What percentage of patients with severe persistent asthma have only one identifiable inflammatory phenotype (eosinophilic, neutrophilic, or paucigranulocytic)?

Inflammatory Phenotype Distribution in Severe Persistent Asthma

The majority of patients with severe persistent asthma do NOT have only one identifiable inflammatory phenotype—instead, approximately 54-64% have either mixed granulocytic inflammation (both eosinophils and neutrophils elevated) or neutrophilic inflammation alone, while only 35-46% present with isolated eosinophilic phenotype. 1, 2

Distribution of Inflammatory Phenotypes

The inflammatory landscape in severe persistent asthma is heterogeneous and frequently involves multiple granulocyte types:

In Large Cross-Sectional Studies

• Eosinophilic phenotype alone: 35% of patients 1
• Neutrophilic phenotype alone: 19% of patients 1
• Mixed granulocytic pattern (both eosinophils ≥2% and neutrophils ≥40%): 10% of patients 1
• Paucigranulocytic phenotype: The remaining patients 1

In Severe Asthma Research Program (SARP) Analysis

When examining patients with reduced lung function and severe disease characteristics, the distribution shifts dramatically:

• Over 83% of severe asthma patients had sputum neutrophilia either alone or with concurrent sputum eosinophilia 2
• Only approximately 17% or less had isolated eosinophilic or paucigranulocytic patterns 2
• The majority demonstrated neutrophil-predominant or mixed granulocytic inflammation 2

Clinical Implications of Mixed Phenotypes

Patients with combined elevated eosinophils (≥2%) and neutrophils (≥40%) represent the most severe clinical phenotype, characterized by:

• Lowest lung function measurements 3
• Increased symptoms and worse asthma control 3
• Higher healthcare utilization requirements 3
• More frequent need for oral corticosteroid maintenance (45% on average) 1
• Higher rates of severe exacerbations (approximately 3 per year) 1

Important Clinical Caveats

The "Paucigranulocytic" Phenotype May Be Misleading

• Even patients classified as paucigranulocytic asthma show significantly increased sputum eosinophils in absolute values compared to healthy subjects 4
• These patients also demonstrate increased absolute blood eosinophils compared to healthy controls 4
• This suggests paucigranulocytic asthma may represent low-grade inflammatory disease rather than truly non-inflammatory asthma 4

Phenotype Stability and Variability

• Neutrophil-dominant inflammation was reported in four studies of severe asthma where inflammatory phenotyping was performed 1
• The inflammatory pattern can vary with disease activity, exacerbations, and treatment responses 1
• Some patients with refractory asthma continue to exhibit persistent eosinophil/lymphocytic inflammation despite high-dose corticosteroids, while others demonstrate neutrophilic predominance 1

Practical Approach to Phenotyping

Blood Eosinophils as a Surrogate Marker

• A blood eosinophil cut-off of ≥220/mm³ or ≥3% can identify sputum eosinophilia ≥3% with reasonable accuracy (AUC = 0.79-0.81) 5
• Blood eosinophils ≥240/μL identify eosinophilic asthma with 64% sensitivity and 72.7% specificity 6

Limitations of Single Biomarker Approach

• Blood neutrophil counts are poorly related to sputum neutrophils and cannot reliably predict neutrophilic airway inflammation 5
• Sputum induction remains the gold standard for accurate phenotyping but is technically demanding and not routinely available 5, 6

Bottom Line for Clinical Practice

In severe persistent asthma, the concept of "one identifiable biomarker or phenotype" is clinically misleading—the majority of patients demonstrate complex, overlapping inflammatory patterns with mixed granulocytic inflammation being common. 1, 2 This heterogeneity explains why targeted biologic therapies must be carefully selected based on comprehensive phenotyping rather than assuming a single dominant inflammatory pathway. 1, 6