Chronic obstructive pulmonary disease

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26 Chronic obstructive pulmonary disease

D. Cripps, K.P. Gibbs

Key points

• Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide.
• COPD is the most prevalent manifestation of obstructive lung disease and mainly comprises chronic bronchitis and emphysema.
• The reduction of exposure to tobacco smoke, occupational dusts, chemicals and pollutants is an important goal to prevent the onset and progression of COPD.
• Risk factors for COPD include host factors (α1-antitrypsin deficiency and airway hyper-responsiveness) and exposures (tobacco smoke, occupational dusts and chemicals, indoor and outdoor pollutants, infections) and socio-economic status.
• Smoking cessation is the single most effective intervention to reduce the risk of developing COPD and slow disease progression. This should be the primary focus of management.
• The management of COPD should follow both national and international guidance.
• COPD care should be delivered by a multidisciplinary team; assessing and managing patients, advising patients on self-management strategies and exercise, identifying and monitoring patients at high risk of exacerbations and educating patients and other health professionals.
• Patients should undergo non-pharmacological pulmonary rehabilitation, such as breathing exercises.

Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases (GOLD, 2009).

COPD is a general term that covers a variety of other disease labels including chronic obstructive airways disease (COAD), chronic obstructive lung disease (COLD), chronic bronchitis and emphysema.

COPD has been defined (National Institute for Health and Clinical Excellence, 2010) as:

• Airflow obstruction with a reduced FEV1/FVC ratio of less than 0.7.
• If FEV1 is ≥ 80% of predicted normal, a diagnosis of COPD should only be made in the presence of respiratory symptoms, for example breathlessness or cough.

Epidemiology

COPD is the fifth leading cause of death in the UK and the fourth in the world. It is expected to rise to third position by 2020. It is estimated that over 3 million people have the disease in the UK, with 2 million having undiagnosed COPD (National Clinical Guideline Centre, 2010). COPD is the largest single cause of lost working days in the UK. It is accountable for more than 10% of all hospital admissions and directly costs the NHS around £491 m/year. The burden of COPD on the UK healthcare system exceeds that of asthma and is outlined in Table 26.1.

Table 26.1 Annual morbidity and mortality from COPD (National Clinical Guideline Centre, 2010)

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Respiratory diseases including chronic bronchitis are more common in areas of high atmospheric pollution and in people with dusty occupations such as foundry workers and coal miners. Areas that are highly industrialised generally have the highest incidence of COPD. The UK has around twice the rate of mortality from respiratory disease compared to the European average.

Pathology

The major pathological changes in COPD affect four different compartments of the lung and all are affected in most individuals to varying degrees (American Thoracic Society/European Respiratory Society Task Force, 2004).

Central airways (<2 mm diameter, cartilaginous)

The bronchial glands hypertrophy and goblet cell proliferation occurs. This results in excessive mucus production (chronic bronchitis). Epidemiologically chronic bronchitis is defined as a chronic or recurrent cough with sputum production on most days for at least 3 months of the year during at least 2 consecutive years, in the absence of other diseases recognised to cause sputum production. There is a loss of ciliary function with increase in inflammatory cells, notably lymphocytes, macrophages and, later in the disease, neutrophils.

Peripheral airways (<2 mm diameter, non-cartilaginous)

Bronchiolitis is present from early disease with a pathological increase in goblet cells and in inflammatory cells in the airway walls. With disease progression, fibrosis develops along with increased deposition of collagen in the airway walls.

Lung parenchyma (respiratory bronchioles, alveoli and capillaries)

In emphysema, elastases destroy elastin, thus resulting in dilation and destruction of the respiratory bronchioles and alveolar sacs and ducts. Because of this there is a loss of the alveolar wall attachments and peripheral airway collapse.

Emphysema is defined as an abnormal enlargement of the air spaces distal to the terminal bronchioles. There are two main forms: (1) centrilobular emphysema which involves dilation and destruction of respiratory bronchioles, alveolar ducts and alveoli and (2) panacinar emphysema which involves destruction of the whole acinus. The former predominates in COPD, the latter in patients with α1-antitrypsin deficiency.

Pulmonary vasculature

Vessel walls thicken early in the course of the disease along with endothelial dysfunction. The vessel walls become infiltrated by inflammatory cells, including macrophages and lymphocytes, and there is increased vascular smooth muscle which can lead to pulmonary hypertension. In advanced disease, there is emphysematous destruction of the vascular bed and collagen deposition.

Aetiology

Tobacco smoking is the most important and dominant risk factor in the development of COPD but other noxious particles also contribute, such as occupational exposure to chemical fumes, irritants, dust and gases. A person’s exposure can be thought of in terms of the total burden of inhaled particles. These cause a (normal) inflammatory response in the lungs. Smokers, however, seem to have an exaggerated response which eventually causes tissue destruction and impaired repair mechanisms. In addition to inflammation, the other main processes involved in the pathogenesis of COPD are an imbalance of proteinases and antiproteinases in the lungs, and oxidative stress.

Not all smokers go on to develop clinically significant COPD; genetic factors seem to modify each individual’s risk. The age at which an individual begins smoking, total pack-years smoked and current smoking status are predictive of COPD mortality. Passive exposure to cigarette smoke may also contribute to respiratory symptoms and COPD by increasing the lungs’ total burden of inhaled particles and gases (GOLD, 2009). Tobacco exposure is quantified in ‘pack-years’:

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Additional risk factors include the natural ageing process of the lungs. Males are currently more at risk of developing chronic bronchitis, but as the number of women who smoke increases, the incidence of chronic bronchitis in females will also rise. The major risk factors are summarised in Table 26.2.

Table 26.2 Risk factors for the development of COPD

Risk factor Comment
Smoking Risk increases with increasing consumption but there is also large interindividual variation in susceptibility
Age Increasing age results in ventilatory impairment; most frequently related to cumulative smoking
Gender Male gender was previously thought to be a risk factor but this may be due to a higher incidence of tobacco smoking in men. Women have greater airway reactivity and experience faster declines in FEV1, so may be at more risk than men
Occupation The development of COPD has been implicated with occupations such as coal and gold mining, farming, grain handling and the cement and cotton industries
Genetic factors α1-Antitrypsin deficiency is the strongest single genetic risk factor, accounting for 1–2% of COPD. Other genetic disorders involving tissue necrosis factor and epoxide hydrolase may also be risk factors
Air pollution Death rates are higher in urban areas than in rural areas. Indoor air pollution from burning biomass fuel is also implicated as a risk factor, particularly in underdeveloped areas of the world
Socio-economic status More common in individuals of low socio-economic status
Airway hyper-responsiveness and allergy Smokers show increased levels of IgE, eosinophils and airway hyper-responsiveness but how these influence the development of COPD is unknown

Inflammation

COPD is characterised by chronic inflammation throughout the airways, parenchyma and pulmonary vasculature. This is a different pattern of inflammation from that of asthma, with an increase in neutrophils, macrophages and T-lymphocytes (particularly CD8+); increased eosinophils occur in some patients during exacerbations. These inflammatory cells cause the release of inflammatory mediators and cytokines such as leukotriene B4, interleukin-8 and tumour necrosis factor-α (TNF-α). Over time the actions of these mediators damages the lungs and leads to the characteristic pathological changes observed.

Proteinase and antiproteinase imbalance

The observation that α1-antitrypsin-deficient individuals are at increased risk of developing emphysema has led to the theory that an imbalance between proteinases and antiproteinases leads to lung destruction. In COPD, there is either an increased production/activity of proteinases or a decreased production/activity of antiproteinases. The main proteinases, proteolytic enzymes such as neutrophil elastin are released by macrophages or neutrophils. The antiproteinases inhibit the damage caused by the proteolytic enzymes. The main antiproteinase is α1-antitrypsin, also known as α1-proteinase inhibitor. Cigarette smoke has been shown to inactivate this protein. Oxidative stress also decreases the activity of antiproteinases.

Oxidative stress

An imbalance of oxidants and antioxidants exists in COPD with the balance in favour of the oxidants. This state of oxidative stress contributes to the development of the disease by damaging the intracellular matrix, oxidising biological molecules which cause cell destruction and promoting histone acetylation. There also seems to be a link between oxidative stress and the poor response to corticosteroids seen in COPD. To work, corticosteroids must recruit histone deacetylase to switch off the transcription of inflammatory genes. In COPD, the activity of histone deacetylase is impaired by the oxidative stress, thereby reducing the responsiveness to corticosteroids. Cigarette smoke also impairs the function of histone deacetylase.

Pathophysiology

The pathogenic mechanisms and pathological changes described above lead to the physiological abnormalities of COPD: mucus hypersecretion, ciliary dysfunction, airflow limitation and hyperinflation, gas exchange abnormalities, pulmonary hypertension and systemic effects (American Thoracic Society/European Respiratory Society Task Force, 2004).

Mucus hypersecretion, ciliary dysfunction and complications

Enlarged mucus glands cause hypersecretion of mucus and the squamous metaplasia of epithelial cells results in ciliary dysfunction. These are typically the first physiological abnormalities in COPD.

Normally, cilia and mucus in the bronchi protect against inhaled irritants, which are trapped and expectorated. The persistent irritation caused by cigarette and other smoke causes an exaggeration in the response of these protective mechanisms and leads to inflammation of the small bronchioles (bronchiolitis) and alveoli (alveolitis). Cigarette smoke also inhibits mucociliary clearance, which causes a further build-up of mucus in the lungs. As a result, macrophages and neutrophils infiltrate the epithelium and trigger a degree of epithelial destruction. This, together with a proliferation of mucus-producing cells, leads to plugging of smaller bronchioles and alveoli with mucus and particulate matter.

This excessive mucus production causes distension of the alveoli and loss of their gas exchange function. Pus and infected mucus accumulate, leading to recurrent or chronic viral and bacterial infections. The primary pathogen is usually viral but bacterial infection often follows. Common bacterial pathogens include Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae.

Bronchiectasis is a pathological change in the lungs where the bronchi become permanently dilated. It is common after early attacks of acute bronchitis during which mucus both plugs and stretches the bronchial walls. In severe infections, the bronchioles and alveoli can become permanently damaged and do not return to their normal size and shape. The loss of muscle tone and loss of cilia can contribute to COPD because mucus has a tendency to accumulate in the dilated bronchi.

Airflow limitation and hyperinflation

Fibrosis and narrowing (airway remodelling) of the smaller conducting airways (<2 mm diameter) is the main site of expiratory airflow limitation in COPD. This is compounded by the loss of elastic recoil (destruction of alveolar walls), destruction of alveolar support/attachments and the accumulation of inflammatory cells mucus and plasma exudates during exercise. The degree of airflow limitation is measured by spirometry.

This progressive destructive enlargement of the respiratory bronchioles, alveolar ducts and alveolar sacs is referred to as emphysema. Adjacent alveoli can become indistinguishable from each other, with two main consequences. The first is loss of available gas exchange surfaces, which leads to an increase in dead space and impaired gas exchange. The second consequence is the loss of elastic recoil in the small airways, vital for maintaining the force of expiration, which leads to a tendency for them to collapse, particularly during expiration. Increased thoracic gas volume and hyperinflation of the lungs result. The causes of airflow limitation in COPD are summarised in Box 26.1.

Box 26.1 Causes of airflow limitation in COPD (GOLD, 2009)

Irreversible
• Fibrosis and narrowing of the airways
• Loss of elastic recoil due to alveolar destruction
• Destruction of alveolar support that maintains patency of small airways

Reversible
• Accumulation of inflammatory cells, mucus and plasma exudates in the bronchi
• Smooth muscle contraction in peripheral and central airways
• Dynamic hyperinflation during exercise

Gas exchange abnormalities

This occurs in advanced disease and is characterised by arterial hypoxaemia with or without hypercarbia. The anatomical changes during COPD result in an abnormal distribution of ventilation and perfusion within the lungs and create the abnormal gaseous exchange.

Pulmonary hypertension and cor pulmonale

Pulmonary hypertension develops late in COPD after gas exchange abnormalities have developed. The thickening of the bronchiole and alveolar walls resulting from chronic inflammation and oedema leads to blockage and obstruction of the airways. Alveolar distension and destruction result in distortion of the blood vessels that are closely associated with the alveoli. This causes a rise in the blood pressure in the pulmonary circulation. Reduction in gas diffusion across the alveolar epithelium leads to a low partial pressure of oxygen in the blood vessels (hypoxaemia) due to an imbalance between ventilation and perfusion. By a mechanism that is not clearly established, chronic vasoconstriction results and causes a further increase in blood pressure and further compromises gas diffusion from air spaces into the bloodstream. The chronic low oxygen levels lead to polycythaemia, thereby increasing blood viscosity. In advanced disease, persistent hypoxaemia develops along with pathological changes in the pulmonary circulation. Sustained pulmonary hypertension results in a thickening of the walls of the pulmonary arterioles, with associated pulmonary remodelling and an increase in right ventricular pressure within the heart.

The consequence of continued high right ventricular pressure is eventual right ventricular hypertrophy, dilation and progressive right ventricular failure (cor pulmonale). Pulmonary oedema develops as a result of physiological changes subsequent to the hypoxaemia and hypercapnia, such as activation of the renin–angiotensin system, salt and water retention and a reduction in renal blood flow.

Systemic effects

Systemic inflammation and skeletal muscle wasting can occur in COPD which limit exercise capacity and worsen prognosis. Osteoporosis, depression, normocytic normochromic anaemia are potential sequelae, as well as increased risk of cardiovascular disease associated with elevated levels of C-reactive protein.

Clinical manifestations

Diagnosis

A diagnosis of COPD should be considered in any patient who has symptoms of cough, wheeze, regular sputum production or exertional dyspnoea and/or a history of exposure to COPD risk factors (see Table 26.2). Spirometry is then used to confirm the diagnosis. There is no single diagnostic test for COPD.

Clinical features

COPD is a progressive disorder, which passes through a potentially asymptomatic mild phase, before the moderate phase and then severe disease. The traditional description of COPD symptoms, particularly in severe disease, depends on whether bronchitis or emphysema predominate. Chronic bronchitic patients exhibit excess mucus production and a degree of bronchospasm, resulting in wheeze and dyspnoea. Hypoxia and hypercapnia (high levels of carbon dioxide in the tissues) are common. This type of patient has a productive cough, is often overweight and finds physical exertion difficult due to dyspnoea. The bronchitic patient is sometimes referred to as a ‘blue bloater’. This term is used because of the tendency of the patient to retain carbon dioxide caused by a decreased responsiveness of the respiratory centre to prolonged hypoxaemia that leads to cyanosis, and also the tendency for peripheral oedema to occur. Bronchitic patients lose the ability to increase the rate and depth of ventilation in response to persistent hypoxaemia. The reason for this is not clear, but decreased ventilatory drive may result from abnormal peripheral or central respiratory receptors. As the disease progresses, patients will experience an increasing frequency of exacerbations of acute dyspnoea triggered by excess mucus production and obstruction. In severe disease, the chest diameter is often increased, giving the classic barrel chest. As obstruction worsens, hypoxaemia increases, leading to pulmonary hypertension. Right ventricular strain leads to right ventricular failure, which is characterised by jugular venous distension, hepatomegaly and peripheral oedema, all of which are consequences of an increase in systemic venous blood pressure. Recurrent lower respiratory tract infections can be severe and debilitating. Signs of infection include an increase in the volume of thick and viscous sputum, which is yellow or green in colour and may contain bacterial pathogens, squamous epithelial cells, alveolar macrophages and saliva, but pyrexia may not be present. Eventually, cardiorespiratory failure with hypercapnia will occur, which may be severe, unresponsive to treatment and result in death.

The clinical features of emphysema are different from those of bronchitis. A patient with emphysema will experience increasing dyspnoea even at rest, but often there is minimal cough and the sputum produced is scanty and mucoid. Generally, bronchial infections tend to be less common in emphysema. The patient with emphysema is sometimes referred to as a ‘pink puffer’ because he or she hyperventilates to compensate for hypoxia by breathing in short puffs. As a result, the patient appears pink with little carbon dioxide retention and little evidence of oedema. The patient will breathe rapidly (tachypnoea), because the respiratory centres are responsive to mild hypoxaemia, and will have a flushed appearance. Typically, a patient with emphysema will be thin and have pursed lips in an effort to compensate for a lack of elastic recoil and exhale a larger volume of air. Such a patient will tend to use the accessory muscles of the chest and neck to assist in the work of breathing. Hypoxaemia is not a problem until the disease has progressed. Emphysema patients will become progressively dyspnoeic, without exacerbations triggered by increased sputum production. Eventually, cor pulmonale will develop very rapidly, usually in the late stages of the disease, leading to intractable hypercapnia and respiratory arrest. The bronchitic ‘blue bloater’ and emphysemic ‘pink puffer’ represent two ends of the COPD spectrum. In reality, the underlying pathophysiology may well be a mixture, and the resulting signs and symptoms somewhere between the two extremes described.

The clinical progress of COPD depends on whether bronchitis or emphysema predominates.

Additional specific problems are also common in patients with COPD:

• Obstructive sleep apnoea hypopnoea syndrome (OSAHS)
• Acute respiratory failure

The sleep apnoea syndrome is a respiratory disorder characterised by frequent or prolonged pauses in breathing during sleep. It leads to a deterioration in arterial blood gases and a decrease in the saturation of haemoglobin with oxygen. Hypoxaemia is often accompanied by pulmonary hypertension and cardiac arrhythmias, which may lead to premature cardiac failure.

Acute respiratory failure is said to have occurred if the PaO2 suddenly drops and there is an increase in PaCO2 that decreases the pH to 7.3 or less. The most common cause is an acute exacerbation of chronic bronchitis with an increase in volume and viscosity of sputum. This further impairs ventilation and causes more severe hypoxaemia and hypercapnia. The clinical signs and symptoms of acute respiratory failure include restlessness, confusion, tachycardia, cyanosis, sweating, hypotension and eventual unconsciousness.

Investigations

Lung function tests are used to assist in diagnosis. A spirometer is used to measure lung volumes and flow rates. The main measurement made is the forced expiratory volume in the first second of exhalation (FEV1). Other tests can be performed, such as:

• Vital capacity (VC): the volume of air inhaled and exhaled during maximal ventilation;
• Forced vital capacity (FVC): the volume of air inhaled and exhaled during a forced maximal expiration after full inspiration;
• Residual volume (RV): the volume of air left in the lungs after maximal exhalation.

Airflow obstruction is defined as:

• FEV1 less than 80% of that predicted for the patient and
• FEV1/FVC less than 0.7.

VC decreases in bronchitis and emphysema. RV increases in both cases but tends to be higher in patients with emphysema due to air being trapped distal to the terminal bronchioles. Total lung capacity is often normal in patients with bronchitis but is usually increased in emphysema, again due to air being trapped. Smoking increases the normal deterioration in FEV1 over time, from about 30 mL/year to about 45 mL/year. The major criticism of measuring FEV1 and FVC is that they detect changes only in airways greater than 2 mm in diameter. As airways less than 2 mm in diameter contribute only 10–20% of normal resistance to airflow, there is usually severe obstruction and extensive damage to the lungs by the time the lung function tests (FEV1 and FVC) detect abnormalities. Additionally, lung function tends to deteriorate with age even in the absence of COPD, and so use of FEV1/FVC can lead to overdiagnosis in the elderly. Underdiagnosis may also be a problem in patients under 45 years of age.

Both UK and international COPD guidelines use spirometry to categorise the severity of COPD. These are summarised in Table 26.3. Testing should be carried out after a dose of inhaled bronchodilator to prevent overdiagnosis or overestimation of severity.

Table 26.3 Assessment of severity of airflow obstruction

FEV1 Severity (NICE) Severity (GOLD)
Greater than 80% predicted   Stage I: Mild
50–80% predicted Mild Stage II: Moderate
30–49% predicted Moderate Stage III: Severe
Less than 30% predicted Severe Stage IV: Very severe

(adapted from National Institute for Health and Clinical Excellence, 2010; GOLD, 2009)

At diagnosis and evaluation, patients may receive other investigations as outlined in Table 26.4.

Table 26.4 Additional investigations at the diagnosis of COPD

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Investigation Note
Chest X-ray To exclude other pathologies
Full blood count To identify anaemia or polycythaemia
Serial domiciliary peak flow measurements To exclude asthma if there is a doubt about diagnosis
α1-Antitrypsin Particularly with early-onset disease or a minimal smoking/family history
Transfer factor for carbon monoxide To investigate symptoms that seem disproportionate to the spirometric impairment
CT scan of the thorax

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