What is the definition and management of non-eosinophilic asthma in adults with a long-standing history of poorly controlled asthma?

Definition of Non-Eosinophilic Asthma

Non-eosinophilic asthma is defined as asthma characterized by the absence of elevated blood eosinophils (<150 cells/μL) and low FeNO after ruling out other chronic obstructive airway diseases. 1

Diagnostic Criteria

Non-eosinophilic asthma requires the following features to establish the diagnosis:

• Confirmed asthma diagnosis with variable expiratory airflow limitation or airway hyperresponsiveness 1

• Absence of eosinophilic inflammation defined by:

  • Blood eosinophils <150 cells/μL 1
  • Low fractional exhaled nitric oxide (FeNO) 1
  • Sputum eosinophils <2% (when sputum analysis is available) 2, 3, 4

• Exclusion of other chronic obstructive airway diseases such as COPD, bronchiectasis, or other structural lung diseases 1

Clinical Subtypes Within Non-Eosinophilic Asthma

The non-eosinophilic phenotype is heterogeneous and can be further classified based on sputum neutrophil counts when available 4:

• Neutrophilic asthma: Elevated sputum neutrophils (typically >61%) with normal eosinophils 4, 5
• Paucigranulocytic asthma: Normal levels of both eosinophils and neutrophils in sputum 4, 6

Approximately 47-50% of patients with mild-to-moderate asthma have persistently non-eosinophilic disease, making this a substantial clinical phenotype 3, 5

Key Clinical Characteristics

Non-eosinophilic asthma demonstrates distinct features that differentiate it from eosinophilic asthma:

• Poor response to inhaled corticosteroids: This phenotype shows significantly less improvement with standard ICS therapy compared to eosinophilic asthma 2, 3, 6, 5
• Constitutes approximately 50% of severe asthma cases due to corticosteroid insensitivity 2
• Stable phenotype over time: The non-eosinophilic classification remains consistent over both short-term (4 weeks) and long-term (5 years) follow-up 4

Important Clinical Caveats

Do not confuse non-eosinophilic asthma with non-asthmatic eosinophilic bronchitis, which is an entirely different condition characterized by chronic cough, sputum eosinophilia (≥3%), but normal airway hyperresponsiveness and no variable airflow obstruction 1. Non-asthmatic eosinophilic bronchitis responds well to corticosteroids, whereas non-eosinophilic asthma does not 1, 6.

Repeated sputum measurements are critical when available, as single measurements may misclassify patients with intermittent eosinophilia as persistently non-eosinophilic 3. In the absence of sputum analysis, blood eosinophils and FeNO provide reliable surrogate markers 1.

Management Implications

Non-eosinophilic asthma represents a major therapeutic challenge because most current biologic therapies specifically target type 2 inflammation pathways (anti-IL5, anti-IL4R, anti-IgE) and are ineffective in this phenotype 2, 5. The exception is tezepelumab (anti-TSLP), which may have efficacy in non-type 2 asthma 1.

Bronchodilator responses to albuterol remain preserved in non-eosinophilic asthma, similar to eosinophilic asthma, making short-acting beta-agonists appropriate for symptom relief 3.

For patients with poorly controlled non-eosinophilic asthma, consider alternative approaches beyond standard ICS therapy, including assessment for smoking cessation, occupational exposures, obesity management, and evaluation for macrolide antibiotics in select cases 5.