What is the best approach to diagnose and manage a chronic cough in a patient, potentially with a history of smoking or exposure to irritants, and with possible underlying conditions such as Chronic Obstructive Pulmonary Disease (COPD) or Gastroesophageal Reflux Disease (GERD)?

Chronic Cough: Diagnostic and Management Approach

Begin with an empiric sequential treatment protocol targeting the three most common causes—upper airway cough syndrome (UACS), asthma, and GERD—rather than extensive upfront testing, as this approach is more cost-effective and achieves resolution in the majority of cases. 1, 2

Initial Assessment and Risk Stratification

Immediate Actions

• Discontinue ACE inhibitors immediately if the patient is taking one, regardless of when the cough started, as resolution typically occurs within days to 2 weeks (median 26 days) 2
• If the patient currently smokes, prioritize smoking cessation above all else, as most patients achieve cough resolution within 4 weeks of cessation 1, 2
• Obtain a chest radiograph to rule out serious pathology (mass, infection, heart failure, interstitial disease) 1

Red Flags Requiring Direct Investigation (Not Empiric Treatment)

• Hemoptysis, significant dyspnea, fever, or systemic symptoms 2
• Unintentional weight loss, night sweats 2
• History of cancer, tuberculosis, or AIDS 2
• Chest radiograph findings suggestive of mass or malignancy 2
• If any red flags are present, proceed directly to advanced imaging (CT chest) and specialist referral rather than empiric treatment 2

Sequential Empiric Treatment Protocol

Step 1: Treat for Upper Airway Cough Syndrome (UACS) First

• Start with a first-generation antihistamine-decongestant combination (e.g., chlorpheniramine-pseudoephedrine), as UACS is the single most common cause of chronic cough 1, 2
• Expect noticeable improvement within days to 1-2 weeks; complete resolution may take several weeks to months 1
• If partial response occurs, add topical nasal corticosteroid, nasal anticholinergic, or nasal antihistamine 1
• If nasal symptoms persist despite topical therapy, obtain sinus imaging (CT or plain films) to evaluate for sinusitis 1
• Treat documented sinusitis with antibiotics; consider ENT referral if refractory 1

Step 2: Evaluate and Treat for Asthma

• Proceed to asthma evaluation if cough persists after adequate UACS treatment (typically 2-4 weeks) 1
• Perform spirometry; if normal, obtain bronchoprovocation challenge testing if available 1
• If bronchoprovocation testing is unavailable, initiate empiric trial of inhaled corticosteroids with or without bronchodilators, as many patients with cough-variant asthma lack sufficient reversibility on spirometry to meet traditional asthma criteria 2
• Consider measuring exhaled nitric oxide and blood eosinophil count to support asthma diagnosis 3
• Also evaluate for nonasthmatic eosinophilic bronchitis (NAEB) with induced sputum for eosinophils (≥3% eosinophils diagnostic) 1

Step 3: Treat for Gastroesophageal Reflux Disease (GERD)

• If cough persists after treating UACS and asthma, initiate intensive acid suppression therapy for at least 3 months, as GERD is frequently overlooked and requires prolonged treatment 2
• GERD can be "silent" (no heartburn or regurgitation symptoms) and still cause chronic cough 1
• Do not rely on presence or absence of GI symptoms to rule in or out GERD as a cause 1

Critical Concept: Multifactorial Etiology

• Up to 25% of patients have two or more simultaneous causes of chronic cough 1
• Cough will not resolve until ALL contributing causes are adequately treated 1
• Continue sequential addition of therapies rather than stopping previous treatments when moving to next diagnostic category 1

When to Pursue Advanced Testing

Indications for High-Resolution CT (HRCT) Chest

• Proceed to HRCT only after sequential empiric treatment for all three common causes has failed AND adequate treatment duration has been allowed (several weeks for UACS/asthma, ≥3 months for GERD) 2
• HRCT identifies abnormalities in up to 42% of patients with normal chest radiographs and is diagnostic in 24% of chronic cough patients who failed initial protocols 2
• HRCT is the reference standard for detecting bronchiectasis, which accounts for up to 8% of chronic cough cases and may be missed on chest radiography 2

Additional Diagnostic Considerations

• Consider bronchoscopy if HRCT suggests endobronchial lesion, infection (tuberculosis), or interstitial lung disease requiring tissue diagnosis 1
• Evaluate for less common causes only after common causes excluded: bronchiectasis, interstitial lung disease, cardiac disease, retained foreign body 1

Special Populations and Considerations

Patients with Smoking History or COPD

• Smoking cessation is the definitive intervention; most achieve resolution within 4 weeks 2
• Chronic bronchitis from smoking is a diagnosis of exclusion after other causes ruled out 1
• Consider HRCT to evaluate for emphysema, bronchiectasis, or lung cancer if cough persists after smoking cessation 2

Patients with Possible Environmental/Occupational Exposures

• Assess for hypersensitivity pneumonitis if reduced DLCO (especially <70%), ground-glass opacities on imaging, or exposure to organic dusts/molds 4
• Evaluate home environment for water damage, visible mold, contaminated humidifiers, or hot tubs 4
• Early identification and removal from exposure are key treatment components 4

Refractory Chronic Cough Management

Definition and Approach

• Refractory chronic cough is diagnosed only after thorough evaluation, appropriate treatment trials (adequate duration), and exclusion of uncommon causes 1
• Consider cough hypersensitivity syndrome in patients with persistent cough despite optimal treatment of underlying conditions 5, 6

Treatment Options for Refractory Cough

• Low-dose morphine is the preferred neuromodulatory agent 3
• Gabapentin or pregabalin are alternative neuromodulatory options 3, 5, 6
• Speech and language therapy may provide benefit 6
• New P2X3 receptor antagonists (gefapixant, cafiglimab) are under investigation but not yet approved 3, 6

Common Pitfalls to Avoid

• Do not rely on cough characteristics (timing, quality, presence of sputum) to diagnose or exclude specific etiologies, as these features are not diagnostically reliable 1
• Do not order extensive testing upfront; sequential empiric treatment is more cost-effective than comprehensive initial investigation 2
• Do not rely on chest radiography alone to exclude bronchiectasis, as up to 34% of CT-proven cases have normal chest radiographs 2
• Do not stop previous treatments when adding new ones; continue all therapies as you work through the algorithm since multiple causes often coexist 1
• Do not undertreated GERD; requires at least 3 months of intensive acid suppression, not just brief trials 2