Therapeutics for severe asthma

Article information

J Korean Med Assoc. 2025;68(7):451-458

Publication date (electronic) : 2025 July 10

doi : https://doi.org/10.5124/jkma.25.0076

¹Department of Pulmonary, Allergy and Critical Care Medicine, College of Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University, Seoul, Korea

²Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea

Corresponding author: Sang-Heon Kim E-mail: sangheonkim@hanyang.ac.kr

Received 2025 May 29; Accepted 2025 July 2.

Abstract

Purpose

Although severe asthma affects fewer than 10% of patients with asthma, it accounts for a disproportionately high burden of morbidity, mortality, and healthcare costs. It is defined by persistent symptoms and frequent exacerbations despite high-step pharmacologic therapy. Patients with severe asthma also experience marked impairment in quality of life and are at increased risk of adverse effects associated with long-term systemic corticosteroid use.

Current Concepts

Asthma is now recognized as a heterogeneous disease with multiple phenotypes, among which type 2 (T2) inflammation is central in many severe cases. Recent advances have enabled the development of biologic therapies targeting key T2 pathways, including immunoglobulin E, interleukin (IL)-5, IL-5 receptor α, IL-4 receptor α, and thymic stromal lymphopoietin. The identification of biomarkers—such as elevated blood or sputum eosinophils, increased fractional exhaled nitric oxide, and allergen-driven responses—is crucial for guiding biologic selection and improving disease control.

Discussion and Conclusion

Effective management of severe asthma requires a stepwise approach: confirming the diagnosis, addressing modifiable risk factors, optimizing inhaler technique, and initiating biologic therapy according to T2 inflammation status. Conventional add-on treatments such as theophylline, leukotriene receptor antagonists, and long-acting muscarinic antagonists have shown limited efficacy and often necessitate ongoing oral corticosteroid use, with its attendant adverse effects. The introduction of biologics has significantly improved clinical outcomes, reducing exacerbation rates, enhancing symptom control and lung function, and lessening dependence on oral corticosteroids in patients with severe asthma.

Keywords: Asthma; Therapeutics; Biologics

Introduction

1. Background

Severe asthma accounts for fewer than 10% of all asthma cases [1], yet it is responsible for a disproportionate share of asthma-related healthcare expenditures and overall disease burden due to emergency department visits, hospitalizations, and medication-related adverse events [2]. Severe asthma is generally defined as a condition in which symptoms remain uncontrolled and acute exacerbations occur frequently despite high-dose inhaled corticosteroid (ICS) therapy combined with a long-acting β₂-agonist (LABA), which represents the highest step of pharmacologic treatment [3,4].

Traditional pharmacotherapy for severe asthma has focused on intensifying controller therapy by adding agents such as theophylline, leukotriene receptor antagonists (LTRAs), and long-acting muscarinic antagonists (LAMAs) to a regimen based on high-dose ICS/LABA combinations. However, the therapeutic efficacy of these add-on agents has been limited [5]. As a result, many patients require maintenance oral corticosteroids (OCSs) or receive frequent courses of systemic corticosteroids during exacerbations [6,7]. Exposure to systemic corticosteroids increases the risk of adverse effects and mortality in a dose-dependent manner, imposing substantial socioeconomic costs [8].

Although asthma is characterized by chronic airway inflammation and reversible airway obstruction, it is now recognized as a heterogeneous disease with diverse inflammatory and immunologic mechanisms. With greater understanding of asthma pathogenesis and pathophysiology, the disease is increasingly stratified into distinct phenotypes and endotypes [9]. As a result, asthma management is shifting from a uniform approach to a precision medicine strategy that targets modifiable factors specific to each patient [10]. Following the introduction of omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody, additional biologic agents targeting cytokines implicated in type 2 (T2) inflammation have recently become available for clinical use [11]. These biologics have markedly advanced the control and remission of severe asthma by reducing exacerbation frequency, improving symptom control and quality of life, and enhancing lung function.

2. Objectives

This review aims to equip clinicians and researchers with an evidence-based understanding of severe asthma. The specific goals are as follows: first, to delineate contemporary diagnostic criteria while excluding asthma mimickers; second, to summarize modifiable traits, comorbidities, and environmental triggers affecting asthma control; third, to explain pathobiologic differences between type 2 and non-type 2 phenotypes; fourth, to critically appraise currently available pharmacologic options, including high-dose inhaled therapies, long-acting bronchodilators, leukotriene modifiers, macrolides, and biologics targeting including IgE, interleukin (IL)-5, IL-5Rα, IL-4Rα, and thymic stromal lymphopoietin (TSLP); and finally, to propose phenotype-guided, patient-centered treatment algorithms aimed at achieving sustained remission.

Diagnosis of Severe Asthma

Establishing a diagnosis of severe asthma first requires confirmation that asthma is present and exclusion of diseases with similar clinical presentations, such as chronic obstructive pulmonary disease or heart failure [12]. Once asthma has been conclusively diagnosed, a comprehensive assessment of modifiable factors is essential. These include inhaler technique errors, suboptimal medication adherence, and comorbidities such as gastroesophageal reflux disease, chronic rhinosinusitis, and obstructive sleep apnea. Environmental contributors, especially exposure to inhalant allergens or occupational sensitizers, should also be identified, as should medications that can precipitate exacerbations (e.g., non-steroidal anti-inflammatory drugs), overuse of short-acting β₂-agonists, and psychosocial determinants including anxiety, depression, and social stress. Any treatable trait identified during this evaluation should be actively addressed. Simultaneously, patient education regarding proper inhaler technique should be reinforced, and non-pharmacologic interventions—including smoking cessation, regular exercise, weight management, and appropriate vaccinations—should be implemented.

If asthma remains uncontrolled on step-4 pharmacotherapy with a medium-dose ICS/LABA combination, escalation to a high-dose ICS/LABA maintenance regimen or the addition of controller agents such as a LAMA or LTRA should be considered [13]. After approximately 3 to 6 months of these intensified measures, asthma control should be reassessed. Persistent lack of control at this stage warrants a diagnosis of severe asthma and necessitates referral to an asthma specialist or a dedicated severe asthma clinic.

Type 2 Inflammatory Phenotype in Severe Asthma

Asthma develops through the interplay of genetic susceptibility and organ- and tissue-level changes that accumulate over time and interact with diverse environmental stimuli. Exposure to allergens, viruses, bacteria, fungi, and pollutants, such as tobacco smoke or fine particulate matter, influences both the onset and progression of the disease [14]. These heterogeneous triggers contribute to the broad spectrum of asthma phenotypes. With the advent of biologic agents targeting cytokines involved in T2 inflammation and immune responses, identifying the T2-inflammatory phenotype has become pivotal in the diagnosis and management of severe asthma [15].

T2 inflammation is present in approximately 80% of untreated individuals with asthma and in about 50% of those receiving therapy [16]. Although it is predominantly associated with allergic asthma, T2 inflammation can also occur in non-allergic forms of the disease [17]. In allergic asthma, dendritic cells respond to stimuli such as TSLP, activating T-helper-2 (Th2) cells. These cells secrete type 2 cytokines, including IL-4, IL-5, and IL-13, that drive eosinophil recruitment and survival, IgE production, bronchoconstriction, and mucus hypersecretion [18]. In non-allergic asthma, epithelial-derived alarmins (IL-25, IL-33, and TSLP) stimulate type 2 innate lymphoid cells (ILC2s), thereby promoting T2-mediated inflammation [19]. In patients with severe asthma, the presence of T2 inflammation is inferred from any of the following: peripheral blood eosinophils ≥150 cells/μL, exhaled nitric oxide ≥20 ppb, sputum eosinophils ≥2%, or clinical evidence of allergen-driven disease [20].

Non-T2 inflammation is less clearly defined. It typically presents as late-onset, non-allergic asthma that responds poorly to corticosteroid therapy [21] and is thought to involve T1 or T17 pathways or the activation of type 3 innate lymphoid cells (ILC3s). However, the precise pathophysiology remains to be fully elucidated [22].

Pharmacologic Management of Severe Asthma

The cornerstone of severe asthma therapy is a medium- to high-dose ICS/LABA combination, to which controller agents such as an LAMA, an LTRA, or theophylline may be added as needed [23]. Step 5 in both the Global Initiative for Asthma guideline and the Korean Asthma Management Guideline (Figure 1) marks the level at which specialist care becomes essential [13]. Both guidelines recommend referral to an asthma expert for detailed phenotypic assessment and consideration of biologic therapy [4].

Figure 1.

Stepwise treatment of asthma. Adapted from The Korean Academy of Asthma, Allergy and Clinical Immunology (KAAACI). Korean guideline for asthma 2021. KAAACI; 2021 [13]. ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; SABA, short-acting β₂-agonist; LTRA, leukotriene receptor antagonist; Ig, immunoglobulin; IL, interleukin; IL-5R, IL-5 receptor; IL-4R, IL-4 receptor; HDM, house dust mite. ^a)Patients prescribed to use a controller and a reliever medication concurrently. ^b)Consider in cases with FEV1>70%, HDM sensitization, and comorbid rhinitis. ^c)Tiotropium add-on (age≥6 years), use of ICS/LABA/LAMA (triple) combination (age≥18 years).

In patients with severe asthma characterized by pronounced T2 inflammation or an eosinophilic endotype, treatment may be intensified with high-dose ICS or with biologic agents that block T2-cytokine pathways—namely, anti-IgE, anti-IL-5/IL-5 receptor (IL-5R), anti-IL-4 receptor (IL-4R)-α, and anti-TSLP monoclonal antibodies. When biologic therapy is limited by reimbursement criteria or cost, combination regimens that include high-dose ICS, LAMA, LTRA, and low-dose azithromycin can be employed. Conversely, in the absence of T2-inflammatory evidence, clinicians should reassess diagnostic and therapeutic fundamentals and counsel patients to avoid triggers such as smoking, allergens, and irritants. Additional investigations—such as chest computed tomography, induced sputum analysis, or bronchoscopy—may be warranted, and pharmacologic options such as LAMA or low-dose azithromycin can be considered.

1. High-dose ICS/LABA

High-dose ICS/LABA therapy may be considered for adults and adolescents; however, the incremental clinical benefit from dose escalation is modest, and both local and systemic adverse effects may occur [24,25]. Local toxicities include oropharyngeal candidiasis, dysphonia, and cough due to upper-airway irritation. These adverse effects can be mitigated by administering ICS through a spacer with a pressurized metered-dose inhaler and by rinsing the mouth after inhalation. Prolonged use of high-dose ICS is associated with adrenal suppression, decreased bone mineral density, and easy bruising; the risk of adrenal suppression increases in proportion to cumulative dose and treatment duration. Although high-dose ICS slightly increases the risk of extra-vertebral fractures in older adults, its relative contribution is less than that of other fracture risk factors. No definitive association has been established between ICS use and cataract or glaucoma. In regions with a high prevalence of tuberculosis, clinicians must be aware that high-dose ICS can increase susceptibility to Mycobacterium tuberculosis infection.

2. LAMAs

LAMAs induce bronchodilation and reduce mucus secretion by antagonizing muscarinic M3 receptors on airway smooth muscle and submucosal glands [26]. They may be prescribed via a separate inhaler or as part of a single-inhaler triple-therapy formulation (ICS/LABA/LAMA). LAMAs also serve as alternative bronchodilators for patients who experience β₂-agonist–related adverse effects, such as arrhythmia or tremor. When asthma remains uncontrolled despite medium- or high-dose ICS/LABA therapy, adding a LAMA confers modest improvements in lung function and small reductions in exacerbation risk [27–29]. Before initiating a LAMA, clinicians should confirm that the patient is already receiving at least a medium-dose ICS regimen [30]. Common adverse effects include dry mouth, bitter taste, abdominal discomfort, constipation, and dysphonia.

3. LTRAs

Leukotriene-modifying agents (e.g., montelukast, pranlukast, and zafirlukast) competitively inhibit cysteinyl-leukotriene receptors. Clinical trials have shown that LTRAs provide mild bronchodilation, alleviate cough and other asthma symptoms, improve lung function, attenuate airway inflammation, and reduce the frequency of exacerbations [31,32]. For patients whose symptoms remain uncontrolled on high-dose ICS, adding an LTRA may improve overall control.

Severe adverse reactions are rare, but some individuals may experience central nervous system–related effects, such as headache, dizziness, or fatigue. Evidence regarding montelukast-associated neuropsychiatric reactions is mixed; however, reports of suicidal ideation, especially in children and adolescents, prompted the U.S. Food and Drug Administration to issue a boxed warning in March 2020 about potential mental health side effects [33,34]. Prescribers should therefore balance therapeutic benefits with these risks and involve patients and caregivers in shared decision-making.

4. Azithromycin

Thrice-weekly azithromycin may be considered for adults whose symptoms persist despite medium- or high-dose ICS/LABA therapy. Prior to initiation, sputum analysis should be performed to rule out atypical mycobacterial infection, and a baseline electrocardiogram should be obtained to assess the corrected QT interval; the potential for antimicrobial resistance must also be evaluated [35]. Gastrointestinal side effects, particularly diarrhea, are common. Randomized trials have demonstrated that in adults receiving at least medium-dose ICS/LABA, azithromycin administered for a minimum of 6 months reduces exacerbations in both eosinophilic and noneosinophilic asthma phenotypes [36–38].

5. Biologic agents targeting T2 inflammation

In patients with severe asthma exhibiting evidence of T2 inflammation, a range of biologic therapies, including anti-IgE, anti-IL-5/IL-5R, anti-IL-4Rα, and anti-TSLP monoclonal antibodies, may be considered (Figure 2) [39]. Across randomized trials and real-world studies, these agents have been shown to prevent exacerbations, improve symptoms and lung function, enhance quality of life, and reduce the need for maintenance OCS (Table 1). The ability of biologics to induce and sustain clinical remission in a substantial proportion of patients with severe asthma has intensified interest in remission as a therapeutic goal.

Figure 2.

Biologics targeting type 2 inflammation in severe asthma. Adapted from The Korean Academy of Asthma, Allergy and Clinical Immunology. Asthma and allergic diseases. 3rd ed. Yeomungak Publishing; 2023, with permission [39]. TSLP, thymic stromal lymphopoietin; IL, interleukin; IL-5R, IL-5 receptor; Th, T-helper; ILC, innate lymphoid cell; Ig, immunoglobulin.

Table 1.

Biologics for severe asthma

1) Anti-IgE antibody

Omalizumab is a monoclonal antibody that binds circulating IgE and is indicated for patients aged 6 years or older with severe allergic asthma. Eligibility depends on the total IgE level, evidence of sensitization to perennial aeroallergens, and recent exacerbation history [40]. In severe asthma, omalizumab reduces both severe exacerbations and OCS use [41]. It is administered subcutaneously every 2 to 4 weeks; dose and injection interval are determined by baseline serum IgE concentration and body weight.

2) Anti-IL-5/IL-5R antibodies

Because IL-5 is essential for eosinophil growth and survival, agents in this class reduce airway and peripheral eosinophilia in severe eosinophilic asthma. The anti-IL-5 antibodies mepolizumab, reslizumab, and benralizumab bind IL-5 directly, while benralizumab also targets IL-5Rα. (1) Mepolizumab: 100 mg subcutaneously every 4 weeks lowers severe-exacerbation rates and OCS dosage; treatment response should be assessed after at least 4 monthly injections [42]; (2) Reslizumab: 3 mg/kg intravenously every 4 weeks likewise reduces severe exacerbations [43]; (3) Benralizumab: 30 mg subcutaneously at 4-week intervals for the first 3 doses, then every 8 weeks, decreases exacerbations and permits OCS tapering [44].

3) Anti-IL-4Rα antibody

Dupilumab targets IL-4Rα, simultaneously inhibiting IL-4 and IL-13 signaling, and is used as add-on therapy in uncontrolled severe eosinophilic asthma. Steroid-dependent patients receive an initial 600 mg subcutaneous dose, followed by 300 mg every 2 weeks. Non-dependent patients receive an initial dose of 400 mg or 600 mg, followed by 200 mg or 300 mg every 2 weeks. Dupilumab reduces severe exacerbations and OCS requirements regardless of atopic status [45]. Transient eosinophilia occurs in 4% to 13% of recipients, generally resolving with at least 6 months of therapy and requiring careful monitoring.

4) Anti-TSLP antibody

Tezepelumab is a monoclonal antibody that inhibits TSLP, a key epithelial cytokine involved in early T2-inflammatory pathways. It is administered at 210 mg subcutaneously every 4 weeks in patients aged 12 years or older with severe asthma and demonstrates efficacy even when conventional T2 biomarkers are not elevated [46].

When selecting a biologic, clinicians must consider asthma control parameters (e.g., exacerbation frequency), disease phenotype, current pharmacotherapy (including OCS maintenance), comorbidities, predictive biomarkers, cost, and route of administration. Treatment response should be evaluated after a minimum of 4 months; if effective, reassessment should occur every 3 to 6 months, with a focus on tapering or discontinuing OCS whenever possible [47]. Subsequent reduction of ICS dose may be considered, but the ICS/LABA backbone should be maintained. If the response to a given biologic is inadequate, switching to an alternative T2-targeted agent or discontinuing biologic therapy is recommended.

6. OCS

When severe asthma remains uncontrolled despite high-dose ICS/LABA therapy, additional controller medications, and biologic agents, or when biologics are not feasible, maintenance OCSs may be used as a last resort. In such cases, the dose should be titrated to the lowest effective level, and cumulative annual exposure should be carefully monitored. Since the incidence of adverse effects increases with total dosage, whether for short courses during exacerbations or for long-term maintenance, clinicians must remain vigilant regarding risks such as osteoporosis, hypertension, hyperglycemia, dyslipidemia, adrenal insufficiency, cataract, glaucoma, obesity, skin atrophy, and muscle weakness [6,48].

Conclusion

Severe asthma imposes a substantial clinical and socioeconomic burden due to persistent symptoms, frequent exacerbations, intensive healthcare utilization, and treatment-related adverse effects. Patients whose disease remains uncontrolled despite high-level pharmacotherapy and correction of treatable traits require specialist evaluation, with therapeutic strategies guided primarily by the presence or absence of T2 inflammation. Biologic agents targeting IgE, IL-5/IL-5R, IL-4Rα, and TSLP have demonstrated efficacy in improving symptom control, reducing acute exacerbations, tapering OCS use, enhancing lung function, and improving quality of life. Optimal management of severe asthma, therefore, requires personalized treatment strategies, principally the judicious use of biologic therapies, tailored to each patient’s unique clinical characteristics and inflammatory phenotype.

Notes

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Funding

This paper was supported by the Korea National Institute of Health research project (project No.2025-ER1206-00).

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Biologics (brand name)	Mechanism of action	Approved age (yr)	Dosing and route of administration	Indications
Omalizumab (Xolair)	Anti-IgE	≥6	SC every 2–4 weeks depending on weight and IgE levels (150–300 mg for CSU)	Severe allergic asthma, CSU (≥12 yr), CRSwNP (≥18 yr)
Mepolizumab (Nucala)	Anti-IL-5	≥18 (≥6 by FDA)	SC 100 mg every 4 weeks (300 mg for EGPA and HES)	Severe eosinophilic asthma, EGPA (≥18 yr), HES (≥18 yr), CRSwNP (≥18 yr) (FDA)
Reslizumab (Cinquair)	Anti-IL-5	≥18	IV 3 mg/kg every 4 weeks	Severe eosinophilic asthma
Benralizumab (Fasenra)	Anti-IL-5R	≥18 (≥12 by FDA)	SC 30 mg every 4 weeks first 3 doses, then every 8 weeks	Severe eosinophilic asthma
Dupilumab (Dupixent)	Anti-IL-4R	≥12 (≥6 by FDA)	SC 200–300 mg every 2 weeks (initial dose: 400 mg or 600 mg)	Severe eosinophilic or steroid-dependent asthma, CRSwNP (≥18 y), atopic dermatitis (≥6 mo), COPD (≥18 y), eosinophilic esophagitis (≥12 yr) (FDA), prurigo nodularis (≥18 yr) (FDA)
Tezepelumab (Tezspire)	Anti-TSLP	≥12	SC 210 mg every 4 weeks	Severe asthma