The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 10 S Afr Fam Pract ISSN 2078-6190 EISSN 2078-6204 © 2019 The Author(s) REVIEW Introduction Chronic obstructive airway disease (COPD) is a progressive lung disease characterised by airflow obstruction that is not fully reversible and is associated with abnormal inflammatory responses of the lung to noxious particles or gases. The global prevalence of COPD is between 7–19%, with variations in different regions of the world, and a predominance in men and people aged over 40 years.1 In Cape Town, South Africa, the prevalence of COPD is 22.2% for men and 16.7% for women.1 Mintz et al. have determined that 21% of patients aged 30 years or more with more than 10 years of smoking history seen in primary care settings are likely to have COPD.2 The Global Burden of Disease Study 2010 reported a prevalence estimate of 8.9%3 and it is expected that it will be the 6th cause of death in the world with an increase in economic and social burden.4 Risk factors Tobacco use is the most important cause and contributing factor for COPD progression. Occupational exposures from gold mining, coal mining and cotton textile dust, indoor air pollution from burning wood and other biomass fuels, and poorly burning stoves also play a causative role. In addition, infections such as childhood respiratory infections and pulmonary TB, airway hypersensitivity, α1-antitrypsin deficiency, and demographic factors such as age, family history of atopy and low socioeconomic status, all contribute to the development of COPD. Clinical presentation The two subtypes of COPD – chronic bronchitis and emphysema – often coexist with their pathologic and clinical features (Table 1).5 The onset of COPD is insidious, with chronic cough, expectoration, and exertional dyspnoea. A high index of suspicion should be considered in every patient with risk factors of the disease.4 South African Family Practice 2019; 61(5):10-14 Open Access article distributed under the terms of the Creative Commons License [CC BY-NC-ND 4.0] http://creativecommons.org/licenses/by-nc-nd/4.0 Management of the patient with chronic obstructive airway disease (COPD) in a primary health care context I Govender,1 HI Okonta,2 S Rangiah,3 D Nzaumvila2 1 Department of Family Medicine, University of Pretoria, South Africa 2 Department of Family Medicine, Sefako Makgatho Health Sciences University, South Africa 3 Department of Family Medicine, University of KwaZulu-Natal, South Africa Corresponding author, email: indiran.govender@gmail.com This paper describes the incidence of chronic obstructive airway disease (COPD), the risk factors, staging, investigations and management of COPD. The differential diagnosis for COPD is also presented as COPD can be confused with other clinical conditions. This paper is presented in practical terms for the clinician working in a primary health care context. Table 1. Features distinguishing chronic bronchitis from emphysema Features Chronic bronchitis (Blue bloaters) Emphysema (Pink puffers) Definition Definition is clinical: Productive cough on most days for at least 3 consecutive months in 2 successive years Definition is pathological: Dilatation and destruction of air spaces distal to the terminal bronchiole without obvious fibrosis Pathology Obstruction due to narrowing of the airway lumen by mucosal thickening and excess mucus Decreased elastic recoil of lung parenchyma due to air trapping, airway collapse and decreased expiratory driving pressure In smokers the lesions are centriacinar primarily affecting the upper lung zones In patients with α1-antitrypsin deficiency the lesions are panacinar primarily affecting the lower lobes Clinical presentation Symptoms: Chronic productive cough, purulent sputum Signs: Cyanosis, peripheral oedema, crackles, wheezes, prolonged expiration, obesity Symptoms: Exertional dyspnoea, minimal cough, tachypnoea, decreased exercise tolerance Signs: Pink skin, pursed-lip breathing, use of accessory muscles, cachexia, barrel chest, hyperresonant percussion, decreased breath sounds, decreased diaphragmatic excursion Investigations PFT: ↓FEV1, ↓FEV1/FVC, normal TLC, ↓or normal DLco CXR: Normal AP diameter, ↑bronchovascular markings, enlarged heart with cor pulmonale PFT: ↓FEV1, ↓FEV1/FVC, ↑TLC, ↑RV, ↑DLco CXR: ↑AP diameter, flat hemidiaphragm (on lateral x-ray, ↓cardiac silhouette, ↑retrosternal space, bullae, ↓peripheral markings) PFT = Pulmonary function tests; FEV1=Forced expiratory volume in 1 second; FVC=Forced vital capacity; TLC=Total lung capacity; DLco=Carbon monoxide diffusing capacity of lung Management of the patient with chronic obstructive airway disease (COPD) in a primary health care context 11 The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 11 During acute exacerbations, patients may present with fever, chest pain and severe shortness of breath. Physical examination may reveal respiratory distress with use of accessory muscles and intercostal recession, decreased chest expansion, barrel chest with hyper-resonant percussion, distant breath sounds and poor air entry on auscultation. There may be crackles and wheezes with prolonged expiration. The presence of cyanosis and asterixis may indicate respiratory failure secondary to hypoxemia and hypercapnia. Distended neck veins, hepatomegaly with hepatojugular reflux and bilateral pedal oedema are suggestive of cor pulmonale. The severity of dyspnoea in COPD can be assessed using the Modified British Medical Research Council (MMRC) scale4 (Table 2). Table 2. Modified British Medical Research Council Dyspnoea scale Scale Severity of dyspnoea 0 No breathlessness except with strenuous exercise 1 Shortness of breath when hurrying on the level or walking up a slight hill 2 Walks slower than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level 3 Stops for breath after walking about 100 metres or after a few minutes on the level 4 Too breathless to leave the house or breathless when dressing or undressing Investigations • Spirometry is used to determine the extent of airflow obstruction, assess the severity of COPD and monitor the disease progression. Spirometry is not recommended in acute exacerbation as this may be difficult to perform and may not be accurate. A post-bronchodilator FEV1/FVC of <  0.70 is diagnostic of COPD. • The severity of airflow obstruction is assessed using the Global Initiative for Chronic Obstructive Lung Disease (GOLD)4 criteria. (Table 3) Table 3. COPD severity grading – GOLD criteria Grade FEV1/FVC FEV1 Mild COPD (GOLD 1) < 0.7 ≥ 80% of predicted Moderate COPD (GOLD 2) < 0.7 < 80% but ≥ 50% of predicted Severe COPD (GOLD 3) < 0.7 < 50% but ≥ 30% of predicted Very severe COPD (GOLD 4) < 0.7 < 30% of predicted or FEV1 < 50% with respiratory failure or right-sided heart failure • Chest x-ray is done to exclude other conditions or identify co- morbidities. Radiographic signs of hyperinflation are: • Increased anteroposterior diameter, increased retrosternal airspace, reduced cardiac silhouette with a vertical heart, flattening of the diaphragms, (better demonstrated on lateral chest x-ray), enlarged central pulmonary arteries and reduced peripheral vascular markings. • Chest CT scan can demonstrate emphysema, cystic and bullous lesions. • Echocardiogram is recommended if the physical examination findings are suggestive of cor pulmonale. • Full blood count may show polycythaemia due to hypoxia or anaemia • Eosinophil count > 100 cells/uL in recurrent exacerbations determines need for inhaled corticosteroid4 • Blood gases may reveal hypoxia if peripheral oxygen saturation is < 92% or respiratory failure if PCO2 > 45 • Serum α1-antitrypsin level is indicated in patients aged ≤  45 years with minimal or no smoking history, positive family history of COPD and lower lobe emphysema. Differential diagnosis The differential diagnosis of a patient with dyspnoea and persistent productive cough includes the following conditions: • Asthma Begins in childhood and is usually episodic. There may be personal or family history of allergy, eczema or rhinitis. The episodes are characterised by wheezing and the airway obstruction is reversible with bronchodilators. • Bronchiectasis This may be difficult to differentiate from chronic bronchitis. The sputum is copious with occasional haemoptysis. There may be past history of pneumonia, pertussis, tuberculosis and nontuberculous mycobacterium infection. Chest x-ray finding of tram tracking (parallel narrow lines) radiating from the hilum and cystic spaces are suggestive of bronchiectasis. A high-resolution chest CT will show bronchial dilatation and bronchial wall thickening to confirm the diagnosis. • Pneumonia Usually presents with fever, chills and pleuritic chest pain. Chest percussion is dull and auscultation may reveal crackles or bronchial breath sounds. The area of infiltration is confirmed by chest x-ray. • Tuberculosis Usually manifests with chronic productive cough, fever, night sweats and weight loss. Chest x-ray may reveal infiltrates, cavitation or fibrosis. A positive sputum Acid Fast Bacilli (AFB), GeneXpert or culture confirms the diagnosis. • Congestive heart failure Usually presents with orthopnoea and basilar crackles may be heard on auscultation. Brain natriuretic peptide level is elevated, chest x-ray shows cardiomegaly with increased pulmonary vascular congestion, and echocardiogram confirms the diagnosis. • Lung cancer Patients with lung cancer may present with cough, haemoptysis, dyspnoea, chest pain, weight loss and night sweats. This needs to be considered as smoking is a risk S Afr Fam Pract 2019;61(5):10-1412 The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 12 factor for lung cancer and COPD. The physical examination and chest x-ray or chest CT findings will suggest further diagnostic investigations (bronchoscopy, lung/pleural biopsy, thoracenthesis) towards tissue pathology diagnosis of lung cancer. Management The management of COPD is based on the GOLD grade and exacerbation history (Table 4). Tobacco use must be explored and discussed with patients at all visits and if necessary motivational interviewing to stop tobacco use must be initiated as early as possible.4 There are management interventions that prolong survival5 (Table 5). All other management interventions provide symptom relief with no mortality benefit. The progress of COPD is fraught with gradual decrease in FEV1 and episodes of acute exacerbations. Acute exacerbation of COPD is defined as sustained worsening of dyspnoea, cough, or sputum production of acute onset leading to increased use of medications. The most common trigger is viral or bacterial upper respiratory infection. Other causes include irritants from air pollution, pulmonary embolism, myocardial infarction, anaemia, and congestive heart failure. The investigations in the setting of acute exacerbation of COPD include FBC, chest x-ray, ECG and pulse oximetry and/or arterial blood gas. Spirometry is not recommended in acute exacerbation as this may be difficult to perform and may not be accurate. The management of acute exacerbation of COPD includes the following: • The airway should be secured and ventilation assisted in patients with altered level of consciousness. Table 4. Management of COPD based on GOLD grade and exacerbation history Patient group Description Non-pharmacological treatment Pharmacological treatment A Few symptoms and low risk of exacerbation: MMRC grade 0–1 or CAT score < 10 0–1 exacerbations per year not requiring hospitalisation Smoking cessation Physical activity Vaccinations SAMA or SABA prn SAMA + SABA prn (Combination therapy is superior to monotherapy)5 B More symptoms and low risk of exacerbation: MMRC grade ≥ 2 or CAT ≥ 10 0–1 exacerbation per year not requiring hospitalisation Smoking cessation Physical activity Vaccinations Pulmonary rehabilitation LAMA or LABA LAMA + LABA (combination therapy is superior to monotherapy)5-7 C Few symptoms but high risk of exacerbation: MMRC grade 0–1 or CAT < 10 ≥ 2 exacerbations per year, or one or more requiring hospitalisation Smoking cessation Physical activity Vaccinations Pulmonary rehabilitation LAMA LAMA + LABA or LABA + ICS (ICS increases risk of pneumonia and consequently less preferred) D More symptoms and high risk of exacerbation: MMRC grade ≥ 2 or CAT ≥ 10 ≥ 2 exacerbations per year, or one or more requiring hospitalisation Smoking cessation Physical activity Vaccinations Pulmonary rehabilitation LAMA + LABA LAMA + LABA + ICS LAMA + LABA +ICS + Roflumilast or Macrolide or stop ICS MMRC = Modified British Medical Research Council dyspnoea scale; SAMA = Short acting muscarinic antagonist; SABA = Short acting beta 2 agonist; LAMA = Long acting antimuscarinic antagonist; LABA = Long acting beta 2 agonist; ICS= Inhaled corticosteroid Table 5. Management interventions that prolong survival Interventions Details Smoking cessation The most effective intervention for preventing progression of COPD and includes: Behavioural therapy, nicotine replacement, varenicline (Champix), bupropion and reinforcement of cessation at every contact Vaccination Influenza vaccination annually Pneumococcal vaccination at least once per lifetime but can be repeated in 5–10 years Home oxygen Prevents cor pulmonale and decreases mortality if used > 15 hours/day Indications include: • PaO2 ≤ 55 mmHg • PaO2 ≤ 60 mmHg with cor pulmonale or haematocrit > 55% 70 ml improvement vs Indacaterol2 90 ml improvement vs Glycopyrromium2 70 ml improvement vs Indacaterol2 90 ml improvement vs Glycopyrromium2 70 ml improvement vs Indacaterol2 90 ml improvement vs Glycopyrromium2 70 ml improvement vs Indacaterol2 90 ml improvement vs Glycopyrromium2 70 ml improvement vs Indacaterol2 90 ml improvement vs Glycopyrromium2 1 1 1 1,2 LAMA-Long acting muscaranic antagonist; LABA-long acting beta 2 agonist; COPD: chronic obstructive pulmonary disease 70 ml improvement vs Indacaterol2 90 ml improvement vs Glycopyrromium2 Novartis South Africa (Pty) Ltd. Magwa Crescent West, Waterfall City, Jukskei View, Johannesburg, 2090. Tel. (011) 347-6600. Fax. (011) 929-2038. Co. Reg. No. 1946/020671/07. Customer Careline: 0861 929 929. ZA1909732335 09/2019 ULTIBRO BREEZHALER dry powder inhalation capsules Reg. No. 47/10.2.1/1183. Composition: Each capsule contains indacaterol maleate equivalent to 110 micrograms indacaterol and glycopyrronium bromide equivalent to 50 micrograms glycopyrronium. The delivered dose (the dose that leaves the mouthpiece of the inhaler) is equivalent to 85 micrograms indacaterol and 43 micrograms glycopyrronium. PHARMACOLOGICAL CLASSIFICATION: A10.2.1 Bronchodilators (inhalants) INDICATIONS: ULTIBRO BREEZHALER is indicated for the treatment of chronic obstructive pulmonary disease (COPD) in patients who are still symptomatic despite treatment with a long acting ß2 adrenergic agonist (LABA) or a long acting muscarinic antagonist (LAMA). Dosage: Adults: The recommended dosage of ULTIBRO BREEZHALER is the once-daily inhalation of the content of one 110/50 microgram capsule using the ULTIBRO BREEZHALER inhaler. Children and adolescents: ULTIBRO BREEZHALER should not be used in patients under 18 years of age. Elderly: ULTIBRO BREEZHALER can be used at the recommended dose in elderly patients 75 years of age and older without significant renal impairment. Special patient populations: Renal impairment: ULTIBRO BREEZHALER can be used at the recommended dose in patients with mild to moderate renal impairment. ULTIBRO BREEZHALER has not been studied in patients with severe renal impairment or end-stage renal disease requiring dialysis and no dosage recommendations can be made. Hepatic impairment: ULTIBRO BREEZHALER can be used at the recommended dose in patients with mild and moderate hepatic impairment. No data are available for subjects with severe hepatic impairment. Contraindications: ULTIBRO BREEZHALER is contraindicated in patients with hypersensitivity to indacaterol, glycopyrronium, lactose or to any of the excipients. Warnings and Special Precautions: ULTIBRO BREEZHALER should not be administered concomitantly with products containing other long acting beta-adrenergic agonists or long-acting muscarinic antagonists, medicine classes to which the components of ULTIBRO BREEZHALER belong. ◊ Asthma: ULTIBRO BREEZHALER should not be used for the treatment of asthma. ◊ Not for acute use: ULTIBRO BREEZHALER is not indicated for the treatment of acute episodes of bronchospasm. ◊ Hypersensitivity related to indacaterol: If signs suggesting allergic reactions occur, ULTIBRO BREEZHALER should be discontinued immediately and alternative therapy instituted. ◊ Paradoxical bronchospasm: Administration of ULTIBRO BREEZHALER may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, ULTIBRO BREEZHALER should be discontinued immediately and alternative therapy instituted.◊ Anticholinergic effects related to glycopyrronium: ULTIBRO BREEZHALER should be used with caution in patients with narrow-angle glaucoma or urinary outflow tract obstruction. ◊ Patients with severe renal impairment: The use of ULTIBRO BREEZHALER is not recommended for these patients. ◊ Systemic effects of betaagonists: ULTIBRO BREEZHALER should be used with caution in patients with cardiovascular disorders, in patients with convulsive disorders, hyperthyroidism or diabetes mellitus, and in patients who are unusually responsive to beta2-adrenergic agonists. ULTIBRO BREEZHALER should not be used more often or at higher doses than recommended. ◊ Cardiovascular effects of beta-agonists: ULTIBRO BREEZHALER may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. In such cases the medicine may need to be discontinued. In addition, beta-adrenergic agonists, such as indacaterol, have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QT interval and ST segment depression. The clinical significance of these findings is unknown. ◊ Hypokalaemia with beta-agonists: Beta2-adrenergic agonists, such as indacaterol may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment which may increase the susceptibility to cardiac dysrhythmias. ◊ Hyperglycaemia with beta-agonists: Inhalation of high doses of beta2-adrenergic agonists, such as indacaterol, may produce increases in plasma glucose. Upon initiation of treatment with ULTIBRO BREEZHALER plasma glucose should be monitored more closely in diabetic patients. ◊ Lactose: ULTIBRO BREEZHALER contains lactose. Patients with the rare hereditary condition of lactose or galactose intolerance e.g. galactosaemia, Lapp lactase deficiency, glucose- galactose malabsorption or fructose intolerance should not use ULTIBRO BREEZHALER. Pregnancy and breast-feeding: Safety in pregnancy and lactation has not been demonstrated. Interactions: ◊ No specific drug-drug interaction studies were conducted with ULTIBRO BREEZHALER. Information on the potential for interactions is based on the potential for each of its two components. ◊ should not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons for their use ◊ should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QT-interval. Drugs known to prolong the QT-interval may increase the risk of ventricular arrhythmia. ◊ concomitant administration of other sympathomimetic agents may potentiate the undesirable effects ◊ concomitant treatment with methylxanthine derivatives, steroids, or non-potassium sparing diuretics may potentiate the possible hypokalemic effect of beta2- adrenergic agonists. ◊ inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-gp, has no impact on safety of therapeutic doses. ◊ co-administration with other inhaled anticholinergic-containing drugs has not been studied and is therefore not recommended. ◊ no clinically relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport. Adverse reactions: ◊ Common (≥1% to <10%): Hyperglycemia and diabetes mellitus, hypersensitivity ◊ Uncommon (≥0.1% to <1%) and potentially serious: Glaucoma, hypersensitivity, diabetes mellitus and hyperglycemia, ischemic heart disease, atrial fibrillation, paradoxical bronchospasm ◊ Very common (≥10%): Upper respiratory tract infection ◊ Common (≥1% to <10%): Nasopharyngitis, urinary tract infection, sinustitissinusitis, rhinitis, dizziness, headache, cough, oropharyngeal pain including throat irritation, dyspepsia, dental caries, musculoskeletal pain, pyrexia, chest pain, bladder obstruction including urinary retention ◊ Uncommon (≥0.1% to <1%): Musculoskeletal pain, Insomniainsomnia, paresthesia, tachycardia, palpitations, epistaxis, dry mouth, pruritus/rash, muscle spasm, myalgia, bladder obstruction including urinary retention, peripheral edema, fatigue, gastroenteritis, pain in extremity. ◊ Rare (≥0.01% to <0.1%): Paresthesia. ◊ Spontaneous reports, post marketing: Angioedema, dysphonia. Packs: 30 capsules packed in PA/AL/PVC blister and one Breezhaler inhaler. Note: Before prescribing consult full prescribing information. This BSS is for use on promotional material linked to MCC approved package insert dated 23 November 2017. References: 1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2019 Report). Available from: https://goldcopd.org/wp-content/uploads/2018/11/GOLD-2019-v1.7-FINAL-14Nov2018-WMS.pdf. Accessed. 3 September 2019. 2. Bateman ED, Fergusen GT, Barnes N, et al. Dual bronchodilation with QVA149 versus single bronchodilatory therapy: the SHINE study. Eur Resp J 2013; 42: 1484-1494. 3. Ultibro Breezhaler Package Insert, 23 Nov 2017. 4. IMS DATA 08/2019 Reg. No. for Namibia 18/10.2/0090 NS2 Combining two fast acting bronchodilators 3 LA BA a nd L AM A The only4 once-daily3 dual bronchodilator available in South Africa and Namibia S Afr Fam Pract 2019;61(5):10-1414 The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 14 • Oxygen is administered to maintain the SaO2 between 88–92% for CO2 retainers. • Bronchodilators: Escalated use of SAMA + LAMA delivered by metered-dose inhaler (MDI) with spacer or nebuliser. • Systemic corticosteroids: Oral prednisone 40 mg daily, for 5–7 days without tapering. Alternatively, IV methylprednisolone 125 mg 12 hourly could be used but this has increased risk of side effects. • Antibiotics: These are indicated for exacerbations with increased sputum production plus either increased dyspnoea or increased sputum purulence. The choice of antibiotics is based on patient risk factors and local antibiotic resistance patterns as follows5,8: 1. For simple exacerbation with no risk factors (FEV1 >  50% predicted, ≤  4 exacerbations/year, no cardiac disease): 5-day course of Amoxicillin, Macrolide, Trimethoprim/ sulphamethoxazole, 2nd and 3rd generation cephalosporins. 2. For complicated exacerbation (FEV1 <  50% predicted, ≥ 4 exacerbations/year, cardiac disease): 7–10 day course of Amoxicillin-clavulanate, levofloxacin or moxifloxacin. 3. For patients at risk of pseudomonas infection (FEV1 < 35% predicted, chronic steroid use, persistent purulent sputum): Ciprofloxacin. Prognosis The prognosis of COPD is variable, depending on genetic predisposition, environmental exposures, comorbidities and acute exacerbations. The single best prognostic predictor is the level of dyspnoea. The BODE index is a 10-point measure of four factors (body mass index, obstruction, dyspnoea and exercise capacity) used to predict mortality in COPD (Table 6). The probability that the patient will die from COPD increases as the BODE index score increases. Table 6. BODE index score to predict mortality in COPD4 Prognostic factor BODE index score + 1 point + 2 points + 3 points Body mass index (BMI) ≤ 21 Obstruction (FEV1) 50–64% 36–49% ≤ 35% Dyspnoea (MMRC scale) 2 3 4 Exercise capacity (6-minute walk distance) 250–349 metres 150–249 metres ≤ 149 metres Another prognostic tool that is sometimes used is the codex index which uses 4 factors (comorbidities, obstruction, dyspnoea and previous severe exacerbations) to predict the course of COPD. Follow-up Patients with COPD should be followed up regularly to monitor disease progression or development of complications. Stable COPD patients can be followed up at three to six monthly intervals while patients with severe frequent exacerbations or recently discharged from hospitalisation should be followed up at two to four weekly intervals. At each follow up visit, determine the level of dyspnoea at rest and with exercise, the number of exacerbations and hospitalisations. The COPD assessment test (CAT) questionnaire can be used for monitoring. Smoking cessation or avoidance of air pollution should be reinforced. Assess the effectiveness of medications and side effects. If medication appears ineffective, observe inhaler technique to ensure optimal delivery of current medications before adjustments. Oxygen saturation should be determined to identify COPD patients in need of supplemental oxygen. Annual spirometry is recommended to monitor decline in pulmonary function. References 1. Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28:523-532. 2. Mintz ML, Yawn BP, Mannio DM, et al. Prevalence of airway obstruction, assessed by lung function questionnaire. May Clin Proc. 2011 May;86(5):375-81. 3. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Buren of Disease study. Lancet. 1997;349:1498-504. 4. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease 2019 report. Available from: https://goldcopd.org/wp-content/ uploads/2018/11/GOLD-2019-v1.7-FINAL-14Nov2018-WMS.pdf. Accessed 4 September 2019 5. Waleed A, Fernandes S, Thang M, et al. Respirology. Toronto Notes 35th Ed. Shafarenko, Tofighi: Toronto; 2019. 6. Canavan N. Dual-action bronchodilator eases COPD exacerbations. Medscape [Serial online]. Available from: http://www.medscape.com/viewarticle/810739. 7. Rabe KF, Martinez FJ, Rodriguez-Roisin R, et al. LAMA/LABA glycopyrrolate/ formoterol fixed-dose combination, delivered using a novel MDI co-suspension delivery technology reduces risk of clinically important deteriorations in COPD versus placebo and monocomponent MDIs. AJRCCM 2017;195:A3594. 8. O’Toole D. Family Medicine Notes 7th Ed; 2019.