What are the potential causes and diagnostic approaches for a chronic cough?

Chronic Cough Differential Diagnosis

Most Common Causes (The "Pathogenic Triad")

In nonsmoking adults with chronic cough (>8 weeks) and normal chest radiograph who are not taking ACE inhibitors, focus your diagnostic approach on three conditions: upper airway cough syndrome (UACS), asthma, and gastroesophageal reflux disease (GERD), as these account for 92-100% of cases, either alone or in combination. 1, 2

Upper Airway Cough Syndrome (UACS) - Most Common Single Cause

• Previously called postnasal drip syndrome 1
• Can be completely "silent" with no nasal symptoms whatsoever 2
• Caused by rhinosinusitis, allergic rhinitis, vasomotor rhinitis, or other rhinosinus conditions 2
• Accounts for approximately 56-58% of chronic cough cases 1, 3

Asthma - Second Most Common

• May present as "cough variant asthma" with cough as the only symptom—no wheezing or dyspnea required for diagnosis 2
• Accounts for approximately 46-59% of cases 1, 3
• Critical pitfall: Normal spirometry does NOT exclude asthma 4, 2
• Bronchial hyperresponsiveness may be the only finding 4

Gastroesophageal Reflux Disease (GERD) - Third Most Common

• Can be "silent GERD" without heartburn or regurgitation, with cough as the sole manifestation 2
• Accounts for approximately 32-41% of cases 1, 3
• Critical pitfall: Reflux-associated cough frequently occurs without typical GI symptoms 4

Nonasthmatic Eosinophilic Bronchitis (NAEB) - Increasingly Recognized

• Should be considered early in evaluation 2, 5
• Characterized by eosinophilic infiltration, normal spirometry, lack of bronchial hyperresponsiveness 1
• Responds predictably to inhaled corticosteroids 1, 2, 5
• Prevalence ranges from 13-33% in international series 1

Critical Concept: Multifactorial Etiology

Up to 62% of patients have multiple contributing diagnoses—cough will NOT resolve until ALL contributing factors are treated. 1, 3

• Two or even all three common causes frequently coexist 1, 2
• Sequential and additive therapy is crucial 1

Less Common But Important Causes

Medication-Induced

• ACE inhibitor-induced cough can occur anytime within the first year of therapy 2
• Median resolution time is 26 days after discontinuation (range: few days to 2 weeks) 2, 5

Smoking-Related

• Chronic bronchitis from cigarette smoking 1
• Majority resolve within 4 weeks of cessation, though some take longer 1

Infectious/Post-Infectious

• Bordetella pertussis (may occur in localized clusters) 1
• Tuberculosis (especially in endemic areas or immunocompromised patients) 1

Structural/Pulmonary

• Bronchiectasis 1, 3
• Interstitial lung diseases 1
• Endobronchial abnormalities (tumors, sarcoidosis, retained sutures) 1, 5
• Tracheobronchial collapse 3

Other

• Congestive heart failure 1
• Thyroid disease 1
• Mediastinal mass 1
• Neuromuscular disorders 1
• Habitual or psychogenic cough 1

Diagnostic Approach Algorithm

Step 1: Mandatory Initial Assessment

• Chest radiograph for all patients to rule out malignancy, infection, or structural abnormalities 4
• Spirometry with bronchodilator response to identify airflow obstruction and reversibility 4
• Detailed history focusing on:
  • ACE inhibitor use 1, 4
  • Smoking status 1, 4
  • Geographic location (TB or fungal disease endemic areas) 1
  • Previous history of cancer, tuberculosis, or AIDS 1
  • Systemic symptoms: fever, sweats, weight loss 1
  • Occupational exposures 4

Critical point: The character, timing, or productivity of cough has NO diagnostic value and should not be used to rule in or rule out any diagnosis. 1, 2

Step 2: Sequential Empiric Treatment (for normal chest X-ray)

First: Treat for UACS

• Begin with first-generation antihistamine-decongestant combination 1, 4
• Allow at least 1-2 weeks for response 1, 4

Second: Evaluate for Asthma

• If UACS treatment fails, perform bronchial provocation testing (methacholine challenge) 4
• A negative methacholine challenge essentially excludes asthma 4
• If testing unavailable, trial 2-week oral corticosteroids (e.g., prednisone) 4
• Improvement with corticosteroids confirms eosinophilic airway inflammation 4

Third: Treat for GERD

• Empiric treatment trial preferred over diagnostic testing initially 4
• Critical pitfall: GERD treatment requires at least 3 months of intensive acid suppression for proper evaluation 4
• 24-hour esophageal pH monitoring only if empiric treatment fails 4

Step 3: Consider NAEB Early

• Obtain induced sputum for eosinophil staining 1
• Trial of inhaled corticosteroids if eosinophilia present 1, 2, 5

Step 4: Further Investigation if Initial Approach Fails

• High-resolution CT chest to evaluate for bronchiectasis, interstitial lung disease, or occult malignancy 4
• Bronchoscopy if structural abnormalities or endobronchial lesions suspected 1, 4
• Consider uncommon causes: nonacid reflux, swallowing disorder, habit cough 1

Special Populations

Interstitial Lung Disease Patients

• Before diagnosing ILD as the sole cause of cough, common etiologies (UACS, asthma, GERD) must be excluded 1
• ILD as cause of cough should be considered a diagnosis of exclusion 1
• At least 50% of chronic cough in ILD patients is due to other diagnoses 1

Immunocompromised Patients

• Use same initial algorithm but expand differential based on type and severity of immune defect 2
• Consider tuberculosis and opportunistic infections more aggressively 1

When to Refer to Specialist

• Chronic cough should only be labeled as idiopathic after thorough assessment at a specialist cough clinic 4
• Consider referral if complete workup and appropriate therapeutic trials fail to identify cause 1
• Pulmonology referral recommended if cough persists despite sequential empiric therapy 5

Key Clinical Pitfalls to Avoid

1. Overlooking silent presentations: UACS, asthma, and GERD can each present with cough as the ONLY symptom 1, 2
2. Inadequate treatment duration: GERD requires ≥3 months of therapy for proper evaluation 4
3. Stopping after finding one cause: 62% have multiple causes—treat all identified conditions 1, 3
4. Relying on spirometry alone: Cough variant asthma presents with normal spirometry 4, 2
5. Forgetting ACE inhibitors: Always check medication list first 1, 4
6. Premature diagnosis of idiopathic cough: Only after specialist evaluation excludes all common and uncommon causes 1, 4