Cough
Cough is a protective reflex involving forceful expulsion of air from the lungs to clear the airways of irritants, secretions, or foreign particles.
Cough
Let's start from first principles. Cough is a vital protective reflex mechanism that clears the airways of secretions, inhaled particles, and noxious substances. It becomes pathological when it is excessive, prolonged, or occurs without a clear protective purpose.
Breaking down the word: "Cough" derives from Old English cohhian — it's onomatopoeic, mimicking the sound itself.
Clinically, cough is defined as a forced expulsive manoeuvre, usually against a closed glottis, which is associated with a characteristic sound. It can be:
- Voluntary (consciously initiated)
- Reflex (involuntary, triggered by stimulation of cough receptors)
The cough reflex arc consists of five components:
- Cough receptors (afferent limb) — located in the pharynx, larynx, trachea, major bronchi, and also in the ear canal (Arnold's nerve — auricular branch of vagus), diaphragm, pericardium, and oesophagus
- Afferent nerves — primarily the vagus nerve (CN X), also the glossopharyngeal nerve (CN IX) and trigeminal nerve (CN V)
- Cough centre — located in the medulla oblongata (nucleus tractus solitarius)
- Efferent nerves — vagus, phrenic, and spinal motor nerves
- Effector muscles — diaphragm, intercostal muscles, abdominal muscles, laryngeal muscles
The mechanics of a cough involve three phases:
- Inspiratory phase: Deep inhalation to increase lung volume (provides the air column for expulsion)
- Compressive phase: Glottis closes, expiratory muscles contract → intrathoracic pressure rises dramatically (up to 300 mmHg)
- Expulsive phase: Glottis opens suddenly → high-velocity airflow (up to 500 mph) expels mucus and foreign material
Why does cough matter clinically? Cough is one of the most common reasons for primary care consultation worldwide. It is often a symptom of an underlying condition — identifying the cause is the key clinical task, not merely suppressing the cough.
Classification by Duration — Must Know
Cough is classified by duration: [1]
- Acute cough: < 3 weeks — usually infectious (viral URTI most common)
- Subacute cough: 3–8 weeks — often post-infectious
- Chronic cough: > 8 weeks — requires systematic investigation
This classification is high-yield because the differential diagnosis, urgency of investigation, and management differ dramatically between these categories.
Epidemiology
- Cough is the single most common symptom for which patients seek medical attention in primary care [1]
- Prevalence of chronic cough in the general population: ~10–12% globally
- More common in females than males (particularly chronic cough — ratio approximately 2:1), likely related to heightened cough reflex sensitivity in women (oestrogen may upregulate sensory nerve function)
- More common in smokers: prevalence of chronic cough in current smokers is 20–30% vs. 5–10% in non-smokers
- In Hong Kong, key aetiologies to consider include: [2]
- Tuberculosis (TB) — Hong Kong remains an intermediate-burden TB region (~4,000 cases/year, incidence ~55 per 100,000). Any chronic cough in HK must have TB excluded
- GERD — rising incidence in HK (2.5% in 2002 → 3.7% in 2011) and a significant cause of chronic cough [3]
- Asthma — prevalence ~8.6% in HK [4]
- COPD — ~10% of those > 70y in HK [5]
- Lung cancer — HK has a high incidence of lung cancer (both smoking-related and non-smoking-related adenocarcinoma, particularly in women)
- Air pollution — worsening urban air quality contributes to cough
Hong Kong Red Flags
In Hong Kong, never forget to consider tuberculosis and lung cancer in any patient presenting with chronic cough, even if they are non-smokers. Non-smoking-related adenocarcinoma of the lung is increasingly prevalent in Asian women.
Risk Factors
| Risk Factor | Mechanism |
|---|---|
| Female sex | Enhanced cough reflex sensitivity (possibly oestrogen-mediated upregulation of TRPV1 receptors on sensory neurones) |
| Advancing age | Accumulated exposure to noxious stimuli; immunosenescence → ↑ infection susceptibility; ↑ prevalence of GERD, HF, and malignancy |
| Atopy / Asthma | Eosinophilic airway inflammation → bronchial hyperresponsiveness → cough (may be the sole manifestation — "cough-variant asthma") |
| Obesity | ↑ Intra-abdominal pressure → GERD → cough; restrictive lung physiology; association with obstructive sleep apnoea |
| Immunosuppression | Predisposition to opportunistic infections (TB, PCP, fungal) |
| Risk Factor | Mechanism |
|---|---|
| Cigarette smoking | Direct irritation of airways; chronic airway inflammation → chronic bronchitis/COPD; impaired mucociliary clearance; ↑ risk of lung cancer [5] |
| Passive smoking / Environmental tobacco smoke | Same mechanisms as above at lower intensity |
| Occupational exposure | Dusts, fumes, chemicals → occupational asthma, pneumoconiosis |
| Air pollution | Particulate matter (PM2.5, PM10) and NO₂ → airway inflammation |
| Indoor biomass fuel combustion | Relevant in rural areas → COPD, chronic bronchitis |
| Drug | Mechanism |
|---|---|
| ACE inhibitors (ACEi) | Inhibition of bradykinin and substance P degradation → accumulation of these pro-tussive mediators in the airway mucosa → stimulation of C-fibre cough receptors. Affects ~5–35% of patients on ACEi. Dry, persistent, tickly cough. Class effect — occurs with ALL ACEi. Resolves within 1–4 weeks of stopping. [1] |
| ARBs | Very rarely cause cough (< 3%), so are the standard switch from ACEi-induced cough |
ACEi Cough — Classic Exam Trap
ACEi-induced cough is one of the most commonly tested causes of chronic cough. The mechanism is NOT related to angiotensin — it is due to accumulation of bradykinin and substance P because ACE (= kininase II) normally degrades these mediators. This is why ARBs do not cause cough (they block the angiotensin receptor without affecting bradykinin metabolism).
Anatomy and Physiology of the Cough Reflex
Understanding cough requires understanding where cough receptors live and how the reflex arc works. This is the foundation for understanding every aetiology.
Cough receptors are sensory nerve endings found in:
| Location | Key Point |
|---|---|
| Larynx | Most sensitive area — even minimal stimulation triggers violent cough (protective against aspiration) |
| Trachea and carina | Highly sensitive; carina is the "cough hot spot" — this is why bronchoscopy passing the carina induces intense coughing |
| Major bronchi | Decreasing sensitivity as you go distally |
| Pharynx | Contributes to cough from post-nasal drip |
| External auditory canal | Arnold's nerve (auricular branch of vagus) — stimulation by cerumen, foreign body, or even otoscopy can trigger cough ("Arnold's reflex" or "ear-cough reflex") |
| Oesophagus | Vagal afferents — explains cough in GERD even without aspiration (the "oesophago-bronchial reflex") |
| Pericardium, diaphragm | Explains cough in pericarditis, subdiaphragmatic irritation |
| Nose and sinuses | Trigeminal afferents → sneeze and cough from rhinosinusitis |
Two main types of sensory nerve fibres mediate cough:
-
Rapidly adapting receptors (RARs) — myelinated Aδ fibres
- Respond to mechanical stimulation (inhaled particles, mucus, bronchospasm)
- Mediate the "irritant" cough
- Concentrated in larynx and large airways
-
C-fibre receptors — unmyelinated
- Respond to chemical stimulation (capsaicin, bradykinin, prostaglandins, acid)
- Mediate the "chemical" cough
- Found throughout airways and oesophagus
- Express TRPV1 (transient receptor potential vanilloid 1) and TRPA1 channels — these are the molecular sensors for capsaicin, acid, and inflammatory mediators
- This is why bradykinin accumulation in ACEi cough stimulates C-fibre TRPV1 receptors
Before cough is needed, the mucociliary escalator clears particles:
- Goblet cells and submucosal glands produce mucus (sol layer + gel layer)
- Ciliated columnar epithelium beats in coordinated waves to move the mucus carpet upwards towards the pharynx
- When this system fails (e.g., smoking destroys cilia; cystic fibrosis produces thick mucus; primary ciliary dyskinesia has dysmotile cilia), cough becomes the backup clearance mechanism
Aetiology
The aetiology of cough is best approached by duration and anatomical compartment (from nose to alveolus, plus extra-pulmonary causes).
| Category | Aetiology | Notes |
|---|---|---|
| Infection (most common) | Viral URTI (common cold) | Rhinovirus, coronavirus, influenza, parainfluenza, RSV, adenovirus. Self-limiting. Post-nasal drip + airway inflammation → cough |
| Acute bronchitis | Usually viral; productive cough ± wheeze. No CXR infiltrate (distinguishes from pneumonia) | |
| Pneumonia | Bacterial (Streptococcus pneumoniae, H. influenzae, atypicals), viral, fungal. Cough + fever + dyspnoea + CXR consolidation | |
| Acute exacerbation of COPD | Infection triggers ↑ airway inflammation in already damaged airways → ↑ cough and sputum [5] | |
| COVID-19 | SARS-CoV-2 — dry cough is a cardinal symptom; can progress to pneumonia/ARDS | |
| Pertussis (whooping cough) | Bordetella pertussis. Paroxysmal cough with inspiratory "whoop". Consider in prolonged cough post-URTI, especially in unvaccinated | |
| Acute asthma exacerbation | Triggered by allergen, infection, exercise, cold air | Cough + wheeze + dyspnoea; reversible airflow obstruction [4] |
| Allergic rhinitis | Allergen exposure → nasal congestion + post-nasal drip → cough | Seasonal or perennial |
| Foreign body aspiration | Sudden onset cough ± stridor/wheeze, especially in children or elderly | Acute upper or lower airway obstruction |
| Pulmonary embolism | Dry cough ± haemoptysis ± pleuritic chest pain ± dyspnoea | Reflex cough from pulmonary infarction/ischaemia stimulating C-fibres |
| Pneumothorax | Dry cough + sudden pleuritic pain + dyspnoea | Pleural irritation → cough |
| Acute heart failure | Pulmonary oedema → fluid stimulates airway receptors → cough (often worse lying flat) | Pink frothy sputum in severe cases |
| Toxic inhalation | Smoke, chlorine, ammonia, tear gas | Direct airway epithelial injury → inflammation → cough |
| Aetiology | Mechanism |
|---|---|
| Post-infectious cough (most common) | Following URTI/acute bronchitis. Airway epithelium damaged by infection → exposed sensory nerve endings + transient bronchial hyperreactivity → ↑ cough sensitivity. Self-limiting over weeks. |
| Post-nasal drip / Upper airway cough syndrome | Persistent rhinosinusitis → ongoing secretion dripping onto pharyngeal/laryngeal cough receptors |
| Pertussis | "100-day cough" — may persist into subacute and even chronic timeframes |
| Undiagnosed new asthma | May present with isolated cough for several weeks before diagnosis |
C. Chronic Cough ( > 8 weeks)
This is where the systematic approach truly matters. The "Big Three" causes of chronic cough account for > 90% of cases in non-smokers with a normal CXR who are not on ACEi [1]:
1. Upper Airway Cough Syndrome (UACS) / Post-Nasal Drip Syndrome (PNDS)
- Most common cause of chronic cough [1]
- Mechanism: Secretions from the nose/sinuses drip posteriorly onto the pharynx and larynx → mechanical stimulation of cough receptors (RARs) + chemical irritation (inflammatory mediators stimulate C-fibres)
- Underlying causes:
- Allergic rhinitis (most common)
- Non-allergic rhinitis (vasomotor rhinitis)
- Chronic sinusitis
- Rhinitis medicamentosa (overuse of topical decongestants)
2. Asthma and Related Conditions
- Cough-variant asthma (CVA): Cough is the SOLE or predominant symptom — no wheeze, no dyspnoea. Airway inflammation and bronchial hyperresponsiveness are still present. Responds to bronchodilators and inhaled corticosteroids. [4]
- Eosinophilic bronchitis (EB): Sputum eosinophilia ( > 3%) WITHOUT bronchial hyperresponsiveness (i.e., negative methacholine challenge). Responds to inhaled corticosteroids. Distinguished from CVA by normal spirometry AND normal bronchoprovocation testing.
- Classic asthma: cough + wheeze + dyspnoea (but cough may dominate) [4]
3. Gastro-Oesophageal Reflux Disease (GERD)
- GERD is a significant cause of chronic cough, and may present WITHOUT typical heartburn or regurgitation ("silent reflux") [3]
- Mechanisms of GERD-related cough:
- Micro-aspiration: Small amounts of gastric acid reflux into the larynx/trachea → direct irritation of airway cough receptors → cough
- Oesophago-bronchial reflex (vagal reflex): Acid in the distal oesophagus stimulates vagal afferents → reflex bronchoconstriction and cough, even without aspiration reaching the airways
- Heightened cough reflex sensitivity: Chronic acid exposure sensitises airway C-fibre receptors (lowers the cough threshold)
- GERD is rising in incidence in HK (2.5% → 3.7%) [3]
- Asians tend to present atypically — with non-cardiac chest pain, acid feeling, and extra-oesophageal symptoms (chronic cough, hoarseness) rather than classic heartburn [3]
| Category | Aetiology | Mechanism / Key Points |
|---|---|---|
| Drug-induced | ACEi | Bradykinin/substance P accumulation → C-fibre stimulation. 5–35% of users. Dry cough. Resolves 1–4 weeks after stopping. [1] |
| Smoking-related | Chronic bronchitis (COPD) | Defined clinically as cough with sputum on most days for ≥ 3 months in 2 consecutive years. Chronic airway inflammation → goblet cell hyperplasia → mucus hypersecretion → productive cough. [5] |
| Infection | Tuberculosis | Must exclude in HK. Chronic cough ± haemoptysis ± night sweats ± weight loss. Granulomatous inflammation destroying lung parenchyma. AFB smear/culture, CXR. |
| Bronchiectasis | Permanently dilated bronchi → impaired mucociliary clearance → chronic sputum retention → recurrent infections → productive cough ("vicious cycle" hypothesis). | |
| Lung abscess | Necrotic lung tissue → foul-smelling purulent sputum + cough | |
| Neoplasm | Lung cancer | Cough may be from endobronchial tumour irritating airway receptors, post-obstructive pneumonia, or lymphangitic spread. In HK, non-smoking adenocarcinoma in women is rising. |
| Mediastinal tumour | Compression of airways or vagus nerve → cough | |
| Interstitial lung disease | Idiopathic pulmonary fibrosis (IPF) | Dry cough — fibrotic distortion of airways stimulates mechanoreceptors; associated restrictive physiology |
| Sarcoidosis | Granulomatous inflammation in airways and parenchyma → cough | |
| Cardiac | Left heart failure | ↑ pulmonary venous pressure → pulmonary congestion/interstitial oedema → stimulation of juxtacapillary (J) receptors and airway C-fibres → cough, especially nocturnal/supine |
| Pleural | Pleural effusion | Cough from diaphragmatic/phrenic nerve irritation or compression of adjacent airways |
| Other | Obstructive sleep apnoea (OSA) | Chronic pharyngeal inflammation → ↑ cough reflex sensitivity; associated GERD |
| Post-nasal drip from chronic sinusitis | Overlaps with UACS | |
| Chronic tonsillar/adenoidal enlargement | Pharyngeal irritation | |
| Psychogenic / Habit cough | Diagnosis of exclusion; "honking" or "barking" quality; absent during sleep; more common in adolescents | |
| Ear pathology (Arnold's reflex) | Cerumen impaction, foreign body, or otitis externa stimulating auricular branch of vagus | |
| Somatic cough syndrome / Cough hypersensitivity syndrome | Emerging concept: heightened sensitivity of the cough reflex arc at peripheral (receptor) or central (brainstem) level. May explain "unexplained chronic cough" after all causes excluded |
The Cough Hypersensitivity Syndrome
Modern understanding views many cases of "unexplained chronic cough" as a cough hypersensitivity syndrome — an upregulation of the cough reflex at peripheral (TRPV1/TRPA1 receptor sensitisation) or central (medullary) level. This is analogous to central sensitisation in chronic pain syndromes. Triggers that would not normally cause cough (talking, laughing, cold air, perfumes) become sufficient. This concept unifies UACS, CVA, and GERD-related cough as conditions that sensitise the reflex, with the cough threshold lowered.
Pathophysiology — Mechanism-by-Mechanism
Let me walk through the pathophysiology of each major category so you understand why the cough occurs.
- Pathogen → airway epithelial injury → release of inflammatory mediators (prostaglandins, bradykinin, histamine, substance P)
- These mediators directly stimulate C-fibre receptors (TRPV1, TRPA1)
- Epithelial shedding exposes bare nerve endings → lowered cough threshold (even normal stimuli now trigger cough)
- Mucus hypersecretion (from goblet cell hyperplasia and submucosal gland stimulation) → mechanical stimulation of RARs → productive cough
- Why does post-infectious cough persist? Because epithelial regeneration takes weeks → nerve endings remain exposed, and transient bronchial hyperreactivity persists even after the infection has cleared
- Allergen/trigger → Type 2 (Th2) immune response → IL-4, IL-5, IL-13 → eosinophil recruitment and activation → release of eosinophil granule proteins (major basic protein, eosinophil cationic protein) → epithelial damage
- Mast cell degranulation → histamine, leukotrienes → bronchospasm + mucus secretion + oedema
- All three → airway narrowing → wheezing
- Epithelial damage → exposed nerve endings → ↑ cough reflex sensitivity
- In cough-variant asthma, the predominant response is cough rather than bronchospasm — possibly due to the distribution of inflammation (more central vs. peripheral airways) or individual variation in cough reflex sensitivity
As detailed above, three pathways:
- Micro-aspiration (acid reaching larynx/trachea)
- Oesophago-bronchial vagal reflex (distal oesophageal acid → vagal-mediated bronchoconstriction)
- Cough reflex sensitisation (chronic acid exposure upregulates TRPV1 receptors on airway C-fibres)
Why does GERD worsen cough, and cough worsen GERD? A vicious cycle: [3]
- Coughing increases intra-abdominal pressure → promotes reflux → more acid exposure → more cough
- This is why GERD and chronic cough frequently coexist and are hard to treat
- ACE (angiotensin-converting enzyme) = kininase II
- Normally degrades bradykinin and substance P in the lungs
- ACEi blocks this enzyme → accumulation of bradykinin and substance P in airway mucosa
- Bradykinin stimulates C-fibre receptors (TRPV1) → cough
- Substance P is a neuropeptide that also stimulates C-fibres and promotes neurogenic inflammation
- Genetic variation in bradykinin receptor or ACE gene may explain why some patients develop cough and others don't
- Cigarette smoke contains > 7,000 chemicals including acrolein, formaldehyde, hydrogen cyanide
- Acute: direct chemical irritation of C-fibres → cough
- Chronic: oxidative stress → chronic airway inflammation → goblet cell metaplasia + hyperplasia → mucus hypersecretion → productive "smoker's cough"
- Chronic bronchitis component of COPD: sputum-producing cough on most days for ≥ 3 months in 2 consecutive years [5]
- Ciliary dysfunction (smoking destroys cilia) → impaired mucociliary clearance → reliance on cough for clearance
- COPD is responsible for ~10% of public medical bed days in HK [5]
- Mycobacterium tuberculosis → granulomatous inflammation → caseous necrosis of lung parenchyma
- Airway involvement: endobronchial TB → ulceration → cough
- Cavitation: necrotic material irritates airways → productive cough ± haemoptysis
- Pleural involvement: pleuritis → cough from pleural C-fibre stimulation
- Central tumours: grow endobronchially → direct mechanical irritation of airway cough receptors
- Post-obstructive pneumonia/atelectasis: tumour obstructs bronchus → distal infection/collapse → cough
- Lymphangitis carcinomatosa: tumour cells in pulmonary lymphatics → interstitial oedema → stimulation of juxtacapillary receptors → dry cough
- Mediastinal lymphadenopathy: compression of vagus nerve or airways → cough
- Pleural involvement: malignant pleural effusion → diaphragmatic irritation → cough
- LV failure → ↑ left atrial pressure → ↑ pulmonary venous pressure → pulmonary congestion and interstitial oedema
- Fluid in the interstitium stimulates juxtacapillary (J) receptors (unmyelinated C-fibres in alveolar walls near capillaries) → reflex cough
- Bronchial mucosal oedema → mechanical stimulation of RARs → cough
- Why worse at night / lying flat? Supine position → redistribution of blood to pulmonary vasculature (↑ preload) → ↑ pulmonary congestion → ↑ cough (also explains PND and orthopnoea)
- Severe: frank pulmonary oedema → pink frothy sputum
Classification
| Category | Duration | Most Common Causes |
|---|---|---|
| Acute | < 3 weeks | Viral URTI, acute bronchitis, pneumonia, acute asthma, PE, pneumothorax, HF |
| Subacute | 3–8 weeks | Post-infectious, pertussis, undiagnosed asthma |
| Chronic | > 8 weeks | UACS/PNDS, asthma/CVA/EB, GERD, ACEi, COPD/smoking, TB, lung cancer, ILD, HF |
| Character | Description | Common Associations |
|---|---|---|
| Dry (non-productive) | No sputum | Viral URTI, CVA, ACEi, GERD, ILD (IPF), early lung cancer, psychogenic |
| Productive (wet) | Sputum present | Pneumonia, chronic bronchitis/COPD, bronchiectasis, TB, lung abscess |
| Barking / Croupy | Harsh, seal-like | Croup (laryngotracheobronchitis) in children; subglottic oedema |
| Whooping | Paroxysmal with inspiratory whoop | Pertussis |
| Brassy / Bovine | Non-explosive, flat quality | Recurrent laryngeal nerve palsy (vocal cord paralysis) — loss of glottic closure means cough cannot generate adequate pressure. Causes: lung cancer (left hilar), aortic aneurysm, thyroid surgery, mediastinal lymphadenopathy |
| Staccato | Short, choppy bursts | Chlamydia pneumonia in neonates |
| Sputum | Association |
|---|---|
| Mucoid (clear/white) | Viral infection, asthma, COPD |
| Mucopurulent (yellow) | Bacterial infection, acute exacerbation of COPD |
| Purulent (green) | Bacterial pneumonia, bronchiectasis (myeloperoxidase from neutrophils gives green colour) |
| Rusty | Pneumococcal pneumonia (blood mixed with purulent sputum) |
| Blood-streaked / Haemoptysis | TB, lung cancer, bronchiectasis, PE, mitral stenosis |
| Pink frothy | Acute pulmonary oedema (LVF) |
| Foul-smelling | Anaerobic lung abscess, aspiration pneumonia |
| Large volume (cupfuls) | Bronchiectasis ("postural" — worse in morning and with position change), lung abscess |
Clinical Features
Symptoms (History-Taking Framework)
When a patient presents with cough, the history should systematically address:
- Onset: Acute vs. gradual vs. insidious
- Sudden onset → foreign body, PE, pneumothorax
- Gradual onset → infection, asthma, GERD
- Insidious over months → malignancy, ILD, TB
- Duration: Acute / subacute / chronic (as classified above)
- Character: Dry vs. productive; barking, whooping, bovine (as above)
- Diurnal variation:
- Nocturnal / lying flat → asthma, GERD, LVF (all worsen supine)
- Why? Asthma: circadian cortisol nadir at night → ↑ inflammation. GERD: supine → loss of gravity → ↑ reflux. LVF: supine → ↑ preload → ↑ pulmonary congestion
- Morning (on waking) → COPD/chronic bronchitis (accumulated overnight secretions), bronchiectasis
- Throughout day, absent at sleep → psychogenic cough
- Nocturnal / lying flat → asthma, GERD, LVF (all worsen supine)
- Triggers / Aggravating factors:
- Exercise/cold air → asthma
- Meals / lying flat / bending → GERD
- Dust/allergen exposure → allergic rhinitis/asthma
- Talking/laughing/perfumes → cough hypersensitivity
- Positional → bronchiectasis
- Sputum: Colour, consistency, volume, presence of blood (see sputum table above)
| Associated Symptom | Pathophysiological Link | Suggests |
|---|---|---|
| Nasal congestion, rhinorrhoea, post-nasal drip, facial pressure | Sinusitis / rhinitis → secretions drip onto pharyngeal cough receptors | UACS / PNDS |
| Sneezing, itchy eyes/nose | IgE-mediated nasal inflammation → post-nasal drip | Allergic rhinitis |
| Wheeze | Bronchospasm → turbulent airflow through narrowed airways | Asthma, COPD |
| Dyspnoea | Airflow limitation (obstructive) or gas exchange impairment | Asthma, COPD, ILD, HF, PE |
| Heartburn, regurgitation, acid brash, epigastric discomfort | Acid reflux → oesophageal mucosal injury → oesophago-bronchial reflex or micro-aspiration [3] | GERD |
| Hoarseness | Laryngeal inflammation from acid reflux (laryngo-pharyngeal reflux) or vocal cord pathology | GERD/LPR, recurrent laryngeal nerve palsy |
| Throat clearing | Mucus on pharynx from UACS or LPR | UACS, GERD |
| Haemoptysis | Airway mucosal erosion, cavitary disease, tumour vasculature | TB, lung cancer, bronchiectasis, PE, mitral stenosis |
| Fever, rigors, malaise | Systemic inflammatory response to infection | Pneumonia, TB, lung abscess |
| Night sweats, weight loss | Chronic systemic inflammation / malignancy | TB, lung cancer, lymphoma |
| Pleuritic chest pain | Inflammation of parietal pleura (somatic pain) | Pneumonia, PE, pleurisy |
| Orthopnoea, PND, peripheral oedema | LV failure → pulmonary congestion worsened supine; RV failure → venous congestion | Heart failure |
| Dysphagia | Oesophageal stricture from chronic GERD or extrinsic compression | GERD complication, mediastinal mass |
| Joint pains, skin rashes | Systemic autoimmune disease → associated ILD | Sarcoidosis, connective tissue disease-ILD |
Red Flags in Cough — Do Not Miss
The following should prompt urgent investigation:
- Haemoptysis — must exclude lung cancer, TB, PE
- Unexplained weight loss — malignancy, TB
- New onset in age > 45 years, especially smoker — lung cancer
- Voice change / hoarseness — recurrent laryngeal nerve involvement (lung cancer, aortic aneurysm)
- Persistent fever — underlying infection or malignancy
- Significant dyspnoea or worsening exercise tolerance
- Systemic symptoms (night sweats, fatigue)
- Chest pain
- Swallowing difficulty
- Recurrent pneumonia — endobronchial obstruction (tumour, foreign body)
- ACEi use — must always ask! This is one of the commonest iatrogenic causes of chronic cough
- Smoking history (pack-years)
- Atopy history (eczema, allergic rhinitis, asthma)
- TB contact history (especially important in HK)
- Occupational history (dusts, fumes, asbestos)
- Immunosuppression (HIV status, medications)
- Previous TB treatment
- GERD history
- Cardiac history (heart failure)
Signs (Physical Examination Findings)
A systematic examination in a patient with cough should cover:
| Sign | Pathophysiological Basis | Suggests |
|---|---|---|
| Cachexia / weight loss | Chronic catabolic state from malignancy or chronic infection | Lung cancer, TB, advanced COPD |
| Finger clubbing | Mechanism debated; likely VEGF/PDGF released by tumour or chronic hypoxia → nail bed vascular proliferation | Lung cancer, bronchiectasis, ILD (IPF), lung abscess, empyema. NOT seen in COPD or asthma |
| Tar staining of fingers | Nicotine/tar deposition from cigarettes | Smoker → COPD, lung cancer risk |
| Cyanosis (central) | Desaturated Hb > 5 g/dL — from V/Q mismatch or shunt | Severe pneumonia, COPD, ILD, massive PE |
| Peripheral oedema | ↑ hydrostatic pressure from RHF (back-pressure from LHF or cor pulmonale) OR hypoalbuminaemia | Heart failure, cor pulmonale in COPD |
| Lymphadenopathy (cervical/supraclavicular) | Metastatic spread or reactive lymphadenopathy | Lung cancer (esp. left supraclavicular = Virchow's node), TB, lymphoma |
| Pallor | Anaemia from chronic disease | Malignancy, chronic infection |
| Sign | Basis | Suggests |
|---|---|---|
| Nasal mucosal oedema, "boggy" turbinates, nasal polyps | Chronic allergic inflammation | Allergic rhinitis → UACS |
| Cobblestone pharynx | Chronic post-nasal drip → pharyngeal lymphoid hyperplasia | UACS / PNDS |
| Pharyngeal erythema / granularity | Acid-induced inflammation of posterior pharynx | Laryngo-pharyngeal reflux (GERD) |
| Tonsillar enlargement / exudate | Infection or chronic inflammation | Tonsillitis, chronic pharyngitis |
| Sign | Pathophysiological Basis | Suggests |
|---|---|---|
| Wheeze (expiratory polyphonic) | Turbulent airflow through multiple narrowed small airways | Asthma, COPD |
| Wheeze (fixed monophonic / localised) | Single large airway narrowed by tumour or foreign body | Endobronchial lesion — lung cancer, foreign body |
| Stridor (inspiratory) | Turbulent airflow through narrowed extrathoracic upper airway | Upper airway obstruction — croup, epiglottitis, tumour, foreign body, anaphylaxis |
| Crackles / Crepitations (fine, bilateral basal inspiratory) | Opening of collapsed alveoli or fluid in alveoli | Pulmonary fibrosis (ILD): "Velcro" crackles; Pulmonary oedema (HF) |
| Crackles (coarse, localised) | Air bubbling through secretions in larger airways | Pneumonia, bronchiectasis |
| Bronchial breathing | Consolidation transmits breath sounds with characteristic tubular quality | Lobar pneumonia |
| Dullness to percussion | Fluid (effusion) or solid tissue (consolidation, tumour) replacing air | Pleural effusion, pneumonia, lung cancer |
| Hyperresonance | Excess air (emphysema) or free air (pneumothorax) | COPD/emphysema, pneumothorax |
| Reduced breath sounds | Airway obstruction (COPD) or barrier to sound transmission (effusion, pneumothorax) | COPD, effusion, pneumothorax |
| Increased AP diameter ("barrel chest") | Hyperinflation from air trapping | COPD/emphysema |
| Sign | Basis | Suggests |
|---|---|---|
| Elevated JVP | ↑ right atrial pressure from RHF or biventricular failure | Heart failure |
| Displaced apex beat | LV dilatation | LV failure, dilated cardiomyopathy |
| S3 gallop | Rapid ventricular filling in a volume-overloaded ventricle | LV failure |
| Pansystolic murmur at apex → axilla | Mitral regurgitation → LV volume overload → pulmonary congestion → cough [6] | MR causing LHF |
| Mid-diastolic rumble at apex | Mitral stenosis → ↑ LA pressure → pulmonary hypertension → cough ± haemoptysis | Mitral stenosis |
| Bilateral basal crepitations | Transudative pulmonary oedema | LHF |
| Sign | Basis | Suggests |
|---|---|---|
| Epigastric tenderness | Gastric/oesophageal inflammation | GERD |
| Hepatomegaly / ascites | Hepatic congestion from RHF (↑ hydrostatic back-pressure in hepatic veins) | Right heart failure complicating chronic lung disease (cor pulmonale) or biventricular failure |
Chronic cough itself can cause complications (which may bring patients to seek help):
| Complication | Mechanism |
|---|---|
| Cough syncope (tussive syncope) | Sustained coughing → markedly ↑ intrathoracic pressure → ↓ venous return → ↓ cardiac output → transient cerebral hypoperfusion → syncope |
| Rib fractures | Repetitive mechanical stress on ribs (especially in osteoporotic patients) → pathological or stress fractures |
| Urinary stress incontinence | ↑ intra-abdominal pressure from coughing overwhelms pelvic floor muscles → urine leakage (common in women) |
| Cough headache | ↑ intrathoracic and intracranial pressure → transient ↑ CSF pressure |
| Subconjunctival haemorrhage | ↑ venous pressure during Valsalva → rupture of conjunctival capillaries |
| Abdominal wall hernia | Chronic ↑ intra-abdominal pressure → weakening of fascial planes → inguinal/umbilical hernia [7] |
| Pneumomediastinum / Pneumothorax | Alveolar rupture from high airway pressure during violent coughing |
| Quality of life impairment | Sleep disturbance, social embarrassment, depression, exhaustion |
| Worsening GERD | Cough → ↑ intra-abdominal pressure → ↑ reflux → more cough (vicious cycle) [3] |
| Worsening haemorrhoids | Chronic cough → chronic ↑ intra-abdominal pressure → ↑ haemorrhoidal venous pressure [8] |
| Condition | Why It Causes Cough |
|---|---|
| Viral URTI | Airway epithelial inflammation + post-nasal drip → exposed nerve endings + mechanical stimulation |
| Post-infectious | Epithelial regeneration incomplete → persistent nerve ending exposure + transient hyperreactivity |
| Asthma / CVA | Eosinophilic inflammation → epithelial damage → nerve exposure + airway hyperresponsiveness |
| COPD | Chronic inflammation → goblet cell hyperplasia → mucus hypersecretion + impaired mucociliary clearance |
| GERD | Micro-aspiration + vagal reflex + receptor sensitisation |
| UACS / PNDS | Post-nasal secretions mechanically + chemically stimulate pharyngeal/laryngeal receptors |
| ACEi | Bradykinin + substance P accumulation → C-fibre stimulation |
| TB | Granulomatous destruction → cavitation, ulceration → airway irritation |
| Lung cancer | Endobronchial irritation + post-obstructive pneumonia + vagal compression + lymphangitic spread |
| LHF | Pulmonary oedema → J-receptor and C-fibre stimulation |
| ILD / IPF | Fibrotic distortion → mechanoreceptor stimulation; "Velcro" crackles |
| Bronchiectasis | Permanent airway dilatation → mucus pooling → chronic infection → productive cough |
High Yield Summary
-
Cough classification by duration: Acute ( < 3 wk), Subacute (3–8 wk), Chronic ( > 8 wk) — this dictates the differential.
-
Big Three causes of chronic cough (normal CXR, non-smoker, no ACEi): UACS/PNDS, Asthma/CVA/EB, GERD — account for > 90%.
-
ACEi cough: Mechanism = bradykinin/substance P accumulation (NOT angiotensin-related). Class effect. Switch to ARB.
-
GERD-related cough may occur WITHOUT heartburn ("silent reflux"). Three mechanisms: micro-aspiration, oesophago-bronchial reflex, cough reflex sensitisation. Rising in HK.
-
In Hong Kong: Always exclude TB and lung cancer in chronic cough. Non-smoking lung adenocarcinoma in Asian women is increasingly common.
-
Red flags: Haemoptysis, weight loss, age > 45 + smoker, hoarseness, recurrent pneumonia — require urgent investigation.
-
Cough-variant asthma: Cough is SOLE symptom; responds to ICS + bronchodilator. Distinguished from eosinophilic bronchitis (normal methacholine challenge in EB).
-
Bovine cough (non-explosive, flat) → recurrent laryngeal nerve palsy → think lung cancer, aortic aneurysm.
-
Chronic cough can worsen: GERD (↑ intra-abdominal pressure), hernias, haemorrhoids — a vicious cycle.
-
Cough hypersensitivity syndrome: Emerging unifying concept for unexplained chronic cough — upregulated TRPV1/TRPA1 receptors.
Active Recall - Cough: Definition, Epidemiology, Risk Factors, Aetiology, Pathophysiology, Classification, and Clinical Features
[1] Lecture slides: murtagh merge.pdf [2] Clinical context: Hong Kong Centre for Health Protection — TB surveillance data; general HK epidemiology [3] Senior notes: Ryan Ho GI.pdf (Section 2.2.1 Gastroesophageal Reflux Disease) [4] Senior notes: Ryan Ho Respiratory.pdf (Section 3.2.1 Asthma) [5] Senior notes: Ryan Ho Respiratory.pdf (Section 3.2.2 Chronic Obstructive Pulmonary Disease) [6] Senior notes: Ryan Ho Cardiology.pdf (Section on Mitral Regurgitation, p155) [7] Senior notes: felixlai.md (Section III: Etiology of Hernia — chronic cough as risk factor) [8] Senior notes: felixlai.md (Section III: Etiology of Haemorrhoids — chronic cough increases intra-abdominal pressure)
Differential Diagnosis of Cough
The differential diagnosis of cough is vast — the key to navigating it efficiently is to always anchor your thinking to duration first, then layer on the clinical context. Think of cough as a signpost pointing to something deeper. Your job is to figure out what that something is.
The most practical clinical framework uses Murtagh's Diagnostic Strategy adapted for cough [1]:
- What is the probability diagnosis? (the most common cause in this context)
- What serious disorders must not be missed?
- What conditions are often missed (pitfalls)?
- What is on the masquerades checklist? (common conditions masquerading as something else)
- Is the patient trying to tell me something? (psychogenic, secondary gain)
This framework prevents you from jumping to rare diagnoses while ensuring you don't miss dangerous ones.
A. Differential by Duration
| Category | Differential | Key Distinguishing Features | Why It Causes Cough |
|---|---|---|---|
| Probability diagnosis | Viral URTI / common cold | Rhinorrhoea, sore throat, low-grade fever, self-limiting. Most common cause of acute cough worldwide | Airway epithelial inflammation + post-nasal drip stimulating pharyngeal RARs |
| Acute bronchitis | Productive cough ± wheeze, NO CXR infiltrate, usually viral | Lower airway inflammation → mucus hypersecretion + exposed nerve endings | |
| Acute exacerbation of asthma | Wheeze + dyspnoea + cough; triggers identifiable; reversible on bronchodilator [4] | Bronchospasm + eosinophilic inflammation → airway narrowing + C-fibre stimulation | |
| Acute exacerbation of COPD | Known COPD + ↑ cough, ↑ sputum volume/purulence, ↑ dyspnoea [5] | Infective trigger → amplified chronic airway inflammation in already damaged airways | |
| Serious not to miss | Pneumonia | Fever, productive cough (rusty/purulent sputum), dyspnoea, pleuritic pain, CXR consolidation | Alveolar exudate stimulates J-receptors; airway inflammation stimulates C-fibres and RARs |
| Pulmonary embolism | Acute dyspnoea, pleuritic chest pain, haemoptysis, tachycardia; risk factors for VTE [9] | Pulmonary infarction → pleural inflammation → C-fibre stimulation; reflex bronchoconstriction | |
| Pneumothorax | Sudden pleuritic pain + dyspnoea; reduced breath sounds, hyperresonance on affected side | Pleural C-fibre irritation from air in pleural space | |
| Acute heart failure | Orthopnoea, PND, pink frothy sputum, bilateral basal crepitations, raised JVP, S3 | Pulmonary oedema stimulates juxtacapillary J-receptors and airway C-fibres | |
| Foreign body aspiration | Sudden onset, unilateral wheeze/stridor; children or elderly | Mechanical stimulation of laryngeal/bronchial RARs by foreign object | |
| Acute epiglottitis / croup | Stridor, drooling, tripod position (epiglottitis); barking cough (croup) | Upper airway oedema → stimulation of laryngeal cough receptors | |
| Pitfalls | Pertussis | Paroxysmal cough with inspiratory whoop; post-tussive vomiting; unvaccinated/waning immunity | Bordetella pertussis toxin → ciliated epithelium destruction + sustained neuronal sensitisation ("100-day cough") |
| Inhaled irritant / toxic exposure | Occupational or accidental; acute onset after exposure | Direct chemical injury to airway epithelium → inflammation → cough | |
| Allergic rhinitis with post-nasal drip | Sneezing, rhinorrhoea, nasal congestion; may present as acute cough [1] | Allergen → IgE-mediated nasal inflammation → post-nasal secretions stimulate pharyngeal RARs |
| Category | Differential | Key Distinguishing Features | Why It Causes Cough |
|---|---|---|---|
| Probability diagnosis | Post-infectious cough | Follows recent URTI; no new symptoms; gradually improving | Epithelial regeneration incomplete → bare nerve endings + transient bronchial hyperreactivity |
| Serious not to miss | Pertussis | Can persist for weeks to months; paroxysms | Sustained epithelial damage + neuronal sensitisation by pertussis toxin |
| New-onset asthma / CVA | Cough ± wheeze, responds to bronchodilators/ICS | Eosinophilic inflammation → bronchial hyperresponsiveness | |
| TB (early presentation) | Chronic cough just reaching subacute timeframe; HK intermediate-burden area; contact history | Granulomatous airway inflammation → mucosal ulceration | |
| Pitfalls | Unrecognised GERD | No heartburn ("silent reflux"); cough worse after meals or lying flat [3] | Oesophago-bronchial vagal reflex + micro-aspiration |
| Unrecognised ACEi use | Newly started ACEi; dry tickly cough beginning weeks after initiation | Bradykinin/substance P accumulation → C-fibre stimulation |
This is where the differential becomes most complex and clinically important. The approach should be systematic and layered.
| Category | Differential | Key Distinguishing Features | Why It Causes Cough |
|---|---|---|---|
| "Big Three" — account for > 90% with normal CXR, non-smoker, no ACEi | |||
| 1 | Upper Airway Cough Syndrome / PNDS | Nasal congestion, post-nasal drip, cobblestone pharynx, throat clearing; responds to nasal steroids + antihistamines. Most common cause of chronic cough [1] | Post-nasal secretions mechanically stimulate pharyngeal/laryngeal RARs + chemical irritation of C-fibres |
| 2 | Asthma / Cough-variant asthma / Eosinophilic bronchitis | CVA: cough as sole symptom, positive methacholine challenge, responds to ICS + LABA. EB: sputum eosinophilia but NEGATIVE methacholine [4] | Eosinophilic inflammation → epithelial damage → exposed nerve endings + bronchial hyperresponsiveness (CVA) or pure cough reflex sensitisation (EB) |
| 3 | GERD | May have heartburn/regurgitation; may be "silent" — no GI symptoms. Cough worse post-prandial / supine. Asians present atypically — NCCP, acid feeling, extra-oesophageal symptoms [3] | Micro-aspiration + oesophago-bronchial vagal reflex + TRPV1 receptor sensitisation. Vicious cycle with cough ↑ intra-abdominal pressure ↑ reflux |
| Drug-induced | ACEi-induced cough | Dry, persistent, tickly cough. Onset days to months after starting ACEi. Class effect. 5–35% of users. Resolves 1–4 weeks after stopping | Bradykinin + substance P accumulation (ACE = kininase II normally degrades them) → C-fibre stimulation via TRPV1 |
| Smoking-related | COPD / Chronic bronchitis | Cough with sputum on most days for ≥ 3 months in 2 consecutive years. Smoking history. Progressive dyspnoea. Obstructive spirometry [5] | Chronic airway inflammation → goblet cell hyperplasia → mucus hypersecretion + impaired mucociliary clearance |
| Infection | Tuberculosis | Chronic cough ± haemoptysis ± night sweats ± weight loss ± fever. Contact history. Must exclude in HK — intermediate-burden region | Granulomatous inflammation → caseous necrosis → cavitation → airway mucosal ulceration and irritation |
| Bronchiectasis | Copious purulent sputum production; recurrent infections; clubbing possible. CT shows dilated thick-walled bronchi | Permanently dilated airways → mucus retention → chronic infection → productive cough ("vicious cycle") | |
| Lung abscess | Foul-smelling purulent sputum, fever, clubbing; air-fluid level on CXR | Necrotic cavity contents drain into airways → stimulate cough | |
| Chronic sinusitis | Facial pressure, nasal congestion, purulent nasal discharge → overlaps with UACS | Chronic post-nasal drip → pharyngeal/laryngeal RAR stimulation | |
| Neoplasm | Lung cancer | New cough or change in chronic cough in smoker > 45y; haemoptysis, weight loss, hoarseness (recurrent laryngeal nerve invasion). Non-smoking adenocarcinoma rising in HK women | Endobronchial tumour → mechanical RAR stimulation; post-obstructive pneumonia; lymphangitis carcinomatosa → J-receptor stimulation; vagal nerve compression |
| Mediastinal tumour / lymphadenopathy | Constitutional symptoms; CXR mediastinal widening | Compression of trachea/bronchi or vagus nerve → cough | |
| Interstitial lung disease | Idiopathic pulmonary fibrosis (IPF) | Progressive dyspnoea, dry cough, bilateral "Velcro" crackles, clubbing; restrictive spirometry, ↓ DLCO | Fibrotic distortion of airway architecture → mechanical stimulation of RARs + J-receptors |
| Sarcoidosis | Young adults, bilateral hilar lymphadenopathy on CXR, non-caseating granulomas; may have erythema nodosum | Airway granulomatous inflammation → RAR + C-fibre stimulation | |
| Connective tissue disease-associated ILD | Joint pains, skin rashes, Raynaud's; HRCT ground-glass or UIP pattern | Autoimmune-driven pulmonary fibrosis / alveolitis → same mechanism as IPF | |
| Cardiac | Left heart failure | Exertional dyspnoea, orthopnoea, PND, bilateral crepitations, elevated JVP, S3 | ↑ Pulmonary venous pressure → interstitial oedema → J-receptor and C-fibre stimulation |
| Mitral stenosis | Exertional dyspnoea, haemoptysis; opening snap + mid-diastolic rumble | ↑ LA pressure → pulmonary venous hypertension → bronchial mucosal congestion + haemoptysis from bronchial vein rupture | |
| Mitral regurgitation | Fatigue initially; dyspnoea late when LV fails; pansystolic murmur at apex to axilla [6] | Chronic MR → LV volume overload → eventual LV failure → pulmonary congestion → cough | |
| Pleural | Pleural effusion | Dullness to percussion, reduced breath sounds, stony dull note | Diaphragmatic/phrenic nerve irritation by fluid → reflex cough |
| Other respiratory | Obstructive sleep apnoea | Snoring, daytime somnolence, morning headache; associated GERD | Chronic pharyngeal inflammation → ↑ cough reflex sensitivity; GERD from nocturnal reflux |
| Tracheobronchomalacia | Expiratory wheeze, "barking" cough; may follow prolonged intubation | Dynamic airway collapse during expiration → stimulation of RARs | |
| Non-pulmonary | Ear pathology (Arnold's reflex) | Cerumen impaction, foreign body, otitis externa; cough triggered by ear examination | Auricular branch of vagus (Arnold's nerve) stimulation → vagal cough reflex |
| Chronic tonsillar / adenoidal enlargement | Snoring, mouth breathing, recurrent tonsillitis; children predominant | Pharyngeal irritation → mechanical stimulation of pharyngeal cough receptors |
Multiple Aetiologies Are Common!
In up to 25–40% of chronic cough patients, more than one cause coexists. For example, a patient may have UACS + GERD + CVA simultaneously. This is why empiric sequential therapy (treating one cause at a time) may fail, and why you should always consider combination aetiologies if single-cause treatment is insufficient.
Murtagh's framework specifically for cough:
| Murtagh Category | Differentials for Cough |
|---|---|
| Probability diagnosis | Viral URTI / common cold; Acute bronchitis; Post-infectious cough; UACS/PNDS; Asthma/CVA; GERD; Smoking/COPD |
| Serious disorders not to be missed | |
| — Vascular | Pulmonary embolism; Aortic aneurysm (compressing airway/recurrent laryngeal nerve) |
| — Infection | Pneumonia; Tuberculosis; Lung abscess; Empyema |
| — Cancer/tumour | Lung cancer; Mediastinal tumour/lymphoma; Laryngeal cancer |
| — Other | Heart failure; Foreign body aspiration |
| Pitfalls (often missed) | ACEi-induced cough; Silent GERD; Eosinophilic bronchitis; Pertussis; Bronchiectasis; Ear pathology (Arnold's reflex); Aspiration from dysphagia (e.g., neurological disease) |
| Masquerades checklist | Drugs (ACEi); Depression/anxiety (psychogenic cough); Thyroid (goitre compressing trachea); Anaemia (not a direct cause but contributes to dyspnoea misinterpreted as cough); Diabetes (gastroparesis → GERD) |
| Is the patient trying to tell me something? | Psychogenic / habit cough; Somatic cough syndrome / cough hypersensitivity; Factitious disorder |
Murtagh's Masquerade — Drugs
Drugs are on the masquerades checklist for a reason. ACEi-induced cough is one of the most commonly overlooked causes of chronic cough. Always take a thorough drug history. Other drugs that can cause cough include: methotrexate (pulmonary toxicity), amiodarone (pulmonary fibrosis), nitrofurantoin (pneumonitis), beta-blockers (bronchospasm in asthmatics). [1]
| Condition | Why Emphasised in HK |
|---|---|
| Tuberculosis | HK incidence ~55/100,000. Must be excluded in any chronic cough, especially with haemoptysis, night sweats, weight loss, or TB contact |
| Lung cancer (including non-smoking adenocarcinoma) | High incidence in HK; non-smoking-related adenocarcinoma is increasingly common in Asian women. Any new or changed cough in age > 40y warrants CXR |
| GERD | Rising incidence in HK (2.5% in 2002 → 3.7% in 2011); Asians present atypically with extra-oesophageal symptoms [3] |
| Asthma | 8.6% prevalence in HK; cough-variant asthma commonly presents to primary care [4] |
| COPD | ~10% of > 70y in HK; major contributor to public hospital bed-days [5] |
| Nasopharyngeal carcinoma (NPC) | Endemic in Southern Chinese. Chronic post-nasal drip, bloody nasal discharge, unilateral serous otitis media, cervical lymphadenopathy. May present with cough from post-nasal drip or direct airway involvement |
This table helps you pattern-match from the clinical picture to the most likely diagnosis:
| Clinical Pattern | Most Likely Diagnosis |
|---|---|
| Acute cough + rhinorrhoea + sore throat + low-grade fever | Viral URTI |
| Acute productive cough + fever + CXR consolidation | Pneumonia |
| Chronic dry cough + nasal congestion + throat clearing + cobblestone pharynx | UACS / PNDS |
| Chronic cough (sole symptom) + normal CXR + positive methacholine | Cough-variant asthma |
| Chronic cough + sputum eosinophilia + negative methacholine + normal spirometry | Eosinophilic bronchitis |
| Chronic cough ± heartburn + worse post-prandial/supine | GERD |
| Chronic dry tickly cough + on ACEi + no other explanation | ACEi-induced cough |
| Chronic productive cough + smoking + progressive dyspnoea + obstructive PFT | COPD / chronic bronchitis |
| Chronic cough + haemoptysis + night sweats + weight loss + HK resident | TB (until proven otherwise) |
| Chronic cough + haemoptysis + weight loss + smoker > 45y + CXR mass | Lung cancer |
| Chronic cough + copious purulent sputum daily + recurrent infections + clubbing | Bronchiectasis |
| Chronic dry cough + progressive dyspnoea + bilateral Velcro crackles + clubbing | IPF / ILD |
| Chronic cough + orthopnoea + PND + bilateral crepitations + raised JVP + S3 | Left heart failure |
| Chronic cough + bovine quality (non-explosive) + hoarseness | Recurrent laryngeal nerve palsy → lung cancer, aortic aneurysm |
| Chronic cough + paroxysmal attacks + inspiratory whoop | Pertussis |
| Chronic cough absent during sleep + barking/honking quality + adolescent | Psychogenic / habit cough |
| Cough triggered by ear examination / cerumen removal | Arnold's reflex (auricular branch of vagus) |
| Chronic cough post-allogeneic HSCT + dry cough + progressive dyspnoea | Bronchiolitis obliterans (chronic GvHD) [10] |
When cough presents with haemoptysis, the differential narrows and the urgency increases:
| Category | Causes |
|---|---|
| Infection | TB, pneumonia, lung abscess, bronchiectasis, fungal infection (aspergilloma) |
| Neoplasm | Lung cancer (primary or metastatic) |
| Vascular | PE with pulmonary infarction, AV malformation, Goodpasture's syndrome |
| Cardiac | Mitral stenosis (pulmonary venous hypertension → bronchial vein rupture) |
| Autoimmune | Granulomatosis with polyangiitis (Wegener's), SLE (diffuse alveolar haemorrhage) |
| Other | Anticoagulant use, coagulopathy, iatrogenic (post-bronchoscopy/biopsy) |
Always get a CXR as the first investigation in haemoptysis. If normal but clinical suspicion remains, proceed to CT chest. If massive haemoptysis, this is a medical emergency — secure the airway (lateral decubitus with bleeding side down) and consult interventional radiology (bronchial artery embolisation) or thoracic surgery.
F. Differential of Cough in Special Populations
| Differential | Key Features |
|---|---|
| Viral URTI / croup | Most common; barking cough in croup (parainfluenza) |
| Asthma | Recurrent wheeze + cough, atopic history |
| Foreign body aspiration | Sudden onset, unilateral signs; toddlers |
| Pertussis | Unvaccinated/incomplete vaccination; paroxysmal cough with whoop [1] |
| Cystic fibrosis | Chronic productive cough from infancy, failure to thrive, steatorrhoea |
| Primary ciliary dyskinesia | Chronic wet cough, recurrent otitis media, situs inversus (Kartagener's) |
| Protracted bacterial bronchitis | Wet cough > 4 weeks; responds to prolonged antibiotics |
| Psychogenic cough | School-age children; honking quality; absent during sleep |
| Differential | Key Features |
|---|---|
| Pneumocystis jirovecii pneumonia (PCP) | HIV with CD4 < 200; dry cough, progressive dyspnoea, bilateral ground-glass on CT |
| TB (including extrapulmonary) | ↑ risk; atypical CXR presentations |
| Fungal infections (Aspergillus, Cryptococcus) | Nodules, cavities on imaging |
| CMV pneumonitis | Post-transplant; ground-glass opacities |
| Bronchiolitis obliterans | Post-allogeneic HSCT; dry cough → progressive dyspnoea; part of chronic GvHD [10] |
High Yield Summary — Differential Diagnosis of Cough
-
Use duration as your primary organiser: Acute ( < 3 wk) → mostly infectious. Subacute (3–8 wk) → post-infectious, pertussis, early asthma. Chronic ( > 8 wk) → Big Three (UACS, asthma/CVA/EB, GERD) + ACEi + COPD + serious causes.
-
Chronic cough with normal CXR, non-smoker, no ACEi: > 90% due to UACS, asthma/CVA/EB, or GERD — often in combination.
-
Always ask about ACEi — most commonly missed iatrogenic cause.
-
In HK: TB and lung cancer must be excluded in every chronic cough. GERD is rising and often presents atypically. NPC is endemic in Southern Chinese.
-
Red flags triggering urgent investigation: Haemoptysis, weight loss, new cough in smoker > 45y, hoarseness, recurrent pneumonia.
-
Bovine cough = recurrent laryngeal nerve palsy → think lung cancer, aortic aneurysm.
-
Cough absent during sleep → psychogenic/habit cough.
-
Multiple aetiologies coexist in 25–40% of chronic cough cases.
-
Post-infectious cough is the most common cause of subacute cough — self-limiting but may take weeks.
-
Haemoptysis differential: TB, lung cancer, bronchiectasis, PE, mitral stenosis — CXR is the first investigation.
Active Recall - Differential Diagnosis of Cough
References
[1] Lecture slides: murtagh merge.pdf [3] Senior notes: Ryan Ho GI.pdf (Section 2.2.1 Gastroesophageal Reflux Disease) [4] Senior notes: Ryan Ho Respiratory.pdf (Section 3.2.1 Asthma) [5] Senior notes: Ryan Ho Respiratory.pdf (Section 3.2.2 Chronic Obstructive Pulmonary Disease) [6] Senior notes: Ryan Ho Cardiology.pdf (p155, Mitral Regurgitation) [9] Senior notes: Ryan Ho Haemtology.pdf (p131, Venous Thromboembolism — Pulmonary Embolism) [10] Senior notes: Ryan Ho Haemtology.pdf (p158, Chronic GvHD — Bronchiolitis Obliterans)
Diagnostic Criteria, Algorithm and Investigations for Cough
Cough is a symptom, not a disease. Unlike heart failure or diabetes, there is no set of diagnostic criteria that "diagnoses" cough itself. Instead, the diagnostic task is twofold:
- Classify the cough (acute/subacute/chronic; productive/non-productive; presence of red flags)
- Identify the underlying cause — this is where diagnostic criteria for specific aetiologies come in
The approach is therefore algorithmic: you progress step-by-step, ruling out serious causes first, then systematically evaluating the most common causes.
Diagnostic Criteria for Key Underlying Conditions Causing Cough
While cough itself has no standalone diagnostic criteria, the specific aetiologies do. Here are the diagnostic criteria for the conditions you are most commonly evaluating in a chronic cough workup:
There are no universally validated diagnostic criteria — diagnosis is clinical + therapeutic:
| Feature | Details |
|---|---|
| Clinical features | Nasal congestion, rhinorrhoea, post-nasal drip sensation, throat clearing, cobblestone pharynx on examination |
| Diagnostic confirmation | Response to empiric therapy (1st-generation antihistamine + intranasal corticosteroid) within 2–4 weeks confirms the diagnosis retrospectively |
| Supporting investigation | Sinus imaging (CT sinuses) if chronic sinusitis suspected — shows mucosal thickening, opacification, air-fluid levels |
Why is UACS a diagnosis of therapeutic response? Because there is no gold-standard test that definitively proves post-nasal drip causes cough. The drip itself is a normal physiological event — it becomes pathological only when excessive enough to trigger cough. The best evidence of causality is resolution with targeted therapy.
Cough-variant asthma (CVA) is diagnosed when [4]:
| Criterion | Detail |
|---|---|
| Cough | Chronic cough as the predominant or sole symptom (no wheeze, minimal dyspnoea) |
| Spirometry | May be normal or show reversible airflow obstruction (FEV₁ ↑ ≥ 12% AND ≥ 200 mL post-bronchodilator) |
| Bronchoprovocation testing | Positive methacholine challenge (PC₂₀ < 16 mg/mL) — demonstrates bronchial hyperresponsiveness |
| Therapeutic response | Resolution or significant improvement with inhaled corticosteroids ± bronchodilator |
| Exclusion | Other causes of chronic cough excluded |
| Criterion | Detail |
|---|---|
| Cough | Chronic cough, usually dry |
| Sputum eosinophilia | > 3% eosinophils on induced sputum cytology |
| Normal bronchoprovocation | Negative methacholine challenge (PC₂₀ ≥ 16 mg/mL) — distinguishes from CVA |
| Normal spirometry | No airflow obstruction |
| Therapeutic response | Responds to inhaled corticosteroids |
CVA vs EB — The Crucial Distinction
Both have eosinophilic airway inflammation and respond to ICS. The defining difference is bronchial hyperresponsiveness — present in CVA (positive methacholine), absent in EB (negative methacholine). This matters because CVA can progress to classic asthma (up to 30% over years), while EB generally does not.
There are no universally accepted diagnostic criteria for GERD-related cough — it remains one of the most challenging diagnoses. The Montreal Definition of GERD [3]:
GERD is defined as a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.
For cough specifically attributed to GERD:
| Approach | Detail |
|---|---|
| Clinical suspicion | Chronic cough ± heartburn/regurgitation; worse post-prandial or supine; may be "silent" — no GI symptoms [3] |
| Empiric PPI trial | Standard-dose PPI for 8–12 weeks. A positive response supports the diagnosis but is not definitive (30–40% sensitivity for reflux-cough) |
| Ambulatory pH monitoring (24h) | Gold standard for documenting pathological acid reflux. Positive if DeMeester score > 14.7 or symptom association probability (SAP) > 95% |
| Impedance-pH monitoring | Detects both acid and non-acid reflux; more sensitive than pH alone — captures weakly acidic reflux events that can also cause cough |
| OGD | May show oesophagitis (Los Angeles classification), Barrett's; but many GERD-cough patients have normal endoscopy (NERD — non-erosive reflux disease) |
COPD is diagnosed by [5]:
| Criterion | Detail |
|---|---|
| Symptoms | Chronic dyspnoea, cough, sputum production |
| Risk factor exposure | Significant exposure to noxious particles/gases (esp. smoking) |
| Spirometry (mandatory) | Post-bronchodilator FEV₁/FVC < 0.70 confirms persistent airflow limitation |
Chronic bronchitis is a clinical definition [5]:
Cough with sputum production on most days for ≥ 3 months in 2 consecutive years (after exclusion of other causes)
No single "diagnostic criterion" — diagnosis is composite:
| Component | Detail |
|---|---|
| Clinical | Chronic cough (often > 2–3 weeks) ± haemoptysis, night sweats, weight loss, fever |
| CXR | Upper lobe infiltrate, cavitation, miliary pattern, pleural effusion |
| Microbiological | Sputum AFB smear (Ziehl-Neelsen stain) × 3; mycobacterial culture (gold standard, takes 2–8 weeks); GeneXpert MTB/RIF (rapid molecular, detects rifampicin resistance within 2 hours) |
| Supportive | Tuberculin skin test (Mantoux) or IGRA (interferon-gamma release assay — QuantiFERON) — indicate exposure/latent infection, cannot distinguish latent from active TB |
Diagnosis is clinical + temporal + by exclusion:
| Feature | Detail |
|---|---|
| Temporal relationship | Cough onset days to months after starting ACEi |
| Character | Dry, persistent, tickly cough |
| Exclusion | Other causes evaluated and excluded |
| Diagnostic confirmation | Resolution of cough within 1–4 weeks of stopping ACEi. If cough persists beyond 4 weeks after cessation, ACEi was NOT the cause |
This is the systematic stepwise approach used in clinical practice, based on current guidelines (ERS 2020, ACCP/CHEST 2024 updates, and local HK practice):
Key Principle of the Algorithm
The algorithm is designed to be sequential and empiric: you treat the most common cause first, observe the response, then move to the next most common cause. This is practical because many of these conditions lack a definitive single diagnostic test. Therapeutic trials are both diagnostic AND therapeutic. If the cough resolves, you have your diagnosis.
Common Pitfall — Premature Investigation
Do not order expensive investigations (HRCT, bronchoscopy, 24h pH monitoring) before completing the basic stepwise evaluation. A thorough history, CXR, spirometry, and empiric trials for the Big Three will identify the cause in > 90% of chronic cough with a normal CXR. Over-investigation is costly, may cause iatrogenic anxiety, and rarely yields a diagnosis that the systematic approach would have missed.
Investigations — Modality by Modality
A. Baseline Investigations (For All Patients with Cough Warranting Workup)
The single most important initial investigation in cough evaluation. [1]
| Aspect | Details |
|---|---|
| Indication | All patients with chronic cough; acute cough with red flags (haemoptysis, fever, dyspnoea, suspected pneumonia/PE/pneumothorax); subacute cough not resolving |
| What you're looking for | Mass/nodule (lung cancer), infiltrate/consolidation (pneumonia, TB), cavity (TB, abscess), effusion, fibrosis, hilar lymphadenopathy, hyperinflation (COPD), cardiomegaly + pulmonary congestion (HF), pneumothorax |
| Why it matters | A normal CXR dramatically narrows the differential — eliminates many serious causes and directs you towards the "Big Three." An abnormal CXR redirects you to cause-specific investigation |
| Interpretation pearls | |
| — Upper lobe infiltrate/cavity | TB until proven otherwise, especially in HK |
| — Hilar mass / mediastinal widening | Lung cancer, lymphoma, sarcoidosis |
| — Bilateral diffuse reticular/reticulonodular pattern | ILD (IPF, sarcoidosis, connective tissue disease-ILD) |
| — Cardiomegaly + upper lobe blood diversion + Kerley B lines | Left heart failure — pulmonary venous congestion |
| — Hyperinflation + flat diaphragms | COPD/emphysema |
| — Ring shadows / tramlines | Bronchiectasis (dilated thick-walled airways) |
| Aspect | Details |
|---|---|
| Indication | All patients with chronic cough (especially if dyspnoea or wheeze present); essential to diagnose or exclude asthma and COPD |
| Key parameters | FEV₁ (forced expiratory volume in 1 second), FVC (forced vital capacity), FEV₁/FVC ratio |
| Interpretation | |
| — FEV₁/FVC < 0.70 post-bronchodilator | Obstructive pattern → COPD [5] |
| — FEV₁/FVC < 0.70 with ≥ 12% AND ≥ 200 mL ↑ post-BD | Reversible obstruction → asthma [4] |
| — FEV₁/FVC normal or ↑ with ↓ FVC | Restrictive pattern → ILD, neuromuscular disease |
| — Normal spirometry | Does NOT exclude CVA or EB — proceed to bronchoprovocation |
| Why spirometry first? | It is cheap, non-invasive, reproducible, and immediately tells you whether there is an obstructive or restrictive process. This information fundamentally changes the differential |
| Test | What It Tells You | Key Findings |
|---|---|---|
| CBC with differential | Infection, eosinophilia, anaemia | ↑ WBC with neutrophilia → bacterial infection; eosinophilia → asthma, EB, parasitic infection, eosinophilic granulomatosis with polyangiitis; anaemia → chronic disease |
| CRP / ESR | Systemic inflammation | ↑ in infection, autoimmune, malignancy |
| Sputum microscopy + culture | Identify pathogen | Gram stain, culture for bacteria; ZN stain for AFB → TB |
| Sputum AFB smear × 3 + culture | TB diagnosis | Three early-morning sputum samples; culture is gold standard but takes weeks; GeneXpert MTB/RIF for rapid molecular diagnosis |
B. Second-Line Investigations (Directed by Clinical Suspicion)
| Aspect | Details |
|---|---|
| Principle | Methacholine is a cholinergic agonist that causes bronchoconstriction. In patients with bronchial hyperresponsiveness (asthma/CVA), even low doses trigger significant airway narrowing |
| Procedure | Inhaled methacholine in increasing concentrations; FEV₁ measured after each dose. The provocative concentration causing a 20% fall in FEV₁ (PC₂₀) is recorded |
| Interpretation | |
| — PC₂₀ < 4 mg/mL | High probability of asthma/CVA |
| — PC₂₀ 4–16 mg/mL | Borderline — possible asthma |
| — PC₂₀ ≥ 16 mg/mL | Negative — makes asthma/CVA very unlikely. If sputum eosinophilia present, consider EB |
| Clinical utility | A negative methacholine challenge has a very high negative predictive value for asthma — if negative, you can confidently move on to other diagnoses |
| Contraindications | Severe airflow obstruction (FEV₁ < 60% predicted), recent MI/stroke, uncontrolled hypertension, aortic aneurysm |
| Aspect | Details |
|---|---|
| Principle | Hypertonic saline (3–5%) nebulisation induces sputum production, which is then processed for differential cell count |
| Why it matters | Identifies airway eosinophilia (EB, asthma) or neutrophilia (infection, COPD) |
| Key threshold | > 3% eosinophils = eosinophilic airway inflammation |
| Clinical use | Distinguishes EB from CVA (both eosinophilic, but EB has normal methacholine); guides ICS therapy |
| Aspect | Details |
|---|---|
| Principle | Eosinophilic airway inflammation → ↑ inducible nitric oxide synthase (iNOS) in bronchial epithelium → ↑ NO in exhaled breath. FeNO is a surrogate marker for eosinophilic inflammation |
| Procedure | Patient exhales steadily into a device at a controlled flow rate. Result in parts per billion (ppb) |
| Interpretation | |
| — FeNO > 50 ppb (adults) | High probability of eosinophilic inflammation — likely asthma/CVA/EB |
| — FeNO 25–50 ppb | Intermediate — interpret in clinical context |
| — FeNO < 25 ppb | Low probability of eosinophilic inflammation |
| Limitations | ↑ by allergic rhinitis, viral infection; ↓ by smoking, corticosteroid use. Does not distinguish asthma from EB |
| Aspect | Details |
|---|---|
| Principle | Asthma causes variable airflow obstruction that fluctuates over time. PEF monitoring captures this variability |
| Procedure | Patient records PEF twice daily (morning and evening) for 2–4 weeks |
| Interpretation | Diurnal PEF variability > 10% (mean amplitude as % of mean) suggests asthma |
| Limitations | Effort-dependent; compliance variable; less sensitive than methacholine challenge |
C. Third-Line Investigations (When Basic Workup Non-Diagnostic)
| Aspect | Details |
|---|---|
| Indication | Chronic cough with abnormal CXR requiring further characterisation; suspicion of ILD, bronchiectasis, early lung cancer, or atypical infection when CXR is normal but clinical suspicion persists |
| What it shows | |
| — Ground-glass opacities | Active inflammation/early fibrosis (alveolitis, PCP, drug-induced lung disease) |
| — Honeycombing + traction bronchiectasis + basal predominance | UIP pattern → IPF |
| — Dilated, thick-walled airways ("signet ring" sign) | Bronchiectasis — internal airway diameter > accompanying pulmonary artery |
| — Tree-in-bud pattern | Small airway disease — infection (TB, NTM), aspiration |
| — Nodule/mass with spiculated margins | Lung cancer — requires biopsy [11] |
| — Bilateral hilar lymphadenopathy | Sarcoidosis, lymphoma |
| Why HRCT over plain CT? | Thin-slice (1–2 mm) acquisition with high spatial resolution → much better at detecting subtle parenchymal and airway abnormalities |
| Aspect | Details |
|---|---|
| Indication | Suspected pulmonary embolism; staging of lung malignancy [11] |
| Key finding in PE | Filling defect within pulmonary arteries |
| Key finding in malignancy | Mass characterisation, lymph node involvement, mediastinal invasion |
| Aspect | Details |
|---|---|
| Indication | Suspected endobronchial lesion (tumour, foreign body); haemoptysis with normal or inconclusive CT; need for bronchoalveolar lavage (BAL) or biopsy |
| Flexible vs rigid | Flexible bronchoscopy is standard for diagnostic purposes; rigid bronchoscopy for therapeutic intervention (foreign body removal, massive haemoptysis, stenting) |
| What it provides | Direct visualisation of airways (tumour, inflammation, anatomical abnormality); BAL fluid for cytology, microbiology (TB, fungal, PCP), cell counts; endobronchial biopsy; transbronchial biopsy for parenchymal lesions |
| BAL differential cell count | |
| — ↑ Eosinophils | Eosinophilic lung disease |
| — ↑ Lymphocytes | Sarcoidosis, hypersensitivity pneumonitis |
| — ↑ Neutrophils | Infection, ARDS |
| — Haemosiderin-laden macrophages | Diffuse alveolar haemorrhage |
| Aspect | Details |
|---|---|
| Indication | Chronic cough suspected GERD-related, especially if empiric PPI fails; objective documentation of reflux-cough association |
| Principle | A thin catheter with pH sensor (± impedance electrodes) is placed transnasally into the oesophagus for 24 hours. Patient records cough episodes + meals + position. The system correlates reflux events with cough timing |
| Key metrics | |
| — DeMeester score > 14.7 | Pathological acid reflux |
| — Symptom Association Probability (SAP) > 95% | Statistically significant temporal association between reflux events and cough episodes — supports GERD as cause of cough |
| — Symptom Index (SI) > 50% | > 50% of cough episodes preceded by reflux |
| pH-impedance vs pH alone | Impedance detects all reflux (acid, weakly acid, non-acid); pH alone only detects acid reflux. Important because non-acid reflux can also cause cough — missed by pH-only testing |
| When to perform | Ideally OFF PPI (to detect baseline acid exposure) for diagnostic purposes. If already on PPI and still symptomatic, test ON PPI to detect non-acid reflux |
Why Does Empiric PPI Often Fail for GERD-Cough?
Several reasons: (1) Non-acid reflux (bile, pepsin, weakly acidic) can also cause cough — PPI only suppresses acid. (2) The oesophago-bronchial vagal reflex may be triggered by volume reflux regardless of acidity. (3) Central sensitisation of the cough reflex may persist even after the acid stimulus is removed. (4) GERD may not actually be the cause — it was a coincidental finding. This is why objective testing with impedance-pH monitoring is valuable when empiric therapy fails.
| Aspect | Details |
|---|---|
| Indication | GERD symptoms (heartburn, regurgitation, dysphagia) or to evaluate for complications (oesophagitis, stricture, Barrett's) [3] |
| Findings | Oesophagitis graded by Los Angeles classification (A–D); Barrett's oesophagus (salmon-coloured columnar epithelium); stricture |
| Limitation for cough | Many GERD-cough patients have non-erosive reflux disease (NERD) — normal OGD does NOT exclude GERD as the cause of cough |
| Aspect | Details |
|---|---|
| Indication | Suspected cardiac cause of cough (heart failure, valvular disease) |
| Key findings | ↓ LVEF (systolic HF); diastolic dysfunction (HFpEF); valvular lesions (mitral stenosis/regurgitation); elevated estimated pulmonary artery systolic pressure; pericardial effusion |
| Aspect | Details |
|---|---|
| Indication | Suspected allergic rhinitis contributing to UACS, or atopic asthma |
| Modalities | Skin prick testing (SPT) for common aeroallergens; serum specific IgE (RAST) |
| Interpretation | Positive SPT or specific IgE indicates sensitisation — clinical relevance depends on correlation with symptoms |
| Aspect | Details |
|---|---|
| Indication | Chronic cough with features of chronic rhinosinusitis not responding to empiric treatment for UACS |
| Findings | Mucosal thickening, opacification of sinuses, air-fluid levels, polyps, anatomical variants (deviated septum, concha bullosa) |
| Aspect | Details |
|---|---|
| Indication | Hoarseness, suspected laryngopharyngeal reflux, vocal cord dysfunction, recurrent laryngeal nerve palsy, upper airway pathology |
| Findings | Vocal cord paralysis (lung cancer, aortic aneurysm); posterior laryngeal erythema and oedema (LPR); paradoxical vocal fold motion (vocal cord dysfunction — a mimic of asthma) |
| Aspect | Details |
|---|---|
| Principle | Automated molecular test that detects M. tuberculosis DNA AND rifampicin resistance mutations by PCR in < 2 hours |
| Indication | Suspected pulmonary TB — especially useful in HK for rapid diagnosis |
| Sensitivity | ~95% in smear-positive, ~70% in smear-negative TB |
| Advantage | Rapid (same-day result); simultaneously identifies rifampicin resistance (surrogate for MDR-TB) |
| Suspected Aetiology | First-Line Investigations | Second/Third-Line Investigations |
|---|---|---|
| UACS / PNDS | History + examination; empiric therapy trial | CT sinuses; allergy testing; ENT evaluation |
| Asthma / CVA | Spirometry ± reversibility; PEF diary; FeNO | Methacholine challenge; induced sputum; trial of ICS |
| Eosinophilic bronchitis | Induced sputum (eosinophils > 3%); FeNO | Methacholine challenge (negative); trial of ICS |
| GERD | Empiric PPI trial (8–12 wk) | 24h pH-impedance monitoring; OGD; barium swallow |
| ACEi-induced | Stop ACEi → observe 1–4 wk | None needed if cough resolves |
| COPD | Spirometry (FEV₁/FVC < 0.70 post-BD); CXR | HRCT if atypical; α1-antitrypsin level if young/non-smoker |
| TB | CXR; sputum AFB smear × 3; GeneXpert MTB/RIF | Sputum mycobacterial culture; IGRA/Mantoux; CT chest |
| Lung cancer | CXR; CT thorax with contrast | PET-CT; bronchoscopy + biopsy; CT-guided biopsy; staging |
| Bronchiectasis | CXR (may be normal); HRCT (diagnostic) | Sputum culture; immunoglobulin levels; CF testing; PCD testing |
| ILD / IPF | CXR; spirometry (restrictive); DLCO (↓) | HRCT (UIP pattern); BAL; surgical lung biopsy if needed |
| Heart failure | CXR; ECG; BNP/NT-proBNP | Echocardiography |
| PE | D-dimer (if low probability); CTPA | Duplex USG of legs; V/Q scan if contrast contraindicated [9] |
| Psychogenic / Habit | Diagnosis of exclusion | Observe cough absent during sleep; psychiatric evaluation |
Diagnostic Pitfalls to Avoid
-
Not asking about ACEi — This is the most commonly missed iatrogenic cause of chronic cough. It is embarrassing to order a battery of tests when the answer was in the drug chart all along.
-
Normal CXR does not exclude lung cancer — Small peripheral nodules and early endobronchial lesions may be invisible on CXR. If clinical suspicion is high (smoker > 45y, haemoptysis, weight loss), proceed to CT chest.
-
Normal spirometry does not exclude asthma — Asthma has variable airflow obstruction. Spirometry may be normal between attacks. Bronchoprovocation testing is required to demonstrate hyperresponsiveness.
-
Normal OGD does not exclude GERD-cough — Most GERD-cough patients have non-erosive reflux disease (NERD). pH-impedance monitoring is needed for objective documentation.
-
Failure to consider multiple co-existing aetiologies — Up to 40% of chronic cough patients have more than one cause. If treating one cause gives partial improvement, look for a second cause.
-
Inadequate duration of empiric trials — UACS requires 2–4 weeks; GERD requires 8–12 weeks of PPI. Stopping too early leads to false-negative therapeutic trials.
-
In HK: not ordering sputum AFB in chronic cough — TB must always be excluded. Three early-morning sputum samples for AFB smear and culture should be standard in any undiagnosed chronic cough.
High Yield Summary — Diagnostic Criteria, Algorithm and Investigations
-
Cough has no standalone diagnostic criteria — the task is to identify the underlying cause through a systematic algorithm.
-
The algorithm is sequential: Duration classification → ACEi check → CXR + spirometry → Evaluate Big Three (UACS → Asthma/CVA/EB → GERD) → Further workup if needed.
-
CVA diagnostic triad: Chronic cough as sole symptom + positive methacholine challenge + response to ICS/BD. EB: Same but negative methacholine + sputum eosinophilia > 3%.
-
COPD: Post-bronchodilator FEV₁/FVC < 0.70. Chronic bronchitis: Cough with sputum ≥ 3 months in 2 consecutive years.
-
GERD-cough: Empiric PPI 8–12 weeks; if fails → 24h pH-impedance monitoring (DeMeester > 14.7 or SAP > 95%).
-
CXR is mandatory for all chronic cough and acute cough with red flags. Normal CXR narrows the differential to the Big Three + ACEi + smoking.
-
Methacholine challenge: High negative predictive value for asthma. PC₂₀ < 4 mg/mL = asthma likely; ≥ 16 mg/mL = asthma very unlikely.
-
FeNO > 50 ppb: Suggests eosinophilic airway inflammation (asthma, CVA, EB).
-
In HK: Always send sputum AFB × 3 + GeneXpert in undiagnosed chronic cough. CXR upper lobe cavity = TB until proven otherwise.
-
Therapeutic trials are diagnostic: Resolution with specific therapy confirms the cause retrospectively — this is how UACS, CVA, and GERD-cough are often diagnosed.
Active Recall - Diagnostic Criteria, Algorithm and Investigations for Cough
References
[1] Lecture slides: murtagh merge.pdf [3] Senior notes: Ryan Ho GI.pdf (Section 2.2.1 Gastroesophageal Reflux Disease) [4] Senior notes: Ryan Ho Respiratory.pdf (Section 3.2.1 Asthma) [5] Senior notes: Ryan Ho Respiratory.pdf (Section 3.2.2 Chronic Obstructive Pulmonary Disease) [9] Senior notes: Ryan Ho Haemtology.pdf (p131, Venous Thromboembolism) [11] Senior notes: Ryan Ho Diagnostic Radiology.pdf (p36, p39–40, CT Applications)
Management of Cough
Before diving into specifics, let's establish the fundamental principles — think of these as the "operating system" for managing any patient with cough:
- Treat the cause, not the symptom — Cough is almost always a symptom of an underlying condition. Identifying and treating the cause is the primary goal. Cough suppressants alone are rarely the answer.
- Sequential, empiric, and cause-directed — For chronic cough, management follows the diagnostic algorithm: treat the most likely cause first, assess response, then address the next most likely.
- Give adequate trial duration — Each empiric therapy needs sufficient time to work before declaring failure. Premature switching is the most common management error.
- Consider multiple coexisting causes — Up to 40% of chronic cough patients have more than one aetiology. Partial response to treatment should prompt evaluation for a second cause, not abandonment of the first.
- Address the cough itself when necessary — While treating the underlying cause, symptomatic relief may be needed for severe complications (rib fractures, syncope, incontinence, sleep deprivation, quality of life).
A. Management of Acute Cough
| Component | Management | Rationale |
|---|---|---|
| General | Rest, hydration, warm fluids | Supportive; there is no specific antiviral for most common cold viruses |
| Analgesics / Antipyretics | Paracetamol or ibuprofen | Symptom relief for sore throat, headache, fever |
| Nasal congestion | Intranasal decongestant (e.g., xylometazoline) for ≤ 5 days; saline nasal irrigation | Decongestant: α-adrenergic agonist → vasoconstriction of nasal mucosa → reduces oedema and rhinorrhoea. Limit to 5 days to avoid rhinitis medicamentosa (rebound vasodilatation from receptor downregulation) |
| Cough | Honey (evidence for symptomatic relief, especially in children > 1 year); simple linctus; dextromethorphan for severe dry cough | Honey has mild demulcent and possibly antimicrobial properties. Dextromethorphan is an NMDA receptor antagonist and sigma-1 agonist that acts centrally to raise the cough threshold |
| Antibiotics | NOT indicated for viral URTI or uncomplicated acute bronchitis | No benefit for viral illness; contributes to antimicrobial resistance. Only indicate if bacterial superinfection suspected (persistent high fever, purulent sputum, focal consolidation) |
Antibiotics in Acute Cough
One of the most common clinical errors is prescribing antibiotics for acute bronchitis. Studies consistently show no benefit for uncomplicated acute bronchitis (which is predominantly viral). Antibiotic stewardship matters — explain to the patient that antibiotics will not help and may cause harm (C. difficile, allergy, resistance).
Management depends on severity (CURB-65 or equivalent) and setting (community vs. hospital):
| CURB-65 Score | Setting | Antibiotic Choice | Notes |
|---|---|---|---|
| 0–1 | Outpatient | Oral amoxicillin 500 mg TDS × 5 days (1st line); OR oral doxycycline/macrolide if penicillin-allergic | Covers S. pneumoniae (most common CAP pathogen) |
| 2 | Hospital ward | IV amoxicillin/co-amoxiclav + oral/IV macrolide (e.g., clarithromycin) | Macrolide covers atypical organisms (Mycoplasma, Legionella, Chlamydophila) |
| 3–5 | ITU consideration | IV co-amoxiclav (or piperacillin-tazobactam) + IV macrolide; consider anti-pseudomonal cover if risk factors | Severe CAP requires broad-spectrum + atypical cover |
Why add a macrolide? Atypical pathogens (Mycoplasma pneumoniae, Legionella, Chlamydophila) lack a cell wall → β-lactams are ineffective. Macrolides bind the 50S ribosomal subunit → inhibit bacterial protein synthesis. In severe pneumonia, dual cover is standard because you cannot reliably distinguish typical from atypical on presentation.
Management of acute severe asthma [12]:
| Step | Treatment | Mechanism / Rationale |
|---|---|---|
| 1 | High-flow O₂ to keep SpO₂ 94–98% | Correct hypoxaemia from V/Q mismatch |
| 2 | Nebulised salbutamol 5 mg, repeated as needed | β₂-agonist → bronchial smooth muscle relaxation → rapid bronchodilatation. "Salbutamol" = sal (saligenin) + but (butyl) + amol (amino alcohol) |
| 3 | IV hydrocortisone 100 mg or PO prednisolone 40–50 mg | Systemic corticosteroid → suppresses eosinophilic inflammation → reduces airway oedema and mucus production. Takes 4–6 hours to take effect (genomic mechanism — alters gene transcription) |
| 4 (if unresponsive) | Nebulised ipratropium 0.5 mg | Anticholinergic (muscarinic antagonist) → blocks vagal bronchoconstriction → additive bronchodilatation with salbutamol |
| 5 (if unresponsive) | IV MgSO₄ 2 g over 20 min | Mg²⁺ blocks calcium channels on bronchial smooth muscle → relaxation. Also inhibits acetylcholine release from motor nerve terminals |
| Reassess | Every 15 minutes | Monitor PEF, SpO₂, clinical status |
| Consider discharge | If PEF > 75% at 1 hour post-treatment |
Management approach [5]:
| Component | Treatment | Rationale |
|---|---|---|
| O₂ | Controlled O₂: target SpO₂ 88–92% | COPD patients may have chronic CO₂ retention → hypoxic drive for ventilation. Excessive O₂ suppresses this drive → worsening hypercapnia and respiratory acidosis. Also, O₂ causes release of CO₂ from haemoglobin (Haldane effect) and reverses hypoxic pulmonary vasoconstriction → ↑ V/Q mismatch |
| Bronchodilators | SABA ± SAMA (salbutamol ± ipratropium) via MDI + spacer or nebuliser | Rapid bronchodilatation |
| Steroids | Prednisolone 30–40 mg × 5 days or IV hydrocortisone 100 mg Q6–8H | Shorten recovery, ↑ FEV₁, ↓ risk of early relapse and treatment failure [5] |
| Antibiotics | Only if evidence of infection: ↑ purulent sputum + ↑ dyspnoea or ↑ sputum volume | Need to cover S. pneumoniae, H. influenzae, M. catarrhalis ± P. aeruginosa. Choice: co-amoxiclav, macrolides, cephalosporins, doxycycline [5] |
| NIV (BiPAP) | If respiratory acidosis: pCO₂ ≥ 6 kPa, pH ≤ 7.35 | Positive pressure splints airways open → ↓ work of breathing → improves gas exchange → allows respiratory muscle rest |
| Intubation + IPPV | If NIV fails, haemodynamic instability, impaired consciousness | Definitive airway control |
O₂ Target in COPD — Why 88–92%?
This is one of the most tested concepts. In COPD with chronic CO₂ retention, the body adapts by relying on hypoxic drive (peripheral chemoreceptors in carotid bodies) rather than CO₂ drive (central chemoreceptors become desensitised to chronically elevated CO₂). Giving too much O₂ suppresses the hypoxic drive → hypoventilation → CO₂ narcosis → respiratory arrest. Additionally, excessive O₂ releases CO₂ from Hb (Haldane effect) and reverses hypoxic pulmonary vasoconstriction → worsening V/Q mismatch. 88–92% is the safe zone — enough to prevent tissue hypoxia without eliminating the hypoxic drive.
Post-Infectious Cough (Most Common)
| Component | Management | Rationale |
|---|---|---|
| Reassurance | Explain the mechanism — damaged epithelium takes weeks to heal; cough will self-resolve | Most patients are worried about a persistent cough; education reduces anxiety and unnecessary antibiotic use |
| Simple measures | Honey, warm fluids, simple linctus | Demulcent effect on irritated mucosa |
| If prolonged (> 4 weeks) or distressing | Short course of ICS (e.g., beclometasone 200 µg BD × 2–4 weeks) | Suppresses residual airway inflammation and bronchial hyperreactivity |
| If pertussis suspected | Macrolide (azithromycin 500 mg day 1, 250 mg days 2–5) | Erythromycin/azithromycin eradicates Bordetella pertussis → reduces transmission. Effect on cough itself is minimal if given after paroxysmal phase, but recommended for public health |
C. Management of Chronic Cough — The Cause-Directed Approach
This is the core of chronic cough management. Each empiric step has specific drugs, durations, and criteria for success.
| Action | Details | Rationale |
|---|---|---|
| If on ACEi → STOP | Switch to ARB (e.g., losartan, valsartan). Review in 1–4 weeks | ACEi cough caused by bradykinin/substance P accumulation. ARBs do not affect bradykinin metabolism → no cough. Cough should resolve within 1–4 weeks of cessation |
| If active smoker → smoking cessation | Counselling + pharmacotherapy [5] | Smoking directly causes chronic airway inflammation → cough. Cessation is the single most effective intervention. Cessation associated with improvement in lung function and deceleration in rate of FEV₁ decline [5] |
Smoking cessation pharmacotherapy [5]:
| Drug | Mechanism | Efficacy | Key Adverse Effects / Notes |
|---|---|---|---|
| Nicotine replacement therapy (NRT) | Nicotine from patch/gum/inhaler → satisfies nicotinic receptor craving without the thousands of toxic combustion products in cigarettes | Moderate (doubles quit rate vs placebo) | Still delivers nicotine → CVS effects (tachycardia, vasoconstriction). Local irritation (gum → jaw pain; patch → skin irritation) |
| Bupropion (Zyban) | "Bu" = butyl + "propion" = propiophenone. Norepinephrine-dopamine reuptake inhibitor + weak nicotinic antagonist → ↓ withdrawal symptoms, ↓ craving | Moderate | C/I: seizure disorder, eating disorders, MAOi use. SE: insomnia, dry mouth, seizure risk (0.1%) |
| Varenicline (Champix) | Nicotinic receptor partial agonist → provides partial receptor stimulation (↓ withdrawal symptoms) while blocking full agonist effect of nicotine (↓ reinforcing pleasure of smoking) [5] | Highest efficacy among smoking cessation drugs | Nausea (most common), vivid dreams, mood changes. Rare: CVS events (debated). C/I: caution in severe renal impairment. Efficacy: varenicline > bupropion > NRT [5] |
UACS is the most common cause of chronic cough — treat first [1]:
| Drug | Dose | Duration | Mechanism |
|---|---|---|---|
| 1st-generation antihistamine (e.g., chlorpheniramine 4 mg TDS or diphenhydramine) | As per drug | 2–4 weeks | H₁-receptor antagonist → ↓ histamine-mediated nasal mucosal oedema, rhinorrhoea, and post-nasal drip. 1st-generation preferred over 2nd-generation (cetirizine, loratadine) for cough because the anticholinergic (drying) effect of 1st-gen agents contributes to reducing secretions. "Anti" = against + "histamine" = the mediator |
| Intranasal corticosteroid (e.g., fluticasone, mometasone, budesonide) | 1–2 sprays per nostril daily | 2–4 weeks (continue long-term if allergic rhinitis confirmed) | Topical steroid → suppresses local nasal mucosal inflammation → ↓ oedema, ↓ secretions, ↓ post-nasal drip. Minimal systemic absorption → few systemic side effects |
| Intranasal decongestant (oxymetazoline, xylometazoline) | Short course (≤ 5 days) | Only for initial symptom relief | α-adrenergic agonist → nasal mucosal vasoconstriction → rapid decongestion. Must limit to ≤ 5 days to avoid rhinitis medicamentosa |
| If chronic sinusitis suspected | Add antibiotics (amoxicillin or co-amoxiclav × 10–14 days) | - | Bacterial sinusitis requires antimicrobial treatment in addition to anti-inflammatory therapy |
| Criterion for Success | |
|---|---|
| Resolution or significant improvement of cough within 2–4 weeks confirms UACS as the cause |
Why 1st-Generation Antihistamines for Cough?
This often confuses students. The newer 2nd-generation antihistamines (cetirizine, loratadine) are less sedating because they do not cross the blood-brain barrier easily. However, they also lack the anticholinergic (drying) properties of 1st-generation agents. In cough from UACS, the anticholinergic effect is therapeutically desired — it reduces nasal secretions and post-nasal drip. That's why guidelines specifically recommend 1st-generation antihistamines for UACS-related cough, despite their sedation side effect.
If Step 1 fails or gives only partial response [4]:
| Drug | Dose | Duration | Mechanism |
|---|---|---|---|
| Inhaled corticosteroid (ICS) (e.g., budesonide 400 µg BD, fluticasone 250 µg BD) | Medium-dose ICS | 6–8 weeks | Suppresses eosinophilic airway inflammation → ↓ epithelial damage → ↓ nerve ending exposure → ↓ cough reflex sensitivity. Takes 2–4 weeks for full anti-inflammatory effect |
| LABA (e.g., formoterol, salmeterol) — often as ICS/LABA combination | Standard dose | Same | Long-acting β₂-agonist → sustained bronchodilatation (12+ hours). Complementary to ICS: LABA has mild anti-inflammatory effect and helps ICS reach small airways via bronchodilatation |
| Short-acting β₂-agonist (SABA, e.g., salbutamol) | 200 µg PRN | As needed | Rapid bronchodilatation for acute symptom relief. "Rescue" inhaler |
| LTRA (e.g., montelukast 10 mg nocte) | Add-on if ICS alone insufficient | - | Leukotriene receptor antagonist → blocks leukotriene D₄ → ↓ bronchoconstriction, ↓ mucus secretion, ↓ eosinophil recruitment. Useful in exercise-induced and aspirin-sensitive asthma |
| Criterion for Success | |
|---|---|
| Resolution or significant improvement within 6–8 weeks confirms CVA or EB |
GINA 2023 stepped approach for asthma [4]:
Track 1 (Preferred): ICS-formoterol as both controller AND reliever ("SMART" — Single Maintenance And Reliever Therapy)
- Why preferred? Using ICS-formoterol as the reliever means every time the patient uses their "rescue" inhaler, they also get a dose of ICS → reduces risk of exacerbations compared to SABA-only reliever
- Steps: As-needed low-dose ICS-formoterol → Low-dose ICS-formoterol maintenance + PRN → Medium-dose ICS-formoterol → High-dose ICS-formoterol + add LAMA → Refer for biologics
Track 2 (Alternative): SABA reliever + separate ICS controller
- Steps: ICS whenever SABA taken → Low-dose ICS daily → Medium-dose ICS or add LTRA → Medium-dose ICS/LABA → High-dose ICS/LABA + add LAMA → Refer for biologics
Key GINA Change — Death of the SABA-Only Reliever
GINA no longer recommends SABA-only treatment (without ICS) for asthma at any step. Even in mild intermittent asthma (Step 1), the preferred reliever is ICS-formoterol PRN. The rationale: SABA alone provides symptom relief but does NOT address underlying inflammation → ↑ risk of exacerbations and death. Every puff should include ICS. [4]
If Steps 1 and 2 fail or give only partial response [3]:
| Drug | Dose | Duration | Mechanism |
|---|---|---|---|
| PPI (e.g., omeprazole 20 mg BD, esomeprazole 40 mg daily, lansoprazole 30 mg daily) | Twice daily dosing recommended for cough (more aggressive than standard GERD) | 8–12 weeks (minimum) — some patients need 3–6 months | PPI = proton pump inhibitor. Irreversibly inhibits H⁺/K⁺-ATPase (the proton pump) on gastric parietal cells → ↓ gastric acid secretion by ~95%. By reducing acid, you reduce acid reflux → ↓ micro-aspiration and ↓ oesophageal C-fibre stimulation → ↓ cough |
| H₂ receptor antagonist (e.g., ranitidine, famotidine) | Standard dose BD | Alternative or add-on | H₂ blocker → competitively blocks histamine H₂ receptors on parietal cells → ↓ acid secretion (less potent than PPI). Useful for nocturnal acid breakthrough on PPI |
| Prokinetic (e.g., domperidone 10 mg TDS, metoclopramide 10 mg TDS) | Standard dose, before meals | Adjunct | Dopamine D₂ antagonist in the gut → ↑ gastric motility, ↑ LES tone, ↑ gastric emptying → ↓ reflux. "Prokinetic" = "pro" (forward) + "kinetic" (movement) — promotes forward movement of gut contents |
| Lifestyle modifications | Elevate head of bed 15–20 cm; avoid eating 2–3 hours before lying down; weight loss if obese; avoid trigger foods (fat, chocolate, caffeine, alcohol); avoid tight clothing; small frequent meals | Ongoing | Obesity → ↑ intra-abdominal pressure → ↑ reflux. Supine position → loss of gravity → ↑ reflux. Fatty food → ↓ LES tone. All modifiable. [3] |
| Criterion for Success | |
|---|---|
| Resolution may take 8–12 weeks or longer (up to 3–6 months). Cough may be the LAST GERD symptom to resolve. Premature discontinuation is a very common error. |
Why BID PPI for GERD-Cough?
Standard GERD treatment uses once-daily PPI. For GERD-related cough, twice-daily dosing is recommended because: (1) Cough may be driven by even minor residual acid reflux that once-daily PPI does not fully suppress. (2) PPI has a short plasma half-life (~1–2 hours) so a single dose may not provide 24-hour acid suppression. (3) Nocturnal acid breakthrough is common with once-daily dosing and nocturnal reflux is a key trigger for cough.
PPI side effects (important for long-term use):
| Side Effect | Mechanism |
|---|---|
| ↑ Risk of C. difficile infection | Gastric acid is a barrier against ingested pathogens; acid suppression removes this barrier |
| ↓ Calcium/magnesium absorption | Acid facilitates calcium and magnesium absorption; chronic suppression → ↑ risk of osteoporosis and fractures |
| ↓ Iron/B12 absorption | Acid required for iron reduction (Fe³⁺ → Fe²⁺) and B12 release from food proteins |
| Acute interstitial nephritis | Idiosyncratic reaction (rare) |
| Rebound acid hypersecretion | Chronic PPI → compensatory ↑ gastrin → parietal cell hyperplasia → acid rebound on PPI discontinuation. Taper gradually rather than abrupt stop |
If adequate trials of UACS, asthma/CVA/EB, and GERD treatment all fail:
| Action | Details |
|---|---|
| Revisit the history | Were trials of adequate duration? Is compliance an issue? Are there multiple co-existing causes? Were red flags missed? |
| HRCT chest | Look for bronchiectasis, ILD, early lung cancer, sarcoidosis |
| Bronchoscopy | If endobronchial lesion suspected |
| 24h pH-impedance monitoring | Objective assessment of reflux-cough association (if empiric PPI failed) |
| Echocardiography | If cardiac cause suspected |
| ENT evaluation + laryngoscopy | Vocal cord dysfunction, LPR, upper airway pathology |
| Consider cough hypersensitivity syndrome | If all causes excluded — see below |
D. Management of Specific Chronic Cough Aetiologies
Pharmacological treatment of stable COPD follows a stepped approach based on symptoms and exacerbation risk:
| Step | Treatment | Indication |
|---|---|---|
| Initial | LABA (e.g., salmeterol, indacaterol) or LAMA (e.g., tiotropium) | Dyspnoea or exacerbations |
| Step up for dyspnoea | LABA + LAMA | Persistent dyspnoea on monotherapy |
| Step up for exacerbations | LABA + LAMA if blood eosinophils < 0.3 × 10⁹/L; LABA + LAMA + ICS if eosinophils ≥ 0.3 | ↑ Exacerbation frequency despite dual therapy |
| Add-on | Roflumilast (PDE4 inhibitor) or long-term macrolide (azithromycin) | Persistent exacerbations despite triple therapy |
Non-pharmacological:
- Smoking cessation — single most important intervention [5]
- Pulmonary rehabilitation — multidisciplinary (physiotherapy, exercise training, nutritional support, psychotherapy) [5]
- Vaccination — influenza annually, pneumococcal, COVID-19 [5]
- Long-term O₂ therapy (LTOT) — indicated for chronic respiratory failure with resting PaO₂ < 7.3 kPa (55 mmHg) or SaO₂ ≤ 88%; ≥ 15 hours/day [5]
- Long-term NIV — if severe chronic hypercapnia + history of hospitalisation for acute respiratory failure [5]
| Phase | Regimen | Duration | Rationale |
|---|---|---|---|
| Intensive phase | Rifampicin + Isoniazid + Pyrazinamide + Ethambutol (RIPE) | 2 months | Four drugs to rapidly kill actively dividing bacilli + sterilise semi-dormant populations + prevent resistance emergence |
| Continuation phase | Rifampicin + Isoniazid | 4 months | Two drugs to eliminate remaining semi-dormant bacilli |
| Total | 6 months |
Why four drugs initially? TB has a large bacillary load (~10⁸–10⁹ organisms in a cavity). Spontaneous resistance mutations occur at predictable rates (~10⁻⁶ for isoniazid, ~10⁻⁸ for rifampicin). Using a single drug → resistant mutants survive and proliferate. With four drugs, the probability of simultaneous resistance to all four is negligibly small (~10⁻²⁴).
Drug mnemonics: RIPE (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol)
| Drug | Mechanism | Key Side Effects |
|---|---|---|
| Rifampicin | Inhibits bacterial DNA-dependent RNA polymerase → blocks mRNA synthesis | Hepatotoxicity, orange discolouration of body fluids (warn patient), potent CYP450 inducer (↓ efficacy of OCP, warfarin, HIV protease inhibitors) |
| Isoniazid (INH) | Inhibits mycolic acid synthesis (component of mycobacterial cell wall) | Peripheral neuropathy (due to pyridoxine/B6 depletion → co-prescribe pyridoxine), hepatotoxicity |
| Pyrazinamide | Disrupts membrane energetics and fatty acid synthesis (active in acidic environment of macrophages) | Hepatotoxicity, hyperuricaemia (↓ renal uric acid excretion → gout) |
| Ethambutol | Inhibits arabinosyltransferase → blocks arabinogalactan synthesis (cell wall component) | Optic neuritis (dose-related → monitor visual acuity and colour vision) |
| Component | Treatment | Rationale |
|---|---|---|
| Airway clearance | Postural drainage, active cycle of breathing, oscillating positive expiratory pressure devices | Physical removal of retained secretions → breaks the vicious cycle of mucus retention → infection → inflammation [13] |
| Mucoactive agents | Hypertonic saline nebulisation; consider carbocisteine | ↑ Mucus hydration → easier expectoration |
| Long-term antibiotics | Macrolide (azithromycin 500 mg 3×/week or 250 mg daily) for ≥ 3 months if ≥ 3 exacerbations/year | Immunomodulatory effect → ↓ airway inflammation → ↓ exacerbation frequency. Exclude NTM infection before initiation (macrolide is a key NTM drug — using it as monotherapy risks NTM resistance) [13] |
| Inhaled antibiotics | Inhaled colistin or gentamicin — 1st line for Pseudomonas aeruginosa colonisers [13] | Direct delivery to airways → high local concentration, minimal systemic absorption |
| Treat underlying cause | Immunoglobulin replacement (if antibody deficiency), CF-specific therapies, treat ABPA/NTM | Address the root cause of bronchiectasis if identifiable |
| Treatment | Indication | Mechanism |
|---|---|---|
| Opioid antitussives (codeine, morphine) | Distressing cough from endobronchial tumour or advanced disease | Central cough suppression (μ-opioid receptors in medulla → ↑ cough threshold) |
| Cough suppressants (see Section E below) | Symptomatic relief when cause cannot be treated | |
| Bronchoscopic intervention (laser, stenting) | Endobronchial obstruction causing cough, dyspnoea [14] | Relieve mechanical obstruction → ↓ stimulation of cough receptors |
| Palliative radiotherapy | Endobronchial tumour, haemoptysis | Tumour shrinkage → ↓ airway irritation |
| Pleurodesis | Malignant pleural effusion causing cough [14] | Chemical irritant (talc) instilled into pleural space → inflammatory adhesion between visceral and parietal pleura → obliterates pleural space → prevents effusion re-accumulation |
Cough from heart failure resolves when the heart failure is treated:
| Treatment | Mechanism of Cough Relief |
|---|---|
| Diuretics (furosemide, spironolactone) | ↓ Intravascular volume → ↓ pulmonary venous pressure → ↓ pulmonary congestion → ↓ J-receptor and C-fibre stimulation → ↓ cough |
| ACEi / ARB / ARNI | ↓ Afterload + ↓ preload → ↓ LV filling pressure → ↓ pulmonary congestion. Note: ACEi itself can cause cough — a clinical dilemma. If ACEi cough in a HF patient, switch to ARB or ARNI (sacubitril/valsartan) |
| β-blocker (bisoprolol, carvedilol, metoprolol) | ↓ HR → ↑ diastolic filling time → improved cardiac output long-term |
| SGLT2i (dapagliflozin, empagliflozin) | Osmotic diuresis + cardioprotective mechanisms → ↓ congestion |
When the underlying cause cannot be quickly treated, or the cough itself is causing significant morbidity (syncope, rib fractures, incontinence, sleep deprivation), antitussive therapy may be needed:
| Drug | Mechanism | Indication | Key Concerns |
|---|---|---|---|
| Codeine | μ-Opioid receptor agonist in medulla → ↑ cough threshold centrally | Moderate to severe dry cough not responding to other measures | Sedation, constipation, respiratory depression, dependence. Prodrug — converted to morphine by CYP2D6 (poor metabolisers get no effect; ultra-rapid metabolisers get toxicity). C/I in children < 12y (FDA black box) |
| Dextromethorphan | NMDA receptor antagonist + sigma-1 receptor agonist → central cough suppression | Mild to moderate dry cough; OTC availability | Fewer side effects than codeine; no significant respiratory depression. Abuse potential at high doses ("robo-tripping"). C/I with MAOi (serotonin syndrome risk) |
| Pholcodine | Opioid derivative; central cough suppression | Dry cough | Fewer side effects than codeine. Withdrawn in EU/Australia (2023) due to risk of anaphylaxis to neuromuscular blocking agents if later exposed during anaesthesia (cross-sensitisation via IgE to quaternary ammonium groups) |
| Simple linctus / honey | Demulcent → coats pharyngeal mucosa → ↓ stimulation of pharyngeal RARs | Mild cough, children (honey > 1 year) | No significant side effects. Evidence for honey in children is modest but positive |
| Gabapentin / pregabalin | Binds α2δ subunit of voltage-gated calcium channels → ↓ excitatory neurotransmitter release → central cough reflex desensitisation | Refractory chronic cough / cough hypersensitivity syndrome | Sedation, dizziness, weight gain. Emerging evidence for use in unexplained chronic cough |
| Low-dose morphine (5–10 mg BD) | μ-Opioid receptor agonist → central cough suppression | Refractory chronic cough in adults (RCT evidence) | SE: constipation, nausea, sedation. Risk of dependence — use cautiously |
Cough Suppressants — When NOT to Suppress
Never suppress a productive cough in conditions where sputum clearance is critical:
- Bronchiectasis
- COPD with sputum retention
- Pneumonia
- Post-operative patients
Suppressing cough in these conditions → sputum retention → atelectasis → secondary infection → clinical deterioration. Cough is the patient's defence mechanism — do not take it away when it is needed.
Only suppress dry, non-productive cough that is causing complications or significant distress.
When all identifiable causes have been treated and cough persists, the concept of cough hypersensitivity syndrome applies — an upregulation of the cough reflex arc:
| Treatment | Evidence | Mechanism |
|---|---|---|
| Speech and language therapy (SLT) | RCT evidence supports efficacy | Teaches cough suppression techniques, breathing exercises, laryngeal hygiene, education about cough triggers → desensitises the hypersensitive reflex |
| Gabapentin (300–1800 mg/day) | RCT evidence; NNT ~4 for 50% improvement | Central desensitisation of cough reflex (α2δ calcium channel modulation) |
| Pregabalin (75–300 mg/day) | Limited RCT evidence | Same mechanism as gabapentin |
| Low-dose morphine (5–10 mg BD) | Positive RCTs | Central cough reflex suppression via μ-opioid receptors in NTS |
| Gefapixant (P2X3 receptor antagonist) | FDA-approved 2025 for refractory chronic cough | P2X3 receptors on vagal afferent C-fibres detect ATP released from damaged airway epithelium → trigger cough. Gefapixant selectively antagonises P2X3 → ↓ afferent cough signalling. "Gefa" = gefitinib-inspired naming; "pixant" = P2X antagonist |
| Main SE: taste disturbance (dysgeusia) — due to P2X2/3 blockade in taste buds. Highly selective P2X3 antagonists (e.g., camlipixant) in trials aim to minimise this |
Gefapixant — The First Mechanism-Based Antitussive
Traditional antitussives (codeine, dextromethorphan) suppress cough centrally and non-specifically. Gefapixant is the first drug designed to target the peripheral cough reflex mechanism specifically — it blocks the P2X3 receptor on vagal afferent nerve terminals, preventing ATP-mediated cough signalling. This represents a paradigm shift in cough pharmacology, moving from symptom suppression to mechanism-targeted therapy.
| Drug | Key Contraindications / Cautions |
|---|---|
| 1st-gen antihistamine (chlorpheniramine) | Sedation → caution in elderly (falls), drivers. Anticholinergic → C/I in urinary retention, narrow-angle glaucoma, BPH |
| Intranasal decongestant | Max 5 days (rhinitis medicamentosa). C/I: severe hypertension, MAOi use |
| ICS | Local SE: oral candidiasis (rinse mouth after use), dysphonia. High-dose: adrenal suppression, osteoporosis, cataracts |
| PPI | Long-term: ↑ C. difficile, ↓ Ca/Mg/Fe/B12, AIN, rebound hypersecretion. Drug interactions: ↓ clopidogrel activation (CYP2C19 — omeprazole worst; use pantoprazole if on clopidogrel) |
| Codeine | C/I: children < 12y, post-tonsillectomy, breastfeeding (ultra-rapid CYP2D6 metabolisers → infant toxicity). C/I: respiratory depression, paralytic ileus |
| Dextromethorphan | C/I: concurrent MAOi (serotonin syndrome risk) |
| Rifampicin | Potent CYP450 inducer → ↓ efficacy of warfarin, OCP, HIV PIs, cyclosporine. Hepatotoxicity |
| Isoniazid | Hepatotoxicity; peripheral neuropathy (co-prescribe pyridoxine B6) |
| Ethambutol | Optic neuritis — visual acuity and colour vision monitoring mandatory |
| β₂-agonists (salbutamol, salmeterol) | Tremor, tachycardia, hypokalaemia (β₂-mediated K⁺ shift into cells). Caution: thyrotoxicosis, cardiac arrhythmia |
| Varenicline | Nausea (commonest). Caution: severe renal impairment. Previously flagged for neuropsychiatric events but large RCT (EAGLES) showed no significant increase |
| Gabapentin/pregabalin | Sedation, dizziness, weight gain, peripheral oedema. Dose adjustment in renal impairment. Abuse potential (schedule V in some jurisdictions) |
High Yield Summary — Management of Cough
-
Treat the cause, not just the symptom. Cough suppressants alone are rarely sufficient and can be harmful if they suppress productive cough.
-
Acute viral URTI / bronchitis: Supportive only. No antibiotics.
-
Acute asthma: O₂ → nebulised salbutamol → systemic steroid → add ipratropium → IV MgSO₄ if refractory. Reassess every 15 min.
-
AECOPD: Controlled O₂ 88–92% → SABA ± SAMA → prednisolone 5 days → antibiotics only if ↑ purulent sputum → BiPAP if acidotic.
-
Chronic cough algorithm: Stop ACEi → Smoking cessation → Treat UACS (intranasal steroid + 1st-gen antihistamine, 2–4 wk) → Treat CVA/EB (ICS ± LABA, 6–8 wk) → Treat GERD (PPI BID, 8–12 wk) → Further workup if all fail.
-
GINA 2023: ICS-formoterol as preferred reliever at all steps. SABA-only treatment is no longer recommended.
-
Smoking cessation: Varenicline > Bupropion > NRT in efficacy.
-
PPI for GERD-cough: BID dosing, minimum 8–12 weeks. Cough may be the last symptom to resolve. Do not stop prematurely.
-
TB: RIPE × 2 months → RI × 4 months. Co-prescribe pyridoxine with isoniazid. Monitor LFTs and vision.
-
Cough hypersensitivity / refractory: Gabapentin, low-dose morphine, SLT. Gefapixant (P2X3 antagonist) is the first mechanism-targeted antitussive.
-
Never suppress productive cough in bronchiectasis, COPD, or pneumonia — you need the clearance mechanism.
Active Recall - Management of Cough
References
[1] Lecture slides: murtagh merge.pdf [3] Senior notes: Ryan Ho GI.pdf (Section 2.2.1 Gastroesophageal Reflux Disease) [4] Senior notes: Ryan Ho Respiratory.pdf (Section 3.2.1 Asthma, GINA 2023) [5] Senior notes: Ryan Ho Respiratory.pdf (Section 3.2.2 COPD, Management) [6] Senior notes: Ryan Ho Cardiology.pdf (p155, Mitral Regurgitation; heart failure general) [12] Senior notes: Ryan Ho Critical Care.pdf (p13, Management of Acute Severe Asthma and AECOPD) [13] Senior notes: Ryan Ho Respiratory.pdf (p131, Bronchiectasis Long-Term Treatment) [14] Senior notes: Ryan Ho Respiratory.pdf (p149, Lung Cancer Supportive Treatment)
Complications of Cough
Cough is not just a nuisance. It is a forceful mechanical event that generates enormous intrathoracic, intra-abdominal, and intracranial pressures. When chronic or violent, these pressures cause real, sometimes serious, structural and physiological damage. Additionally, the underlying conditions that cause cough have their own disease-specific complications that must be considered.
This section covers two categories:
- Complications of the cough itself (the mechanical act of coughing causing harm)
- Complications of the underlying conditions that cause cough (disease-specific)
A. Complications of Cough Itself (Mechanism-Based)
The physics of cough matters here. During the compressive phase, intrathoracic pressure can rise to 300 mmHg and expiratory airflow velocity can reach 500 mph. This creates a pressure wave that transmits simultaneously to the thorax, abdomen, pelvis, and cranium. Every complication below flows directly from this biomechanical reality.
| Complication | Mechanism | Clinical Significance |
|---|---|---|
| Rib fractures | Repetitive mechanical stress on ribs from forceful contraction of intercostal and abdominal muscles during the compressive and expulsive phases of cough. The middle ribs (5–9) along the lateral chest wall are most vulnerable because they are the thinnest and bear the greatest bending moment | Most common in elderly, osteoporotic patients, and those on chronic corticosteroids (e.g., COPD patients on long-term oral steroids). Often presents as localised chest wall pain exacerbated by coughing, breathing, and movement. Point tenderness over the fracture site. CXR may miss undisplaced fractures — CT is more sensitive |
| Intercostal muscle strain | Overuse injury of intercostal muscles from sustained forceful coughing → microscopic muscle fibre tears → inflammation → pain | Presents as pleuritic-type chest wall pain. Distinction from rib fracture: no point tenderness over bone, pain is more diffuse over the intercostal space |
| Rectus abdominis muscle strain / tear | Vigorous abdominal contraction during the compressive phase → strain or rupture of the rectus sheath | Presents as acute abdominal wall pain ± haematoma within the rectus sheath. Can mimic an acute abdomen if haematoma is large |
Why do rib fractures matter beyond pain? A rib fracture from coughing creates a vicious cycle: the fracture causes pleuritic pain → the patient splints (avoids deep breathing and coughing to reduce pain) → sputum retention → atelectasis → secondary infection → more cough → more pain and risk of further fractures. This is why adequate analgesia is critical — you must break the cycle.
| Complication | Mechanism | Clinical Significance |
|---|---|---|
| Cough syncope (tussive syncope) | Paroxysmal coughing → sustained ↑ intrathoracic pressure (similar to a Valsalva manoeuvre) → ↓ venous return to the right heart → ↓ cardiac output → transient cerebral hypoperfusion → loss of consciousness. May also involve a vasovagal component (cough stimulates vagal afferents → cardioinhibitory response → bradycardia) | More common in middle-aged men with COPD or chronic cough. Typically brief (seconds), with rapid recovery. Dangerous if occurs while driving or operating machinery. Important differential: exclude cardiac arrhythmia, aortic stenosis, and seizure disorder |
| Cough-induced arrhythmia | Rapid fluctuations in intrathoracic pressure → altered cardiac preload/afterload → can trigger transient arrhythmias (premature ventricular complexes, paroxysmal AF) | Usually benign and self-limiting, but can be symptomatic |
| Subconjunctival haemorrhage | Valsalva-like ↑ venous pressure during forceful cough → rupture of fragile conjunctival capillaries → subconjunctival extravasation of blood | Alarming in appearance (bright red eye) but benign and self-limiting. No treatment needed. Resolves over 1–3 weeks |
| Petechiae / purpura (facial/periorbital) | Same Valsalva mechanism → ↑ venous pressure in the head and neck → capillary rupture in skin/subcutaneous tissue | Often in the distribution of the SVC territory (face, periorbital region). Self-limiting |
Cough Syncope vs Seizure
Cough syncope can be misdiagnosed as epilepsy. Key differences: cough syncope has a clear cough trigger preceding the event, is very brief, has no post-ictal state (rapid return to normal), and the patient is typically standing or seated. EEG and Holter monitoring can help differentiate if uncertain.
| Complication | Mechanism | Clinical Significance |
|---|---|---|
| Cough headache | Coughing → ↑ intrathoracic pressure → impeded venous drainage from the cranium → transient ↑ intracranial pressure (ICP) → distension of pain-sensitive intracranial structures (meninges, venous sinuses) | Typically bilateral, explosive onset with each cough, lasting seconds to minutes. "Primary cough headache" is benign. However, must exclude secondary causes — particularly Chiari type I malformation (cerebellar tonsils herniate through foramen magnum → ↑ susceptibility to pressure changes) and posterior fossa lesions. MRI brain indicated for new-onset cough headache [15] |
| Cervical disc herniation | Coughing ↑ intradiscal pressure (same mechanism as Valsalva → axial loading of the spine). In pre-existing degenerative disc disease, this may precipitate acute disc prolapse | Presents with radiculopathy (neck/arm pain, dermatomal sensory loss, weakness). Important to ask about cough, sneeze, and strain as triggers |
| Complication | Mechanism | Clinical Significance |
|---|---|---|
| Urinary stress incontinence | Coughing → sudden ↑ intra-abdominal pressure → transmitted to the bladder → overcomes the resistance of the urethral sphincter and pelvic floor muscles → involuntary urine leakage | Very common in women with chronic cough, especially if pre-existing pelvic floor weakness (multiparous, post-menopausal, obesity). May be the presenting complaint that brings a chronic cough patient to seek medical attention |
| Inguinal hernia / abdominal wall hernia | Chronic coughing → repetitive ↑ intra-abdominal pressure → progressive weakening of fascial defects (inguinal canal, umbilical ring, previous surgical incisions) → herniation of abdominal contents through the defect [7] | Chronic cough is a recognised risk factor for inguinal hernia [7]. Hernia repair will have a high recurrence rate if the chronic cough is not addressed — you must treat the cough as well as the hernia |
| Worsening of haemorrhoids | Chronic cough → chronic ↑ intra-abdominal pressure → ↑ pressure in the haemorrhoidal venous plexus → engorgement and prolapse of haemorrhoidal cushions [8] | Chronic cough is listed as a risk factor for haemorrhoids alongside constipation, pregnancy, and obesity [8] |
| Worsening of GERD (vicious cycle) | Coughing → ↑ intra-abdominal pressure → overcomes LES pressure → promotes gastro-oesophageal reflux → acid in oesophagus → stimulates vagal cough reflex → more coughing [3] | This is the GERD-cough vicious cycle. GERD causes cough, and cough worsens GERD. Both must be treated simultaneously [3] |
| Uterine prolapse (exacerbation) | Same mechanism as stress incontinence — chronic ↑ intra-abdominal pressure on a weakened pelvic floor → descent of the uterus into the vaginal canal | Relevant in elderly women with chronic cough |
| Complication | Mechanism | Clinical Significance |
|---|---|---|
| Pneumothorax | Violent coughing → alveolar rupture (especially in emphysematous blebs or bullae in COPD) → air leaks into the pleural space → pneumothorax | More common in COPD/emphysema patients (secondary spontaneous pneumothorax). Presents with sudden pleuritic chest pain + dyspnoea during a coughing episode |
| Pneumomediastinum | Alveolar rupture → air dissects along bronchovascular sheaths into the mediastinum → pneumomediastinum ± subcutaneous emphysema | Presents with sudden retrosternal chest pain ± subcutaneous crepitus in the neck. Usually self-limiting but must exclude oesophageal rupture (Boerhaave's syndrome — see below) |
| Subcutaneous emphysema | Extension of pneumomediastinum or pneumothorax → air tracks into subcutaneous tissues of neck, chest wall, face | Palpable crepitus. Usually benign unless associated with tension pneumothorax |
| Tracheobronchial injury | Extremely rare; violent paroxysmal cough → mucosal tear in membranous trachea/bronchi | May present with haemoptysis, pneumomediastinum |
| Complication | Mechanism | Clinical Significance |
|---|---|---|
| Mallory-Weiss tear | Violent retching/coughing → sudden ↑ intra-abdominal and intra-gastric pressure against a closed glottis → mucosal tear at the gastro-oesophageal junction (GEJ) | Presents with haematemesis following a bout of violent coughing or vomiting. Usually self-limiting (90% stop spontaneously). Endoscopic treatment if persistent |
| Boerhaave's syndrome (oesophageal perforation) | Extreme ↑ intra-oesophageal pressure from violent coughing/retching → full-thickness rupture of the oesophagus (usually left posterolateral distal oesophagus) | Rare but life-threatening. Presents with severe chest/epigastric pain, subcutaneous emphysema, and rapid haemodynamic deterioration. Mackler's triad: vomiting + chest pain + subcutaneous emphysema. Requires emergency surgical repair |
| Complication | Mechanism | Clinical Significance |
|---|---|---|
| Sleep disturbance | Nocturnal cough disrupts sleep architecture → insomnia, daytime somnolence, fatigue | Significant impact on quality of life and functional capacity |
| Anxiety and depression | Chronic, uncontrolled cough → social embarrassment, functional limitation, exhaustion, fear of serious underlying disease → psychological distress | Up to 30% of chronic cough patients report significant anxiety or depressive symptoms |
| Social isolation | Fear of coughing in public (especially post-COVID-19 era where coughing in public attracts stigma) → avoidance of social situations | Real and under-recognised consequence |
| Impaired work productivity | Chronic cough → fatigue, poor concentration, frequent medical visits → ↓ occupational performance | Economic burden — cough is one of the commonest reasons for work absenteeism |
B. Complications of Underlying Conditions Causing Cough
Beyond the mechanical complications of coughing itself, the diseases that produce cough have their own progression and complications:
| Complication | Mechanism |
|---|---|
| Status asthmaticus | Severe, unrelenting bronchospasm not responding to standard therapy → progressive respiratory failure, hypoxaemia, respiratory acidosis → death if untreated |
| Airway remodelling | Chronic uncontrolled inflammation → subepithelial fibrosis, smooth muscle hypertrophy, goblet cell hyperplasia → fixed airflow obstruction (irreversible component) → overlap with COPD |
| Pneumothorax | Air trapping → hyperinflation → alveolar rupture |
| Mucus plugging | Tenacious mucus from eosinophilic inflammation → segmental atelectasis |
| Complication | Mechanism |
|---|---|
| Acute exacerbation | Viral/bacterial infection or environmental trigger → amplified airway inflammation → ↑ cough, ↑ sputum, ↑ dyspnoea → if hospitalised, 5-year mortality ~50% [5] |
| Respiratory failure (Type 2) | Progressive airflow limitation + V/Q mismatch → chronic hypoxaemia + hypercapnia |
| Cor pulmonale | Chronic hypoxia → pulmonary arteriolar vasoconstriction → pulmonary hypertension → right ventricular hypertrophy and eventual right heart failure |
| Pneumothorax | Rupture of emphysematous bullae → secondary spontaneous pneumothorax |
| Lung cancer | Smoking is the shared risk factor; COPD itself is an independent risk factor for lung cancer (chronic inflammation → DNA damage → carcinogenesis) [5] |
| Complication | Mechanism |
|---|---|
| Oesophagitis | Chronic acid exposure → mucosal inflammation and erosion (Los Angeles classification A–D) |
| Stricture | Chronic oesophagitis → fibrosis → luminal narrowing → dysphagia [3] |
| Barrett's oesophagus | Chronic acid damage → intestinal metaplasia of squamous epithelium to columnar epithelium at the GEJ → premalignant condition [3] |
| Oesophageal adenocarcinoma | Barrett's oesophagus → dysplasia → carcinoma sequence. Surveillance OGD recommended for Barrett's [3] |
| Laryngopharyngeal reflux (LPR) complications | Chronic acid exposure to larynx → posterior laryngitis, vocal cord granulomas, subglottic stenosis, dental erosions |
| Aspiration pneumonia | Macro-aspiration of gastric contents → chemical pneumonitis → secondary bacterial infection |
| Complication | Mechanism |
|---|---|
| Cavitation | Caseous necrosis → cavity formation → communication with bronchial tree → spread of bacilli → ↑ infectivity |
| Haemoptysis (potentially massive) | Erosion of pulmonary artery branches (Rasmussen aneurysm) within a TB cavity → may cause fatal haemorrhage |
| Bronchiectasis | Healed TB → fibrosis and distortion of airways → permanent bronchial dilatation → chronic productive cough |
| Miliary TB | Haematogenous dissemination → diffuse miliary pattern on CXR → multi-organ involvement |
| TB meningitis | Haematogenous spread to meninges → basal meningeal adhesions → cranial nerve palsies (CN 3, 4, 6, 8), hydrocephalus → high morbidity and mortality [15] |
| Pleural effusion / empyema | Extension of infection to pleura → exudative effusion; caseation → empyema |
| Aspergilloma | Residual TB cavity becomes colonised by Aspergillus → fungus ball (mycetoma) → recurrent haemoptysis |
| Complication | Mechanism |
|---|---|
| Post-obstructive pneumonia | Endobronchial tumour obstructs a bronchus → distal mucus retention → secondary bacterial infection → pneumonia that fails to resolve ("non-resolving pneumonia") |
| Recurrent laryngeal nerve palsy | Left hilar tumour or mediastinal lymphadenopathy compresses the left recurrent laryngeal nerve (which loops under the aortic arch) → vocal cord paralysis → hoarseness + bovine cough + aspiration risk [16] |
| SVC obstruction | Tumour or lymph node mass in the right upper mediastinum compresses the SVC → impeded venous drainage from head, neck, and upper limbs → facial/neck swelling, engorged veins, plethora, dyspnoea |
| Malignant pleural effusion | Tumour invades or seeds the pleura → exudative effusion → cough, dyspnoea |
| Paraneoplastic syndromes | SCLC: SIADH (hyponatraemia), ectopic ACTH (Cushing's); Squamous: PTHrP (hypercalcaemia); Lambert-Eaton myasthenic syndrome |
| Haemoptysis | Erosion of tumour vasculature into airways; pulmonary artery invasion in advanced disease can cause fatal haemoptysis |
| Pancoast syndrome | Apical lung tumour invading brachial plexus (C8-T1) → ipsilateral shoulder/arm pain, hand weakness/wasting + Horner's syndrome (sympathetic chain involvement: miosis, ptosis, anhidrosis) [14] |
| Complication | Mechanism |
|---|---|
| Acute pulmonary oedema | Decompensated LV failure → massive ↑ pulmonary capillary wedge pressure → transudation of fluid into alveoli → severe dyspnoea, pink frothy sputum, cough |
| Recurrent chest infections | Pulmonary congestion → impaired mucociliary clearance → ↓ local immune defences → ↑ susceptibility to pneumonia |
| Atrial fibrillation | LA dilatation from chronic mitral valve disease or LV failure → atrial remodelling → AF → ↑ risk of thromboembolism (stroke) |
| Complication | Mechanism |
|---|---|
| Parapneumonic effusion → empyema | Pleural inflammation adjacent to pneumonic consolidation → sterile exudative effusion (simple parapneumonic) → bacterial invasion of pleural space → empyema (pus in pleural space) [17] |
| Lung abscess | Necrosis within consolidated lung (especially with anaerobes, Klebsiella, S. aureus) → cavity filled with pus → presents with swinging fever, foul-smelling sputum [17] |
| Septicaemia and multi-organ failure | Bacteraemia from pneumonia → systemic inflammatory response → sepsis → septic shock → end-organ damage [17] |
| Respiratory failure | Extensive consolidation → V/Q mismatch → hypoxaemia (Type 1) or exhaustion/COPD → hypercapnia (Type 2) |
| Post-pneumonia cough persistence | Clinical resolution of SOB and systemic upset occurs in 2–3 days, but cough may persist for up to 2 weeks. Radiological resolution may be delayed up to 10 weeks in severe cases [17] |
| Complication | Mechanism |
|---|---|
| Recurrent infections | Dilated, damaged airways → mucus pooling → chronic bacterial colonisation (H. influenzae, P. aeruginosa, S. aureus) → vicious cycle of infection-inflammation-damage [13] |
| Haemoptysis (potentially massive) | Chronic inflammation → hypertrophy of bronchial arteries (systemic pressure) → erosion → haemoptysis. Can be massive and life-threatening → bronchial artery embolisation |
| Respiratory failure | Progressive destruction of functional lung tissue → ↓ gas exchange capacity |
| Amyloidosis (rare) | Chronic inflammatory stimulus → AA amyloidosis → amyloid deposition in kidneys (nephrotic syndrome), liver, spleen |
Treatment itself can cause complications — always weigh benefit vs harm:
| Treatment | Complication | Mechanism |
|---|---|---|
| Opioid antitussives (codeine, morphine) | Sedation, respiratory depression, constipation, dependence | μ-opioid receptor agonism → central depression + ↓ GI motility |
| Long-term PPI | C. difficile, ↓ Ca/Mg/Fe/B12, AIN, osteoporotic fractures, rebound acid hypersecretion | Loss of gastric acid barrier; impaired mineral absorption; parietal cell hyperplasia from chronic gastrin stimulation |
| Long-term ICS | Oral candidiasis, dysphonia, adrenal suppression (high doses), pneumonia risk in COPD | Local immunosuppression → Candida overgrowth; systemic absorption at high doses → HPA axis suppression |
| Long-term oral corticosteroids | Osteoporosis → rib fractures (ironic: treating asthma/COPD may predispose to cough-related rib fracture), adrenal suppression, DM, immunosuppression | Catabolic effects on bone; ↑ gluconeogenesis; ↓ immune function |
| Anti-TB drugs | Hepatotoxicity (INH, RIF, PZA), optic neuritis (EMB), peripheral neuropathy (INH), hyperuricaemia (PZA) | Drug-specific mechanisms as detailed in management section |
| 1st-gen antihistamines | Sedation, falls in elderly, urinary retention, dry mouth | Central anticholinergic and antihistaminic effects |
| System | Complication | Most Associated With |
|---|---|---|
| Musculoskeletal | Rib fracture | Chronic cough + osteoporosis |
| Cardiovascular | Tussive syncope | COPD, paroxysmal cough |
| Subconjunctival haemorrhage | Violent cough | |
| Neurological | Cough headache | Any chronic cough; exclude Chiari malformation |
| Urogenital | Stress incontinence | Women with chronic cough + pelvic floor weakness |
| Abdominal wall | Inguinal hernia | Chronic cough + fascial weakness [7] |
| Anorectal | Haemorrhoids | Chronic cough (↑ intra-abdominal pressure) [8] |
| GI | GERD worsening (vicious cycle) | Chronic cough + GERD [3] |
| Mallory-Weiss tear | Violent paroxysmal cough | |
| Thoracic | Pneumothorax / pneumomediastinum | COPD + violent cough |
| Psychological | Anxiety, depression, social isolation | Chronic unexplained cough |
High Yield Summary — Complications of Cough
-
Cough generates intrathoracic pressures up to 300 mmHg — this is the root cause of most mechanical complications.
-
Tussive syncope: ↑ intrathoracic pressure → ↓ venous return → ↓ cardiac output → cerebral hypoperfusion. More common in COPD. Must exclude cardiac arrhythmia and seizure.
-
Rib fractures: Common in elderly/osteoporotic patients. Creates a vicious cycle: pain → splinting → sputum retention → infection → more cough. Break the cycle with adequate analgesia.
-
Stress incontinence: Very common in women with chronic cough. ↑ intra-abdominal pressure overwhelms pelvic floor.
-
GERD-cough vicious cycle: Cough → ↑ intra-abdominal pressure → ↑ reflux → more cough. Both must be treated simultaneously.
-
Chronic cough → inguinal hernia, haemorrhoids: Chronic ↑ intra-abdominal pressure weakens fascial planes and engorges haemorrhoidal plexus.
-
Cough headache: Usually benign "primary cough headache," but must exclude Chiari I malformation and posterior fossa lesions with MRI.
-
Pneumothorax: Alveolar rupture from violent cough, especially in COPD/emphysema.
-
COPD complications: Acute exacerbation (50% 5-year mortality if hospitalised), cor pulmonale, respiratory failure, lung cancer.
-
TB complications: Haemoptysis (Rasmussen aneurysm), bronchiectasis, miliary spread, TB meningitis, aspergilloma in residual cavity.
-
Treatment complications: Long-term PPI → C. difficile, osteoporosis; ICS → oral candidiasis, pneumonia in COPD; opioid antitussives → respiratory depression, dependence.
Active Recall - Complications of Cough
References
[3] Senior notes: Ryan Ho GI.pdf (Section 2.2.1 Gastroesophageal Reflux Disease) [4] Senior notes: Ryan Ho Respiratory.pdf (Section 3.2.1 Asthma) [5] Senior notes: Ryan Ho Respiratory.pdf (Section 3.2.2 COPD) [6] Senior notes: Ryan Ho Cardiology.pdf (p155, Mitral Regurgitation; heart failure) [7] Senior notes: felixlai.md (Section III: Etiology of Hernia — chronic cough as risk factor) [8] Senior notes: felixlai.md (Section III: Etiology of Haemorrhoids — chronic cough and intra-abdominal pressure) [13] Senior notes: Ryan Ho Respiratory.pdf (p131, Bronchiectasis) [14] Senior notes: Ryan Ho Respiratory.pdf (p149, Lung Cancer Supportive Treatment and Complications) [15] Senior notes: Ryan Ho Neurology.pdf (p58, Headache approach; p144, TB Meningitis) [16] Senior notes: felixlai.md (Thyroidectomy complications — RLN injury mechanism) [17] Senior notes: Ryan Ho Respiratory.pdf (p65, Pneumonia Complications)
High Yield Summary
-
Cough classification by duration: Acute ( < 3 wk), Subacute (3–8 wk), Chronic ( > 8 wk) — this dictates the differential.
-
Big Three causes of chronic cough (normal CXR, non-smoker, no ACEi): UACS/PNDS, Asthma/CVA/EB, GERD — account for > 90%.
-
ACEi cough: Mechanism = bradykinin/substance P accumulation (NOT angiotensin-related). Class effect. Switch to ARB.
-
GERD-related cough may occur WITHOUT heartburn ("silent reflux"). Three mechanisms: micro-aspiration, oesophago-bronchial reflex, cough reflex sensitisation. Rising in HK.
-
In Hong Kong: Always exclude TB and lung cancer in chronic cough. Non-smoking lung adenocarcinoma in Asian women is increasingly common.
-
Red flags: Haemoptysis, weight loss, age > 45 + smoker, hoarseness, recurrent pneumonia — require urgent investigation.
-
Cough-variant asthma: Cough is SOLE symptom; responds to ICS + bronchodilator. Distinguished from eosinophilic bronchitis (normal methacholine challenge in EB).
-
Bovine cough (non-explosive, flat) → recurrent laryngeal nerve palsy → think lung cancer, aortic aneurysm.
-
Chronic cough can worsen: GERD (↑ intra-abdominal pressure), hernias, haemorrhoids — a vicious cycle.
-
Cough hypersensitivity syndrome: Emerging unifying concept for unexplained chronic cough — upregulated TRPV1/TRPA1 receptors.
High Yield Summary — Differential Diagnosis of Cough
-
Use duration as your primary organiser: Acute ( < 3 wk) → mostly infectious. Subacute (3–8 wk) → post-infectious, pertussis, early asthma. Chronic ( > 8 wk) → Big Three (UACS, asthma/CVA/EB, GERD) + ACEi + COPD + serious causes.
-
Chronic cough with normal CXR, non-smoker, no ACEi: > 90% due to UACS, asthma/CVA/EB, or GERD — often in combination.
-
Always ask about ACEi — most commonly missed iatrogenic cause.
-
In HK: TB and lung cancer must be excluded in every chronic cough. GERD is rising and often presents atypically. NPC is endemic in Southern Chinese.
-
Red flags triggering urgent investigation: Haemoptysis, weight loss, new cough in smoker > 45y, hoarseness, recurrent pneumonia.
-
Bovine cough = recurrent laryngeal nerve palsy → think lung cancer, aortic aneurysm.
-
Cough absent during sleep → psychogenic/habit cough.
-
Multiple aetiologies coexist in 25–40% of chronic cough cases.
-
Post-infectious cough is the most common cause of subacute cough — self-limiting but may take weeks.
-
Haemoptysis differential: TB, lung cancer, bronchiectasis, PE, mitral stenosis — CXR is the first investigation.
High Yield Summary — Diagnostic Criteria, Algorithm and Investigations
-
Cough has no standalone diagnostic criteria — the task is to identify the underlying cause through a systematic algorithm.
-
The algorithm is sequential: Duration classification → ACEi check → CXR + spirometry → Evaluate Big Three (UACS → Asthma/CVA/EB → GERD) → Further workup if needed.
-
CVA diagnostic triad: Chronic cough as sole symptom + positive methacholine challenge + response to ICS/BD. EB: Same but negative methacholine + sputum eosinophilia > 3%.
-
COPD: Post-bronchodilator FEV₁/FVC < 0.70. Chronic bronchitis: Cough with sputum ≥ 3 months in 2 consecutive years.
-
GERD-cough: Empiric PPI 8–12 weeks; if fails → 24h pH-impedance monitoring (DeMeester > 14.7 or SAP > 95%).
-
CXR is mandatory for all chronic cough and acute cough with red flags. Normal CXR narrows the differential to the Big Three + ACEi + smoking.
-
Methacholine challenge: High negative predictive value for asthma. PC₂₀ < 4 mg/mL = asthma likely; ≥ 16 mg/mL = asthma very unlikely.
-
FeNO > 50 ppb: Suggests eosinophilic airway inflammation (asthma, CVA, EB).
-
In HK: Always send sputum AFB × 3 + GeneXpert in undiagnosed chronic cough. CXR upper lobe cavity = TB until proven otherwise.
-
Therapeutic trials are diagnostic: Resolution with specific therapy confirms the cause retrospectively — this is how UACS, CVA, and GERD-cough are often diagnosed.
High Yield Summary — Management of Cough
-
Treat the cause, not just the symptom. Cough suppressants alone are rarely sufficient and can be harmful if they suppress productive cough.
-
Acute viral URTI / bronchitis: Supportive only. No antibiotics.
-
Acute asthma: O₂ → nebulised salbutamol → systemic steroid → add ipratropium → IV MgSO₄ if refractory. Reassess every 15 min.
-
AECOPD: Controlled O₂ 88–92% → SABA ± SAMA → prednisolone 5 days → antibiotics only if ↑ purulent sputum → BiPAP if acidotic.
-
Chronic cough algorithm: Stop ACEi → Smoking cessation → Treat UACS (intranasal steroid + 1st-gen antihistamine, 2–4 wk) → Treat CVA/EB (ICS ± LABA, 6–8 wk) → Treat GERD (PPI BID, 8–12 wk) → Further workup if all fail.
-
GINA 2023: ICS-formoterol as preferred reliever at all steps. SABA-only treatment is no longer recommended.
-
Smoking cessation: Varenicline > Bupropion > NRT in efficacy.
-
PPI for GERD-cough: BID dosing, minimum 8–12 weeks. Cough may be the last symptom to resolve. Do not stop prematurely.
-
TB: RIPE × 2 months → RI × 4 months. Co-prescribe pyridoxine with isoniazid. Monitor LFTs and vision.
-
Cough hypersensitivity / refractory: Gabapentin, low-dose morphine, SLT. Gefapixant (P2X3 antagonist) is the first mechanism-targeted antitussive.
-
Never suppress productive cough in bronchiectasis, COPD, or pneumonia — you need the clearance mechanism.
High Yield Summary — Complications of Cough
-
Cough generates intrathoracic pressures up to 300 mmHg — this is the root cause of most mechanical complications.
-
Tussive syncope: ↑ intrathoracic pressure → ↓ venous return → ↓ cardiac output → cerebral hypoperfusion. More common in COPD. Must exclude cardiac arrhythmia and seizure.
-
Rib fractures: Common in elderly/osteoporotic patients. Creates a vicious cycle: pain → splinting → sputum retention → infection → more cough. Break the cycle with adequate analgesia.
-
Stress incontinence: Very common in women with chronic cough. ↑ intra-abdominal pressure overwhelms pelvic floor.
-
GERD-cough vicious cycle: Cough → ↑ intra-abdominal pressure → ↑ reflux → more cough. Both must be treated simultaneously.
-
Chronic cough → inguinal hernia, haemorrhoids: Chronic ↑ intra-abdominal pressure weakens fascial planes and engorges haemorrhoidal plexus.
-
Cough headache: Usually benign "primary cough headache," but must exclude Chiari I malformation and posterior fossa lesions with MRI.
-
Pneumothorax: Alveolar rupture from violent cough, especially in COPD/emphysema.
-
COPD complications: Acute exacerbation (50% 5-year mortality if hospitalised), cor pulmonale, respiratory failure, lung cancer.
-
TB complications: Haemoptysis (Rasmussen aneurysm), bronchiectasis, miliary spread, TB meningitis, aspergilloma in residual cavity.
-
Treatment complications: Long-term PPI → C. difficile, osteoporosis; ICS → oral candidiasis, pneumonia in COPD; opioid antitussives → respiratory depression, dependence.
Constipation
Constipation is a functional bowel disorder characterized by infrequent, difficult, or incomplete evacuation of hard stools.
Diarrhoea
Diarrhoea is the passage of three or more loose or watery stools per day, or more frequently than is normal for the individual, resulting from increased intestinal secretion, decreased absorption, or altered motility.