Differential Diagnosis

  • >20% of cough may be multifactorial and persist until all etiologies are treated
  • In adults, the timing and character of the cough is not predictive of the cause
  • In immunocompetent non-smoking patients with chronic cough, normal CXR, and not taking an ACE-inhibitor, the most likely diagnosis is upper airway cough syndrome (UACS), asthma and non-asthmatic eosinophilic bronchitis (NAEB) which are often grouped together as "asthma syndrome", or GERD (alone or in combination up to 25% of the time)
    • UACS - post nasal drip accompanying rhinitis/sinusitis
      • Postinfectious (post-viral) rhinitis
      • Allergic rhinitis, non-allergic rhinitis (e.g. vasomotor, NARES)
      • Bacterial sinusitis
      • Allergic fungal sinusitis
      • Rhinitis due to anatomic abnormalities
      • Rhinitis due to physical or chemical irritants
      • Occupational rhinitis
      • Rhinitis medicamentosa
      • Rhinitis of pregnancy
    • GERD - cough often associated with phonation, rising, eating, throat clearing
      • LPR - laryngophryngeal reflux, often including chronic cough, throat clearing, hoarseness, globus sensation, and VCD
        • Interpret laryngoscopy with caution because chronic cough itself can cause edema and inflammation of the vocal cords and other changes in the larynx.
      • Nonacid esophageal reflux disease - reflux of pepsin and other digestive enzymes may also initiate cough
    • Eosinophilic airway disease or "asthma syndrome"
      • Asthma, cough variant asthmaEos_vs_non_eos_cough.png
        • Decrease/resolution of cough can take up to 6-8 weeks with treatment
        • Negative methacholine rules out asthma in these patients
      • NAEB - cough with >3% eosinophils on BAL, normal CXR and methacholine challenge, no reversible obstruction on spirometry; treated with corticosteroids, with clinical response requiring up to 8 weeks of adequate ICS dose or oral steroids. Generally benign/self-limiting. May be caused by occupational allergen which should be avoided.
        • NAEB differs from asthma in that localization of mast cells is only in the airway epithelia (and not in airway smooth muscle as in asthma)
      • Other eosinophilic pneumonias

Eosinophilic cough syndromes.png


  • Medications
    • ACE inhibitors - cough occurs in 5-20%, onset can occur up to 6 months, resolution after discontinuation can take up to 1-3 months
      • ARBs have been speculated to increase cough but this is unproven
    • Beta blockers - exacerbating asthma
    • Aspirin/NSAIDs - causing aspirin-exacerbated respiratory disease
  • COPD
    • Chronic bronchitis - defined as cough productive of sputum on most days for >3 months and for >2 consecutive years
  • Atopic cough - dry cough in patients with allergies, resistant to treatment with bronchodilators, normal airway responsiveness to methacholine, but excess eosinophils in induced sputum/bronchial biopsy; treated with ICS
  • VCD - may be elicited by GERD/LPR and UACS
    • Laryngeal dysfunction with chronic cough and throat clearing - chronic laryngeal irritation that can predispose the larynx to become hypersensitive to external stimuli and trigger paradoxical VCD during inspiration; treated with behavioral and speech therapy
    • Irritable larynx syndrome - measured by histamine inhalation challenge demonstrating paradoxical vocal cord adduction causing decreased inspiratory flow rate (laryngeal hyperreactivity)
  • Obstructive sleep apnea (OSA) - cough can be the sole manifestation of OSA and can be effectively treated with CPAP
  • Bronchiectasis - suggests CF, ABPA, immunodeficiency
  • CF
  • Alpha1-antitrypsin deficiency
  • Occupational cough - exposure to irritants, allergens
  • Ciliary dyskinesia
  • Immunodeficiency
  • Non-bronchiectactic suppurative airway disease (bronchiolitis)
    • Infectious bronchiolitis
    • Bronchiolitis associated with inflammatory bowel disease
    • Diffuse panbronchiolitis (DPB)
  • Chronic infections
  • Interstitial lung disease
  • Aspiration
    • Recurrent due to swallowing dysfunction, neurological conditions (e.g. stroke)
    • Foreign body
    • Due to anatomic abnormalities, e.g. small occult tracheoesophageal fistula
  • Middle lobe syndrome - includes all causes of recurrent or chronic atelectasis of the right middle lobe
  • Cardiac disease
  • Tumors - Lung cancer has been found to be the cause of chronic cough in less than 2% of all patients presenting with chronic cough
  • Cough nerve reflex (Arnold nerve) - stimulation of the auricular branch of the vagus nerve or the posterior-inferior wall of the external acoustic meatus (e.g. foreign body, hair touching tympanic membrane, wax in ear)
  • Habit/psychogenic/tic cough - harsh, dry, often honking repetitive cough occurring intermittently throughout the day, often with great frequency, child is usually indifferent, with significant improvement with distraction and absence when asleep
    • Note that almost all patients with chronic cough have physiologic decreased frequency at night
  • Rheumatological
  • Postmenopausal
  • Dialysis
  • Premature ventricular contractions (PVCs) - may rarely cause a chronic cough, with cough disappearing upon spontaneous resolution of the PVCs or markedly improved with treatment of the arrhythmia
  • Holmes-Adie syndrome - autonomic dysfunction affecting the vagus nerve also causing anisocoria, abnormal deep tendon reflexes, and patchy areas of hyperhidrosis or anhidrosis
  • Tonsillar enlargement - has been reported as a cause of chronic cough in both children and adults
  • Post-viral coughNeuropathic cough table.png
    • Post-viral non-asthmatic cough - in patients without asthma who have chronic cough originating with a viral URI, prednisone 25-30 mg/day or divided BID x 5-7 days has been reported to be effective
    • Post-viral vagal neuropathy (PVVN) - motor or sensory neuropathy caused by viral illness, most commonly affects adult females, may present with chronic cough, “throat tickle”, globus sensation, odynophagia, increased mucus, laryngospasm, with symptoms triggered by laughing, prolonged phonation, and noxious stimuli, treated with pregabalin, gabapentin, amitryptiline
  • Idiopathic cough, or chronic cough hypersensitivity syndrome (CCHS) - up to 40% of patients do not have a definable underlying cause. Idiopathic cough or CCHS may include vagal neuropathy and laryngeal/VCD causes
    • CCHS proposed criteria include duration >2 months, minimal or no sputum production, one or more cough reflex triggers (cold air, speech, eating, odors such as perfume), urge to cough (tickle or itch) located in throat area (laryngeal hypersensitivity), adverse impact of cough on QOL, positive cough reflex challenge test (capsaicin), and female predominance
    • Note that diseases such as nonacid reflux or chronic rhinosinusitis that do not have perfect or guaranteed successful treatment outcomes are often diagnosed as neuropathic cough

Work-related Chronic Cough

Wrcc overview.png

Relative Frequency of Chronic Cough Etiologies

Chronic cough etiology.png
  • Irwin, Kasetelik - adult studies (Big 3 = UACS + asthma + GERD)
  • Marchant - pediatric study (PBB = protracted bacterial bronchitis, NR = natural resolution)




Management Algorithms


CHEST Guidelines (2006)


Subacute Cough

  • Patients aged ≥15 years with cough lasting >3-8 weeks
subacute_cough.png



Chronic Cough
  • Patients aged ≥15 years with cough lasting >8 weeks
chronic_cough.png

A/D - drying 1st generation antihistamine/decongestant


Rank Simplified Algorithm

Oppenheimer_Kelkar_adult_cough_algo.png


Pavord

Pavord_cough.png





Treatment


Treatment Response Time

Chronic cough response time.png

Rank

Chronic_cough_treatment_table.png


Approach to UACS (CHEST)

  • Upper airway cough syndrome = post-nasal drip syndrome
  • Treated with empiric 1st generation antihistamine/decongestant, e.g. brompheniramine with pseudoephedrine
    • Typical response is at least some improvement within days to 1-2 weeks. Marked improvement or resolution of cough may take several weeks and occasionally as long as a few months.
    • If the resolution is only partial, then the next step in the evaluation can be guided by patient symptoms.
      • If the patient no longer has nasal signs or symptoms but cough persists, proceed to the evaluation for asthma.
      • If the patient has persistent nasal symptoms, then the addition of a topical nasal steroid, nasal anticholinergic agent, or nasal antihistamine may be effective.
        • Persistent UACS symptoms after the addition of topical therapy would be an indication for sinus imaging (CT or X-ray) to look for evidence of acute or chronic sinusitis.
          • Air-fluid levels in the sinuses would be an indication for antibiotic therapy and perhaps short- term nasal topical vasoconstrictor therapy with an alpha-agonist.
          • Mucosal thickening is not as diagnostic of sinusitis, but in the setting of chronic cough that is unresponsive to treatment for UACS, patients with mucosal thickening should be treated presumptively for sinusitis.
          • The lack of response to medical therapy for documented sinusitis should lead to:
            • Consultation with an ENT
            • Serum immunoglobulin levels
            • Allergy testing
            • Evaluation of the patient’s home and workplace



Approach to ACE-inhibitor cough (CHEST)

  • Discontinue ACE-inhibitor
  • If unable to discontinue, possible treatments for ACEI cough include: sodium cromoglycate, theophylline, sulindac, indomethacin, amlodipine, nifedipine, ferrous sulfate, and picotamide


Alternative Drugs for Chronic Idiopathic Cough

Drug
Dose
Notes
Pregabalin (Lyrica)
75 mg PO BID to 150 mg PO BID, titrated over 3-4 weeks
Somnolence, dry mouth, blurred vision, dizziness
Gabapentin (Neurontin)
  • 100 mg PO QD to 300 mg PO TID, titrated over 4 weeks
  • 300-1800 mg in a chronic cough study
Dizziness, headache, somnolence, ataxia, fatigue
Baclofen
10 mg PO QD x 1 week, then BID x 1 week, then TID

Amitryptiline
10-20 mg PO QHS

Duloxetine (Cymbalta)
start at 30-60 mg PO QD

Lidocaine 2-4% solution (without epi)
2 mL nebulized BID-QID
With or without albuterol added; may irritate lower airways
TRPV1 antagonists

In clinical trials




References


CHEST - Diagnosis and Management of Cough