Essay: Chronic Obstructive Pulmonary Disease (COPD)

Chronic Obstructive Pulmonary Disease (COPD) is an umbrella term used to describe a set of progressive lung diseases including emphysema, chronic bronchitis, and chronic asthma. Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines it as ‘a disease state characterised by persistent airflow limitation that is usually progressive and is associated with a chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity of individual patients’ (MacNee and Drummond, 2016). Common symptoms of the disease include inflammation, bronchoconstriction, airflow obstruction and not fully reversible structural changes in the airways. Individuals who have progressive symptoms such as cough, dyspnoea, exacerbations, and smoking history are likely to be diagnosed (Price, 2004). There is no current cure for COPD, but treatments do aim to prevent progression. Treatment options include bronchodilators, inhaled corticosteroids, and system corticosteroids, which target inflammation, oxidative stress and aging (Bestpractice.bmj.com, 2019).
Aetiology:
Smoking is the primary risk factor, with long-term smoking causing 80-90% of cases. Prolonged exposure to harmful particles and gases due to atmospheric pollution or occupation, as well as intrinsic factors such as family history are common aetiologies (Bestpractice.bmj.com, 2019). It has been investigated that in countries like India, China, Latin America, and the Middle East, women that are more exposed to high particulate matter indoors (due to cooking with biomass fuel and poorly ventilated homes) have similar COPD levels as men, regardless of the difference in smoking (Pauwels and Rabe, 2004). A study done during the Southeast Asian haze (October until December 1997) showed that an increase in the particulate matter did not affect the pulmonary function of the recruits, but caused an increase in circulating leukocytes and proinflammatory cytokines produced by alveolar macrophages. As the haze cleared the number of cytokines that stimulate the bone marrow decreased (van EEDEN et al., 2001).
Alpha- 1 antitrypsin deficiency is seen in 2% of patients, whether or not the individual smokes. The deficiency causes an imbalance between the protease-anti-protease ratio, as it acts as an inhibitor for serine proteases in the lungs and inhibits neutrophil elastase causing emphysema. It is equally distributed throughout both genders and is autosomal dominant (Patel, Gwilt and McGowan, 2008). Other genetic factors have been associated with COPD, such as alpha-1- antichymotrypsin, microsomal epoxide hydrolase, glutathione S-transferase, haem oxygenase-1, and TNF alpha, however, there has been no conclusive evidence.
COPD is a progressive disease, therefore once diagnosed patients are advised to reduce exposure to risk factors as it can cause rapid lung deterioration and increase the risk of exacerbations. Lung function does naturally decline with age and accumulation of respiratory damage, therefore even if exposure is stopped COPD can still progress. However, patients are advised to stop the exposure as improvements can be seen in some patients (Pauwels and Rabe, 2004).
Epidemiology:
In the UK and worldwide COPD is the fifth biggest killer. The annual number of deaths is 30,000 in the UK, which is one in 20 of all deaths. It is the only cause of death that has significantly increased in incidence levels over the years (+163% from 1965 to 1998) and is estimated to become the third leading worldwide cause of death by 2020. The disease affects 3 million people in the UK, with 2 million still undiagnosed (Bestpractice.bmj.com, 2019).
Pathophysiology
COPD can be diagnosed regardless of the severity using the patient’s symptoms, lung function measurements, and their medical history. Diagnosis is done by spirometry to show the not fully reversible airflow limitation by a decreased ratio (<0.70) of forced expiratory volume in 1 sec (FEV1) over forced vital capacity (FVC) (Price, 2004). As COPD management is based on symptoms, a more practical approach is necessary when determining the severity as physical symptoms such as tachypnea, wheezing or long expirations are more often seen in advanced stages after significant damage is done to the lung function. There is a grading system that predicts COPD mortality using BMI, airflow limitation, dyspnoea and exercise capacity (BODE score) (O’Reilly, 2016). Currently, GOLD guidelines are used to separate COPD into 4 stages as seen in figure 1.
There are two major underlying pathologies in COPD patients: Chronic bronchitis and Emphysema.
Chronic bronchitis
Chronic bronchitis is diagnosed when sputum production and chronic cough occur frequently over at least three months over two consecutive years. Longitudinal studies of chronic bronchitis on human lung tissue showed that in patients with severe airflow limitation and bronchitis the lung deterioration was rapid and had higher risks of hospitalisation in comparison with a patient who does not have chronic bronchitis but does have airflow limitation. It is characterised by chronic inflammation and excess mucus production (figure 2) as a result of toxic chemicals and gases linked with smoking. This is due to hyperplasia of the goblet cells in the epithelium as well as hyperplasia and hypertrophy of the submucosal glands in the large cartilaginous airways. The chronic inflammation brings in activated T lymphocytes and macrophages which cause the narrowing of the small airways and fibrotic changes. The remodelling of the walls of the large and small bronchi causes deregulation of the healing process in tissues as a result of cigarette smoke. This causes the presence of chronic productive coughs, which can progress over time to intermittent dyspnoea. Airway fibrosis is due to the reduced expression of Smad-7 in airway epithelium, which was seen in bronchial biopsies of patients showing reduced mRNA expression of inhibitory Smad6 and Smad7 (Hogg and Timens, 2009).
Emphysema
Emphysema is defined as ‘abnormal permanent enlargement of airspaces distal to the terminal bronchioles accompanied by destruction to their walls’ (MacNee and Drummond, 2016). It is characterised by the damages to the alveolar units that deliver oxygen and remove the carbon dioxide. The airspaces are larger than the normal size from the distal to the terminal bronchiole, resulting in the appearance of holes in the lung tissue. The classic symptoms include a long history of progressive dyspnoea with the presence of the chronic non-productive cough, mucopurulent relapse, and eventual cachexia.
Immunohistochemical staining of lung tissue from patients that have mild and severe emphysema showed that there was a significant reduction in the staining of proteoglycans (such as decorin and biglycan) in the adventitia layer of the small airways in moderate to severe COPD. A reduction in decorin suggests a reduced collagen fibre attraction, resulting in the loosening of collagen in the adventitia and loss of elastic recoil (Hogg and Timens, 2009). The loss of elastic recoil (figure 2) and support for the small airways increases the tendency for it to collapse when obstructed. Animal studies done by (Sirianni, Chu and Walker, 2003) showed that fibroblasts in the alveolar wall link type 2 epithelial cells to the capillary endothelium by doing 3-D reconstructions at an electron microscopic level. The surface of type 2 cells and endothelial cells is used by migratory inflammatory cells to move through the alveolar wall interstitial space. In emphysema, this function is disturbed due to changes in fibroblast architecture and damage to the basal lamina. Hence there is an increased number of inflammatory cells, macrophages, and CD8+ lymphocytes.
Emphysema can be split into three main types based on the distribution of the enlarged airspaces (figure 3).
1. Centriacinar (centrilobular) emphysema is characterised by the clustering of the enlarged airspaces in the centre of the acinus surrounding the terminal bronchiole. It is believed that chronic inflammation in the terminal bronchioles can cause centrilobular emphysema destruction. This process is linked with the tissue repair and remodelling mechanism that is important in small airway obstructions and emphysematous destruction as there is a change from matrix build up to the destruction of the respiratory bronchioles. This is the most common type seen in smokers and is distributed in the upper zones of the lungs. In Guinea Pigs exposed to cigarette smoke for 80 days showed mild small airway wall thickening with fibrosis, which correlates to mild centriacinar emphysema. The epithelium was more permeable as the tight junctions were damaged, but this damage was restored once the exposure was stopped. However, in human’s restoration could take 3 to 5 years due to the low-grade inflammatory response (Hogg and Timens, 2009).
2. Panacinar (panlobular) emphysema is characterised by the enlarged airspaces being distributed throughout the acinus. It is more severe in the lower lobe but can be present anywhere in the lungs. High rates are seen in patients with alpha- 1 antitrypsin deficiency and are rarely seen in smokers.
3. Periacinar (paraseptal) emphysema is the least common of the three types. It can be characterised by enlarged airspaces along the periphery of the acinar unit near fixed structures, such as vessels or pleura. (MacNee and Drummond, 2016)
Clinical Features
There are similarities in symptoms in patients with chronic bronchitis and emphysema, (and to a lesser extent with chronic asthma) hence patients have been known to show a combination of features.
Alveolar macrophages (AM) are involved in phagocytosis of inhaled particles and in a study when AM were subjected to those particles there was an increase in phagocytic activity, oxidative stress, and release of pro-inflammatory mediators (van EEDEN et al., 2001). Pro-inflammatory mediators are regulated by the activation of transcription factors nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) that result in increased expression of inflammatory genes. Reactive oxygen species (ROS) induce carbonylation of proteins, which prolongs inflammation by the production of autoantibodies in severe COPD. ROS can cause fibrosis by activating transforming growth factor-β (TGFβ), which is also released by AM (Barnes et al., 2015).
Cross-sectional studies of the pathology show that the inflammatory immune responses found in smoker’s lungs get more amplified in severe and very severe COPD. This due to the activation of the adaptive immune response that results in the increase in activated antigen-specific T and B lymphocytes. These cells can be seen in mature lymphoid collections in the lungs in 5% of smokers that have normal maximum expiratory flow, and in smokers with mild to moderate COPD. The number of collections increase as the disease progresses with there being 25-30% in severe COPD.
In advanced COPD the involvement of antigens is still not understood, but it is believed to be linked with viral or bacterial colonisation, autoimmunity and increased exposure to neoantigens in the damaged ECM (Hogg and Timens, 2009). Infections can cause an acute worsening of the patient’s condition, and in severe exacerbations, the condition can progress, with a rapid decline in FEV1 in those who still smoke and had mild COPD (investigated in U.S. Lung health study), as well as in patients with severe COPD (How tobacco smoke causes disease, 2010). On the other hand, in other investigations patient’s acute exacerbations were not linked with bacterial load, but more to do with the immune response against new strains of bacteria that have previously stimulated the immune system. (Hargreave et al., 1996) conducted bronchial biopsies and obtained sputum in patients with chronic bronchitis. Immunohistochemical techniques showed that exacerbations were linked with increased eosinophilia and to a smaller degree an increase in neutrophils and activated T lymphocytes.
Another feature is the increased airflow resistance and obstruction, which is a result of airway narrowing caused by inflammation, fibrosis, mucus obstruction and loss of elastic recoil (figure 4). Measurements of the pressure and flow in the lung showed that the small bronchi and bronchioles (<2 mm diameter) is where the majority of obstructions occur. The connective tissue deposition due to chronic inflammation narrows the lumen (Hogg and Timens, 2009). The changes in the muscular pulmonary arteries, include increased vascular resistance due to hypoxic vasocontraction (figure 2), intima thickening and smooth muscle proliferation which are believed to be caused by inflammation (Barnes et al., 2015).
As the disease progresses comorbidities become common and will further increase mortality. COPD is a risk factor for lung cancer and is one of the most frequent causes of deaths for patients with mild to moderate COPD. Another common comorbidity is cardiovascular diseases, which are treated with cardioselective beta-blockers (O’Reilly, 2016).
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