In an adult aged 30‑60 years with a chronic dry cough lasting >8 weeks, normal spirometry, negative methacholine (or mannitol) challenge, and induced sputum eosinophil percentage ≥3% after excluding asthma, gastro‑oesophageal reflux disease, upper‑airway cough syndrome and smoking‑related disease, how should non‑asthmatic eosinophilic bronchitis be diagnosed and managed, including first‑line inhaled corticosteroid (e.g., budesonide or fluticasone propionate) dosing, second‑line leukotriene‑receptor antagonist (montelukast) or oral prednisone use, biologic therapy (mepolizumab) considerations, and criteria for tapering therapy?

Non-Asthmatic Eosinophilic Bronchitis: Comprehensive Guide for Pulmonologists

Definition and Diagnostic Criteria

Non-asthmatic eosinophilic bronchitis (NAEB) is definitively diagnosed when a patient presents with chronic cough lasting ≥8 weeks, normal spirometry showing no variable airflow obstruction, normal airway hyperresponsiveness (methacholine PC₂₀ >16 mg/mL), and induced sputum eosinophilia ≥3% of non-squamous cells. 1, 2

The diagnosis requires all four elements simultaneously:

• Chronic cough duration: Minimum 8 weeks of persistent cough, often dry or minimally productive 1, 2
• Normal spirometry: FEV₁/FVC ratio within predicted limits with no significant bronchodilator response, confirming absence of variable airflow obstruction 1, 2
• Normal airway hyperresponsiveness: Methacholine challenge with PC₂₀ >16 mg/mL, which distinguishes NAEB from cough-variant asthma 1, 2
• Sputum eosinophilia: ≥3% eosinophils on induced sputum analysis (normal <1.1%), which is the gold standard diagnostic test 1, 2, 3

Epidemiology and Clinical Significance

NAEB accounts for 10-30% of chronic cough cases referred to specialist clinics, making it one of the most common causes of chronic cough after asthma and rhinitis. 1, 2, 3 The condition was first described in 1989 following wider application of non-invasive airway inflammation assessment. 1

Pathophysiology and Distinguishing Features

NAEB shares extensive immunopathological overlap with asthma, including similar degrees of sputum, BAL, and biopsy eosinophilia, as well as comparable basement membrane thickening. 1 However, the critical distinguishing feature is the absence of mast cell infiltration into airway smooth muscle bundles, which explains why NAEB presents with bronchitis and cough rather than airway hyperresponsiveness and variable airflow obstruction characteristic of asthma. 1, 4

Key Differentiating Features from Asthma:

Feature	NAEB	Cough-Variant Asthma	Classic Asthma
Airway hyperresponsiveness	Absent (PC₂₀ >16 mg/mL)	Present	Present
Bronchodilator response	Absent	Good	Good
Spirometry	Normal	Normal	Abnormal
Sputum eosinophilia	Always present (≥3%)	Usually present	Usually present
Mast cells in airway smooth muscle	No	Yes	Yes

1, 2

Diagnostic Workup Algorithm

Step 1: Exclude Other Causes

Before pursuing NAEB diagnosis, systematically exclude:

• Chest radiograph: Rule out structural lung disease, malignancy, infection 5, 2
• Asthma: Perform spirometry with bronchodilator testing and methacholine challenge 1, 2
• GERD: Consider empiric PPI trial, as it commonly coexists with eosinophilic airway disease 5
• Upper airway cough syndrome: Clinical assessment for rhinitis/sinusitis 1
• Smoking-related disease: Detailed smoking history 1

Step 2: Induced Sputum Analysis (Gold Standard)

Induced sputum is the definitive diagnostic test and requires same-day processing for accurate cell counts. 1, 2

Technique: 1, 2

• Pre-medicate with short-acting bronchodilator
• Inhale hypertonic saline in increasing concentrations (3% → 4% → 5%) for 5 minutes each via ultrasonic nebulizer
• Disperse expectorated sputum with mucolytic agent
• Filter through 48-μm mesh gauze to remove excess mucus
• Centrifuge filtrate to produce cytospin
• Count 400 non-squamous cells for differential

Diagnostic threshold: ≥3% eosinophils (normal <1.1%) 1, 2, 3

Alternative when sputum induction fails or is unavailable: Bronchoscopy with bronchial wash fluid or BAL showing >25% eosinophils provides comparable diagnostic information. 1, 5, 2

Step 3: Adjunctive Tests

• Fractional exhaled nitric oxide (FeNO): Often elevated in NAEB but lacks sufficient validation as standalone diagnostic tool; sputum eosinophil count remains definitive 1, 2
• Allergy skin testing: Assess for common inhaled allergens and occupational sensitizers, as exposure may be causative 1, 2, 4

Treatment Algorithm

First-Line: Inhaled Corticosteroids

The CHEST guideline recommends inhaled corticosteroids as first-choice treatment for NAEB (Grade 2B recommendation). 1

Specific dosing regimen: 5, 3, 6

• Budesonide 400 μg twice daily or equivalent (e.g., fluticasone propionate 250 μg twice daily)
• Initial treatment duration: Minimum 4 weeks
• Expected response time: Within 4 weeks of initiating therapy, with some patients responding within 6 hours to 2 weeks 5, 3

Monitoring response: 5, 3, 6

• Repeat induced sputum analysis at 2-4 weeks to confirm reduction in eosinophil count
• Expect 50-70% decrease in sputum eosinophils (from mean 40% to <5%)
• Clinical improvement in cough should parallel eosinophil reduction

Treatment duration considerations: 7

• Treatment duration is inversely correlated with relapse rate
• Longer treatment courses reduce risk of relapse
• Specific optimal duration remains unknown due to limited evidence

Second-Line: Escalation for Incomplete Response

If response to ICS is incomplete after 4 weeks, the CHEST guideline suggests stepping up the inhaled corticosteroid dose and considering a therapeutic trial of a leukotriene receptor antagonist after reconsideration of alternative causes of cough (Grade 2C recommendation). 1

Step-up approach: 1, 7

• Increase ICS dose: Double the initial dose (e.g., budesonide 800 μg twice daily)
• Add leukotriene receptor antagonist: Montelukast 10 mg once daily
• Reassess diagnosis: Ensure no missed alternative causes of cough

Third-Line: Oral Corticosteroids

For persistent disease despite optimized ICS and leukotriene receptor antagonist: 7, 4

• Oral prednisone 30 mg daily for 2 weeks
• Reserve for refractory cases
• Monitor for treatment response and consider maintenance ICS after oral steroid course

Emerging Therapy: Biologic Agents

Anti-IL-5 biologics (mepolizumab) show promise in NAEB but lack robust evidence from randomized controlled trials. 7

Consider biologic therapy in:

• Severe, refractory NAEB despite maximal ICS and oral corticosteroids
• Patients with frequent relapses requiring repeated oral corticosteroid courses
• Presence of high blood eosinophil counts (>300 cells/μL)

Important caveat: Anti-IL-5 therapy has shown limited efficacy for cough in asthma, questioning whether eosinophilic inflammation is causative or epiphenomenal. 4 Use biologics judiciously and monitor response carefully.

Tapering and Long-Term Management

Criteria for tapering ICS: 7, 6

• Complete resolution of cough for minimum 4-8 weeks
• Documented normalization of sputum eosinophil count (<3%)
• No recurrence of symptoms during observation period

Tapering strategy:

• Reduce ICS dose by 50% every 4-8 weeks
• Repeat sputum analysis at each dose reduction
• If eosinophils increase or cough recurs, return to previous effective dose

Monitoring schedule: 7

• Sputum eosinophil counts every 3-6 months during maintenance therapy
• Persistent sputum eosinophilia despite treatment predicts future relapses
• Sputum-guided therapy approach optimizes outcomes

Natural History and Prognosis

The natural history of NAEB remains incompletely characterized. 1

• Early data (10-year follow-up, n=12): Suggested NAEB is generally benign and self-limiting 1
• Larger series: Indicate the condition is rarely self-limiting and often requires ongoing treatment 1
• Progression risk: Some patients may develop asthma or COPD over time, though exact rates are uncertain 7
• Overall prognosis: Generally good with appropriate corticosteroid therapy, though some patients require long-term maintenance treatment 4

Common Pitfalls and Clinical Pearls

Pitfall #1: Failing to perform methacholine challenge

• Normal spirometry alone does not exclude asthma
• Methacholine PC₂₀ >16 mg/mL is essential to distinguish NAEB from cough-variant asthma 1, 2

Pitfall #2: Accepting peripheral blood eosinophilia as diagnostic

• Sputum eosinophilia is required for diagnosis; blood eosinophils do not correlate reliably 1, 2
• Induced sputum analysis is the gold standard and cannot be substituted 1, 2

Pitfall #3: Inadequate treatment duration

• Minimum 4 weeks of ICS required before assessing response 5, 3
• Premature discontinuation leads to high relapse rates 7

Pitfall #4: Missing occupational or allergen exposure

• Always assess for workplace sensitizers and common inhaled allergens 1, 2, 4
• Avoidance of identified triggers may be therapeutic and reduce medication requirements 2, 4

Pitfall #5: Not monitoring treatment response objectively

• Repeat sputum eosinophil count is essential to confirm treatment efficacy 5, 3, 6
• Clinical improvement without eosinophil reduction suggests alternative diagnosis or concurrent pathology 6

Evidence Quality and Guideline Limitations

The CHEST guideline acknowledges that recommendations for NAEB are based on very few therapeutic trials with small subject numbers, resulting in weak recommendations (Grade 2B-2C). 1 The evidence base is substantially weaker than for asthma management. Specific gaps include:

• Optimal ICS dose and type remain unknown 7
• Ideal treatment duration is undefined 7
• No randomized controlled trials for second-line treatments 7
• Limited data on long-term outcomes and progression risk 1

Despite these limitations, the consistent finding across multiple studies is that ICS therapy produces both subjective clinical improvement and objective reduction in sputum eosinophils, supporting their use as first-line therapy. 3, 6, 4