Chronic Cough Workup

Risk factors

• Cigarette smoking and secondhand smoke (most common cause overall when included)
• ACE inhibitor use (5-20% develop cough; can begin weeks to months after starting)
• Allergic rhinitis and post-nasal drip
• Asthma, eosinophilic bronchitis, GERD
• Occupational and environmental exposures (dust, fumes, mold)
• Recent viral respiratory infection (post-infectious cough may persist 8 weeks)
• Comorbidities: bronchiectasis, ILD, lung cancer, HF, OSA

Pathophysiology

Cough hypersensitivity syndrome describes a state of neuronal sensitization in which low-level airway and pharyngeal stimuli trigger cough reflexes via vagal afferents. Upper airway cough syndrome (formerly post-nasal drip) stimulates pharyngeal cough receptors. Eosinophilic airway inflammation (asthma, non-asthmatic eosinophilic bronchitis) heightens cough sensitivity. Refluxate (acidic or non-acidic) stimulates vagal afferents at the lower esophageal sphincter. ACE inhibitor cough arises from accumulation of bradykinin and substance P.

Clinical presentation

Differential diagnosis

• Upper airway cough syndrome (UACS) — Post-nasal drainage, throat clearing, cobblestoning of posterior pharynx; responds to first-generation antihistamine/decongestant or intranasal steroid
• Cough-variant asthma — Cough as the dominant symptom; bronchodilator-responsive; positive methacholine challenge or FEV1 reversibility
• Non-asthmatic eosinophilic bronchitis (NAEB) — Sputum eosinophilia without airway hyperresponsiveness; responds to inhaled corticosteroids
• Gastroesophageal reflux disease — Heartburn, regurgitation, worse postprandial or supine; responds to PPI + lifestyle modification
• ACE inhibitor cough — Dry cough beginning weeks-months after ACEi initiation; resolves 1-4 weeks after discontinuation
• Post-infectious cough — Recent viral URI; gradual resolution over weeks; consider pertussis if paroxysmal with whoop or post-tussive emesis
• Smoking-related chronic bronchitis / COPD — Pack-year history, productive cough most days for ≥3 months over 2 years; spirometry confirms airflow obstruction
• Lung cancer — Smoker, weight loss, hemoptysis, mass on imaging
• Bronchiectasis — Daily mucopurulent sputum, recurrent infections, tram-track CT findings
• Interstitial lung disease — Dry cough with dyspnea, crackles, restrictive PFTs
• Heart failure — Orthopnea, PND, S3, elevated BNP
• Obstructive sleep apnea — Snoring, daytime sleepiness; cough may improve with CPAP
• Refractory/unexplained chronic cough — Cough persists after evaluation and empirical treatment; consider neuromodulators (gabapentin, pregabalin, low-dose morphine, P2X3 antagonists)

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[Cough >8 weeks] --> B[Stop smoking<br/>Stop ACEi<br/>CXR + spirometry]
  B --> C{Red flags?<br/>hemoptysis, wt loss,<br/>>20 PY smoker}
  C -->|Yes| D[Chest CT + pulm referral]
  C -->|No| E[Empirical trial: UACS<br/>1st-gen AH/D + INCS]
  E --> F{Improved?}
  F -->|No| G[Empirical asthma:<br/>ICS ± methacholine]
  G --> H{Improved?}
  H -->|No| I["GERD: lifestyle + weight loss<br/>PPI only if heartburn,<br/>regurgitation, or proven reflux"]
  I --> J{Improved?}
  J -->|No| K[FeNO, induced sputum,<br/>HRCT, pH-impedance]
  K --> L[Refractory cough:<br/>speech therapy +<br/>gabapentin/pregabalin/morphine]

Treatment

Complications

• Sleep disruption, fatigue, reduced quality of life
• Urinary incontinence (especially women), syncope (cough syncope)
• Musculoskeletal: rib fractures, intercostal muscle strain
• Social isolation, anxiety, depression
• Delayed diagnosis of malignancy or serious underlying disease

PANCE pearls

• ACE inhibitor cough is dose-INDEPENDENT and resolves within 1-4 weeks of discontinuation; substitute with ARB.
• Always check a CXR before empirical treatment for adult chronic cough.
• First-generation antihistamines (chlorpheniramine) are preferred for UACS — second-generation antihistamines are far less effective for the cough component.
• GERD-related cough can occur without heartburn, but PPI therapy alone is unlikely to help when heartburn and regurgitation are absent (CHEST 2016, ERS 2020); use lifestyle measures and weight loss, reserve PPI for typical reflux symptoms or objective acid reflux, and consider pH-impedance testing for refractory cases.
• Refractory cough is now recognized as a neurogenic disorder (cough hypersensitivity syndrome) — gabapentin, pregabalin, and speech pathology therapy carry weak (conditional) guideline recommendations, and ERS 2020 recommends a trial of low-dose slow-release morphine.

References

• CHEST 2018 — Irwin RS et al. Classification of Cough as a Symptom in Adults and Management Algorithms: CHEST Guideline and Expert Panel Report. CHEST 2018;153:196-209
• ERS 2020 — Morice AH et al. ERS Guidelines on the Diagnosis and Treatment of Chronic Cough in Adults and Children. Eur Respir J 2020;55:1901136
• ACCP 2006 — Diagnosis and Management of Cough Executive Summary: ACCP Evidence-Based Clinical Practice Guidelines. CHEST 2006;129(1 Suppl):1S-23S
• CHEST 2016 (reflux cough) — Kahrilas PJ, Altman KW, Chang AB, et al. Chronic Cough Due to Gastroesophageal Reflux in Adults: CHEST Guideline and Expert Panel Report. Chest 2016;150(6):1341-1360
• CHEST 2016 (unexplained cough) — Gibson P, Wang G, McGarvey L, et al. Treatment of Unexplained Chronic Cough: CHEST Guideline and Expert Panel Report. Chest 2016;149(1):27-44