百年回顾COPD

Chronic obstructive pulmonary diseaseV .K. Vijayan *Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India **Received November 6, 2012The global prevalence of physiologically defined chronic obstructive pulmonary disease (COPD) in adults aged >40 yr is approximately 9-10 per cent. Recently, the Indian Study on Epidemiology of Asthma, Respiratory Symptoms and Chronic Bronchitis in Adults had shown that the overall prevalence of chronic bronchitis in adults >35 yr is 3.49 per cent. The development of COPD is multifactorial and the risk factors of COPD include genetic and environmental factors. Pathological changes in COPD are observed in central airways, small airways and alveolar space. The proposed pathogenesis of COPD includes proteinase-antiproteinase hypothesis, immunological mechanisms, oxidant-antioxidant balance, systemic inflammation, apoptosis and ineffective repair. Airflow limitation in COPD is defined as a postbronchodilator FEV1 (forced expiratory volume in 1 sec) to FVC (forced vital capacity) ratio <0.70. COPD is characterized by an accelerated decline in FEV1. Co morbidities associated with COPD are cardiovascular disorders (coronary artery disease and chronic heart failure), hypertension, metabolic diseases (diabetes mellitus, metabolic syndrome and obesity), bone disease (osteoporosis and osteopenia), stroke, lung cancer, cachexia, skeletal muscle weakness, anaemia, depression and cognitive decline. The assessment of COPD is required to determine the severity of the disease, its impact on the health status and the risk of future events (e.g., exacerbations, hospital admissions or death) and this is essential to guide therapy. COPD is treated with inhaled bronchodilators, inhaled corticosteroids, oral theophylline and oral phosphodiesterase-4 inhibitor. Non pharmacological treatment of COPD includes smoking cessation, pulmonary rehabilitation and nutritional support. Lung volume reduction surgery and lung transplantation are advised in selected severe patients. Global strategy for the diagnosis, management and prevention of Chronic Obstructive Pulmonary Disease guidelines recommend influenza and pneumococcal vaccinations.Key words A irflow limitation - air pollution - bronchodilators - chronic obstructive pulmonary disease - exacerbations - lung -pulmonary rehabilitation - smokingCentenary Review ArticleIndian J Med Res 137, February 2013, pp 251-269251IntroductionChronic obstructive pulmonary disease (COPD) is a name coined for the diseases that were previouslyPresent address : *Advisor to Director General, ICMR Bhopal Memorial Hospital & Research Centre & National Institute for Research inEnvironmental Health, Bhopal known as chronic bronchitis and emphysema. The British Medical Research Council (BMRC) defined chronic bronchitis as “daily productive cough for at least three consecutive months for more than two**Former Directorsuccessive years1. American Thoracic Society (ATS) in 1962 defined emphysema as an “anatomic alteration of the lung characterized by an abnormal enlargement of the air spaces distal to the terminal, non-respiratory bronchiole, accompanied by destructive changes of the alveolar walls”2. The definition of emphysema put forth by the National Heart, Lung and Blood Institute in 1984 is as “a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by the destruction of their walls, and without obvious fibrosis”3. Reid reported that “the diagnosis of emphysema by itself is incomplete unless it is taken into account the presence or absence of chronic bronchitis and vice versa”4. McDonough et al5have recently reported extensive obliteration of terminal bronchioles in patients with COPD who have emphysema, suggesting that “the permanent enlargement of the distal airspaces may serve only as a structural biomarker, being a secondary result of small airway inflammation and destruction”6. Thus, COPD has both airway (central and small airways) and airspace abnormalities. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recently defined COPD as “a common preventable and treatable disease characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patient7”. It is worthwhile to mention that William Osler in 1892 in his “Textbook of Medicine” has described hypertrophic emphysema as “a well-marked clinical affection, characterized by enlargement of the lungs due to distension of the air cells and atrophy of their walls, and clinically by imperfect aeration of the blood and more or less dyspnea”8, a beautiful clinical description of emphysema. Epidemiology(i) Global scenarioThere are wide variations in the prevalence of COPD across countries. This variation in the estimated prevalence is due to the method of diagnosis and classification of COPD9. It has been observed that the prevalence estimates were higher when COPD has been diagnosed by spirometry compared with methods using symptoms10. COPD is common in older population and is highly prevalent in those aged more than 75 yr. The global prevalence of physiologically defined chronic obstructiv e pulmonary disease (GOLD stage 2 or more) in adults aged ≥40 yr is approximately 9-10 per cent11. The Burden of Obstructive Lung Disease (BOLD) study from 12 sites involving 9425 subjects who had completed post bronchodilator spirometry testing found that the overall prevalence of COPD of GOLD stage II or higher was 10.1 per cent and the prevalence was 11.8 per cent for men and 8.5 per cent for women12. This study had also revealed that there were differences between countries, the prevalence ranging from 9 per cent in Reykjavik, Iceland to 22 per cent in Cape Town, South Africa for men and from 4 per cent in Hannover, Germany to 17 per cent in Cape Town for women.The multicentre PLATINO study that described the burden of COPD in five Latin American countries using post-bronchodilator spirometry had reported that the prevalence of airway obstruction was 14.3 per cent and the proportion of subjects in stages II- IV of the GOLD classification was 5.6 per cent13. The reported prevalence of COPD in China varied between 5 and 13 per cent in different provinces/cities14. (ii) Indian scenarioOne of the earliest studies to know the prevalence of COPD in India was carried out by Wig et al in 196415 in rural Delhi. The prevalence was 3.36 per cent in males and 2.54 per cent in females in this study. Viswanathan in 196616 reported 2.12 per cent prevalence in males and 1.33 per cent in females in Patna. Radha and colleagues18 noticed that the prevalence in New Delhi in 1977 was 8.1 per cent in men and 4.6 per cent in women17. Jindal in 199318 reported that the prevalence was 6.2 per cent in men and 3.9 per cent in women in rural area, and 4.2 and 1.6 per cent, respectively in urban area. All these studies were from north India and information from south India was scanty. Thiruvengadam et al in 197719 from Madras (south India) reported the prevalence of COPD of 1.9 per cent in males and 1.2 per cent in females. However, Ray et al in 199520 from south India found that the prevalence was 4.08 per cent in males and 2.55 per cent in females. Recently, the Indian Study on Epidemiology of Asthma, Respiratory Symptoms and Chronic Bronchitis in Adults (INSEARECH) involving a total of 85105 men, 84470 women from 12 urban and 11 rural sites was reported21. This study had shown that the overall prevalence of chronic bronchitis in adults >35 yr was 3.49 per cent (ranging 1.1% in Mumbai to 10% in Thiruvananthapuram). Thus there are wide variations in the prevalence of COPD in India subcontinent. Based on this study, the national burden of chronic bronchi tis was estimated as 14.84 million.252 INDIAN J MED RES, FEBRuARy 2013Risk fa ctorsThe development of COPD is multifactorial and the risk factors of COPD include genetic and environmental factors. The interplay of these factors is important in the development of COPD.(i) Genetic factorsΑlpha1-antitrypsin deficiency is an established genetic cause of COPD especially in the young and it has been reported that α1-antitrypsin deficiency occurs in 1-2 per cent of individuals with COPD22. Alpha1- antitrypsin is mainly produced in the liver and normal alpha1 antitrypsin is due to the M allele. Severe alpha1-antitrypsin deficiency results from mutation in the SERPINA 1 gene [located on the long arm of chromosome 14 (14q31-32.3)] and this gives rise to the Z allele23.Genome-wide association (GWA) study has identified three loci (CHRNA3/CHRNA5/IREB2, HHIP, and FAM13A) that are associated with COPD susceptibility24-26. A new COPD locus has also been identified on chromosome 19q13, which harboured the RAB4B, EGLN2, MIA, and CYP2A6 genes27. GWA study on forced expiratory volume in 1 second (FEV1)and FEV1/FVC (forced vital capacity) ratio has identified five genome-wide significant loci for pulmonary function, three [2q35 (TNS1), 4q24 (GSTCD), and 5q33 (HTR4)] for FEV1, and two for FEV1/FVC [6p21 (AGER) and 15q23 (THSD4)]28. Another GWA study found significant associations with FEV1/FVC ratio for SNPs located in seven previously unrecognized loci: 6q24 (GPR126), 5q33 (ADAM19), 6p21 (AGER and PPT2), 4q22 (F AM13A), 9q22 (PTCH1), 2q36 (PID1), and 5q33 (HTR4). One new locus for FEV1 on 4q24 annotated by three genes (INTS12, GSTCD, and NPNT) was identified for FEV128. 4q24 (GSTCD), 5q33 (HTR4) and 6p21 (AGER) were common in both studies28,29. The first GWA study on lung-function decline has recently reported one locus on chromosome 13q14.3 containing the DLEU7 gene that is strongly associated with FEV1 decline30.(ii) Environmental factorsTobacco smoking is the main cause of obstructive pulmonary disease31. Other important environmental factors associated with COPD are outdoor air pollution, occupational exposure to dusts and fumes, biomass smoke inhalation, exposure to second-hand smoke and previous tuberculosis32.(a)Tobacco smoking:Though tobacco smoking is the most important cause of COPD, the population-attribu table fraction for smoking as a cause of COPD ranged from 9.7 to 97.9 per cent32. A Swedish cohort study had observed that population-attributable fraction for smoking as a cause of COPD was 76.2 per cent33. In another Denmark study, the reported population-attributable fraction as a cause of COPD was 74.6 per cent34. Thus, a significant proportional subjects with COPD had causes other than tobacco smoking. In our country, bidi smoking is an important factor in addition to cigarette smoking that causes COPD35.(b) Outdoor air pollution: Outdoor air pollution mainly from emission of pollutants from motor vehicles and industries is an important public health problem36. In a community-based study, it has been observed that higher traffic density was significantly associated with lower FEV1 and FVC in women37. In the Danish Diet, Cancer and Health cohort study involving 57,053 participants, it has been shown that COPD incidence was significantly associated with nitrogen dioxide levels38. Particulate pollutants, ozone and nitrogen dioxide can produce bronchial hyper reactivity, airway oxidative stress, pulmonary and systemic inflammation36. However, a causal relationship between outdoor air pollution and COPD is still not established.(c) Indoor air pollution: Important indoor air pollutants are environmental tobacco smoke, particulate matter, nitrogen dioxide, carbon monoxide, volatile organic compounds and biological allergens37. Among these, environmental tobacco smoke39,40 and biomass smoke exposure are related to the development of COPD42. Globally, it has been estimated that about 2.4 billion people (about 50% of world’s population) use biomass fuel as the primary energy source for domestic cooking, heating and lighting43. Biomass (wood, crop residue and animal drug) are burnt in rural areas using substandard stoves in poorly ventilated indoors. Women, spending more time indoors for cooking than men, are exposed to biomass fuel combustion products and are prone to develop COPD41,42,44. A meta-analysis has shown that biomass smoke exposure was a risk factor for developing COPD in both women and men44.(d) Other risk factors: Other risk factors associated with COPD and reduced FEV1 are occupational exposure to dusts and fumes, previous tuberculosis, maternal smoking, childhood asthma and childhood respiratory infections45.PathologyPathological changes in COPD are observed in central airways, small airways and alveolar space46.VIJAYAN: CHRONIC OBSTRUCTIVE PULMONARY DISEASE253Mucus glands and goblet cells are found in the lining of trachea-bronchial tree in normal individuals and mucus is produced by these cells. In chronic bronchitis patients, the mucus glands are enlarged and goblet cells undergo metaplasia. The excess mucus secreted by these cells as a result of irritation from cigarette smoke, air pollutants, etc. and cough are the cardinal features of chronic bronchitis. The size of the mucus glands can be determined by the Reid index which is measured by calculating the ratio of bronchial gland to the thickness of bronchial wall4. Narrowing and destruction of terminal bronchioles (airways <2 mm in diameter) are characteristic changes in COPD. Small airways offer <20 per cent of the total resistance below the larynx47and the resistance of the small airways is increased 4- to 40-fold in lungs from patients with COPD48. Thus, the small airways are the major site of increased resistance in persons with COPD. The cellular events that occur in the small airways in COPD include replacement of Clara cells with mucus-secreting and infiltrating mononuclear cells and goblet cell metaplasia46. Smooth muscle hypertrophy is also an important finding. As a result of excess mucus secretion, oedema formation and cellular infiltration and the resultant fibrosis cause airway narrowing. Pathological changes that occur in alveolar space include accumulation of macrophages and neutrophils. There is also an increase in T-lymphocytes particularly CD8+ T cells. Chronic inflammation and destruction of alveolar space lead to either cetriacinar or panacinar emphysema.PathogenesisThe proposed pathogenesis of COPD includes proteinase-antiproteinase hypothesis, immunological mechanisms, oxidant-antioxidant balance,systemic inflammation, apoptosis and ineffective repair46. (i) The proteinase-antiproteinase hypothesisThe proteinase-antiproteinase hypothesis is based on the assumption that tissue destruction and emphysema occur due to an imbalance between the proteinases and their inhibitors. It has been proposed that there is an increase in the quantity of elastic-degrading enzymes compared to their inhibitors in emphysema. This concept has been suggested in emphysema that has been described in α1antitrypsin (α1AT) deficiency, first reported by Laurell and Eriksson in 196349. The patients with α1AT deficiency have mutations in the α1AT gene. Z mutation is the common mutation and these mutations impair secretion of the protein from hepatocytes. As a result, there is markedly decreased circulating level of serine proteinase inhibitor. PiZ-α1AT is less effective than the normal PiM-α1AT. It has been recently reported that PiZ-α1AT is prone to polymerization which can inhibit hepatic secretion, impair neutrophil elastase (NE) inhibition and promote inflammation46. Chronic cigarette smoke exposure leads to accumulation of activated macrophages, neutrophils and CD8+ T lymphocytes in the distal airways and alveolar spaces50. Macrophages and neutrophils are the main sources of proteases in lungs. Excess neutrophil elastase produced by the activated neutrophils overwhelms the serine proteinase inhibitors leading to the development of emphysema. Cigarette smoke also activates airway epithelium to trigger airway remodelling51. Studies have demonstrated that there are correlations between the degree of macrophage and neutrophil inflammation and severity of airflow obstruction52.Matrix metalloproteinases (MMP), increased in many lung diseases including COPD, have the capacity to cleave structural proteins such as collagen and elastin and these MMPs are linked to the pathogenesis of COPD53. Increases in many MMPs are reported in smoking-related emphysema and three MMPs (MMP-2, -9, and 12) are shown to degrade elastin53. MMP-9 and MMP-12 are expressed in alveolar macrophages from COPD patients. Cigarette smoke causes macrophages to produce MMP-12 which can cleave elastin into fragments. Elastin fragments are chemotactic to monocytes and fibroblasts and this increases the inflammatory and protease burden in the lung and leads to subsequent lung destruction. This creates a positive feedback loop that results in continuous destruction of lung parenchyma54. A single-nucleotide polymorphism in MMP-12 has been identified as a protective factor for COPD55. Other proteases that play important roles in COPD are cathapsins S, L (in macrophages), and G, and proteinase-3 (in neutrophils)56. However, subsequent studies have unravelled a more complex pathogenesis in emphysema57.(ii) Immunological mechanismsCOPD is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, most commonly cigarette smoke7. Patients with COPD have been reported to have increased numbers of neutrophils in sputum, lung tissue and bronchoalveolar lavage (BAL)58and neutrophils are important cells in the pathogenesis of COPD. Serum levels of254 INDIAN J MED RES, FEBRuARy 2013immunoglobulin free light chains (IgLC) were found to be increased in smoking-induced COPD59. IgLC were found to bind neutrophils and cross-linking of IgLC on neutrophils results in increased production of IL8/CXCL8 which is a selective attractant of neutrophils. B cells have been found to be increased in COPD and these cells produce IgCL, in addition to IgG and IgA in COPD60. It has also been reported that serum IgE levels are increased in patients with COPD and this may be related to smoking61. Both IgE and IgLC can exert similar proinflammatory effects via neutrophils59. However, the role of immunoglobulins in the pathogenesis of COPD is not understood. (iii) Oxidant-antioxidant balanceAbnormally accumulated inflammatory cells including neutrophils and macrophages and cigarette smoke produce reactive oxygen species which play an important role in the pathogenesis of COPD. Oxidative stress can impair vasodilation and endothelial cell growth. When the oxidant load exceeds the antioxidant capacity of the lung, modification of proteins, lipids, carbohydrates and DNA occurs in the local milieu resulting in tissue injury. Though the oxidants cannot degrade extracellular matrix, these can modify elastin. Modified elastin is then more susceptible to proteolytic cleavage. Cigarette smoke can inactivate histone deacetylase (HDAC2) and this leads to NF-kB-mediated transcription of neutrophil chemokines/cytokines (TNF-α and IL-8) and MMPs. Neutrophil elastase and MMPs overwhelm their respective inhibitors. This can augment the matrix-degrading capacity which can promote emphysema formation46.(iv) Systemic inflammationIn addition to the pulmonary component, COPD has several extrapulmonary manifestations. It has been postulated that persistent pulmonary inflammation may promote the release of pro-inflammatory chemokines and cytokines into the circulation62. These mediators can stimulate liver, adipose tissue and bone marrow to release excessive amounts of leucocytes, C-reactive protein (CRP), interleukin (IL)-6, IL-8, fibrinogen and tumour necrosis factor-α (TNF-α) into the circulation62,63. This may lead to a persistent low-grade systemic inflammation62. Systemic inflammation may initiate or worsen comorbid diseases, such as ischaemic heart disease, heart failure, osteoporosis, normocytic anaemia, lung cancer, depression and diabetes64. Two Danish population studies involving 8656 COPD patients had revealed that simultaneously elevated levels of CRP, fibrinogen, and leukocyte count were associated with a 2- to 4-fold increased risk of major comorbidities (myocardial infarction, heart failure, diabetes, lung cancer and pneumonia) in COPD65. (v) ApoptosisRecent studies have highlighted that apoptosis is involved in the development of COPD and it has been demonstrated that there is an increase in apoptotic alveolar epithelial and endothelial cells in the lungs of COPD patients. Since this is not counterbalanced by an increase in proliferation of these structural cells, the net result is destruction of lung tissue and the development of emphysema. It has been suggested that there is a role for vascular endothelial growth factor (VEGF) in the induction of apoptosis of structural cells in the lung. Other mediators involved in apoptosis are caspase-3 and ceramide51,66-68.(vi) Ineffective repairThere is ineffective repair in emphysema and this is due to the limited ability of the adult lung to repair the damaged alveoli. Studies have shown that treatment of normal rats with all-trans-retinoic acid increases the number of alveoli and this prompted the investigators to study whether a similar effect would occur in rats with emphysema. In experimentally produced emphysema in rats, it has been shown that treatment with all-trans-retinoic acid reversed the changes associated with emphysema. A similar effect in humans is a possibility69. Advances in regenerative medicine and stem cell biology may answer some of these issues.(vii) Endothelial microparticlesPulmonary vascular disease is an important consequence of COPD. Endothelial microparticles (EMPs) which are microvesicles released from apoptotic endothelial cells are increased in smokers with normal spirometry and low diffusing capacity70. The majority of microparticles are angiotensin-converting enzyme positive and this observation suggests that EMPs are of pulmonary vascular origin. EMPs can be a potential biomarker for pulmonary vascular disease associated with COPD. PathophysiologyPathophysiological changes in COPD are due to the pathological changes seen in central airways, small peripheral airways, pulmonary parenchyma and pulmonary vasculature. Mucus hypersecretionVIJAYAN: CHRONIC OBSTRUCTIVE PULMONARY DISEASE255is common in patients with predominant central airway involvement. Chronic obstructive pulmonary disease is characterized by an accelerated decline in FEV171. Airflow limitation in COPD is defined as a postbronchodilator FEV1 (forced expiratory volume in 1 sec) to FVC (forced vital capacity) ratio <0.70, usually without reversibility to bronchodilators. Bronchodilator reversibility and bronchial hyper-reactivity are variable in COPD and, therefore, have limited value in distinguishing COPD from bronchial asthma72. Overall 23 to 42 per cent of patients with COPD have responsiveness to bronchodilators and 59 per cent of men and 85 per cent of women with moderate COPD have airway hyper responsiveness73,74. The severity of airflow limitation in COPD is classified based on post-bronchodilator FEV1value into four groups (GOLD 1, GOLD 2, GOLD 3 and GOLD 4). In patients with FEV1/FVC <70, if FEV1 >80 per cent predicted, they are classified as mild (GOLD 1), if FEV1 predicted < 80 per cent and > 50 per cent as moderate (GOLD 2), if FEV1 predicted <50 per cent and >30 per cent as severe (GOLD 3) and if FEV1 predicted <30 per cent as very severe (GOLD 4) airflow limitation7. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study has shown that the rate of decline in FEV1 over a 3-year period was highly variable76. In this study, the mean rate of change in FEV1 was a decline of 33 ml per year with significant variation and only 38 per cent of patients had an estimated decline in FEV1 of more than 40 ml per year. The rate of decline in FEV1 in this study in more than half of the patients was no greater than that observed in subjects without lung disease suggesting that COPD is not invariably progressive. Current smokers, patients with bronchodilator reversibility, and patients with emphysema had increased rates of decline in FEV175. The ECLIPSE study further observed that Clara cell protein (CC-16) was significantly associated with a greater decline in FEV1 of 4 ± 2 ml per year for each decrease in one standard deviation of the CC-16 level75. Patients with COPD have pulmonary hyperinflation characterized by an increase in functional residual capacity and a decreased inspiratory capacity. Patients with emphysema have low carbon monoxide diffusing capacity. Low arterial oxygen and high carbon dioxide levels are observed in patients with COPD with respiratory failure. Pulmonary arterial hypertension (PAH) develops late in the course of the natural history of patients with COPD. This can be associated with the development of severe hypoxaemia and is a major cardiovascular complication of COPD. Chronic pulmonary hypertension leads to the development of right ventricular hypertrophy and cor pulmonale and has a poor prognosis76. Wells et al77observed that computerised tomography-detected pulmonary artery enlargement defined as a ratio of the diameter of the pulmonary artery to the diameter of the aorta (PA: A ratio of >1) was independently associated with acute exacerbations of COPD77.Co-morbiditiesExtrapulmonary manifestations in COPD, in addition to pulmonary component, are common. It has been observed in the ECLIPSE study that comorbidities were significantly higher in patients with COPD than in smokers and never smokers78. The important comorbidities associated with COPD are cardiovascular disorders (coronary artery disease and chronic heart failure, hypertension), metabolic diseases (diabetes mellitus, metabolic syndrome and obesity), bone disease (osteoporosis and osteopenia), stroke, lung cancer, cachexia, skeletal muscle weakness, anaemia, depression and cognitive decline79. Risk factors such as advancing age, cigarette smoking and environmental pollution are common to both COPD and ischaemic heart disease. The potential mechanisms of increased risk of cardiovascular disease in COPD are systemic inflammation, increased oxidative stress, neurohumoral disturbances and increased thrombotic tendency62. A systematic review of literature had shown that reduced FEV1 nearly doubles the risk for cardiovascular mortality independent of age, sex and cigarette smoking80. It has been reported that a 10 per cent decrease in FEV1 among COPD patients increases the cardiovascular event rate 28 per cent81. COPD patients were 1.76 times more likely to have arrhythmias, 1.61 times more likely to have angina, 1.61 times more likely to develop acute myocardial infarction and 3.84 times more likely to develop congestive heart failure82. There was also an inverse relationship between lung function and ischaemic stroke in subjects who had never smoked83. In a study of 12,04,110 patients aged >35 yr, COPD patients (n=29870) were five times more likely to have a cardiovascular disease compared with those without COPD (n=11,74,240)84. Analysis of data from 20,296 subjects aged ≥45 yr at baseline in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) has revealed that subjects with GOLD stages 3 or 4 COPD had a higher prevalence of diabetes, hypertension and cardiovascular disease85. Lucas-Ramos et al86in a study of 1200 COPD patients and 300 control subjects showed that the COPD group had a significantly higher256 INDIAN J MED RES, FEBRuARy 2013。