Chronic Obstructive Pulmonary Disease: Diagnosis, Inhaled Therapy and Exacerbations

Introduction

Chronic obstructive pulmonary disease (COPD) is a common, preventable and treatable condition defined by persistent respiratory symptoms and airflow limitation that is not fully reversible. It affects around 1.2 million people diagnosed in the UK, with a similar number thought to be undiagnosed, and is the second commonest cause of emergency hospital admission.^1,2

The term covers two overlapping processes that almost always coexist in the same patient:

• Chronic bronchitis - a clinical definition: a productive cough on most days for at least 3 months in each of 2 consecutive years. It reflects mucous gland hypertrophy, goblet cell hyperplasia and small airway inflammation.
• Emphysema - a pathological definition: permanent dilatation of the airspaces distal to the terminal bronchioles with destruction of their walls and no obvious fibrosis. Loss of alveolar attachments removes the radial traction that holds small airways open, so they collapse on expiration.

The two produce the same physiological result - expiratory airflow limitation - and it is this that generates every clinical feature of the disease. Air trapping causes hyperinflation, hyperinflation flattens the diaphragm and puts the inspiratory muscles at a mechanical disadvantage, and the resulting increased work of breathing is experienced as dyspnoea.

Aetiology and pathophysiology

Causes

• Tobacco smoking - responsible for around 90% of UK cases. Risk is dose-related, and roughly one in four long-term smokers develops COPD.
• Alpha-1 antitrypsin deficiency - an autosomal co-dominant condition causing early-onset, lower-zone, panlobular emphysema, often with liver disease. Suspect it in a patient under 45, a non-smoker, or where there is a strong family history.
• Biomass fuel exposure - indoor cooking and heating fires, the dominant cause worldwide and an important one in migrant populations
• Occupational dusts, fumes and vapours - coal, silica, cadmium, welding fumes
• Air pollution
• Childhood factors - low birth weight, prematurity, recurrent childhood respiratory infection, which reduce the peak lung function ever attained

Mechanisms

Inhaled irritants recruit neutrophils, macrophages and CD8 T lymphocytes to the airway. These release proteases - principally neutrophil elastase and matrix metalloproteinases - which, when they overwhelm the antiprotease defences, destroy the alveolar wall. Oxidative stress inactivates antiproteases further and directly damages the epithelium. In contrast to asthma, the inflammatory infiltrate is neutrophilic rather than eosinophilic, which is why COPD responds far less well to corticosteroids.

Two consequences deserve particular attention because they explain much of what is seen clinically:

• Dynamic hyperinflation - on exercise, the respiratory rate rises and expiratory time shortens, so progressively more air is trapped. Lung volumes rise, the diaphragm flattens further, and breathlessness escalates disproportionately. This is why patients instinctively adopt pursed-lip breathing, which raises airway pressure and splints the collapsing airways open.
• Ventilation-perfusion mismatch - producing hypoxaemia and, as disease advances, carbon dioxide retention. Chronic hypoxaemia causes pulmonary vasoconstriction, pulmonary hypertension and eventually cor pulmonale, and drives secondary polycythaemia.

Clinical features

Symptoms

• Breathlessness on exertion - progressive, persistent and, unlike asthma, showing little day-to-day or diurnal variation
• Chronic productive cough - typically worse in the morning, with clear or white sputum when stable
• Wheeze
• Frequent winter chest infections and a long recovery from each
• Fatigue, weight loss and reduced exercise tolerance in advanced disease
• Ankle swelling - suggesting cor pulmonale

Ask specifically about smoking pack-years, occupational exposure, exacerbation frequency and hospital admissions, and the functional impact - what the patient can no longer do.

The MRC dyspnoea scale

Examination

• Hyperinflated barrel chest with a reduced cricosternal distance and loss of the normal cardiac and hepatic dullness
• Pursed-lip breathing and use of accessory muscles, with tripod positioning
• Reduced chest expansion and a hyper-resonant percussion note
• Quiet breath sounds with a prolonged expiratory phase, and expiratory wheeze
• Tar staining of the fingers, and the smell of tobacco
• Signs of CO2 retention - a bounding pulse, warm peripheries, a flapping tremor (asterixis), drowsiness and confusion
• Signs of cor pulmonale - raised JVP, peripheral oedema, a loud pulmonary second heart sound, a right ventricular heave, and hepatomegaly with a pulsatile liver if there is tricuspid regurgitation
• Cachexia in advanced disease, an independent marker of poor prognosis

Investigations

Spirometry - the diagnostic test

Post-bronchodilator spirometry is required to confirm the diagnosis in every patient.¹ Consider COPD in anyone over 35 with a risk factor - usually smoking - and exertional breathlessness, chronic cough, regular sputum production, frequent winter bronchitis or wheeze.

• FEV1/FVC ratio below 0.7 after a bronchodilator confirms persistent airflow obstruction
• FEV1 as a percentage of predicted grades the severity
• The pattern is obstructive: FEV1 reduced disproportionately to FVC, with a normal or increased total lung capacity and residual volume from air trapping
• Transfer factor (TLCO) is reduced in emphysema because alveolar surface area is lost - a useful discriminator, as TLCO is normal or high in asthma

Other investigations at diagnosis

• Chest X-ray - to exclude other diagnoses, particularly lung cancer. Findings in COPD are hyperinflation (more than 6 anterior ribs above the diaphragm in the midclavicular line), flattened hemidiaphragms, a narrow vertical heart, and bullae.
• Full blood count - secondary polycythaemia from chronic hypoxaemia, or anaemia which worsens breathlessness. The eosinophil count also guides inhaled corticosteroid use.
• Body mass index - a baseline, since weight loss is prognostically important
• ECG and echocardiogram - if cor pulmonale or another cardiac diagnosis is suspected. Look for P pulmonale, right axis deviation and right ventricular hypertrophy.
• Alpha-1 antitrypsin level - in early-onset disease, minimal smoking history or a family history
• Sputum culture - if sputum is persistently purulent
• CT thorax - if symptoms are disproportionate to spirometry, if the chest X-ray is abnormal, to assess bullae for surgery, or to investigate suspected bronchiectasis or fibrosis
• Serial home peak flow - to exclude asthma where the history is ambiguous

Chronic management

Only a handful of interventions alter the natural history of COPD, and they are not the inhalers. Cover the fundamentals at every review before considering escalation of inhaled therapy.¹

Interventions that change outcome

1. Smoking cessation - the only intervention that slows the rate of decline in FEV1, and the single most important thing to offer. Combine behavioural support with pharmacotherapy (nicotine replacement, varenicline or bupropion) at every opportunity.
2. Vaccination - annual influenza, pneumococcal and COVID-19 vaccination for all patients
3. Pulmonary rehabilitation - a structured exercise and education programme, offered to anyone with MRC grade 3 or above or after a hospital admission for exacerbation. It improves exercise capacity and quality of life more than any drug.
4. Long-term oxygen therapy - the only treatment shown to improve survival in COPD, and only in patients who are chronically hypoxaemic
5. Treating comorbidities - cardiovascular disease, osteoporosis, depression, anxiety, lung cancer, malnutrition and obstructive sleep apnoea are all more common and all worsen outcomes

Inhaled therapy

Start with a short-acting bronchodilator as needed - either a SABA (salbutamol) or a SAMA (ipratropium). If breathlessness or exacerbations persist, the next step depends on whether the patient has asthmatic features or features suggesting steroid responsiveness:

• A previous secure diagnosis of asthma or of atopy
• A higher blood eosinophil count
• Substantial variation in FEV1 over time - at least 400 ml
• Substantial diurnal variation in peak flow - at least 20%

Additional treatments

• Oral theophylline - only after trials of short- and long-acting bronchodilators, or in patients unable to use inhaled therapy. A narrow therapeutic index with important interactions: macrolides and ciprofloxacin raise levels and the dose must be reduced.
• Mucolytics (carbocisteine) - consider in patients with a chronic productive cough; continue only if symptoms improve
• Prophylactic azithromycin - for selected patients who continue to exacerbate despite optimal therapy. Before starting, ensure the patient does not smoke, obtain a CT thorax to exclude bronchiectasis and sputum culture to exclude atypical infection and tuberculosis, and check an ECG for QT prolongation and liver function tests.
• Roflumilast - a phosphodiesterase-4 inhibitor, for severe COPD (FEV1 under 50%) with two or more exacerbations in 12 months despite triple therapy
• Prophylactic antibiotic and rescue packs - a supply of prednisolone and an antibiotic kept at home for patients who can recognise an exacerbation and act on a self-management plan
• Pulmonary rehabilitation and nutritional support, with dietetic referral if the BMI is low or falling
• Lung volume reduction surgery, endobronchial valves or transplantation - for carefully selected patients with predominantly upper-lobe emphysema and preserved exercise capacity

Long-term oxygen therapy

LTOT improves survival in chronic hypoxaemia and must be used for at least 15 hours a day to do so. Assess with two arterial blood gases at least 3 weeks apart in a clinically stable patient.

• PaO2 below 7.3 kPa, or
• PaO2 between 7.3 and 8 kPa with one of: secondary polycythaemia, peripheral oedema, pulmonary hypertension, or nocturnal hypoxaemia

Acute exacerbation of COPD

An exacerbation is a sustained worsening of symptoms beyond normal day-to-day variation, typically increased breathlessness, cough, sputum volume or sputum purulence.³ Around half are triggered by bacteria, a third by viruses, and the remainder by pollutants or have no identifiable cause.

• Bacterial - Haemophilus influenzae (the commonest), Streptococcus pneumoniae, Moraxella catarrhalis, and Pseudomonas aeruginosa in severe disease or bronchiectasis
• Viral - rhinovirus above all, plus influenza, RSV and coronaviruses

Assessment

Assess with an ABCDE approach and consider the alternatives, because breathlessness in a patient with COPD is not always an exacerbation. Pneumonia, pneumothorax (particularly in bullous disease), pulmonary embolism, heart failure and arrhythmia all present the same way and are all missed regularly.

• Arterial blood gas - essential in anyone unwell enough to need hospital assessment, to identify hypercapnia and acidosis
• Chest X-ray - to look for consolidation and pneumothorax
• ECG, FBC, U&Es, CRP and blood cultures if febrile
• Sputum culture if the sputum is purulent
• Theophylline level if the patient takes it

Treatment

1. Controlled oxygen therapy - start with a 24-28% Venturi mask targeting saturations of 88-92% in anyone at risk of hypercapnic respiratory failure, and adjust once the blood gas is back. If the gas shows a normal PaCO2, the target can be raised to 94-98%.
2. Nebulised bronchodilators - salbutamol 5 mg and ipratropium 0.5 mg. In a patient at risk of CO2 retention, drive the nebuliser with air rather than oxygen, giving supplementary oxygen by nasal cannulae alongside.
3. Oral prednisolone 30 mg once daily for 5 days - in all but the mildest exacerbations
4. Antibiotics only if the sputum is purulent or there is clinical or radiological evidence of pneumonia - first line is amoxicillin, doxycycline or clarithromycin according to local guidance
5. Non-invasive ventilation if respiratory acidosis persists (see below)
6. Treat the precipitant and any comorbidity, and consider prophylactic low molecular weight heparin

Non-invasive ventilation

NIV, delivered as bilevel positive airway pressure (BiPAP), is indicated when there is a persistent respiratory acidosis with pH 7.25 to 7.35 and PaCO2 above 6 kPa after no more than one hour of optimal medical therapy.⁴ It reduces intubation rates and mortality and is one of the clearest evidence-based interventions in acute respiratory medicine.

• A pH below 7.25 indicates more severe acidosis: NIV may still be used but in a higher-dependency setting with immediate access to intubation
• Contraindications include an untreated pneumothorax, facial trauma or burns, vomiting with an unprotected airway, severe agitation or an inability to cooperate, and impending respiratory arrest
• Agree a ceiling of care and an escalation plan before starting, documented clearly - for many patients with advanced COPD, NIV is the ceiling of treatment
• CPAP is not the correct mode here: it does not augment ventilation and will not clear CO2. CPAP is for cardiogenic pulmonary oedema and obstructive sleep apnoea.

Before discharge

• Check inhaler technique and review the inhaled regimen
• Provide a written self-management plan and, where appropriate, a rescue pack
• Offer smoking cessation support and refer to pulmonary rehabilitation - referral within a month of an admission is a quality standard
• Ensure vaccinations are up to date and arrange follow-up, including an oxygen assessment at least 3 weeks after recovery if hypoxaemia was present

Complications

• Recurrent exacerbations and hospital admission - each severe exacerbation accelerates decline and increases mortality
• Type 2 respiratory failure - hypoxaemia with hypercapnia
• Cor pulmonale - right heart failure secondary to pulmonary hypertension from chronic hypoxaemic vasoconstriction. Managed with LTOT and diuretics for oedema; ACE inhibitors and calcium channel blockers are not indicated.
• Secondary polycythaemia - raising blood viscosity and thrombotic risk
• Pneumothorax - from rupture of a bulla, and easily mistaken for an exacerbation
• Lung cancer - shares the same principal risk factor and is several times more common in COPD than in smokers without it
• Cachexia and muscle wasting - an independent predictor of mortality
• Osteoporosis - from corticosteroids, immobility, smoking and low BMI
• Depression and anxiety - present in around 40% of patients and consistently under-treated
• Pneumonia - both as a precipitant and as a complication of inhaled corticosteroid use

Red flags

Prognosis

COPD is progressive and, once established, the airflow obstruction does not reverse. What can change is the rate of decline, and smoking cessation at any stage slows it towards that of a person who has never smoked - which is why cessation remains worth pursuing even in advanced disease.

Prognosis is estimated better by a composite than by FEV1 alone. The BODE index combines Body mass index, degree of Obstruction (FEV1), Dyspnoea (MRC grade) and Exercise capacity (6-minute walk distance), and predicts mortality more accurately than any single variable. Frequent exacerbations, low BMI, hypoxaemia, cor pulmonale and significant comorbidity all indicate a poorer outlook.

Advanced COPD carries a mortality comparable to many cancers, yet patients are far less likely to receive palliative input. Advance care planning - discussing ceilings of treatment, the acceptability of NIV and intubation, and preferred place of care - should happen while the patient is stable rather than during an acute admission. Opioids and benzodiazepines have an established role in relieving refractory breathlessness at the end of life, and fear of respiratory depression should not prevent their appropriate use.