Asthma-COPD Overlap Syndrome

Asthma-COPD overlap describes persistent airflow limitation in a patient who has features of both asthma and chronic obstructive pulmonary disease. It is a descriptive label and not a single disease, and it accounts for about 15 to 25% of adults with chronic airway obstruction.

It arises in two common ways: a long standing asthmatic who smokes or has another exposure and develops fixed obstruction, or a patient with COPD who has eosinophilic inflammation and variable airflow. Outcomes are worse than in either condition alone, with more exacerbations, faster decline in lung function and a heavier burden of hospital admission.

Pathophysiology. Type 2 (eosinophilic) inflammation from asthma coexists with neutrophilic inflammation, small airway fibrosis and emphysema from smoking or biomass smoke. Airway remodelling in long standing asthma leaves fixed obstruction, and eosinophilic COPD is steroid responsive.

Wood and charcoal smoke, occupational dusts and childhood respiratory disease add to the risk in many settings.

Age is usually over 40 years. Chronic dyspnoea and cough with sputum are persistent, with wheeze, nocturnal symptoms and day-to-day variation. Many give a history of childhood asthma, atopy, nasal polyps or rhinitis, together with a smoking history of 10 pack years or more, or years of cooking over open fires.

Exacerbations are frequent and often eosinophilic. Examine for hyperinflation, wheeze, prolonged expiration, nasal polyps and signs of right heart strain in advanced disease.

Inability to speak in sentences, silent chest, oxygen saturation under 92%, confusion or exhaustion mark a life threatening exacerbation and need emergency care.

• Post-bronchodilator spirometry showing FEV1/FVC under 0.70 (or under the lower limit of normal) that does not fully reverse, together with variability: an FEV1 rise of over 12% and 200 mL after salbutamol 400 micrograms, or peak flow variability of over 20% across 2 weeks.
• Blood eosinophil count (a count of 300 cells/microlitre or more, or 150 or more on repeated testing, supports eosinophilic disease and steroid benefit) and fractional exhaled nitric oxide (over 35 ppb in adults supports type 2 inflammation).
• Total IgE and specific IgE or skin prick tests for atopy, and sputum eosinophils where available.
• Full lung function with diffusing capacity: a low transfer factor points to emphysema, while a normal or high value points to asthma.
• Chest radiograph, and CT chest when emphysema, bronchiectasis or a nodule is suspected.
• Alpha-1 antitrypsin level in all patients with COPD features, especially under 45 years, or with basal emphysema or a family history.
• Electrocardiogram and echocardiography when dyspnoea is out of proportion to spirometry.

Differential diagnosis.

• Asthma with fixed obstruction
• COPD with bronchodilator reversibility
• Bronchiectasis
• Heart failure
• Bronchiolitis obliterans
• Allergic bronchopulmonary aspergillosis

• Stop smoking: varenicline 0.5 mg daily for days 1 to 3, 0.5 mg twice daily for days 4 to 7, then 1 mg twice daily for 12 weeks (reduce to 0.5 mg twice daily when eGFR is under 30), or nicotine patch 21 mg daily (14 mg if under 10 cigarettes daily) with a short acting form. Reduce biomass smoke exposure with vented stoves and cleaner fuel.
• Always include an inhaled corticosteroid. A long acting bronchodilator alone, without corticosteroid, is avoided because it can worsen eosinophilic disease.
• Initial maintenance: budesonide formoterol 160/4.5 micrograms, two inhalations twice daily (maximum 8 inhalations daily), or beclometasone formoterol 100/6 micrograms, two inhalations twice daily. Salbutamol 100 micrograms, 1 to 2 puffs as needed for rescue, unless budesonide formoterol is used as reliever.
• Step up to triple therapy for persisting symptoms or exacerbations: beclometasone-formoterol-glycopyrronium 87/5/9 micrograms, two inhalations twice daily, or fluticasone furoate-umeclidinium-vilanterol 92/55/22 micrograms, one inhalation once daily. Rinse the mouth after use.
• Severe disease with frequent exacerbations and eosinophils over 300 cells/microlitre or high FeNO: add a biologic, such as mepolizumab 100 mg subcutaneously every 4 weeks, benralizumab 30 mg subcutaneously every 4 weeks for 3 doses then every 8 weeks, or dupilumab 400 mg subcutaneously then 200 mg every 2 weeks.
• Exacerbation: prednisolone 40 mg orally daily for 5 days, with antibiotics when sputum is purulent: doxycycline 200 mg on day 1 then 100 mg daily for 4 more days, or amoxicillin 500 mg three times daily for 5 days (reduce to 500 mg every 12 hours at eGFR 10 to 30). Controlled oxygen to a saturation of 88 to 92% in hypercapnic patients.
• Add roflumilast 500 micrograms daily for FEV1 under 50% with chronic bronchitis and exacerbations on triple therapy (avoid in depression and low weight). Add azithromycin 250 mg daily or 500 mg three times weekly for persisting exacerbations in former smokers, after checking QTc, hearing, liver function and sputum for nontuberculous mycobacteria.
• Vaccinate against influenza each year, against pneumococcus and COVID-19, and against respiratory syncytial virus in older adults.
• Pulmonary rehabilitation for 6 to 8 weeks. Long term oxygen for at least 15 hours daily when PaO2 is 7.3 kPa or less (or 8.0 kPa with cor pulmonale or polycythaemia).
• Treat rhinosinusitis and nasal polyps, and treat reflux and obstructive sleep apnoea.

Monitoring. Review at 4 to 8 weeks after any change, then every 3 to 6 months. Check inhaler technique at every visit, spirometry yearly, eosinophils and FeNO periodically, and for steroid effects: oral thrush, bone density in those with heavy exposure and pneumonia on inhaled corticosteroid.

Referral and escalation. Refer to a respiratory specialist for diagnostic doubt, 2 or more moderate or 1 severe exacerbation yearly, need for a biologic, long term oxygen or non-invasive ventilation, and age under 45 with emphysema.