A. Mechanisms [1]

1. Coughr reflext triggered by several pathways
   1. Mechanical
   2. Inflammatory
   3. Inhalation of chemical and mechanical irritants
2. Cough reflex usually initiates from uper airway sites: larynx, carina, proximal airways branches
3. Sensory Nerve Receptors Transmitting Cough
   1. Rapidly adapting receptorts (RARs)
   2. Slowly adapting receptors (SARs)
   3. C-fiber receptors
   4. Cough receptors have voltage-gated sodium channels (acid-sensing ion channel family)
   5. Afferent ibers from cough receptors in airways converge on vagus nerves on brainstem sites in nucleus tractus solitarius
   6. NTS connected to respiratory-related neurons in central respiratory generator
   7. These central respiratory generator neurons coordinate efferent cough (tussive) response
   8. C-fiber activation interacts centrally with activation of RARs or SARs to promote coughing
   9. Cough reflex sensitization can also arise in brainstem neurons
4. Stimulators of RARs
   1. Cigarette smoke
   2. Acidic and alkaline soltions
   3. Hypotonic or hypertonic saline
   4. Pulmonary congestion
   5. Atelectasis
   6. Bronchoconstriction
   7. Reduction in lung compliance
   8. All of these can also cause chronic cough
5. Stimulation of C-fibers
   1. So-called "chemosensors" b Bradykinin - inflammatory mediator
   2. Acidic pH (hydrogen ions) -
   3. Capsaicin - transient receptor potential vaniloid-1 (TRPV1) channel on RARs and C-fibers
   4. TRPV1 inhibitors suppress tussive response cause by allergen challenge

B. Timing

1. Differential diagnosis of cough best made by estimating duration
2. Acute - 2 weeks or less
3. Subacute - 2 to 8 weeks
4. Chronic - 8 weeks or more
5. Trial of cause-directed treatment for 2-weeks or less is usually effective
6. Cough is the fifth most common presenting symptom in primary care

C. Acute Causes

1. Very Common
   1. Common Cold (up to 80% of all acute cough)
   2. Allergic Rhinitis
   3. Beginning smokers
2. Acute Bacterial Sinusitis
3. Acute Bronchitis / Tracheobronchitis
4. Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)
5. Pneumonia
6. Less Common
   1. Bordetella pertussis (whooping cough) - increasing [3,4]
   2. Foreign body aspiration
   3. Inhalation of toxins

D. Subacute Causes

1. Post-Infectious
   1. Extremely common after viral upper respiratory infections (URI)
   2. Bacterial - less common
2. Subacute Bacterial Sinusitis
3. Bordetella pertussis - may present mainly as cough without systemic symptoms [4]
4. Cough variant asthma
5. ACE inhibitors

E. Chronic

1. Smoking
2. Post-Nasal Drip Syndromes
   1. Non-allergic rhinitis
   2. Allergic rhinitis
   3. Vasomotor rhinitis
   4. Chronic sinusitis
3. Cough Variant Asthma
4. Chronic Bronchitis (as part of COPD - baseline or exacerbation)
5. Gastrointestinal Reflux (GERD)
6. Laryngopharyngeal Reflux (LPR) [5]
   1. Cough
   2. Excessive throat clearing
   3. Hoarseness
   4. Globus pharyngeus (sensation of lump in throat)
7. Fistula Involving Pharynx/Larynx [6]
   1. Tracheoesophageal Fistula
   2. Bronchoesophageal Fistula
8. ACE Inhibitors
9. Eosinophilic Bronchitis
   1. May cause >10% of cases of chronic cough
   2. Presence of eosinophils >5% of non-squamous cells in sputum
   3. Not associated with bronchial hyperresponsiveness

F. Very Uncommon Causes

1. Bronchiectasis
2. Aspiration
3. Interstitial Lung Disease
4. Congestive Heart Failure (CHF)
5. Nasal polyps
6. Uvular or tonsilar enlargement
7. Thyroid disorders
8. Psychogenic
9. Vocal cord abnormalities: paralysis, polyps, nodules

G. Evaluation and Treatment of Chronic Cough [1,8]

1. Focus history and physical on most common causes given duration
2. Assess severity of Cough
   1. Standard history
   2. Cough visual analogue score
   3. Cough-specific quality of life score
   4. Cough reflex sensitivity with inhaled capsaicin - not very specific to disease
   5. Cough counts - mean cough frequency: normal <3 / hour; disease often >30/hour
3. Insitute disease cause-specific management whenever possible
4. Common cold and post-nasal drip syndromes are extremely common (see below) [9]
5. Upper Respiratory Infection (URI) [7]
   1. Majority of these infections appear to be viral
   2. Adenovirus, influenza virus, rhinovirus, cocksackievirus, echovirus common
   3. May last up to 6 weeks
   4. Often called "acute bronchitis", usually with fever, sputum production
   5. In early URI, antibiotics provide no benefit, consistent with viral etiology
   6. After prolonged viral infection, bacterial superinfection may occur
   7. Cough during and after clearance of virus is extremely common [7]
   8. Bordetella may cause ~25% of chronic cough (>2 weeks) in adults and adolescents [3]
6. Other Common Causes
   1. Smoking - "Smoker's Cough"
   2. Bronchitis - Mycoplasma, Chlamydia, Pertussis - dry cough, chest pain
   3. COPD - viral syndromes and bacterial infections commonly exacerbate
7. Cough Variant Asthma
   1. Increasing incidence
   2. Cough may be major or only symptom (no wheezing)
   3. Pulmonary Function Testing (PFT) may be helpful
   4. Methocholine challenge results are suggestive but not confirmatory
   5. Improvement with one week trial of inhaled ß-adrenergic agonist is confirmatory
8. Chronic Obstructive Pulmonary Disease
   1. Cough is a part of the definition of COPD
   2. >95% of patients are, or have been, heavy smokers
   3. New cough in a smoker should prompt evaluation for lung cancer
   4. Tuberculosis is also possible and should be ruled out
9. GERD
   1. Elevation of head of bed
   2. Trial of proton pump inhibitors (PPI) initially for up to 2-3 months
   3. If PPI successful, consider switching to H-2 (histamine type 2) recpeptor blocker
   4. Maintenance with H-2 blocker with trial of weaning
   5. 24 hour pH monitoring is not recommended
   6. Consider upper endoscopy to rule out Barrett's Metaplasia if symptoms >1-2 years
10. Tests for Chronic Cough
    1. History and description of cough is rarely helpful in diagnosis of true chronic cough
    2. Response to cause-directed therapy is most effective for confirming diagnosis
    3. Additional testing should usually be reserved for unresolved cough (~2 weeks of therapy)
    4. Pulmonary Function Tests (PFTs)
    5. Chest Radiography or CT Scan
    6. Laryngeal endoscopy
11. Hoarseness Differential [5]
    1. Infection (URI in most cases)
    2. Rhinosinusitis with postnasal drip
    3. Allergies / Allergic Rhinitis
    4. LPR
    5. Benign or malignant vocal cord lesion
12. Laryngeal Endoscopy
    1. GERD versus LPR
    2. Rule out laryngeal lesions, especially in heavy smokers

G. Symptomatic Treatment of Cough [8,9]

1. Central Antitussives
   1. Codeine
   2. Dextromethorphan
   3. Diphenhydramine - 25mg is effective
   4. Baclofen (Lioresal®) - use only third or fourth line
   5. Caution in young children
2. Codeine
   1. 20mg per dose is effective
   2. May be given q4-6 hours
   3. Combined with docongestant as "Robitussin®+Codeine" 5mL po q4-6 hours prn
   4. Side effects: nausea, vomiting, sedation, dizziness, constipation
   5. Abuse potential
3. Dextromethorphan
   1. 20-30mg per dose is effective
   2. Usually given as Robitussin® (various combinations available)
   3. Side effects: confusion, excitation, nervousness, irritability
   4. Mild abuse potential
4. Expectorant
   1. Guaifenesin is only FDA approved nonprescription exectorant
   2. Unclear if nonprescription dosages of 200-400mg q4 hour are effective
   3. Prescription guaifenesin 600-1200mg available (Humibid® LA, Entex®, others)
   4. High doses can cause nausea, vomiting, dizziness, headache, rash, diarrhea, drowsiness
5. Post-Nasal Drip Syndromes
   1. Trial of antihistamine-decongestant for ~2 weeks strongly recommended
   2. Nasal and/or inhaled ipratropium bromide (Atrovent®) may also be used
   3. Inhaled and/or systemic glucocorticoids for short duration very useful
   4. Trial of dextromethorphan q4-6 hours or benzonatate (Tessalon®) 100mg po qid
   5. Codeine for cough suppression is very effective
   6. Trial of ß2-agonists may be also be effective if bronchial hyperresponsiveness present
6. Experimental Therapies [8]
   1. Peripheral µ- or delta- opioid agonist
   2. Nociceptin NOP1 receptor agonist
   3. TRPV1 blocker
   4. Bradykinin B2 receptor antagonist
   5. Tachykinin (NK1, NK3) receptor antagonists
   6. Cannabinoid CB2 agonist
   7. Ion channel modulators
   8. GABA receptor agonist - such as baclofen

References

1. Chung KF and Pavord ID. 2008. Lancet. 371(9621):1364
2. Irwin RS and Madison JM. 2000. NEJM. 343(23):1716
3. Dworkin MS. 2005. Ann Intern Med. 142(10):833
4. Cornia PB, Lipsky BA, Saint S, Gonzales R. 2007. NEJM. 357(14):1432 (Case Discussion)
5. Ford CN. 2005. JAMA. 294(12):1534
6. Kaul DR, Orringer MB, Saint S, Jones SR. 2007. NEJM. 356(18):1871 (Case Discussion)
7. Gonzales R. 2003. JAMA. 289(20):2701
8. Pavord ID and Chung KF. 2008. Lancet. 371(9621):1375
9. Over-The-Counter Cough Remedies. 2001. Med Let. 43(1100):23