What are the next steps for a patient with persistent cough despite being on budesonide-formoterol (corticosteroid and long-acting beta2-adrenergic receptor agonist (LABA)) 80 mcg-4.5 mcg/inhaler as needed?

Management of Persistent Cough Despite Budesonide-Formoterol Therapy

If a patient continues to cough despite being on budesonide-formoterol 80 mcg-4.5 mcg as needed, you should first ensure adequate treatment duration (up to 8 weeks may be required for complete cough resolution), verify proper inhaler technique, then systematically evaluate and treat for the three most common causes: upper airway cough syndrome (UACS), asthma/non-asthmatic eosinophilic bronchitis (NAEB), and gastroesophageal reflux disease (GERD). 1

Initial Assessment and Optimization

Verify Treatment Duration and Technique

• Complete resolution of cough may require up to 8 weeks of treatment with inhaled corticosteroids, even though partial improvement often occurs after 1 week. 1
• Confirm proper inhaler technique, as improper use is a common cause of treatment failure that must be excluded before escalating therapy. 1
• Rule out inhaled steroid-induced cough itself—the aerosol constituents (particularly in beclomethasone) can paradoxically trigger cough. 1

Optimize Current Regimen

• Consider increasing the budesonide-formoterol dose to 160 mcg-4.5 mcg twice daily for maintenance, as the current 80 mcg dose may be insufficient for adequate anti-inflammatory control. 1
• If using as-needed dosing only, transition to scheduled maintenance dosing twice daily, as regular administration provides superior asthma control compared to as-needed use alone. 2, 3

Systematic Evaluation for Common Causes

Step 1: Evaluate and Treat Upper Airway Cough Syndrome (UACS)

UACS should be addressed first, as it is one of the three most common causes of chronic cough. 4, 5

• Prescribe a first-generation antihistamine/decongestant combination (brompheniramine/pseudoephedrine or chlorpheniramine/phenylephrine) starting once-daily at bedtime for 2-3 days, then advance to twice-daily to minimize sedation. 4, 5
• Add intranasal corticosteroid spray (fluticasone or mometasone) to decrease airway inflammation. 4, 5
• If no improvement after 1-2 weeks, proceed to Step 2. 4

Step 2: Escalate Inhaled Corticosteroid Therapy and Assess for Eosinophilic Inflammation

If cough persists despite optimized UACS treatment, step up the inhaled corticosteroid dose and consider adding a leukotriene inhibitor. 1

• Increase budesonide-formoterol to 160 mcg-4.5 mcg twice daily (or higher doses up to 320 mcg-9 mcg twice daily if needed). 1, 3
• Add a leukotriene receptor antagonist (montelukast or zafirlukast) as adjunctive therapy, which has demonstrated efficacy in reducing cough in asthma. 1
• When cough remains refractory to inhaled corticosteroids, assess airway inflammation through induced sputum or bronchoalveolar lavage (BAL) to identify persistent eosinophilia. 1
• If sputum eosinophilia is confirmed (diagnostic of NAEB or poorly controlled asthma), this identifies patients who will benefit from more aggressive anti-inflammatory therapy. 1

Step 3: Consider Oral Corticosteroids for Severe or Refractory Cases

For cough that is severe or only partially responsive to high-dose inhaled corticosteroids, prescribe oral prednisone 40 mg daily for 1 week. 1

• This approach is particularly effective when airway eosinophilia has been documented. 1
• Oral steroids may be followed by a return to inhaled therapy for maintenance. 1
• Before escalating to oral steroids, ensure GERD has been ruled out, as it can make asthma difficult to control. 1

Step 4: Evaluate and Treat GERD

If both UACS and optimized asthma therapy fail after 2 weeks, initiate empiric treatment for GERD. 4, 6

• Prescribe high-dose proton pump inhibitor (PPI) therapy: omeprazole 40 mg twice daily. 4, 6
• Implement dietary modifications and lifestyle changes (avoid late meals, elevate head of bed, avoid trigger foods). 4, 6
• GERD-related cough may require 2 weeks to several months for response, with some patients needing 8-12 weeks, so adequate treatment duration is essential before declaring failure. 4, 6

Additional Therapeutic Options

Adjunctive Bronchodilator Therapy

• Add inhaled ipratropium bromide 2-3 puffs four times daily, which has demonstrated efficacy in attenuating post-infectious and chronic cough with fewer systemic side effects. 1, 4, 5
• This is particularly useful if there is a post-infectious component to the cough. 1, 5

Antitussive Agents

Central-acting antitussives (codeine 15-30 mg or dextromethorphan 30 mg every 6 hours) should be considered when other measures fail. 1, 4, 5

• These provide symptomatic relief but do not address underlying inflammation. 1, 5

Advanced Evaluation if All Empiric Therapy Fails

Diagnostic Testing

• Obtain chest radiograph to rule out persistent pneumonia, masses, interstitial disease, or congestive heart failure. 4, 6
• Order high-resolution CT chest to evaluate for bronchiectasis, interstitial lung disease, or occult masses. 4, 6
• Consider bronchoscopy to evaluate for endobronchial lesions, sarcoidosis, eosinophilic bronchitis, or occult infection. 4, 6
• Order 24-hour esophageal pH monitoring if GERD remains suspected despite failed empiric therapy, as this is the most sensitive and specific test. 4, 6

Special Consideration: Pertussis

If cough is paroxysmal with post-tussive vomiting or inspiratory whooping sound, consider pertussis infection even in vaccinated patients. 1, 5, 6

• Obtain nasopharyngeal culture if pertussis is suspected. 5, 6
• Prescribe macrolide antibiotics (azithromycin or clarithromycin) immediately if pertussis is confirmed or highly suspected. 5, 6

Critical Pitfalls to Avoid

• Do not assume treatment failure after only 1-2 weeks of inhaled corticosteroids—complete cough resolution requires up to 8 weeks. 1
• Do not prescribe antibiotics for post-infectious viral cough, as they provide no benefit and contribute to resistance. 1, 4, 5
• Do not use nasal decongestant sprays for more than 3-5 days due to rebound congestion risk. 4, 6
• Do not diagnose "unexplained cough" until completing systematic evaluation of UACS, asthma/NAEB, and GERD with adequate treatment trials of appropriate duration. 4, 6
• Do not assume GERD is ruled out simply because of prior antireflux surgery, as reflux can persist. 6
• Verify that the patient is not using budesonide-formoterol in conjunction with other long-acting beta-agonists, as this is contraindicated. 7