Cough: Management and Recent Guidelines (2025)

1. Classification by Duration

2. Core Principle of Management

Identify the cause(s) first - then treat the cause(s).

• Murray & Nadel's Textbook of Respiratory Medicine, p. 131

3. Initial Evaluation

• Duration (acute vs. subacute vs. chronic)
• Smoking history (chest X-ray abnormal in 10-30% of smokers with cough)
• ACE inhibitor use (switch to ARB - resolves within 1-4 weeks)
• Occupational/environmental exposure
• Associated symptoms: postnasal drip, heartburn, wheeze, dyspnea, hemoptysis

• Hemoptysis
• High fever
• Shortness of breath at rest
• Suspected malignancy (weight loss, hoarseness, lymphadenopathy)

• Chest X-ray (first-line in all patients)
• Spirometry + bronchodilator reversibility
• CT thorax if CXR normal but suspicion remains
• Methacholine challenge (cough-variant asthma)
• 24-hour pH-impedance monitoring (GERD-related cough)
• Sputum eosinophilia (non-asthmatic eosinophilic bronchitis)
• Fiberoptic bronchoscopy if indicated

4. The "Big Three" Causes of Chronic Cough

A. Upper Airway Cough Syndrome (UACS) / Postnasal Drip

• 1st and 2nd generation antihistamines + decongestants
• Intranasal corticosteroids for allergic rhinitis
• Ipratropium nasal spray for perennial non-allergic rhinitis

B. Cough-Variant Asthma / Eosinophilic Bronchitis

• Inhaled corticosteroids (ICS) - first line
• Long-acting beta-agonists if needed
• Leukotriene receptor antagonists (montelukast) as adjunct

C. Gastroesophageal Reflux Disease (GERD)

• Proton pump inhibitors (PPI) for minimum 8 weeks
• 2025 update (German guideline): Antireflux therapy should only be initiated if cough is associated with typical reflux symptoms - empirical treatment without symptoms is no longer recommended
• Lifestyle modifications (head-of-bed elevation, dietary triggers)
• AGA Expert Review 2023 (PMID 37061897) also supports limiting empirical PPI therapy in atypical GERD-cough presentations

5. Specific Causes

ACE Inhibitor Cough

• Affects 10-15% of users; higher incidence in East Asian populations
• Switch to an angiotensin receptor blocker (ARB)

Post-Infectious Cough

• Usually self-limiting
• Macrolide antibiotics (azithromycin) or trimethoprim-sulfamethoxazole for confirmed Bordetella pertussis - does not shorten cough duration but limits spread
• ICS: variable benefit; oral corticosteroids may help
• Murray & Nadel's, p. 351

Post-COVID Cough (New 2025)

• ~30% of COVID-19 patients develop refractory/chronic cough
• No approved therapy; symptomatic management as for refractory chronic cough (neuromodulators, speech therapy)

IPF-Associated Cough

• Treat comorbidities (GERD, UACS)
• Pirfenidone (antifibrotic) may reduce cough frequency
• Thalidomide has shown benefit in small trial
• Conventional opioids often ineffective
• Murray & Nadel's, p. 358-360

6. Refractory and Unexplained Chronic Cough (RCC/UCC)

Non-pharmacological

• Speech/behavioral therapy: Breathing exercises, cough suppression techniques, laryngeal hygiene - shown to improve cough symptom scores and counts (Murray & Nadel's, p. 386)
• Respiratory physiotherapy: Secretion mobilization for productive cough; cough-preventing techniques for dry cough (German 2025 guideline - new recommendation)

Pharmacological (off-label unless stated)

7. Novel & Emerging Therapies (2024-2026)

Gefapixant (P2X3 receptor antagonist) - Approved

• Selective P2X3 purinoceptor antagonist on sensory nerve endings
• Approved in Japan, EU, UK for RCC/UCC in adults
• Not yet marketed in Germany (reimbursement issue)
• Main side effect: altered taste/dysgeusia (~15-20%)
• Therapeutic Landscape Review, Smith JA, 2024 (PMID 38127133)

Camlipixant (BLU-5937) - Phase 2b (2025)

• Highly selective P2X3 antagonist with much lower dysgeusia rate vs gefapixant
• SOOTHE trial (2025): significantly reduced cough frequency vs placebo with favorable tolerability
• Camlipixant RCT, Smith JA et al., Am J Respir Crit Care Med 2025 (PMID 40043302)

Other agents in pipeline

• Sivopixant - another selective P2X3 antagonist (Phase 3)
• TRPV1 and TRPA1 antagonists - targeting peripheral cough receptors
• Nav1.7 sodium channel blockers - pre-clinical/early phase

8. Summary of Key 2025 Guideline Updates

1. Acute cough: Antibiotics should NOT be routinely prescribed. OTC secretolytics/antitussives are appropriate for symptom relief (short-term only).
2. GERD-cough: Antireflux therapy only when typical reflux symptoms are present.
3. Post-COVID cough: Formally recognized as a new category; treat symptomatically as RCC/UCC.
4. Respiratory physiotherapy: New strong recommendation for both productive and dry cough.
5. Gefapixant: Formally recognized as approved but notes it is not marketed in Germany; other P2X3 agents emerging.
6. Neuromodulators and low-dose morphine: Recommended off-label for RCC/UCC.

9. Practical Management Algorithm

Chronic Cough (>8 weeks)
│
├─ History + Exam + CXR
│
├─ Identify trigger:
│    ├── UACS → Antihistamine ± ICS nasal
│    ├── Asthma/NAEB → ICS ± LABA
│    ├── GERD (with symptoms) → PPI 8 weeks
│    ├── ACE inhibitor → Switch to ARB
│    └── Smoking → Cessation
│
├─ If no cause or treatment fails:
│    → Diagnose RCC/UCC
│    → Speech therapy + Physiotherapy
│    → Neuromodulator (gabapentin/pregabalin)
│    → Low-dose sustained-release morphine
│    → Consider gefapixant (where licensed)
│
└─ Red flags at any point → Urgent imaging / bronchoscopy / oncology referral

• Murray & Nadel's Textbook of Respiratory Medicine (Chapters 37, 20)
• German S3 Cough Guideline 2025 - Kardos P et al., Respiration 2025 (PMID 41385480)
• Camlipixant SOOTHE Trial 2025 - PMID 40043302
• Therapeutic Landscape Review 2024 - PMID 38127133
• Advances in Chronic Cough 2025 - Peters AT et al., Ann Allergy Asthma Immunol (PMID 39722320)