Severe eosinophilic asthma (SEA) is the most common severe asthma phenotype, characterized by eosinophil-driven inflammation that leads to high exacerbation risk, decreased disease control, and progressive airway damage.1–3 Learn more about the central role of eosinophil-driven inflammation in severe asthma pathology, predictive biomarkers of disease, and treatment challenges below.
The majority of patients with severe asthma have an eosinophilic phenotype, with data from the ISAR estimating this as 83.8% of patients.2
In this study, patients most likely to have an eosinophilic phenotype (grade 3) were identified using the following clinical and biomarker features, as defined by an ISAR steering committee:2
As blood eosinophilia increases, the risk of severe exacerbations increases, disease control decreases, and lung function declines, emphasizing the central role eosinophils play in asthma pathology.3,12
Eosinophilic inflammation in tissues is also recognized as a key contributor to the pathophysiology of several diseases, including SEA.13–15
Eosinophils play a central role in driving SEA pathology, through both direct and indirect mechanisms.12 Their activation is closely linked to the airway dysfunction seen in disease.12
When activated, eosinophils orchestrate tissue dysfunction through the release of a range of cytotoxic proteins which directly damage the airway epithelium.5,12,16–18 In parallel, eosinophils secrete pro-inflammatory cytokines and growth factors which promote fibroblast activation, extracellular matrix deposition, and airway wall thickening.16,19,20 Together, these pathological changes lead to progressive loss of epithelial integrity.19,20
Elevated eosinophil levels are associated with impaired structural integrity in asthma, with significantly greater epithelial damage observed in patients with high eosinophilic asthma than in those with lower eosinophil counts.20 In addition, sputum eosinophil levels have been positively correlated with basement membrane thickness, reinforcing the association between eosinophil-driven inflammation and structural airway change.19,20
Eosinophils also drive airway mucus pathology by increasing mucus plug size and stickiness through production of CLCs and EPX, which promotes oxidant formation and cross-linking of mucus.4,16,21 This makes mucus thicker and more elastic, making it harder to clear.4,22
Activated eosinophils in the airways undergo EETosis, which results in the formation of extracellular traps, release of alarmins that increase mucus viscosity and galectin-10, which results in the formation of CLCs.22
In patients with asthma, expression of MUC5AC by epithelial cells is increased, while expression of MUC5B is decreased. Reduced expression of MUC5B has been shown to promote eosinophil survival and is hypothesized to decrease mucus clearance, while MUC5AC increases mucus plugging. MUC5AC also plays roles in allergen-induced airway hyperresponsiveness and mucous metaplasia.23,24
Mucus plugs may persist in the same lung segment for years, and are associated with reduced lung function, airflow obstruction, frequent exacerbations, and increased mortality.4,25,26
Eosinophils contribute to AHR through airway inflammation, structural remodeling, and functional changes in ASM.12 Eosinophil-derived mediators amplify type 2 inflammation, promoting epithelial injury and heightened bronchoconstrictor responses.12,27,28 Structural changes such as subepithelial fibrosis, basement membrane thickening, and increased ASM mass further reduce airway compliance and exacerbate AHR.16,20,28 In addition, eosinophils enhance ASM contractility and are associated with impaired bronchodilator responsiveness, sustaining airflow limitation and persistent symptoms in severe asthma.27–29
In addition to their direct roles in asthma pathology, eosinophils may also indirectly influence asthma pathology by promoting the activation, survival, and function of key effector cells, including T cells, B cells, neutrophils, and mast cells.5,16,17,30
For more information on the direct and indirect mechanisms of eosinophilic inflammation in pathophysiology, please visit the EOS inflammation module
Blood eosinophils are a reliable predictive biomarker of future risk and are an actionable target across patient subgroups.31
Monitoring blood eosinophils in patients with severe asthma has the potential to predict:
Blood eosinophil counts are a readily accessible and minimally invasive biomarker measurable from a simple peripheral blood sample.31 Routine monitoring of blood eosinophil count is straightforward in clinical practice and provides a practical way to assess eosinophil-driven inflammation, which may guide risk stratification and management decisions.2,31,33
Peripheral blood eosinophils have been shown to correlate with airway eosinophilic infiltration in sputum and appear to be a stronger predictor of severe exacerbation risk than total IgE, underscoring their value as a biomarker.33,34
There is some evidence to suggest that earlier intervention in SEA may be associated with a lower risk of:7,35,36
Theoretically, earlier intervention may help to disrupt the inflammatory cascade before irreversible chronic structural damage within the airways develops or before the immunological cascade becomes self-perpetuating.7,37 In contrast, when treatment is delayed until the late or severe disease stage, it becomes more reactive, often referred to as a ‘firefighting’ approach.7 By this point, airway inflammation and remodeling may already be well established, making it harder to restore normal function.7,37
Some authors theorize that eosinophils may represent a prognostic marker that offers clinicians an opportunity for earlier intervention, supporting a predict and prevent approach that aims to reduce airway remodeling and preserve lung function in severe asthma.7,14
Corticosteroids have long been central to asthma management owing to their potent anti-inflammatory effects.38 ICS are recommended for maintenance therapy, while SCS (including OCS) have historically been used for the treatment of exacerbations and patients with severe or uncontrolled disease.9,11,38,39
OCS remain widely overused in asthma care.40,41
A retrospective, descriptive analysis of Canadian claims databases that included 88377 patients with severe asthma reported:
A cross-sectional observational study using UK primary care data that involved 808 patients with severe asthma and 3975 patients with mild or moderate asthma reported that:10
The widespread use of OCS highlights the need for steroid-sparing strategies that can control severe asthma while reducing the risk of corticosteroid side effects.10,41
ICS remain a cornerstone of asthma management, with the potential to reduce symptoms, exacerbations, and asthma-related mortality.9,42 They are widely prescribed, with the majority of patients with persistent asthma receiving ICS therapy at some point during their disease course.43
Importantly, increasing ICS dose may not provide additional benefit.11 Recent estimates state that low-dose ICS (≤200 µg/day) achieves 80–90% of clinical benefit, while higher doses offer limited additional gain and are associated with an increased risk of clinically important side effects, including major CV events, arrhythmias, pulmonary embolism, and pneumonia.11,42
Reducing cumulative corticosteroid exposure, particularly OCS and, where appropriate, high-dose ICS, is an important therapeutic aim in asthma management, given the well-established risks associated with long-term steroid use.11,39,42,44
AHR, airway hyperresponsiveness; ASM, airway smooth muscle; CLC, Charcot-Leyden crystal; CV, cardiovascular; EETosis, eosinophil extracellular trap cell death; EPX, eosinophil peroxidase; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid(s); IgE, immunoglobulin E; IL, interleukin; ISAR, International Severe Asthma Registry; MUC, mucin; OCS, oral corticosteroid(s); R, receptor; SCS, systemic corticosteroid(s); SEA, severe eosinophilic asthma
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Date of preparation: July 2026
