumab)' below and 'Anti-IL-5/5R antibodies' below.)

●Patients with adult-onset asthma and large elevation in peripheral eosinophils (300 to 1500 eosinophils/microL) or eosinophil-driven comorbidities – Because anti-IL-4R, anti-TSLP, anti-IL-5, and anti-IL-5R therapies are all effective for patients with adult-onset asthma whose disease is driven by type 2 eosinophilic inflammation, there is an abundance of reasonable choices for patients in this group.

Dupilumab and tezepelumab are highly effective (more than 50 percent relative risk reduction in exacerbations) in those with elevated eosinophils accompanied by an elevated FeNO (≥25 ppb) or significant allergic component of their asthma [39,40,63,64]. We typically use dupilumab or tezepelumab as first-line therapy for these patients.

For the remainder of patients with elevated eosinophils, we often use benralizumab given its eight-week dosing cycle, but there are minimal data to distinguish between the anti-IL-5/5R biologics in this group (table 9). Mepolizumab is preferred in those with some degree of NP, as benralizumab is ineffective in treating nasal polyps and reslizumab has not been well studied in NP. Due to its intravenous formulation, we typically reserve reslizumab for patients with class III or higher obesity (table 11) who may benefit from weight-based dosing or for those with persistent eosinophilia after treatment with other anti-IL-5/5R agents.

A post hoc analysis has also suggested that omalizumab effectively reduces exacerbation rates in patients with peripheral eosinophils who otherwise qualify for it based on elevated IgE levels [58]. This agent is therefore also a reasonable option for this patient population.

●Patients with hypereosinophilia (>1500 cells/microL) – Patients with this degree of severe peripheral eosinophilia should also be evaluated for specific causes of hypereosinophilia that may require alternative treatment strategies. In patients with such severe elevations in peripheral eosinophils, dupilumab should not generally be used as it may unmask and worsen EGPA. Due to their robust antieosinophilic properties, anti-IL-5/5R agents are the mainstay of asthma therapy for this group when no alternative cause is identified. (See 'Anti-IL-4 receptor alpha subunit antibody (dupilumab)' below and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

Dosing, monitoring, and efficacy of individual biologics

Anti-IL-4 receptor alpha subunit antibody (dupilumab) — Dupilumab is a fully human monoclonal antibody that binds to the alpha subunit of the IL-4 receptor. Through blockade of this receptor, dupilumab inhibits the activity of both IL-4 and IL-13, type 2 cytokines that play a key role in allergy and asthma. Dupilumab reduces asthma exacerbations, enables oral GC tapering, and improves lung function in patients with type 2 inflammation and severe asthma [39,61,65-67]. Dupilumab is approved by the United States Food and Drug Administration (FDA) for the treatment of severe eosinophilic asthma (eg, peripheral blood eosinophils ≥150/microL) in patients aged six years and older [68]; in Europe, it is approved for those six years and older with elevated eosinophils (peripheral blood eosinophils ≥150/microL) or elevated fractional exhaled nitric oxide (FeNO ≥20 ppb) [69]. (See "Pathogenesis of asthma", section on 'Th2 lymphocytes' and "Evaluation and management of severe refractory atopic dermatitis (eczema) in adults", section on 'Dupilumab'.)

●Administration and monitoring – The recommended dose of dupilumab for adolescents and adults with severe asthma is an initial 400 mg (two 200 mg subcutaneous injections), followed by 200 mg given every other week or an initial dose of 600 mg (two 300 mg injections) followed by 300 mg given every other week. The higher dose is suggested for patients with oral GC-dependent asthma or comorbid moderate to severe atopic dermatitis. Patients may self-administer injections at home after proper training and with appropriate preparations for monitoring and treatment of adverse reactions to biologic agents.

Preexisting helminth infections, such as echinococcus or strongyloidiasis, should be treated prior to initiation of dupilumab. (See "Infectious causes of peripheral eosinophilia" and "Echinococcosis: Treatment" and "Strongyloidiasis".)

We assess the response to treatment (eg, exacerbations, symptom control, lung function, adverse effects) after four to six months.

Adverse effects of dupilumab include injection site reactions (in about 15 percent) and transient eosinophilia (4 to 14 percent) with over 3000 cells/microL in many of these patients (1 to 13 percent) [39,61,70,71]. Most of the eosinophilia occurred in those with high baseline eosinophil levels (>500 cells/microL) and was not associated with symptoms or discontinuation of therapy [70,71]. New systemic symptoms (eg, arthralgias, fevers, rash) while on dupilumab should prompt reassessment of peripheral eosinophil levels, as eosinophilia (>1500 cells/microL) can occur months to years after starting treatment. Development or worsening of hypereosinophilic syndrome and EGPA have been reported [66,72].

Antidrug antibody responses were noted in 2 to 5 percent of dupilumab-treated patients and in 1 to 5 percent of placebo-treated groups but did not appear to affect efficacy [39,61].

One study analyzing nearly 38,000 case reports of rare adverse reactions to dupilumab found a significant increase in risk for the development or worsening of several Th17-driven diseases [73]. Seronegative arthritis, psoriasis, enthesitis/enthesopathy, and iridocyclitis were positively associated with dupilumab use, but ankylosing spondylitis was not. The plausible theorized mechanism based on animal studies is that the IL-4/IL-13 axis may act as a restraint on Th17 (as well as Th1) responses. Inhibition of IL-4/IL-13 by dupilumab therefore may bias the immune response towards Th17-associated autoimmune conditions in patients predisposed to these diseases. Whether similar effects on Th1 inflammation occur remains to be understood.

●Impact on exacerbation rates and quality of life – In a multicenter trial, 1902 patients ages 12 years or older with poorly controlled asthma were randomly assigned to one of two add-on dupilumab doses (200 mg after a loading dose of 400 mg or 300 mg after a loading dose of 600 mg) or placebo, administered subcutaneously every two weeks for 52 weeks [39]. The annualized rates of severe exacerbations were decreased by approximately one-half in the dupilumab groups (eg, 0.46 per year [95% CI 0.39-0.53] in the 200 mg of dupilumab group compared with 0.87 [95% CI 0.72-1.05] in the placebo group). There were moderate and statistically significant increases in forced expiratory volume in one second (FEV₁; approximately 0.15 L) with both doses of dupilumab compared with placebo. In a prespecified analysis, the treatment effect was dependent on baseline BEC, with a relative reduction in exacerbation rate of 67 percent, 40 percent, and minus 4 percent among participants with a baseline BEC of ≥300/microL, 150 to 299/microL, and <150/microL, respectively. However, in a post hoc analysis, dupilumab improved asthma exacerbation rates by 69, 58, and 22 percent compared with placebo in patients with a FeNO ≥50, 25 to 50, or <25, respectively, an effect that was found to be independent of blood eosinophil level [60].

In additional post hoc analyses, dupilumab improved exacerbations equally well in patients with ≥150 eosinophils/microL regardless of whether they had an allergic asthma phenotype (elevated total and one specific IgE) [74] but had a less robust effect on exacerbation reduction in those with disease onset before age 18 years compared with those having later-onset disease [56]. Compared with placebo, there were minimal effects of dupilumab treatment on patient-reported outcomes (eg, asthma control and asthma quality of life) in the initial trial; however, a post hoc analysis reported a clinically meaningful improvement in asthma control in patients with a BEC >500/microL [75]. Safety and efficacy were durable for an additional two years beyond the initial study [76], and even patients with exacerbations on dupilumab during the randomized trial had substantial declines in subsequent exacerbations during longer-term treatment [77].

●Glucocorticoid-sparing effect – In a separate trial, 210 participants 12 years of age or older with oral GC-dependent asthma were randomly assigned to dupilumab 300 mg (after a loading dose of 600 mg) or placebo, subcutaneously, every two weeks for 24 weeks [61]. At the start of the study, the mean oral GC dose was 11 mg/day of prednisone (or equivalent, range 5 to 35 mg/day). The dose was tapered from week 4 to week 20, as tolerated, according to a predefined protocol. The oral GC dose decreased by 70 percent in the dupilumab group and by 42 percent in the placebo group; 80 percent of dupilumab-treated patients versus 50 percent of placebo-treated patients had a dose reduction of at least 50 percent. Despite the decrease in oral GC dose, the exacerbation rate was lower with dupilumab than with placebo (rate ratio [RR] 0.59, 95% CI 0.37-0.74). In a 96-week open-label extension, all participants received dupilumab for asthma control [78]. There was a sustained reduction in oral GC use for those who continued dupilumab, as well as a reduction in those who switched to dupilumab from placebo. The relatively slow oral GC wean in this extension study (compared with the rapid down-titration in the initial study) argues in favor of a more aggressive and protocolized weaning strategy after dupilumab initiation.

Anti-thymic stromal lymphopoietin (tezepelumab) — TSLP is an epithelial cell-derived cytokine that participates in asthma inflammation. Tezepelumab is a human monoclonal IG G2-lambda antibody (AMG 157) that binds TSLP and prevents its interaction with the TSLP receptor complex [79]. Tezepelumab is approved in both the United States and Europe for add-on maintenance therapy in patients with severe asthma who are ≥12 years of age [80,81].

●Administration and monitoring – The standard dose of tezepelumab is 210 mg administered subcutaneously every four weeks. A minimum baseline level of blood eosinophils or FeNO is not required. Hypersensitivity and anaphylactic reactions have been reported, including reports of delayed-onset reactions. Some regulatory agencies have approved a prefilled auto-injector device for home administration (after training on technique and with appropriate preparations for monitoring and treating adverse reactions to biologic agents) [80]. We assess the response to treatment (eg, exacerbations, symptom control, lung function, adverse effects) after four to six months.

●Impact on exacerbation rates and quality of life – Two pivotal trials demonstrated a reduction in asthma exacerbations among patients with severe asthma treated with tezepelumab:

•In one trial (PATHWAY), 550 patients with moderate to severe asthma with at least two asthma exacerbations or one exacerbation that required hospitalization in the previous year despite appropriate inhaled therapies (long-acting beta-agonist [LABA]-inhaled corticosteroids [ICS]) were assigned to placebo or one of three different doses of tezepelumab (70 mg every four weeks, 210 mg every four weeks, or 280 mg every two weeks) [64]. After 52 weeks, the tezepelumab groups all had similar decreases in exacerbation rates compared with placebo (relative decreases of 61, 71, and 66 percent, respectively). Additional analyses showed small improvements in standardized asthma symptom and quality-of-life scores and a significantly lower proportion of patients requiring emergency care (1.2 versus 3.6 percent) [82,83].

•In a subsequent trial (NAVIGATOR) that included 1059 participants (age 12 to 80 years) with severe uncontrolled asthma (618 with eosinophil count ≥300 cells/microL; 441 with eosinophil count <300 cells/microL), 210 mg of tezepelumab or placebo were administered every four weeks for 52 weeks on a background of continued inhaled controller therapy [40]. On average, tezepelumab reduced exacerbations by 1.2 per year, a 56 percent relative reduction (0.93 versus 2.1 per year with placebo, RR 0.44, 95% CI 0.37-0.53). In the tezepelumab group, 32 exacerbations were associated with emergency room or inpatient care compared with 149 in the control group (RR 0.21; 95% CI 0.12-0.37). Other secondary outcomes included small, not clinically significant improvements in asthma control and quality of life by standardized questionnaires and a modest improvement in prebronchodilator FEV₁ compared with baseline (+0.14 L mean difference between tezepelumab and placebo). These benefits were durable over an additional 52 weeks with a generally favorable safety profile [84].

•A post-hoc analysis pooling data from both trials (of 210 mg tezepelumab every four weeks versus placebo) demonstrated tezepelumab-associated reductions in asthma-associated exacerbations ranging from 37 percent in patients with both FeNO <25 ppb and BEC <150 cells/microL (0.7 versus 1.1 exacerbations per year, RR 0.63, 95% CI 0.4-1.0) to 73 percent in those with both FeNO ≥25 ppb and BEC ≥300 cells/microL (0.65 versus 2.9 exacerbations/year, RR 0.23, 95% CI 0.16-0.31) [85]. Severe exacerbations requiring emergency department visits or hospitalizations were reduced by 60 to 90 percent across FeNO and BEC subgroups and by 79 percent in the total study population (0.06 per year with tezepelumab versus 0.26 per year with placebo, RR 0.21, 95% CI 0.13-0.35). Oral GC use and allergy to perennial aeroallergen did not impact the effect on acute exacerbations. Severe adverse events were generally lower in the tezepelumab-receiving patients (9 versus 13 percent with placebo), but cardiac events were increased (0.8 versus 0.3 percent with placebo).

●Glucocorticoid-sparing effect – In a separate trial (SOURCE), 150 patients with poorly controlled moderate to severe asthma were optimized on oral GC therapy for eight weeks, assigned tezepelumab 210 mg every four weeks or placebo, and then placed on a symptom-based protocolized GC taper [86]. There was not a significant effect on oral GC reduction in the tezepelumab group compared with placebo. However, there was evidence of improved GC requirements in the prespecified subgroup of participants with a BEC ≥150 eosinophils/microL.

Anti-IL-5/5R antibodies — IL-5 is a proeosinophilic cytokine that is a potent mediator of eosinophil hematopoiesis and contributes to eosinophilic inflammation in the airways. Mepolizumab and reslizumab are anti-IL-5 monoclonal antibodies [87]; benralizumab is an anti-IL-5 receptor alpha antibody (table 9). As with other biologics agents, the response to treatment is quite heterogeneous; patients with the most robust responses to anti-IL-5 therapy are more likely to have adult-onset disease, shorter symptom duration, higher eosinophil levels, and a high fractional exhaled nitric oxide (FeNO) [88]. Earlier studies of anti-IL-5 antibodies, performed in patients with milder asthma that was not necessarily eosinophilic, did not show benefit [89-91]. (See 'Selecting among biologic agents' above.)

Mepolizumab — Mepolizumab, a monoclonal antibody to IL-5, has been found to reduce exacerbations in patients with severe asthma who have BECs of 150/microL or greater (table 9) [92-97]. Based on these data, mepolizumab is used for add-on, maintenance treatment of severe asthma in patients who are age six years or older and have an eosinophilic phenotype including an absolute BEC ≥150/microL [98,99]. However, some European regulators (and United States providers) recommend an absolute BEC ≥300/microL [98,100,101]. The eosinophil count threshold is even less clear in patients on daily systemic GCs. Mepolizumab is also approved for the treatment of chronic rhinosinusitis with NP and EGPA. (See "Aspirin-exacerbated respiratory disease", section on 'Mepolizumab' and "Eosinophilic granulomatosis with polyangiitis: Treatment and prognosis".)

●Administration and monitoring – In adolescents and adults with severe asthma, mepolizumab is administered subcutaneously into the upper arm, thigh, or abdomen, 100 mg every four weeks [102]. Prefilled safety syringes and auto-injector preparations are available for home administration in selected patients aged 12 years and older after training on the technique [103,104]. Appropriate preparations should be in place for monitoring and treatment of adverse reactions. Hypersensitivity reactions have been reported with mepolizumab. In addition, Herpes zoster infections have occurred in a small number of patients receiving mepolizumab. Based on limited data, we administer the varicella-zoster vaccine to adults aged 50 years or older four weeks prior to initiation of mepolizumab. Immunocompromised patients at risk for disseminated varicella-zoster infection (eg, due to the use of prednisone ≥20 mg/day for ≥14 days) require a different vaccination strategy. (See "Vaccination for the prevention of shingles (herpes zoster) in adults" and "Overview of infections associated with immunomodulatory (biologic) agents".)

We typically assess response in terms of symptoms, steroid-sparing effect, and exacerbation frequency at three and six months to determine whether to continue therapy. However, early assessment of asthma control or lung function changes did not predict which patients derived long-term benefit in terms of exacerbation reduction in a post hoc analysis of two large trials [105].

●Impact on exacerbation rates and quality of life – Several trials have found that mepolizumab improved outcomes among patients with severe asthma and blood or sputum eosinophilia [92-96,106-108]. A systematic review including three randomized trials (1071 participants) found that mepolizumab reduces exacerbations in patients with eosinophilic asthma (incidence RR 0.49; 95% CI 0.38-0.66; approximately 592 fewer exacerbations per 1000 patients per year) [109]. Mepolizumab also statistically improved asthma control and quality of life but did not meet the minimum clinically important difference thresholds. A separate systematic review of four studies similarly found that mepolizumab reduced exacerbation rates by approximately one-half [87].

However, a trial of mepolizumab in children and adolescents from lower-income, primarily urban environments with eosinophilic asthma (>150 eosinophils/microL, ≥2 exacerbations per year) showed an attenuated benefit from mepolizumab compared with studies in the adult population (0.96 exacerbations per year with mepolizumab versus 1.3 per year with placebo [RR 0.73, 95% CI 0.56-0.96]) [52]. Whether this lesser performance is due to ongoing environmental exposures, high non-T2 inflammation, pathophysiologic differences between childhood and adult asthma, or other differences in the overall study populations is not well understood.

●Glucocorticoid-sparing effect – In the SteroId ReductIon with mepolizUmab Study (SIRIUS), 135 patients with severe asthma and peripheral blood eosinophilia (300 eosinophils/microL during the 12 months prior to study entry or 150 eosinophils/microL during the optimization phase) despite maintenance systemic GC treatment (5 to 35 mg of prednisone or its equivalent per day) were randomly assigned to mepolizumab 100 mg or placebo administered subcutaneously every four weeks for 20 weeks [92]. The mepolizumab group achieved an approximately 50 percent reduction in maintenance GCs over 20 weeks compared with no reduction in the placebo group. Consequently, the likelihood of a reduction in the GC dose was 2.4 times greater in the mepolizumab group (95% CI 1.3-4.6). In addition, mepolizumab was associated with a decrease in the number of asthma exacerbations and improved control of asthma symptoms.

Reslizumab — Reslizumab, a monoclonal anti-IL-5 antibody, has been approved by the FDA for add-on, maintenance therapy of severe asthma in patients who are age 18 years or older and have an eosinophilic phenotype (table 9) [110,111]. In pivotal trials, an eosinophil phenotype was defined as a peripheral absolute BEC of 400/microL or greater, although the threshold required for patients on systemic GCs is not clear. In these studies, reslizumab reduced asthma exacerbations by approximately 50 percent [87,106,112].

●Administration and monitoring – Reslizumab is administered 3 mg/kg by intravenous infusion over 20 to 50 minutes in a setting prepared to handle anaphylaxis [113]. Infusions are repeated every four weeks. Based on a frequency of anaphylaxis of 0.3 percent, the FDA has placed a boxed warning recommending a period of observation after dosing. Oropharyngeal pain was the most common adverse reaction (incidence ≥2 percent).

We assess the response to treatment (eg, exacerbations, symptom control, lung function, adverse effects) after four to six months.

●Impact on exacerbation rates and quality of life – Multiple studies demonstrate evidence favoring intravenous reslizumab over placebo for eosinophilic asthma treatment [106,109,112,114-116]. A systematic review from three randomized trials (1059 participants) showed that reslizumab reduced exacerbations in patients with eosinophilic asthma (incidence RR 0.46, 95% CI 0.37-0.58; approximately 972 fewer exacerbations per 1000 patients/year) compared with standard of care [109]. Like mepolizumab, reslizumab was associated with a statistically but not clinically significant improvement in asthma control and quality-of-life measures in pivotal trials [112,114].

●Glucocorticoid-sparing effect – Data on GC-sparing effects of reslizumab are limited. Post hoc analyses of pooled data from two placebo-controlled phase III trials found 73 patients in each arm who were taking oral GCs at baseline [116]. Patients receiving reslizumab were issued fewer new systemic GC prescriptions (mean 0.5 versus 1.0 prescriptions) and received a lower total average dose over the 52-week trial (250 versus 610 mg).

Benralizumab — Benralizumab is a monoclonal antibody directed against IL-5 receptor alpha that is approved by regulatory bodies worldwide as add-on therapy in patients with severe asthma and an eosinophilic phenotype (eg, peripheral BEC ≥150 cells/microL) (table 9). In Japan and the United States, it has been approved for adults and children aged ≥6 years; in Canada and Europe, it is approved for ages ≥18 years [117-119]. Benralizumab depletes IL-5 receptor-bearing cells (eosinophils and basophils) via enhanced antibody-dependent cytolysis and also blocks IL-5 binding to its receptor [120-123]. (See "Pathogenesis of asthma", section on 'Airway inflammation'.)

●Administration and monitoring – In adolescents and adults with severe asthma, benralizumab is given subcutaneously, 30 mg every four weeks for the first three doses, and then 30 mg every eight weeks [117]. It is supplied in a prefilled syringe and should be brought to room temperature before use. A prefilled auto-injector device is approved by the FDA and European Medicines Agency (EMA) for home administration after training on technique and with appropriate preparations for monitoring and treating adverse reactions to biologic agents. Pre-existing helminth infections should be treated prior to initiating benralizumab.

We assess the response to treatment (eg, exacerbations, symptom control, lung function, adverse effects) after four to six months.

In clinical trials, benralizumab was well tolerated, and the most common adverse events were headache and pharyngitis [122,123]. Hypersensitivity reactions (anaphylaxis, angioedema, urticaria) occurred in approximately 3 percent of participants, usually within a few hours but occasionally after a few days. Hypersensitivity is a contraindication to further use. There may be an increased risk of parasitic infections or helminthiasis in endemic areas [124].

●Impact on exacerbation rates and quality of life – Three multicenter trials have demonstrated reduced exacerbation rates when benralizumab was given to patients with moderate or severe asthma [53,122,123].

•In one trial (SIROCCO), 1205 adolescent and adult patients with severe asthma and at least two exacerbations in the prior year while taking high-dose inhaled GCs and a LABA were randomly assigned to benralizumab 30 mg every four weeks, benralizumab 30 mg every eight weeks (after 30 mg every four weeks for three doses), or placebo every four weeks, given subcutaneously for 48 weeks [122]. Among those with a peripheral BEC ≥300 cells/microL, benralizumab reduced the exacerbation rate in the every-four- and every-eight-week groups (RR 0.55, 95% CI 0.42-0.71, and RR 0.49, 95% CI 0.37-0.64, respectively). In these patients, both benralizumab regimens improved prebronchodilator FEV₁ more than placebo (by 110 and 160 mL for lower and higher dose groups, respectively), and the eight-week regimen reduced asthma symptom scores by a statistically but not clinically significant degree. Among patients with peripheral BECs <300 cells/microL, the effect on exacerbations was of borderline significance.

•In another trial (CALIMA), a similar population of 1306 adolescent and adult patients with poorly controlled moderate to severe asthma received benralizumab 30 mg every four weeks, benralizumab 30 mg every eight weeks (after 30 mg every four weeks for three doses), or placebo every four weeks, given subcutaneously for 60 weeks [123]. Compared with placebo, the annual exacerbation rate among those with a peripheral eosinophil count ≥300 cells/microL decreased in the "every-four-week" benralizumab group (RR 0.64, 95% CI 0.49-0.85) and in the "every-eight-week" group (RR 0.72, 95% CI 0.54-0.95). For the smaller group of patients with lower eosinophil counts, the relative reduction in exacerbation rates was of similar magnitude but was not statistically significant. Improvements in lung function were smaller in patients with lower eosinophil counts. Benralizumab-treated patients had small but not clinically meaningful increases in quality-of-life scores.

•The multicenter ANDHI trial randomly assigned 656 adults with severe eosinophilic asthma (peripheral eosinophil count ≥150 cells/microL and ≥2 exacerbations in the prior year) to benralizumab or placebo for 24 weeks [53]. Benralizumab decreased annual asthma exacerbations compared with placebo (RR 0.51, 95% CI 0.39-0.65).

Similar results have been seen in other trials and observational studies [125-127]. Benralizumab treatment may also reduce recurrent exacerbations when started (along with prednisone) at the time of an exacerbation [128].

●Glucocorticoid-sparing effect – A GC-sparing effect with benralizumab has been found in two multicenter studies [125,126].

•In one trial (ZONDA), after a run-in phase that determined the minimum oral GC dose needed to maintain asthma control, 220 patients with severe asthma who had ≥150 eosinophils/microL in peripheral blood and required daily oral GCs for the previous six months were randomly assigned to one of three treatment arms: benralizumab 30 mg subcutaneously every four weeks, benralizumab 30 mg every four weeks for the first three doses then every eight weeks, or placebo every four weeks [125]. Oral GCs were tapered after the first four weeks according to a predetermined program (2.5 to 5 mg every four weeks, depending on symptoms). After 28 weeks, the oral GC dose decreased by 75 percent from baseline in the two benralizumab groups compared with 25 percent in the placebo group. Annualized exacerbation rates were significantly lower in the benralizumab group despite the decreased steroid dosing.

•An open-label study (PONENTE) evaluated the safety of protocolized GC withdrawal in 598 patients with oral GC-dependent asthma treated with benralizumab every four weeks for three doses and every eight weeks thereafter [126]. Oral GCs were successfully eliminated in 62 percent of patients, and another 20 percent were tapered to 5 mg or less, with continued use solely for adrenal insufficiency. Exacerbations requiring urgent medical care occurred in 6 percent; the overall exacerbation rate was 0.63 per patient annually.

These data suggest that protocolized weaning of steroids is safe and effective for patients using benralizumab.

Anti-IgE antibody (omalizumab) — The anti-IgE agent omalizumab is approved by the FDA for use in patients age six years and above with moderate to severe persistent allergic asthma, an IgE level of 30 to 700 international units/mL, positive allergen-skin or allergen-specific IgE tests to a perennial allergen, and incomplete symptom control with inhaled GC treatment (table 9) [129-132].

●Administration – Omalizumab is administered by subcutaneous injection every two to four weeks in a dose determined by body weight and the levels of serum IgE (0.016 mg/kg per international units/mL of IgE per month). A dose of 150 to 375 mg is injected subcutaneously every two to four weeks to achieve the monthly target. To prevent local reactions, no more than 150 mg is administered at a single injection site. (See "Anti-IgE therapy", section on 'Administration'.)

We typically use a three- to six-month trial before concluding benefit or lack thereof, similar to that advocated by GINA [15]. In a randomized trial (1070 participants), a composite end-point for omalizumab response (no exacerbations and one of the following: reduced symptom score, reduced usage of rescue medication, improved lung function, improved quality of life) was met at 16 weeks by 64 percent; among these, 87 percent had responded by 12 weeks [129]. (See "Anti-IgE therapy", section on 'Administration'.)

Omalizumab is available for self-administration via prefilled syringes in the United States and other countries, although supervised administration is preferred [133]. Recommended selection criteria for self-administration include the following: no prior history of anaphylaxis; successful administration of three separate doses of omalizumab in the office; ability to recognize and treat symptoms of anaphylaxis; and ability to follow prescribed dosing and proper injection technique [134]. (See "Anti-IgE therapy", section on 'Home administration' and "Overview of infections associated with immunomodulatory (biologic) agents".)

●Efficacy – Overall response rates to omalizumab (eg, reduced inhaled fluticasone dose, rescue medication use, asthma symptoms) in patients with moderate to severe asthma are variable and range from 30 to 60 percent [135]. While total IgE levels are not predictive of response, modest elevations in blood eosinophils and FeNO may identify patients more likely to experience a decrease in exacerbations with omalizumab [38]. Over long-term follow-up, treatment with omalizumab is associated with reduced hospitalizations and oral corticosteroid use [136].

In one trial, 850 patients with severe asthma, elevated IgE levels, and sensitization to perennial allergens were randomly assigned to omalizumab or placebo for 48 weeks [137]. Compared with the placebo group, those receiving omalizumab demonstrated a 25 percent reduction in exacerbations (0.66 versus 0.88 per patient; RR 0.75, 95% CI 0.6-0.9), although the 20 percent early discontinuation rate somewhat limits the results. No significant reduction in exacerbations was noted in the subgroup taking daily oral GCs. However, the lack of effect in this subgroup may be due to an insufficient sample size.

The efficacy of omalizumab and patient selection are discussed in greater detail separately. (See "Anti-IgE therapy", section on 'Efficacy' and "Anti-IgE therapy", section on 'Indications and patient selection'.)

Suboptimal response to initial biologic therapy — Patients with persistent uncontrolled asthma or continued exacerbations after a four- to six-month trial of biologic therapy may benefit from switching to an alternative biologic agent. Before switching, it is important to verify that the patient has been able to obtain and consistently use the initial biologic; poor adherence is common and can arise from personal, logistical, or pecuniary reasons [138]. When changing biologics, we typically use the same approach as with the initial biologic selection (algorithm 1 and algorithm 2), but we then select an agent with an alternative target (for which the patient meets prescribing criteria (table 9)). (See 'Selecting among biologic agents' above.)

As an exception to this approach, it may be reasonable to switch to benralizumab in those with a suboptimal response to mepolizumab. Benralizumab has repeatedly been shown to be more effective than anti-IL-5 antibody therapy in reducing eosinophil numbers, but it has yet to be determined whether this translates to greater clinical efficacy. In one small trial of patients with residual asthma symptoms and sputum eosinophilia despite anti-IL-5 antibody therapy, benralizumab treatment over nine months was effective in eliminating sputum and blood eosinophils in all patients and improving asthma symptoms in 80 percent of those treated [139]. In a separate cohort, the annualized exacerbation rate was reduced by 69 percent (0.86 versus 2.8 exacerbations/year) compared with baseline among patients who had switched to benralizumab after using mepolizumab during the baseline period [127].

There are otherwise minimal additional data to guide transitioning between biologic therapies. Clinical experience and limited observational data suggest that a substantial proportion of patients who do not respond to one type of biologic improve after switching to another agent.

Options for those not able to receive biologics — For patients with persistently uncontrolled asthma who have not responded to or cannot obtain biologic therapies, additional options include a trial of either macrolide antibiotics or BT.

Macrolide antibiotics — For patients with recurrent exacerbations associated with infections or positive sputum cultures who cannot receive biologic therapies, we suggest long-term azithromycin 250 to 500 mg three times weekly. We generally continue this indefinitely if the patient has fewer exacerbations while taking it, but we discontinue it after a six- to twelve-month trial if there is no clear improvement. Macrolide antibiotics have both antimicrobial and anti-inflammatory actions and have been found to reduce the frequency of exacerbations in patients with chronic obstructive pulmonary disease and bronchiectasis. This has raised the possibility of benefit for severe asthma, particularly in those with COPD or bronchiectasis overlap or infectious exacerbations; however, the data from randomized trials have not been entirely consistent [140-143]. Azithromycin may benefit selected patients based on the following studies:

●In a randomized trial (AMAZES), 420 adults with asthma that was poorly controlled despite therapy with an inhaled GC and a LABA were assigned to add-on therapy with azithromycin 500 mg or placebo three times weekly for 48 weeks [144]. Azithromycin decreased the rate of exacerbations (incidence RR 0.59, 95% CI 0·47-0·74) and showed a statistical but clinically unimportant difference in asthma-related quality of life. Patients with positive sputum bacterial cultures appeared to benefit more from chronic azithromycin therapy (incidence RR 0.39). Diarrhea was more common in participants taking azithromycin (34 percent) compared with placebo (19 percent). Patients were excluded if they had a hearing impairment or QT interval prolongation.

●In a smaller trial (AZISAST), the effect of azithromycin was examined in 109 adults with severe asthma and two exacerbations or lower respiratory tract infections requiring antibiotics in the previous year [142]. Participants were randomly assigned to azithromycin 250 mg (after an initial course of 250 mg daily for five days) or placebo three times a week for 26 weeks. No significant between-group differences were noted in the rate of exacerbations or lower respiratory infections, pulmonary function, or use of rescue medication. A prespecified subgroup analysis found that azithromycin decreased exacerbations in participants with noneosinophilic asthma (blood eosinophils ≤200/microL) but increased them in those with eosinophilic asthma.

Thus, the two most significant trials of azithromycin in asthma gave somewhat conflicting results, with the larger suggesting efficacy in eosinophilic (and noneosinophilic) asthma and the smaller suggesting possible harm in the eosinophilic group. We therefore reserve therapy for patients most likely to benefit (those with exacerbations associated with recurrent infections or positive sputum cultures).

Macrolide antibiotics should be avoided in those with a significant prolongation of their QTc interval or pre-existing hearing loss, as long-term macrolide therapy causes these adverse effects. Caution and electrocardiogram monitoring are appropriate when considering use in patients receiving other QTc prolonging medications. (See "Azithromycin and clarithromycin", section on 'Adverse reactions'.)

As a separate indication for a shorter course of azithromycin therapy, some patients may develop asthma after infection with Mycoplasma or Chlamydia pneumoniae, and there is limited evidence that treatment of harbored organisms with macrolides may be helpful [145,146]. We usually prescribe clarithromycin or azithromycin for a four- to six-week trial in patients who report onset of asthma after a respiratory illness suggestive of these organisms.

Bronchial thermoplasty — BT is generally reserved for patients who are not candidates for or have not responded to an optimal controller regimen or biologic agents for asthma, meet other specific criteria described below, and are willing to accept the risks of the procedure [30].

BT refers to a technique of applying heat (via a device that delivers localized controlled radiofrequency waves) to the airways during bronchoscopy, which reduces the increased mass of airway smooth muscle associated with asthma [147-157]. Due to the risk of the procedure and the modest degree of improvement seen in clinical trials, additional data are needed regarding long-term effects and morphologic changes in the airways to determine the ideal role for BT in those with severe asthma. Thus, for patients who meet criteria for BT (table 12) (ie, poorly controlled asthma despite high-dose inhaled GCs and a LABA, nonsmoker for ≥1 year, FEV₁ ≥60 percent of predicted, no history of a life-threatening exacerbation, <3 hospitalizations in the previous 12 months, and willingness to accept the risk of an asthma exacerbation requiring hospitalization as a consequence of the procedure), we advise undergoing BT in the context of a clinical trial or registry [1,15,158]. Of note, a focused update of the National Asthma Education and Prevention Program (NAEPP) guidelines conditionally recommended against BT, citing low certainty of evidence of benefit [30].

●Procedure – The procedure typically entails three separate bronchoscopies under moderate sedation about three weeks apart. A radiofrequency controller and a specialized catheter are used to administer thermal energy (target tissue temperature 65˚C) to the airway walls. All accessible airways distal to the mainstem bronchus that are 3 to 10 mm in diameter are treated once, except those in the right middle lobe, which are left untreated due to difficulty with access.

●Approval status – The FDA has approved the marketing of the Alair Bronchial Thermoplasty System for the treatment of adults (≥18 years old) with severe asthma not well-controlled with inhaled GCs and LABAs [159]. BT has also been approved in the European Union. However, all trials of BT excluded participants with more than three exacerbations per year or an FEV₁ <50 percent of predicted, so the safety and efficacy of BT for these patients are not known.

●Efficacy – Several trials, systematic reviews, and a "real-world" study have assessed the effectiveness of BT [1,150,155,156,158,160-166]; overall, BT compared with a sham procedure does not improve asthma control or hospitalizations, but it may reduce severe exacerbations (requiring systemic GCs) [155].

•One systematic review and meta-analysis including three trials (429 participants) found improved quality of life at 12 months that did not reach clinical significance, no difference in symptoms, and no difference in pulmonary function parameters [158]. In two of the trials, patients were unblinded to the intervention, which could result in bias. Severe exacerbation rates were lower with BT in one of the two trials reporting this data (see below), but the protocols for counting exacerbations were very different and did not allow pooling of the data. There was an increase in hospitalization for respiratory events during the treatment period (8 versus 2 percent, RR 3.5, 95% CI 1.3-9.7), and no detectable change in respiratory hospitalizations in the 12 months following the procedure (5 versus 4 percent, RR 1.1, 95% CI 0.4-2.9). Conclusions were similar to those from an independently performed GRADE analysis as part of the American Thoracic Society (ATS)-European Respiratory Society (ERS) guidelines on severe asthma [1].

•In a large, double-blind trial of BT for severe asthma (Asthma Intervention Research [AIR2]), included in the meta-analysis above, 288 patients with a prebronchodilator FEV₁ ≥60 percent of predicted were randomly assigned to BT or a sham procedure [160]. Patients with a history of life-threatening asthma or three or more hospitalizations for asthma in the previous year were excluded. Overall, there was a statistically significant but not clinically meaningful improvement in asthma quality of life; a slightly higher proportion of patients in the thermoplasty group demonstrated a clinically meaningful improvement in this measure (79 versus 64 percent). Severe exacerbation rates were modestly improved between six and fifty-two weeks following treatment (0.5 versus 0.7 exacerbations per patient per year). Sixteen participants (8 percent) in the BT group required 19 hospitalizations for acute respiratory symptoms in the six-week posttreatment period compared with two control participants (2 percent) who required one hospitalization each.

In a follow-up of 162 patients who underwent BT in the AIR2 trial, the proportions of participants experiencing exacerbations or emergency department visits in years one to five were lower by 44 and 78 percent, respectively, compared with the year before BT [161]. Prebronchodilator FEV₁ values remained stable in years one to five despite an 18 percent reduction in the average daily inhaled GC dose. However, there was no control group follow-up, making comparisons difficult.

•In a subsequent "real-world" study (Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma or PAS2) [164], 190 patients treated with BT were compared with the 190 patients treated with BT in the AIR2 trial described above [160]. The PAS2 participants, compared with AIR2 participants, experienced more exacerbations (74 versus 52 percent) and hospitalizations (15.3 versus 4.2 percent) in the prior 12 months. Three years after BT, severe exacerbations, emergency department visits, and hospitalizations decreased significantly in the PAS2 participants by 45, 55, and 40 percent, respectively, comparable to the AIR2 results. However, adverse reactions, such as severe exacerbations (55.8 percent) and emergency department visits (15.8 percent), were more frequent during the treatment phase than in AIR2.

TAPERING THERAPY

Stepping down standard controller therapies — When asthma control is achieved, the first step is to taper and discontinue oral glucocorticoids (GCs). Reducing the dose of other controller medications is based on perceived efficacy, presence of adverse effects, patient preference, and cost considerations.

●Tapering oral glucocorticoids – Protocols for reducing maintenance systemic GCs vary and usually involve discussing risks and benefits with individual patients, particularly those who have used maintenance GCs for extended periods. For those using dupilumab or anti-IL-5/5R therapies, relatively rapid tapers (2.5 to 5 mg every four weeks, or 50 percent reduction over 20 weeks) were successful in the majority of patients. (See 'Anti-IL-4 receptor alpha subunit antibody (dupilumab)' above and 'Anti-IL-5/5R antibodies' above.)

●Stepping down standard controller therapies for those not on biologics – Reducing the dose of inhaled GCs may be considered in patients who achieve near-complete or complete asthma control once oral GCs have been discontinued. Guidelines for tapering inhaled GCs have not been validated, but we usually decrease by 20 to 25 percent increments at one- to three-month intervals to a medium or low dose [167]. We typically do not discontinue inhaled GCs in patients with a history of severe asthma [168]. Otherwise, this is essentially the same approach used for patients without severe asthma. (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Decreasing (stepping down) therapy'.)

●Stepping down controller therapies for those on biologics – For patients on biologic therapies who have tapered off systemic GCs and maintained good asthma control, it is reasonable to step down inhaled controller therapies to achieve lower inhaled GC doses. Some patients may tolerate anti-inflammatory reliever therapy (table 13) with only biologics as maintenance agents, but the long-term safety of this approach is uncertain.

One randomized trial examined the tapering of inhaled GC therapy in patients well-controlled on a biologic agent. In this open-label trial (SHAMAL), 125 patients with a history of severe asthma well-controlled on benralizumab and high-dose inhaled GCs were assigned to a 32-week tapering protocol of inhaled corticosteroid (ICS)-formoterol and compared with 43 similar patients maintained on benralizumab and high-dose ICS-formoterol [169]. Tapering was based on the asthma control questionnaire (ACQ) and use of as-needed ICS-formoterol; 92 percent of patients in the tapering arm successfully tapered ICS-formoterol (15 percent to medium-dose maintenance and reliever therapy [MART], 17 percent to low-dose MART, and 61 percent to as-needed ICS-formoterol). Exacerbation rates were low (≤0.15 exacerbations per year) in both groups, with only 9 percent of those in the tapering group experiencing an exacerbation during tapering. Rates of adverse and serious adverse events, including those due to asthma, were similar in the two groups, and there were no deaths in either group. However, those using the least as-needed ICS-formoterol after the taper had significant decreases in forced expiratory volume in one second (FEV₁) and increases in the fractional exhaled nitric oxide (FeNO). Thus, the safety and efficacy of tapering to as-needed ICS-formoterol in these patients with more severe asthma require further study.

Tapering biologic therapies — The best approach to tapering biologics in well-controlled patients has not yet been determined and is understudied. We cautiously extend dosing intervals in patients who have had excellent asthma control for more than a year on asthma biologics, typically in combination with the administration of step 4 or higher inhaled therapies (eg, medium-dose ICS-long-acting beta-agonist [LABA]). Those who tolerate one-third of the usual dosing frequency for over a year without significant exacerbation or worsening symptoms are good candidates for discontinuation. We return to the previous well-tolerated dosing schedule for patients who experience exacerbations or worsening symptoms.

●In one trial, 296 patients who had been receiving mepolizumab for three years were randomly assigned to placebo or continued mepolizumab and followed for 52 weeks [170]. Although 41 percent of patients remained exacerbation-free, there was a progressively increasing difference in the cumulative number of patients who experienced a clinically significant exacerbation over the course of the trial (59 versus 46 percent at week 52, odds ratio [OR] 1.99, 95% CI 1.19-3.32). There was also higher unscheduled health care resource use in the discontinuation group (66 versus 49 percent, hazard ratio [HR] 1.81, 95% CI 1.31-2.49) and more significant patient-perceived asthma worsening (68 versus 47 percent at 52 weeks) [171].

●In a separate small, open-label trial, 72 patients free from exacerbations and with low blood eosinophil counts (BECs) on anti-IL-5/5R therapies were randomly assigned to either continue treatment or receive a taper (prolonging intervals between doses, with possible cessation of therapy if prolonged intervals were well tolerated) [172]. Dosing intervals were returned to the previous step for exacerbations, decline in lung function, or BEC ≥300/microL. Although 78 percent of patients could tolerate at least one titration step, only 22 percent of patients successfully discontinued IL-5 therapy, and exacerbations were considerably more common in the titration group than in the therapy continuation group (32 versus 17 percent).

RARELY USED MEDICATIONS

●Theophylline – Oral theophylline has been used as an additional controller agent, although data are lacking regarding its efficacy when added to inhaled glucocorticoid (GC) and a long-acting beta-agonist (LABA). It is usually less efficacious than LABAs when compared head-to-head [15,173-175]. Studies of the withdrawal of theophylline from patients with severe asthma have demonstrated a high rate of asthma flares, suggesting that theophylline may play a role beyond its weak bronchodilator capacity [176]. (See "Theophylline use in asthma".)

●Chromones – Cromolyn sodium, a mast cell stabilizing medication from the chromone class (also called cromoglycates), is not effective enough to be of benefit in severe asthma and has only limited worldwide availability [8,15].

EXPERIMENTAL APPROACHES — 

Numerous novel approaches to improving control of severe asthma are under active investigation. A thorough review of this constantly evolving field is beyond our scope. However, a few promising agents include:

●Anti-IL-33 and anti-IL-33/ST2 monoclonal antibodies – IL-33 is released by several cell types, including airway epithelial and endothelial cells and mast cells, in response to cell stress or damage (eg, from exposure to viruses, tobacco smoke, air pollution, allergens) and is categorized as an "alarmin" [177]. IL-33 activates several effector cells, such as eosinophils, mast cells, basophils, innate lymphoid type 2 cells (ILC2s), and Th2 lymphocytes, thus involving both the innate and adaptive immune systems. Strategies targeting IL-33, such as itepekimab, an anti-IL-33 antibody, and astegolimab, an IL-33/ST2 receptor antibody, may be beneficial in patients with a component of nontype 2 asthma that does not respond to agents focused on type 2 cytokines.

•Itepekimab – Itepekimab, an anti-IL-33 monoclonal antibody, was evaluated in a phase 2 trial comparing four subcutaneous regimens, itepekimab (300 mg), itepekimab plus the IL-4 receptor antibody dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every two weeks for 12 weeks in 296 patients with moderate to severe asthma [178]. Events indicating a loss of asthma control occurred in 22 percent of the itepekimab group, 27 percent of the combination group, and 19 percent of the dupilumab group, compared with 41 percent of the placebo group. Monotherapy with either itepekimab or dupilumab increased the prebronchodilator forced expiratory volume in one second (FEV₁) compared with placebo, but combination therapy did not. Quality of life measures improved in all the active treatment groups.

•Astegolimab – Astegolimab is a monoclonal IgG₂ antibody that interrupts signaling between IL-33, a member of the IL-1 class of cytokines implicated in asthma, and its receptor ST2. A phase 2b multicenter randomized trial (ZENYATTA) assigned 502 adults with poorly controlled severe asthma to one of three doses of astegolimab (70, 210, or 490 mg) or placebo administered subcutaneously every four weeks [179]. Over 52 weeks of treatment, the reductions in the annualized asthma exacerbation rates with astegolimab, relative to placebo, were 43, 22, and 37 percent in the 490, 210, and 70 mg groups, respectively. Results in patients with <300 eosinophils/microL were similar to the overall group, while results in patients with ≥300 eosinophils/microL were not different from placebo.

●Anti-IL-6 monoclonal antibodies – Plasma IL-6 levels are associated with features of metabolic dysfunction (obesity, hypertension, and diabetes), lower lung function, and a history of asthma exacerbations [180]. One prospective study found a strong dose-dependent association between plasma IL-6 levels and exacerbation risk in patients with severe asthma [181]. IL-6 may promote immune dysfunction via impaired natural killer cell function and increased TH17 airway inflammation [182,183]. Whether targeting IL-6 using anti-IL-6 antibodies can improve patients with this asthma phenotype is under investigation in the National Institutes of Health-funded Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) study [184].

●Ultra-long-acting biologics – Antibodies with very high binding affinity for their targets may allow very long dosing intervals between administrations, decreasing the burden of therapy for both patients and providers. In two simultaneous placebo-controlled trials of an ultra-high affinity antibody targeting IL-5 (depemokimab), 792 adolescents or adults with at least two moderate to severe asthma exacerbations in the past year despite medium- or high-dose inhaled glucocorticoids (GCs) and a blood eosinophil count (BEC) ≥300 were randomly assigned to depemokimab (100 mg subcutaneously every six months) or placebo and followed for one year [185]. Patients receiving depemokimab demonstrated 0.51 asthma exacerbations per year, compared with 1.11 exacerbations per year in the placebo group (rate ratio [RR] 0.46, 95% CI 0.36-0.59). Severe exacerbations were very rare but also reduced (0.02 versus 0.09 exacerbations per year, RR 0.28, 95% CI 0.13-0.61). There was a small but not clinically meaningful difference in respiratory quality of life when the trials' results were pooled. Rates of adverse events were similar in the placebo and depemokimab groups, and there were no serious adverse events felt to be related to the drug.

●Inhaled biologics (aka, "nanobodies") – A promising pharmacologic advance is the development of single-domain antibodies, also known as "nanobodies," which are small antibody fragments derived from camelids or engineered through recombinant techniques. These nanobodies are stable enough to withstand aerosolization and maintain efficacy during storage, and their small size enables effective delivery to the airway epithelium [186]. A nanobody targeting human IL-4R with high affinity has shown promise in preclinical testing [187]. Additionally, an inhaled antithymic stromal lymphopoietin (TSLP) antibody fragment improved late asthmatic response (change in lung function three to seven hours after allergen challenge) in those with mild atopic asthma compared with placebo [188]. Allergen-induced sputum eosinophils were also reduced.

●Imatinib – Mast cells are long-lived tissue-dwelling hematopoietic cells that are associated with airway responsiveness and asthma disease severity. The tyrosine kinase inhibitor imatinib reduces the number of bone marrow mast cells and serum tryptase levels (which reflect the number and activation of systemic mast cells). This effect raises the possibility that imatinib may ameliorate severe asthma. In a randomized trial of 62 adults with severe asthma, imatinib (200 mg/day orally for the first two weeks, then 400 mg/day) decreased airway hyperresponsiveness compared with placebo over six months (1.7 versus 1.1 decreased doubling doses of methacholine after treatment) [189]. Serum tryptase levels decreased with imatinib more than with placebo (decrease of 2.02±2.32 versus 0.56±1.39 ng/mL). Participants treated with imatinib also experienced numerically (but not statistically significantly) fewer exacerbations, reduced airway wall thickness on computed tomography (CT) scans, higher peak flows, and better asthma control. The effectiveness of imatinib for patients with type-2 low asthma is under investigation in the National Institutes of Health-funded PrecISE study [184].

●Prostaglandin D2 receptor antagonists – Prostaglandin D2 (PGD2) is the predominant prostaglandin produced by mast cells; it is also produced by Th2 lymphocytes and dendritic cells. PGD2 acts on the PGD2 receptor 2 (DP2 receptor) present on mast cells, eosinophils, and basophils, resulting in bronchoconstriction and chemoattraction of eosinophils, among other responses. The DP2 receptor also mediates migration of Th2 lymphocytes, delays Th2 cell apoptosis, and stimulates Th2 cells to produce IL-4, IL-5, and IL-13. (See "Pathogenesis of asthma", section on 'Early- and late-phase reactions'.)

A pooled analysis of two trials of the DP2 receptor antagonist fevipiprant indicated a 22 percent reduction in exacerbation rates in patients with moderate to severe asthma compared with placebo; neither trial alone was statistically significant [190]. An initial trial of GB001, another oral antagonist, demonstrated improvements in asthma symptoms, rescue inhaler use, and time to worsening; a follow-up study suggested possible modest (30 to 35 percent) improvements in asthma control that were not statistically significant [191,192]. The suggestion of a modest clinical effect in the above trials of oral therapies may lead to further investigation of other agents in their class.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Severe asthma in adolescents and adults".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Inhaled corticosteroid medicines (The Basics)" and "Patient education: How to use your soft mist inhaler (adults) (The Basics)" and "Patient education: How to use your dry powder inhaler (adults) (The Basics)" and "Patient education: How to use your metered dose inhaler (adults) (The Basics)" and "Patient education: Asthma in adults (The Basics)" and "Patient education: Medicines for asthma (The Basics)")

●Beyond the Basics topics (see "Patient education: Asthma treatment in adolescents and adults (Beyond the Basics)" and "Patient education: Inhaler techniques in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – The American Thoracic Society (ATS) classification of "severe asthma" refers to patients who require high-dose inhaled or near-continuous oral glucocorticoid (GC) treatment to maintain asthma control (table 1). (See 'Introduction' above.)

●General treatment principles

•Asthma action plans – All patients with severe asthma should receive a written action plan; the plan may be symptom-based, peak-flow-based, or both. (See 'Patient education' above.)

•Patient education – Inhaler technique should be observed and corrected when necessary. (See 'Patient education' above.)

•Trigger evaluation and control – Exposure to asthma triggers (eg, pets, dust mites, workplace exposures, tobacco smoke) should be controlled as much as possible (table 2). However, allergen control measures will have little to no benefit in patients without an allergic component to their disease. (See 'Assessing and mitigating contributing factors' above.)

•Assessment of comorbidities – Common comorbidities that may impact asthma include obesity, smoking or vaping, obstructive sleep apnea, allergic rhinitis, chronic sinusitis, and gastroesophageal reflux disease. In particular, every effort should be made to achieve smoking cessation because ongoing smoking is a risk factor for fatal asthma. (See 'Assessing and mitigating contributing factors' above.)

Patients should be evaluated for other diseases associated with type 2 inflammation (eg, atopic dermatitis, chronic rhinosinusitis [CRS] with nasal polyposis [NP], allergic bronchopulmonary aspergilloses [ABPA], eosinophilic granulomatosis with polyangiitis [EGPA]), as comanagement of these diseases may impact the choice of asthma treatments and improve asthma control. (See 'Alternative diagnoses and type 2 inflammatory comorbidities' above.)

●Optimizing standard controller therapy

•Usual controller therapies – Patients with severe asthma should be receiving controller therapy with medium- or high-dose inhaled GCs and a long-acting beta-agonist (LABA). They have also usually received a trial of long-acting muscarinic antagonists or antileukotriene agents in accordance with standard step-up therapy advised by national and international guidelines (table 3 and table 4). (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Patients using medium-dose ICS-LABA (Step 4)' and "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Poor control despite three maintenance agents (Step 5)'.)

•Add-on therapies – In patients who do not achieve adequate control with a combination of a high-dose inhaled GC and LABA, we suggest adding or substituting an alternate controller medication (Grade 2C). Choices include an antileukotriene agent or tiotropium. The added medication should be discontinued if asthma control does not improve after a reasonable trial. (See 'Optimizing standard controller therapy' above.)

●Minimization of systemic glucocorticoids – Oral GCs are potent and effective at controlling asthma but have substantial side effects when used for months to years. When possible, we avoid maintenance oral GC therapy in favor of biologic agents. (See 'Minimization of systemic glucocorticoids' above.)

●Persistently uncontrolled asthma

•Patients with elevated type 2 markers – For patients with severe asthma not controlled with standard controller therapies who have an increased blood eosinophil count (BEC) or elevated fractional exhaled nitric oxide (FeNO) and are not receiving chronic systemic GCs, we recommend adding a biologic agent with activity against type 2 inflammation, such as anti-IgE (omalizumab), the anti-IL-5 agents (mepolizumab, benralizumab, reslizumab), anti-IL-4 subunit alpha (dupilumab), or antithymic stromal lymphopoietin (TSLP; tezepelumab), rather than oral GCs (Grade 1B). Selection among the biologic agents is guided by certain patient features (eg, age, age at asthma onset, IgE level, blood eosinophil level, comorbidities), medication administration features (frequency, availability of home administration), and medication availability (table 9 and algorithm 2). (See 'Persistently uncontrolled severe asthma' above.)

•Patients without elevated type 2 markers – For patients with severe, uncontrolled asthma who do not have evidence of type 2 inflammation and are not receiving chronic systemic GCs, we suggest adding tezepelumab rather than oral GCs or other agents (Grade 2B). Omalizumab is a reasonable alternative for those without elevated inflammatory markers but elevated IgE and sensitivity to perennial antigens. (See 'Persistently uncontrolled severe asthma' above.)

•Patients receiving chronic systemic glucocorticoids – For patients with severe, uncontrolled asthma receiving chronic oral GC therapy, we recommend dupilumab or an anti-IL-5/5R biologic to facilitate tapering of GCs rather than continuing oral GC therapy (Grade 1B). The choice of agent is guided by type 2 biomarkers, sensitivity to environmental allergens, and comorbidities (algorithm 1). (See 'Persistently uncontrolled severe asthma' above.)

•Suboptimal response to initial biologic therapy – Patients with persistent uncontrolled asthma or continued exacerbations after a four- to six-month trial of biologic therapy may benefit from a trial of an alternative biologic agent. We use the same approach as with the initial biologic selection (algorithm 1 and algorithm 2), but we then typically select an agent with an alternative target (for which the patient meets prescribing criteria (table 9)). (See 'Suboptimal response to initial biologic therapy' above.)

•Options for those not able to receive biologics

-Macrolides – For patients with recurrent exacerbations associated with infections or positive sputum cultures who cannot receive biologic therapies, we suggest a trial of chronic azithromycin treatment (Grade 2C).

-Bronchial thermoplasty – Bronchial thermoplasty (BT) involves the targeted application of heat (via radiofrequency waves) to the airways. Due to the risk of the procedure and modest improvement in asthma, we rarely use BT. Candidates should meet selection criteria (table 12) and undergo thermoplasty in the setting of a registry or clinical trial. (See 'Bronchial thermoplasty' above.)

●Tapering therapy – When asthma control is achieved, the first step is to taper and discontinue oral GCs. Reducing the dose of other controller medications is based on perceived efficacy, the presence of adverse effects, patient preference, and cost considerations. The best approach to tapering biologics in well-controlled patients receiving biologic therapies has not yet been determined and is understudied. (See 'Tapering therapy' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Sally Wenzel, MD, who contributed to earlier versions of this topic review.