Cough Variant Asthma

A form of asthma in which chronic cough (8 weeks or longer in adults) is the only or the main symptom, with no audible wheeze or breathlessness, and with airway hyperresponsiveness or eosinophilic airway inflammation. It accounts for about 5 to 30% of chronic cough in adults (higher in East Asia) and a large share of chronic cough in children.

• About 30 to 40% of patients develop classic asthma over several years, especially if untreated.
• Mechanism: airway inflammation with eosinophils and hyperresponsive cough receptors, in the absence of marked bronchoconstriction.
• Triggers: viral infection, cold air, exercise, allergens, smoke, perfumes, laughing, talking and lying down. It occurs commonly with allergic rhinitis, and it can follow a respiratory infection.

• Dry, persistent cough, often worse at night or early in the morning, with exercise, cold air, allergen or irritant exposure, and with laughter. Cough sometimes productive of scanty mucus. Throat irritation and a sense of an itch in the airway. No wheeze or dyspnoea, and normal chest examination.
• Differential diagnosis: upper airway cough syndrome (postnasal drip), gastro oesophageal reflux, non-asthmatic eosinophilic bronchitis, ACE inhibitor cough, pertussis and post-infectious cough, tuberculosis, lung cancer, interstitial lung disease, bronchiectasis, heart failure, habit cough, aspiration, and obstructive sleep apnoea.
• Complications: sleep disturbance, urinary incontinence, rib fracture, syncope, and progression to classic asthma.

• History of cough for 8 weeks or longer with no other cause (smoking, ACE inhibitor, abnormal chest X-ray, rhinitis, reflux).
• Chest X-ray and spirometry are normal. Spirometry may show a bronchodilator response (increase in FEV1 of 12% and 200 mL or more) in a minority.
• Objective tests of airway hyperresponsiveness and eosinophilic inflammation:
  • Methacholine or histamine challenge: PC20 less than 8 mg/mL (less than 16 mg/mL is borderline) confirms hyperresponsiveness. A negative test makes asthma unlikely (high negative predictive value).
  • Peak flow variability greater than 10 to 20% over 2 weeks.
  • Exhaled nitric oxide greater than 25 ppb in adults (greater than 20 ppb in children) or sputum eosinophils greater than 2.5% suggest eosinophilic airway disease (this includes non-asthmatic eosinophilic bronchitis, which has normal airway responsiveness).
  • Blood eosinophils and total IgE; skin prick or specific IgE tests for allergens.
• Exclude alternatives: sinus imaging or nasal examination, 24-hour oesophageal pH monitoring or a 4-week course of acid suppression when reflux is suspected, stopping ACE inhibitors for 4 weeks, sputum for pertussis PCR and tuberculosis (Xpert MTB/RIF) when relevant, and CT chest for abnormal films or persisting unexplained cough.
• A therapeutic response confirms the diagnosis retrospectively.

• Explain the diagnosis and that the cough responds to asthma treatment within 1 to 4 weeks. Stop smoking and stop any ACE inhibitor (replace with an ARB, for example losartan 50 to 100 mg daily).
• First line (inhaled corticosteroid with or without a bronchodilator):
  • Budesonide 200 to 400 micrograms twice daily, or beclometasone 100 to 200 micrograms twice daily, or fluticasone propionate 125 to 250 micrograms twice daily, by spacer or dry powder device; assess response at 2 to 4 weeks, and continue for at least 8 weeks and often 6 to 12 months after symptoms resolve.
  • Budesonide formoterol 160/4.5 micrograms, 1 to 2 puffs twice daily as an alternative; salbutamol 100 to 200 micrograms by spacer as needed.
• For severe cough, or a poor response after 2 weeks: prednisolone 20 to 30 mg orally daily for 3 to 7 days, then continue the inhaled corticosteroid.
• Adjuncts and alternatives:
  • Montelukast 10 mg once daily at night (5 mg for ages 6 to 14, 4 mg for ages 2 to 5); effective in about half, and can be used alone for mild disease or with allergic rhinitis; monitor for neuropsychiatric effects.
  • Theophylline modified release 200 to 300 mg twice daily (target level 5 to 15 mg/L; interacting drugs include ciprofloxacin, clarithromycin and cimetidine) in patients who cannot use inhaled treatment (evidence is limited).
  • Leukotriene antagonist plus antihistamine (cetirizine 10 mg daily or loratadine 10 mg daily) for coexisting allergic rhinitis, and intranasal fluticasone furoate 2 sprays each nostril daily or mometasone 2 sprays each nostril daily.
• Non-responders after 4 to 8 weeks: reconsider the diagnosis (non-asthmatic eosinophilic bronchitis responds to inhaled corticosteroid; reflux needs omeprazole 20 to 40 mg daily for 8 weeks; upper airway cough syndrome needs intranasal corticosteroid and first generation antihistamine such as chlorphenamine 4 mg every 6 hours; refractory cough may respond to gabapentin 100 to 300 mg at night titrated to 300 mg three times daily, or to speech therapy).
• Step down inhaled corticosteroid gradually after sustained control (3 to 6 months), with reintroduction at relapse. Because some patients progress to classic asthma, review yearly with spirometry.
• Special groups:
  • Children: budesonide 100 to 200 micrograms twice daily by spacer, or montelukast 4 to 5 mg at night; review the diagnosis if no response by 4 weeks; exclude foreign body, protracted bacterial bronchitis (amoxicillin clavulanate 25 to 45 mg/kg/day in 2 divided doses for 2 to 4 weeks), pertussis and tuberculosis.
  • Pregnancy: inhaled budesonide, salbutamol and intranasal corticosteroid are safe; avoid prolonged oral corticosteroid and montelukast where possible.
  • Elderly: check drug causes (ACE inhibitors) and cardiac disease; use low dose inhaled corticosteroid and check technique.
  • Smokers: stop smoking, because cough variant asthma responds poorly while smoking continues.
• Red flags: haemoptysis, weight loss, fever, night sweats, hoarseness, dysphagia, abnormal chest X-ray, clubbing, age over 55 with smoking history: investigate for tuberculosis, cancer and interstitial lung disease.
• Follow up: review at 2 to 4 weeks for response, at 8 to 12 weeks to plan step down, and yearly with spirometry and a review of symptoms.