Pathophysiology of the Clinical Presentation of Chronic Obstructive Pulmonary Disease (COPD)

– With reference to your chosen case study, describe and explain the underpinning pathophysiology of the clinical presentation and associated dysfunction highlighting any contributing factors.

Pathology: COPD

Chronic Obstructive Pulmonary Disease (COPD) is recognised as a persistent airflow limitation that is associated with an enhanced, progressive and chronic inflammatory response. It occurs within the airways as a result of noxious particles or gases being inhaled [1-4]. COPD is separated into 2 phenotypes, these are identified as: Emphysema and Chronic Bronchitis

1. Emphysema: is clinically defined as the enlargement of the small distal spaces within the airways.
2. Chronic Bronchitis: is clinically diagnosed as a cough that produces sputum and is present on most days in 3 consecutive months over a 2-3 year period.[5]

The inflammatory process has been shown to be orchestrated by a number of cells. Cell migration is stimulated by chemokines and other chamoattractants, as well as the proteinase-antiproteinase system and levels of oxidative stress. These processes play a major role in airway remodelling and are therefore influential in the development of COPD. The risk of COPD increases in obese patients and with age, as it becomes debilitating and lethal. COPD is considered ‘a chronic health condition with increasing worldwide prevalence’ [6].

‘COPD was the fifth leading cause of mortality around the world in 2001 and will be the third most frequent cause of death by the year 2020’ [7] with others  stating that ‘COPD is the fourth leading cause of death worldwide, with increasing prevalence, particularly in the elderly’ [8]. In 2003 the burden of these conditions amounted to a staggering -$32.1 billion in the USA; with this financial cost predicted to increase worldwide [1]. There is a professional division on the exact ‘nature and underlying mechanisms of COPD and its link to obesity’ [9], however COPD aetiology is widely agreed upon; these are shown in Table 1.

TABLE 1

Aetiology	Pathophysiology
Cigarette Smoke	The presence of cigarette smoke in the lungs causes an instinctive inflammatory response that increases the number of Macrophages & Neutrophils that penetrate the lungs parenchyma. The immune response stimulates cytokine, chemokines and elastase numbers to increase which over time causes damage to the lungs functional tissue and breathing efficiency.
Chronic IV Drug use	The use of schedule 5 drugs such as cocaine, methamphetamine or heroin create a higher chance of COPD development; studies have linked this kind of drug use to vascular damage, as it is often cut with insoluble filler such as benzocaine, cellulose, talc, cornstarch.[5]
Alpha – 1 antitrypsin deficiency	Secreted by the liver this serine protease inhibitor is found in the blood and stops the enzyme ‘neutrophil elastase’ from destroying the parenchyma. Lacking in these alpha-1 antitrypsin results in unopposed corrosion of the elastin fibres found in the alveolar walls; this process is called elasteolysis and is recognised as early stage emphysema. (Known as the protease-antiprotease theory)
Occupational exposures to dust and chemicals	Aetiology is uncertain; however, one theory suggests it is comparable to the innate process that occurs during cigarette smoking.[5]

These aetiologies drive the chronic inflammation, eventually leading to degeneration and abnormal remodelling within the parenchyma [10, 11]. This remodelling presents remarkable characteristics such as: Fibrosis and a thickening of the airway walls and lumen resulting in emphysema; inevitably the destruction of the parenchyma occurs due to the fibrosis of functional tissue [12]. This intrinsic reaction is present in all cigarette smokers and will persist up to 1 year after smoking cessation, however in those with COPD an ‘enhanced or abnormal response occurs‘ [13]. The immune response increases the level of oxidative stress within the lungs causing oxidative damage to DNA, lipids, carbohydrates and proteins which overall contributes to the progression of COPD. The oxidative stress activates the lungs epithelial cells and macrophages within the alveolar, when these cells become aroused they generate chemotactic molecules in order to recruit additional inflammatory cells into the lungs [14].

Over an extended period of time adaptations occur, these are: ‘hypersecretion (chronic bronchitis), tissue destruction (emphysema) and the disruption of normal tissue repair and defence mechanisms causing  Bronchiolitis (airway inflammation/fibrosis)’ [13]. These alterations increase airflow resistance within the smaller conducting airways, causing air to become trapped and progressively obstructed. ‘The extent of the inflammation directly relates to the degree of airflow obstruction’[13]. Another clinically important comorbidity associated with COPD is cardiovascular disease, specifically the increase in arteriole thickness, as this increases the risk of pulmonary hypertension [4]. Hypertension increases the chances of blood clotting, arrhythimia and stroke; and will lower a person’s life expectancy and overall life quality.  Aside from systemic inflammation and pulmonary hypertension, two other cellular processes become imbalanced and contribute to the pathogenesis of COPD – 1: an unbalanced proteases and antiproteases system; and 2: an imbalance between the oxidants and antioxidant system (oxidative stress).

Emphysema Process: ‘Emphysema is defined as the enlargement of the distal smaller airspaces, beyond the terminal bronchioles’ [15].As COPD is an inflammatory response it is regularly diagnosed by the rising numbers of eosinophils, macrophages, polymorphonuclear leukocytes, CD4+ and CD8+ lymphocytes within the inner lining of the lungs. The immune response transports antigen wielding cells into the smaller airways, where the activation of neutrophilic chemotactic factors occurs [1, 8]. The increased proteases activity and decreased antiproteases activity creates an imbalance that has a detrimental effect on the lung. Proteases such as neutrophil elastese is believed to be central in the development of emphysema as it leads to break down the elastin fibres that normally contribute to elastic recoil during expiration. Alpha-1 antitrypsin usually keeps the elastase activity in check; however α-1 antitrypsin becomes inactive due to the oxidative stress caused by cigarette smoke and its inherent inflammation causes a neutrophillic release of free radical hydrogen peroxide resulting in epithelial destruction. The epithelial tissue of the alveolar walls and the septae are destroyed due to Macrophages excreting a proteolytic enzyme called ‘matrix metalloproteinases’ [16, 17]. The number of Macrophages contained in alveolar fluid of an emphysematous patient is 5 to 10 times higher than normal [18].  The inflammatory process is amplified further as CD8+ cells discharge chemotactic factors in order to increase pro-inflammatory cytokines and growth factors; causing abnormal remodelling known as Emphysema. Healthcare professionals may check for precursors of emphysema, such as α-1 antitrypsin deficiency, impaired gaseous exchange or air trapping in smokers, as they can be an early indicator for diagnosing COPD. [16, 17, 19]

Chronic Bronchitis Process: Is the result of inflammation within the epithelium of the larger more central airways and mucus glands [20]. Symptoms such as increased sputum/mucous production and increased permeability of the airway epithelial can cause mucociliary dysfunction as they reduce the self-clearing ability of bronchi. An increased number of neutrophils and the distribution of bronchial tissue regulation due to fibrotic changes, is the result of interleukin 8 and inflammatory cells such as  neutrophils, CD8+ T-lymphocytes, B cells and macrophages, releasing a powerful secretion promoter called ‘serine proteases’  which causes hypersecretion[21, 22]. Airway resistance is increased as hypersecretion reduces the size of the airway lumen. The highest amount of airway resistance happens in the small airways although it appears that the majority of dysfunction occurs in the larger airways. It is thought that ‘hypersecretion contributes little in the early stages of COPD, as mucus production in smokers with normal lung function does not appear to predict later development of COPD’ [23]. However hypersecretion over an extended period of time does increase the risk of exacerbations as it can accelerate the loss of one’s’ forced expiration volume (FEV₁). It is hypothesised that hypersecretion may be a result of inflammation within the submucosal glands [24].

The Ageing Process: The average lung will develop until it reaches maximal potential at around 20-25 years; from then on its functionality progressively declines due to structural and physiological changes [25]. In everyone age-related changes within the lungs are ‘attributed to an increased alveolar spacing known as senile emphysema’. Senile emphysema is thought to occur due to a loss of support from the lungs parenchyma [2, 25] this process correlates with age in non-smokers, however ‘in smokers a more progressive increase in alveolar spacing can be observed.’[8].  As age increases the ‘elastic recoil within the lung reduces’[2] this phenomenon is caused by reduced surface tension forces in the alveoli as there diameter size increases, as oppose to degenerative changes happening to the elastin and collagen.

Another aging progression is reduced chest wall compliance. This is attributed to 3 separate processes; firstly, the shape of the thorax may change due to the shrinking of intervertebral discs, thereby reducing intrathoracic volume. Secondly as age increases so does the risk of Osteoporosis and vertebral fractures, in turn these increase the risk of alterations in thoracic structure. Lastly, the stiffness of the ribs will progressively increase; this reduces ones range of motion and movement efficiency. Combined with reduced muscular strength, over time these structural changes affect the strength of the diaphragm, respiratory muscles and efficiency of the parenchyma; overall this diminishes breathing functionality [2, 8, 25].

Exacerbation pathophysiology: Exacerbations are often triggered by air pollution, infection or temperature changes. They are linked with an increase in neutrophillic inflammation and in milder cases an increase in eosinophilic presence. Severe exacerbation is caused by the deterioration of pulmonary gaseous exchange due to an inequality between ventilation & perfusion and an increase in respiratory muscle fatigue. In milder case airflow obstruction is slightly increased or unchanged. As the ventilation-perfusion relationship deteriorates it causes hypersecretion, oedema and bronchoconstriction which in turn impairs perfusion and increases the chances of hypoxic vasoconstriction of the pulmonary arterioles. Hypoxemia, Hypercapnia and respiratory acidosis leading to severe respiratory failure can come as a result of respiratory muscle fatigue and alveolar hyperventilation. As Hypoxia and respiratory acidosis set in they can induce pulmonary vasoconstrictions and increase the strain placed on the right ventricle; when combined with the renal and hormonal changes that occur it can result in peripheral oedema[13].

The patient is a smoker and has a BMI of 32.7 according to the NHS BMI calculator making her clinically obese[26], she also has high cholesterol and is in her fifties. In relation to COPD these are considered yellow and red flags. The red flags and poor lifestyle choices have implications on her condition, previous research shows that ‘the combined restrictive and obstructive deficits that are evident in obese patients with COPD, culminate in worsening symptomatology and activity limitation’ [27-29]. This is evident as the patient says ‘she feels she is stuck in a cycle’, whereby her smoking, poor diet and sedentary lifestyle have accumulated together to make her symptoms worse.

Comorbidities

A universal effect of COPD is systemic inflammation and musculoskeletal atrophy, this is seen as a significant marker of mortality, ‘with TNFα believed to play a major role’ [30]. TNFα gives life to the transcription factor NF-kB; NF-kB promotes the activity of the ubiquitin/proteasome pathway which subsequently catalyses the degradation of muscle proteins, promoting  localised muscle weakness and thus creating a complex mechanism of exercise intolerance [31]. Not only is this intolerance due to TNFα, but a study conducted on 120,000 obese patients without COPD by the American Journal of Respiratory and Critical Care Medicine found that women with a +35 inch and men with a +40 inch waist had poorer lung function than their slimmer compatriots. Showing that not only is it more difficult to move and physically breathe in but also the intrinsic efficiency of breathing decreases as one becomes obese. Another contributing factor is believed to be the inflammation that is associated with fatty tissue and the excessive fat putting a constrictive pressure on the lungs [6]. Furthermore obese patients have ‘expiratory flow limitation at rest which when compounded by high ventilatory requirements, leads to significant air trapping and a dynamic increase in end-expiratory lung volume during exercise’ [6, 32, 33].

Having a sedentary lifestyle is a modifiable risk factor for COPD and a variety of other disease such as dementia, cancer and type 2 diabetes mellitus [34]. It will contribute to the development of Osteoporosis as there is an increase in circulating TNFα [35]. TNFα stimulates osteoclasts in bone resorption, reducing a patient’s mobility and bone density, which could possibly increase the chances of depression and anxiety as these are common in COPD patients, with a prevalence of around 80% [36]. Increasing the amount of ‘regular physical activity will improve a person’s body composition, aerobic enzyme activity, coronary blood flow, psychological well-being, glycolic homeostasis and insulin sensitivity, it also enhances lipid lipoprotein profiles and endothelial function, whilst reducing blood pressure and systemic inflammation’[34].                                                                                                                            Cross sectional studies have shown a significant relationship between activity levels and FEV₁ [37-39]. Higher FEV₁ values were found in patients who had high to moderate levels of activity or achieved a minimum of 30 minutes walking each day compared to those who remained inactive. Sustaining a higher level of FEV₁ in COPD patients can help reduce exacerbations (a main cause of hospital admissions), by increasing a patients activity levels their exercise capacity and muscular function is improved and their Dyspnea reduced. Increased activity and breathing efficiency improves life quality and therefore ones functionality.

Smoking is the primary cause of COPD, in relation to this case study advice for smoking cessation would occur immediately. In addition to this smoking is a major risk factor for lung cancer, as chronic inflammation may play a key role in its pathogenesis with NF-kB activation being a possibly important factor[40]. Furthermore indoor smoking should be avoided as it allows for passive smoking to occur, which again is well known for its harmful action on respiratory health [41].

Diet is crucial to the development of healthy tissue and well-being, a diet that consists of simple sugars, excessive fat and lacking in complex carbohydrates, has been shown to be detrimental to COPD recovery [42]. Studies have shown that ‘increasing salt intake, decreasing intake of fruits and vegetables and changing the amount of fatty acid consumption’ in ones diet, ‘contributes to the increase in COPD mortality and morbidity’ [6, 9, 42, 43]. As only 20% of smokers develop COPD recent research has looked into COPD and its relation to diet and has shown some persistent nutritional abnormalities in patients with COPD. Poor diet leads to malnutrition, malnutrition contributes to respiratory muscle atrophy which in turn increases the likelihood of hospitalisation, Cor Pulmonale and eventually death. Nutritional deficits are indicated by the loss of lean body mass and bodyweight (commonly seen in advanced COPD of the emphysematous type). Factors believed to contribute to nutritional abnormalities are ‘increased resting periods, reduced dietary intake relative to energy expenditure, accelerated negative nitrogen balance, medication effects, and perhaps most importantly an elevated systemic inflammatory response’ [44, 45].

Treatments

The damage caused by COPD is irreversible, however its effects can be lessened and the management improved, so that a patient’s health is maintained. This can be achieved with the aid of a Physiotherapist and other allied health professionals. Pulmonary rehabilitation can significantly improve a patient’s health by reducing their exacerbations, provide a sturdy method of disease control and improve their daily functionality. Pulmonary rehabilitation alters muscular metabolic rate so that a person is able to tolerate a higher magnitude of activity without causing dyspnea. VO₂ max is therefore improved. Other beneficial adaptations that occur during pulmonary rehabilitation are the conversion of type IIb muscle fibres to type IIa fibres and an increase in mitochondrial enzymes such as synthetase and 3-hydroxyacyl-COA dehydrogenase. These encourage extra aerobic metabolism and reduce the amount of lactic acid and CO2 production during exercise, therefore increasing exercise tolerance. Pulmonary rehabilitation can be done at home or with an in-patient or out-patient, the basic goal is to enhance overall quality of life, restore functionality and improve symptoms.

Additional treatments for COPD:

• Bronchodilators and Corticosteroids: tests in the 1990’s showed that although a small subset of patients had a slight improvement in FEV₁ following inhalation of corticosteroids, the rate at which their FEV₁ declined was not dissuaded. However due to the administration of these treatments, symptoms of cough and exacerbations from chronic bronchitis were significantly reduced. The contrast of symptomatic benefit must always be weighed up against the systemic side effects (e.g. reduced bone density) if long term use is being applied.  Bronchodilators work due to β2-agonists being inhaled which act upon specific receptors located on smooth muscle cells causing bronchodilation. In addition anticholinergics are also inhaled which act to block the effect of acetylcholine on muscarinic receptors located in the smooth muscle which also allows for bronchodilation. Inhaled β2-agonists and anticholinergics are both used to treat symptoms, as well as acute exacerbations of COPD. Corticosteroids are used to inhibit the inflammatory response by suppressing transcriptions factors, such as NF-κB, which regulates various cytokines, adhesion molecules, chemokines and a variety of proteins that spread and encourage inflammation.[46]
• Oxygen Therapy: Throughout COPD rehabilitation has been shown to improve a patient’s ability to undergo highly intense exercise [47]. It is frequently used alongside pharmacological interventions to treat hypoxia. Pulmonary vasoconstriction is reduced as a result of decreased levels of hypoxia in the alveoli, in turn this reduces the risk of pulmonary hypertension and improves systolic heart function. Oxygen is usually supplied according to the needs of the patient, whether that be a continuous supply or on a demand basis. Even though there is irrefutable evidence to show that oxygen increases ones exercise capacity in a laboratory, field tests have shown mixed evidence in relation to its effectiveness in everyday life. Therefore it remains to be determined whether supplemental oxygen will be used as an established treatment for exercise enhancement for non-hypoxic patients with COPD [48].
• Surgery: Lung Volume Reduction Surgery improves a patient’s quality of life; however it does not reduce mortality. The procedure involves removing parts of diseased lung. This has 2 physiological effects: 1) reduction of hyperinflation, thus allowing the diaphragm to optimally contract. 2) An improvement in the elastic recoil as the damaged portions are taken away.[5]

To conclude, COPD is an incurable, progressive and exigent pathology for clinicians and patients to manage. Research and clinical knowledge relating to diagnosis, management and prevention can improve patients’ durability and life quality. Results from breakthrough studies will lead to enhanced treatments, improvements in diagnosis and present management techniques and will highlight new correlations in managing COPD.

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