COPD

COPD is the third-leading cause of mortality worldwide and correct and timely diagnosis is vital. On completion of this module, it is expected the reader will have an enhanced understanding of the most common symptoms, how to differentiate COPD from other respiratory diseases, and possible preventive measures. The importance of good inhaler technique and optimum pharmaceutical management are also addressed.

Introduction

Chronic obstructive pulmonary disease (COPD), according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), is a heterogeneous lung condition characterised by chronic respiratory symptoms (dyspnoea, cough, expectoration, and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction.

COPD is the third-leading cause of mortality in the world: There were 3.23 million deaths from COPD in 2019. It is common, preventable, and treatable, but is underdiagnosed.¹ There are an estimated 380,000 people living with COPD in Ireland, however, up to 270,000 of these are not aware that they may have this condition. According to the National Healthcare Quality Reporting System, at least 1,500 people die each year from COPD in Ireland, and over 15,000 patients are admitted to hospital with the disease.² Correct and timely diagnosis significantly impacts both patient outcomes and public health.

Productive cough is a common symptom, present in up to 30 per cent of patients, and chronic dyspnoea is the most characteristic symptom. Physical activity is often limited in COPD. Comorbid diseases may further exacerbate COPD symptoms, ie, cardiovascular disease, skeletal muscle issues, metabolic syndrome, osteoporosis, depression, anxiety, or lung cancer. Appropriate management for any comorbid conditions can also improve COPD prognosis.¹

Symptoms and diagnosis

Both genes and environmental factors contribute to the pathogenesis of COPD, with tobacco smoke and inhalation of toxic gases/particles from pollution being the main environmental contributors. The most significant genetic risk factors for COPD are mutations in the SERPINA1 gene that lead to alpha 1 antitrypsin (AAT) deficiency. AAT is a protein made mainly in the liver that protects the lungs. Without sufficient AAT, lungs are more easily damaged from smoking, pollution, or dust.³

According to NICE guidelines,⁴ a diagnosis of COPD is suspected in people over 35 who have a risk factor (ie, smoking, or history of smoking) who present with one or more of exertional breathlessness, chronic cough, sputum, frequent bronchitis, or wheeze. Table 1 shows clinical risk factors for the diagnosis of COPD from the GOLD guidelines.¹

Dyspnoea that is:	Progressive over time Worse with exercise Persistent
Recurrent wheeze
Chronic cough	May be intermittent, may be unproductive
Recurrent lower respiratory tract infections
History of risk factors	Tobacco smoke Smoke from home cooking, heating fuels Occupational dusts, vapours, fumes, gases, etc. Patient factors (ie, genetics, developmental factors, low birthweight, prematurity, childhood respiratory infections)

Table 1. Clinical Indicators for Potential COPD Diagnosis¹

If any of these clinical indicators are present, COPD should be considered and spirometry performed

Post-bronchodilator spirometry should be performed to confirm COPD diagnosis: The presence of non-fully reversible airflow limitation (FEV1/FVC <0.7 post bronchodilation) as measured by spirometry then confirms diagnosis.^1,4

Spirometry should also be performed to monitor disease progression. Severity of airflow limitation, current symptoms, impact of disease on patient, comorbidities, and risk of future events (exacerbations, hospitalisation, death) should guide treatment. At initial evaluation, NICE recommends a chest radiograph, full blood count, and an estimated BMI.

An exacerbation is a sustained worsening of the patient’s symptoms from their usual stable state which is beyond normal day-to-day variations, and is acute in onset. Commonly reported symptoms are worsening breathlessness, cough, increased sputum production and change in sputum colour.⁴

Initially, untreated asthma and COPD may have similar presentations. Features from history and examination (Table 2) may help to differentiate the conditions.⁴ If uncertainty remains, asthma can be identified over COPD when a large response is seen to bronchodilators or 30mg prednisolone daily for two weeks, or with peak flow measurements showing 20 per cent or greater diurnal/day-to-day variability.

Clinical Feature	COPD	Asthma
Smoker/ex-smoker	Nearly all	Possibly
Symptoms under age 35	Rare	Often
Chronic productive cough	Common	Uncommon
Breathlessness	Persistent, progressive	Variable
Night time waking with breathlessness/wheezing	Uncommon	Common
Significant diurnal/day-to-day symptom variability	Uncommon	Common

Table 2: Clinical features differentiating COPD and asthma

• Chronic cough (productive/unproductive) is often the first symptom of COPD, but frequently attributed to, ie, smoking or environmental exposures by the patient, and not considered any further. It is usually intermittent to start but then progresses to daily.
• The regular production of sputum for three or more months in two consecutive years is indicative of chronic bronchitis, however, sputum production can be tricky to evaluate, as patients may swallow sputum rather than expectorate. Large volumes may indicate bronchiectasis (widening of the airways).
• Wheezing and chest tightness may vary over time, often following exertion. An absence of wheezing and chest tightness does not exclude COPD, or confirm a diagnosis of asthma.
• Fatigue is one of the most distressing symptoms, described as ‘general tiredness’ or ‘drained of energy’ often by COPD patients.¹

Lung cancer is frequently seen in patients with COPD. An annual CT scan for lung cancer in people with COPD due to smoking is recommended in the GOLD guidelines. Osteoporosis and depression/anxiety are also very common comorbidities in COPD and are often missed. Reflux can be linked with exacerbations, and should be treated where necessary.

Spirometry

Forced spirometry is objective, reproducible, cheap, non-invasive and readily available. It has good sensitivity, but cannot be used alone as a diagnostic test due to its weak specificity. Forced expiratory volume in 1 second (FEV1) is the maximum air a person can forcibly expel during the first second following maximal inhalation.⁵

Forced vital capacity (FVC) is the total volume of air exhaled in a single forced breath. The ratio of FEV1 to FVC (FEV1/FVC, also known as FEV1%) can help distinguish obstructive and restrictive lung diseases. In obstructive diseases, FEV1 reduction is due to the increased airway resistance to expiratory flow. In restrictive lung diseases, the FVC may be decreased more as compared to FEV1, giving an FEV1/FVC ratio of more than 70 per cent. However, this fixed value may lead to overdiagnosis in older people and underdiagnosis in young adults, especially in mild disease.¹

There is actually only a weak correlation between the severity of airflow obstruction (Table 3) and the patient’s symptoms/quality of life. Because of this, formal assessment of symptoms in terms of frequency of previous exacerbations, use of validated questionnaires (ie, the modified Medical Research Council, mMRC, dyspnoea scale), and multidimensional questionnaires (ie, the Chronic Respiratory Questionnaire, COPD Assessment Test, St George’s Respiratory Questionnaire) is recommended, rather than just spirometry.¹

GOLD 1	Mild	FEV1 ? 80% predicted
GOLD 2	Moderate	50% ? FEV1 < 80% predicted
GOLD 3	Severe	30% ? FEV1 <50% predicted
GOLD 4	Very Severe	FEV1 < 30% predicted

Table 3: GOLD Grades and Severity of Airflow Obstruction in COPD based on FEV1 (also NICE)

People may present with respiratory symptoms and structural issues like emphysema, and/or physiological abnormalities without a level of airflow limitation. These people may be ‘Pre-COPD’, or ‘PRISm’ (Preserved Ratio Impaired Spirometry), and at risk of developing airflow obstruction, although not all do.¹

Prevention and management

• Smoking cessation: NRT/pharmacotherapy increases long-term smoking abstinence. However, there is no evidence to recommend e-cigarettes as smoking cessation aids currently. About 40 per cent of COPD patients are current smokers despite their diagnosis. With effective use of resources and time, up to 25 per cent of these can achieve long-term quitting success. Smoking bans have contributed to increasing quit rates and reducing second-hand smoke harms.
• Pharmacological treatment reduces COPD symptoms, exacerbations, and improves health, with suggested benefits on lung function and mortality. Regimens need to be suitably individualised depending on symptoms, exacerbations, side-effects, comorbidities, drug availability, patient response and preference, and ability to use devices.
• Inhaler technique should be assessed regularly.
• Vaccinations (influenza, pneumococcal, Covid-19) reduce the incidence of lower RTIs.
• Pulmonary rehabilitation (exercise training, disease specific education) improves symptoms and quality of life in all severities of COPD patients.
• Long-term oxygen therapy improves mortality in COPD patients with severe chronic hypoxaemia.^1,4

Pharmacological treatment

The goal for treatment of stable COPD is to reduce symptoms (relieve symptoms, improve exercise tolerance, improve health status) and to reduce risk (prevent disease progression, prevent exacerbations, reduce mortality). Pharmacotherapy may also be beneficial in terms of reducing the rate of decline of lung function. Where multimorbidity and polypharmacy is present, care should be taken to simplify treatment and minimise polypharmacy.¹

The effectiveness of bronchodilator therapy should not be assessed based on lung function alone: A variety of other measures, like improvement in symptoms, activities of daily living, exercise capacity, and rapidity of symptom relief, should be considered.⁴

Bronchodilators

These increase FEV1, and/or change other spirometric variables. Their mechanism of action is through the alteration of airway smooth muscle tone. Improvements in airflow are due to widening of the airways.

Beta 2 agonists relax airway smooth muscle, stimulating antagonism of bronchoconstriction via beta 2 receptors. Short-acting beta 2 agonists (SABAs, ie, salbutamol) last for four-to-six hours, and long-acting beta 2 agonists (LABAs) last for 12 hours or more.

The LABAs formoterol and salmeterol significantly improve FEV1, lung volumes, health status, exacerbation rate and hospitalisation rates. Beta 2 agonists do not impact mortality or lung function decline.

Some patients can experience cardiac side-effects, ie, resting sinus tachycardia.

Antimuscarinics

These block the effect of acetylcholine on M3 muscarinic receptors on airway smooth muscle, reducing bronchoconstriction. Short-acting muscarinic antagonists (SAMAs, ie, ipratropium), also reduce vagally induced bronchoconstriction via effects on the inhibitory neuronal M2 receptor. Long-acting muscarinic antagonists (LAMAs, ie, tiotropium, umeclidinium) bind for longer to the M3 receptor.

Evidence has shown that ipratropium alone is slightly more beneficial than a SABA in terms of improvement of lung function, health status, and oral steroid requirements. LAMA treatments improve symptoms (cough, sputum, health status), effectiveness of pulmonary rehabilitation, exacerbations, and hospitalisations. LAMA treatment appears to show a greater impact on exacerbation rates than LABA treatment.

The main adverse effect reported from antimuscarinics is dry mouth.

LABAs and LAMAs are preferred over short-acting agents (except for patients with only occasional dyspnoea), and for when immediate relief is required for patients already on LABA/LAMA.

Combination bronchodilator therapy

Using multiple bronchodilators with different mechanisms and durations of action can help to increase effective bronchodilation with a lower risk of side-effects (compared to an increased dose of one alone). SABA/SAMA combinations work better in combination than either alone to improve FEV1 and symptoms.

LABA/LAMA combination inhalers are available, and show improvements consistently greater than use of one alone. However, the magnitude of improvement is not as great as the additive effect of the two drugs that might be expected.

Both regular and as-needed use of SABA or SAMA improves FEV1 and symptoms. In terms of long-acting inhaled therapies, LAMAs have a greater impact on exacerbation reduction compared to LABAs. Importantly, single inhaler therapy may be more convenient than multiple therapies.

Inhaled corticosteroids (ICS)

In vitro evidence that suggests corticosteroids have only limited utility in treating COPD-associated inflammation. Some COPD pharmacotherapies however (beta 2 agonists, theophylline, azithromycin) may lead to an increased sensitivity to corticosteroids in treating COPD. Treatment with ICS alone does not impact the decline of lung function or mortality rate in people with COPD, and trials have not demonstrated conclusive evidence of COPD improvement.

Research suggests that blood eosinophil counts predict how effective ICS will be (as an add-on treatment) for preventing future exacerbations. People with higher counts are likely to have the most benefit.

An ICS in combination with a LABA is more effective than either on its own in terms of lung function improvement, health status, and reducing exacerbations.

Evidence from RCTs shows that ICS modifies the airway microbiome and is linked to an increase in oral candidiasis, hoarse voice, skin bruising, and pneumonia. The following factors predispose people to pneumonia:

• Increased age (55 years or older).
• History of prior exacerbations or pneumonia.
• BMI less than 25 kg/m2.
• Severe airflow obstruction.

Triple therapy (LABA + LAMA + ICS)

This combination has been shown to improve lung function, patient-reported outcomes, and reduce exacerbations in comparison to any monotherapy or dual therapy. Two large RCTs (IMPACT and ETHOS) have shown that inhaled triple combinations (LABA and LAMA and ICS) reduce all-cause mortality compared to dual inhaled LABAs in certain patients.

Methylxanthines

These may act as phosphodiesterase inhibitors, but the exact mechanism is uncertain. Theophylline provides a modest bronchodilator effect compared to placebo. When it is used with salmeterol, FEV1 and breathlessness are improved more significantly than with salmeterol alone. Theophylline does not provide any benefit in exacerbations of severe COPD.

Theophylline has a small therapeutic ratio and toxicity is dose-related. More severe effects include arrhythmias and seizures. Other adverse effects like headaches, insomnia, nausea, and heartburn can occur even when within the therapeutic range. Theophylline also interacts with many commonly used medications (erythromycin, ciprofloxacin, allopurinol, SSRIs) altering its blood levels. It is not recommended unless other bronchodilators are unavailable or unaffordable.

Oral glucocorticoids

These play a role in acute management of exacerbations, but there is no evidence for their use in chronic COPD treatment, and there is also the risk of adverse systemic effects when used.

Phosphodiesterase-4 (PDE4) inhibitors

These drugs decrease inflammation through inhibition of intracellular cAMP breakdown, and have no direct bronchodilation effect as such. Roflumilast improves exacerbations treated with corticosteroids.

There are more adverse effects associated with PDE4 inhibitors than with inhaled COPD therapies. Diarrhoea, nausea, reduced appetite, weight loss, abdominal pain, sleep disturbance and headaches are the most common, and can lead to discontinuation.

Antibiotics

Azithromycin (250mg daily or 500mg three times weekly) or erythromycin reduce risk of exacerbations. However, use of azithromycin has been linked to bacterial resistance, QTc prolongation, and impaired hearing.¹ Before offering prophylactic antibiotics, sputum culture and sensitivity should be performed, as well as training in airway clearance techniques to optimise sputum clearance (physio). A baseline ECG (to rule out prolonged QT interval) and liver function tests should also be carried out. The patient should  be informed about the small risk of hearing loss and tinnitus. Azithromycin therapy should be reviewed after the first three months, and then six-monthly.⁴

Mucolytics and antioxidant agents (N-acetylcysteine, carbocisteine, erdosteine)

In COPD patients not using ICS, these medicines may reduce exacerbations and improve health status. Oral mucolytics should only be used if there is symptomatic improvement, ie, reduction in frequency of cough and sputum production. Studies so far do not provide enough data to identify further any target population or regimen specifically.^1,4

Other drugs

There is insufficient evidence to recommend the use of nedocromil or leukotriene modifiers in COPD patients. Use of infliximab in COPD may do harm, increasing rates of pneumonia and malignancy.

There is no conclusive evidence in favour of the use of antitussives in COPD. Nutritional supplements should be offered to people with COPD with a low BMI.

Non-pharmacological management

Pulmonary rehabilitation should be made available for all appropriate people with COPD. Education is necessary to inform patients, but there is no evidence to show that education alone changes patient behaviour. Pulmonary rehabilitation is a “comprehensive intervention based on thorough patient assessment followed by patient-tailored therapies that include, but are not limited to, exercise training, education, self-management intervention aiming at behaviour change, designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviours”.

This has been shown to improve health status, reduce hospitalisation, and reduce anxiety and depression in patients with COPD, and has been associated with a statistically significant reduction in mortality. Physical activity is also a strong predictor of mortality.

If people with COPD find exacerbations and breathlessness frightening, a cognitive behavioural therapy (CBT) component in their management may be useful. If any exacerbation symptoms occur, the patient should be encouraged to respond to these according to their management plan, ie, by adjusting their SABA therapy to treat symptoms, taking a short course of oral corticosteroids, visiting their GP.

Inhaler technique and adherence

Inhalation technique has been shown to be an issue in up to 50-to-80 per cent of patients, leading to poor disease control, increased side-effects and hospital visits.⁶ Adherence is another issue, with estimates of only 50 per cent in developed countries. A meta-analysis of pharmacist-led interventions in asthma and COPD shows that pharmacists have a positive impact on both technique and adherence.

• Because most COPD pharmacological treatments are inhaled, appropriate use of inhalers is crucial to optimise the treatment benefit.
• Each patient should be using an appropriate device for them, and given education, and have their inhaler technique checked regularly.
• The patient’s dexterity, cognition and strength should be considered.
• Dry powder inhalers require a forceful and deep inhalation, metered-dose inhalers require co-ordination between device triggering and inhalation, using a spacer device if needed.
• For patients who are unable to use inhaler devices, nebulisers are another option. A patient/carer’s ability to use nebuliser therapy should be assessed before prescribing it.
• The number of different inhalers should be minimised where possible. If inhaled pharmacotherapy seems ineffective, it is important to check both compliance and technique before deciding it is not working.
• When a spacer is being used, the drug should be administered by single actuations into the spacer, inhaling after each actuation, and with minimal delay between actuation and inhalation. Normal tidal breathing is as effective with a spacer as single breaths.

Findings from a small Australian study (24 patients) conducted through pharmacies showed that only 12 per cent of patients used their inhalers correctly, even though all patients were at least “somewhat satisfied” with their inhalers.⁷ Most patients reported being confident with their inhaler technique. A person’s perceived effectiveness of the medication itself seemed more important for satisfaction than any objective measure of technique.

From the patient perspective:

• Ease of use was the most important feature.
• Patients did not like that MDIs did not have a dose counter.
• MDIs were reported as the easiest to use.
• Loading of DPIs seemed to be the most troublesome issue.
• Smaller inhalers were perceived as more adherence friendly due to their increased portability.
• MDI hygiene was a concern, as lids come off easily. This was less of a concern with DPIs.
• Inhalers, especially preventers, were considered expensive.

The longer patients used their inhaler, the more confident and satisfied they were with it. However, using an inhaler for a long time actually increases the chance of incorrect technique, especially if there is no reassessment.

Shared decision making in disease management benefits patients, but most patients in this study did not experience involvement with decision making. Lack of knowledge, insufficient physician time and reliance on a trusted physician to make the decisions were the main contributors for this non-involvement.

References

1. Global Initiative for Chronic Obstructive Lung Disease (2023). Pocket Guide to COPD Diagnosis, Management and Prevention. Available https://goldcopd.org/2023-gold-report-2/.
2. COPD Support Ireland (2022). Awareness Campaign. Available https://copd.ie/useful-links/awareness-campaign/#:~:text=It%20is%20estimated%20that%20there,serious%20and%20progressive%20lung%20condition.
3. National Institutes of Health: National Heart, Lung and Blood Institute (2023). COPD Alpha 1 antitrypsin deficiency. Available https://www.nhlbi.nih.gov/health/alpha-1-antitrypsin-deficiency#:~:text=Alpha%2D1%20antitrypsin%20(AAT),or%20dust%20from%20the%20environment.
4. National Institute for Health and Care Excellence (2019). Chronic obstructive pulmonary disease in over 16s: diagnosis and management [NG 115]. Available https://www.nice.org.uk/guidance/ng115/resources/chronic-obstructive-pulmonary-disease-in-over-16s-diagnosis-and-management-pdf-66141600098245.
5. David S, & Edwards CW (2019). Forced expiratory volume. StatPearls. StatPearls Publishing, Treasure Island (FL). PMID: 31082014.
6. Jia X, Zhou S, Luo D, Zhao X, Zhou Y, & Cui YM (2020). Effect of pharmacist?led interventions on medication adherence and inhalation technique in adult patients with asthma or COPD: a systematic review and meta?analysis. Journal of Clinical Pharmacy and Therapeutics, 45(5), 904-917.

Jahedi L, Downie SR, Saini B, Chan HK, & Bosnic-Anticevich, S (2017). Inhaler technique in asthma: how does it relate to patients’ preferences and attitudes toward their inhalers? Journal of Aerosol Medicine and Pulmonary Drug Delivery, 30(1), 42-52.