Review Article
Recent Advances in the Assessment and Management of Chronic Obstructive Pulmonary Disease P. S. Shankar Emeritus-Professor of Medicine, and Director, M.R. Medical College and Associated Hospitals, Gulbarga, and Emeritus-Professor of Medicine, J.N. Medical College, Belgaum, Karnataka, India
ABSTRACT Chronic obstructive pulmonary disease (COPD) is a syndrome of progressive airflow limitation caused by an abnormal inflammatory reaction of the airways and lung parenchyma. It stems from chronic tobacco smoking, and indoor air pollution, and bronchospasm is the predominant cause of the symptoms. The condition is the result of environmental insult and host reaction that is likely to be genetically predetermined. Chronic obstructive pulmonary disease exhibits expiratory airflow limitation due to abnormalities in the airways and/or lung parenchyma. The disease begins with an asymptomatic phase and onset of the symptomatic phase develops with a fall in forced expiratory volume in one second (FEV1) below 70% of the predicted value. There is reduction in diffusing capacity, hypoxaemia and alveolar hypoventilation. However, it is intriguing why only a fraction of smokers develop clinically relevant COPD. [Indian J Chest Dis Allied Sci 2008; 50: 79-88] Key words: Chronic obstructive pulmonary disease, Airway, Smoking, Pollution, Lung, Hypoxaenia, Exacerbation.
INTRODUCTION Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease associated with long-term exposure to toxic gases and particles, mostly related to cigarette smoking. The median prevalence of COPD in India is about 5% in men and 2.7% in women of age above 30 years.1 Global burden of Disease Study has projected COPD to be the third leading cause of death worldwide by 2020. 2 Even though there have been significant advances in the understanding and management of COPD suggesting that the disease may largely be preventable, it remains marginally treatable.
DEFINITION Chronic obstructive pulmonary disease is a syndrome of progressive airflow limitation caused by chronic inflammation of the airways and lung parenchyma.3 It leads to a gradual decline in lung functions and worsening of dyspnoea and health status. Tobacco smoking forms the single most important risk factor for the development of COPD. Exposure to smoke from biomass and solid fuel fires contributes to the development of COPD in some individuals in the developing countries. However, it is intriguing why only 10% to 20% of chronic heavy smokers develop clinically significant COPD. There is an individual
susceptibility to smoking. Chronic obstructive pulmonary disease presents with chronic cough, excess sputum production and exertional dyspnoea. With the progress of the disease, there is worsening of symptoms, exercise intolerance and decreased quality of life. Increasing severity of the disease leads to dyspnoea at rest, hypoxaemia, hypercapnia, pulmonary hypertension and cor-pulmonale. Thus, the condition causes significant morbidity and mortality.
PATHOGENESIS Chronic obstructive pulmonary disease is characterised by a fall in expiratory flow and lung hyperinflation. These changes are due to loss of lung elasticity and inflammatory narrowing of the small airways of the lung. A number of genes in conjunction with environmental factors are likely to influence the development of airway inflammation and parenchymal destruction, in other words, the susceptibility to COPD. At present, most of the genes that contribute to the genetic component to COPD remain undetermined. However, the genes that are implicated in the pathogenesis of COPD are divided into three categories based on their functions: (1) antiproteolysis, (2) xenobiotic metabolism of the toxic substances in the cigarette smoke, and (3) inflammatory response to cigarette smoke.
Correspondence and reprint requests: Dr P.S. Shankar, Deepti, Behind District Court, Gulbarga-585 102 (Karnataka), India; Phone: 91-08472-220439; Fax: 91-08472-247652; E-mail:
[email protected].
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Recent Advances in COPD Assessment and Management
P.S. Shankar
Antiproteolysis
bronchial asthma are presented in table 1.
Imbalance in relative amounts of proteases and antiproteases are thought to play a major role in the pathogenesis of COPD, especially emphysema. Deficiencies or abnormalities in anti-proteases could lead to enhanced lung parenchymal destruction. Among the genes, alpha-1 anti-trypsin deficiency has proved to be an important risk factor.
Table 1. Differences between COPD and bronchial asthma
Xenobiotic Metabolising Enzymes Cigarette smoke contains many toxic and highly reactive compounds that can cause injury to the tissues and inflammation. Any change in the enzyme systems designed to detoxify reactive substances may contribute to an increased risk of development of COPD in smokers. 1. Microsomal epoxide hydrolase. Microsomal epoxide hydrolase (mEH) is a xenobiotic metabolising enzyme that converts reactive epoxides into more soluble dihydrodiol derivatives that are easily eliminated from the body. The mEH plays an important role in the metabolism of different highly reactive compounds found in cigarette smoke. Low levels of mEH make the lung vulnerable to damage by epoxides.4 2. Glutathion S-transferases. The enzymes, glutathione S-transferases (GSTs) play an important role in detoxifying different aromatic hydrocarbons found in cigarette smoke. They conjugate electrophilic substrates with glutathione and facilitate further metabolism and elimination. The GST-M1 is expressed in the bronchiolar epithelium, alveolar macrophages, and type-1 and type-2 pneumocytes. Homozygous deficiency for GST-M1 results in emphysema and severe chronic bronchitis in heavy smokers.5
Inflammatory Mediators Inflammatory mediators play a very important role in the pathogenesis of COPD. Genetic polymorphisms may either augment inflammation or impair antiinflammatory pathways and contribute to individual variability in their susceptibility to cigarette smoke. Chronic obstructive pulmonary disease and asthma are categorised as inflammatory diseases. In the alveoli, interstitium and alveolar capillaries, there is an accumulation of macrophages, neutrophils and CD8+ lymphocytes in COPD. These cells release the mediators such as tumour necrosis factor-alpha (TNF-α), leucotriene (LT)-B4, and the potent neutrophil chemoattractant, interleukin (IL)-8. Unlike COPD, asthma is associated with accumulation of activated eosinophils, mast cells and TH2 CD4+ lymphocytes and there is release of entirely different mediators, such as IL-4, IL5 and IL-13. 6 The differences between COPD and
Characteristics
Asthma
Age of onset Allergic history
younger age
elderly age
may be present
no such history
generally no
heavy smoking
variable may be present not common
progressive present excess
episodic
progressive
reversible good
partially reversible poor
Smoking Symptoms dyspnoea cough sputum
COPD
Airflow limitation Response to treatment Bronchodilators Corticosteroids
The line of distinction gets faded when COPD and bronchial asthma co-exist. Long-standing cases of severe asthma may exhibit airway remodeling resulting in fixed airflow limitation. Patients with COPD may exhibit asthmatic element with reversibility of airflow limitation. These characteristics may cause difficulty to differentiate between an asthmatic episode and an acute exacerbation of COPD. Tumour necrosis factor-alpha is produced by macrophages. It not only induces the release of neutrophils from the bone marrow, but also stimulates other cells such as monocytes, epithelial cells and smooth muscle cells in the airway that are also involved in the production of IL-8. Interleukin-8 in addition to being a neutrophil chemo-attractant, acts as an activator of neutrophils.7 In COPD there is an increased protease activity and action of free radicals, cytokines and chemokines in the inflammatory infiltrate to result in narrowing of airways and loss of alveolar tethering. Neutrophils and macrophages are involved in the synthesis and secretion of proteinases such as neutrophil elastase and macrophage-derived tryptases, and other metalloproteinases. These digest lung tissue and cause fibrosis. These are involved in airway remodeling and stimulate excess production of mucus.8, 9 The CD8+ cells are likely to be involved in apoptosis of epithelial cells in the alveolar walls. The action of perforins and TNF-α leads to the development of emphysema.6 There are goblet cell hyperplasia, squamous metaplasia and minimal smooth muscle hypertrophy.10 There is destruction of lung parenchyma. The focal damage is evident in central areas of acinus (centriacinar emphysema). There can be a uniform destruction of walls of airspaces distal to the terminal bronchioles (panacinar emphysema).11 There is loss of elastic recoil of the lung to result in hyperinflation, a premature collapse of airways and air trapping.12 Unlike asthma, the inflammatory process in COPD is not associated with accumulation of an increased number of activated eosinophils in the lungs. This is the
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The Indian Journal of Chest Diseases & Allied Sciences
reason for ineffectiveness of corticosteroids in COPD. They are indicated only when there is an exacerbation of the disease or in the presence of concomitant asthma, wherein there is a significant accumulation of activated eosinophils in the lungs.13 Eosinophils get activated only during exacerbation of the disease. The glucocorticosteroid-sensitive TH2 pathway is not active in COPD in contrast to asthma. 8 All these basic abnormalities make steroids to be ineffective during stable COPD. The study of bronchoalveolar lavage (BAL) fluid and sputum samples from patients with COPD has revealed presence of large number of neutrophils and macrophages.14 Sputum also shows a greater amount of IL-8 and TNF-α.15
GUIDELINES The collaborative efforts of the World Health Organization and the National Heart Lung and Blood Institute have resulted in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. The guidelines include the following components:16 (i) assessment and monitoring of the disease, (ii) reduction of risk factors, and (iii) treatment of patients with stable COPD.
Assessment and Monitoring of COPD Successful management of COPD depends on correct diagnosis that includes two distinct patho-physiologic processes, such as chronic bronchitis and emphysema. The pathologic hallmarks of COPD are destruction of the lung parenchyma (pulmonary emphysema), inflammation of the small peripheral airways (respiratory bronchiolitis) and inflammation of the central airways. Chronic bronchitis is associated with excessive mucus secretion into the bronchial tree on most days out of three months in at least for two consecutive years. Emphysema presents with dyspnoea of insidious onset due to an abnormal permanent enlargement of the airspaces distal to the terminal bronchioles accompanied by destruction of alveolar septa and without obvious fibrosis. Most COPD patients exhibit a mixture of emphysema and chronic bronchitis and they appear normal for a prolonged period of time but present with respiratory symptoms only when the disease has been advanced. This slowly progressive destructive process of the lung is poorly reversible when manifested clinically. Although the disease affects the lungs, it also produces significant systemic consequences, and often associated with significant comorbid diseases. Systemic effects of COPD involve respiratory and skeletal muscles. There is muscle weakness and fatigue. There is a preferential loss of skeletal muscles especially in the lower extremities and
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the muscle wasting is increasingly noticed in quadriceps muscle. Patients exhibit weight loss and osteoporosis also. The patients, especially those 40 years of age or older, who have risk factors of the disease such as history of smoking are to be screened for COPD. Though the diagnosis is suggested by symptoms, it needs confirmation by spirometry.17 Cough, sputum, wheeze and dyspnoea are the common presenting symptoms. The patients with advanced COPD may exhibit hyperinflation of the chest. However, patients with chronic bronchitis may not exhibit over inflation of the chest. The best physical signs of COPD are a prolonged expiratory phase and decreased distant breath sounds. Breathing in and out deeply and rapidly with mouth open fails to improve breath sounds. Advanced emphysema on chest roentgenography exhibits low, flat diaphragm, increased retro-sternal air space, decreased vascular markings in the outer-third of the lung fields, all features of lung hyperinflation. Coarse lung markings and peri-bronchial cuffing may be present in chronic bronchitis. Chronic obstructive pulmonary disease is defined as airflow limitation that is not fully reversible, and it is confirmed by spirometry.16 The airflow limitation is generally progressive. Airflow limitation used to be described ‘irreversible’. Of late it has been recognised incorrect. Repeated testing before and after bronchodilator challenge has shown a significant degree of reversibility at some point of disease in many patients.17 But it must be noted that the lung functions in COPD patients does not return to normal after bronchodilator challenge. Hence, the airflow limitation is ‘not fully reversible’.18 The severity of COPD is established by measuring the forced expiratory volume in one second (FEV1) and the ratio of FEV 1 to forced vital capacity (FVC). The GOLD has introduced a five-stage classification to determine the severity of COPD based on measurements of airflow limitation during forced expiration (Table 2).2 Abnormalities in these tests reflect both the reduction in the force available to drive air out of the lung as a result of emphysematous lung destruction and obstruction to airflow in the smaller conducting airways.2 Table 2. Stages of COPD according to GOLD2 Stage
Manifestations
0 I II III IV
at risk Mild Moderate Severe Very severe
FEV1(%)
Symptoms
≥ 80 ≥ 80 50-79 30-49
