Recent Advances in the Assessment and Management of Chronic Obstructive Pulmonary Disease

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1 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 (FEV 1 ) 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 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 (Karnataka), India; Phone: ; Fax: ; psshankar@hotmail.com.

2 80 Recent Advances in COPD Assessment and Management P.S. Shankar Antiproteolysis 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. 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 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, IL- 5 and IL The differences between COPD and bronchial asthma are presented in table 1. Table 1. Differences between COPD and bronchial asthma Characteristics Asthma COPD Age of onset younger age elderly age Allergic history may be present no such history Smoking generally no heavy smoking Symptoms dyspnoea variable progressive cough may be present present sputum not common excess Airflow limitation episodic progressive Response to treatment Bronchodilators reversible partially reversible Corticosteroids good poor 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

3 2008; Vol. 50 The Indian Journal of Chest Diseases & Allied Sciences 81 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 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 (FEV 1 ) 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 GOLD 2 Stage Manifestations FEV 1 (%) Symptoms 0 at risk 80 - I Mild 80 ± II Moderate III Severe IV Very severe < The disease begins with an asymptomatic phase in which lung function deteriorates. The onset of subsequent symptom phase is variable, but often does

4 82 Recent Advances in COPD Assessment and Management P.S. Shankar not occur until FEV 1 falls to nearly 50% of the predicted values. 19 It is intriguing that only 18.5% of the patients progress to more severe airflow limitation at 15 years. 20 Thus, it is difficult to predict which patient belonging to stage 0 make a progress to an advanced disease. When the patients are symptomatic, there is a substantial decline in airflow. They exhibit hyperinflation. It occurs at rest and gets worsened with exercise. This is noted in patients with moderate-to-severe COPD. There is an increase in the functional residual capacity (FRC), placing the respiratory muscles at a mechanical disadvantage. It increases the work of breathing and reduces exercise tolerance. The patients exhibit other physiological abnormalities that include a reduction in diffusing capacity for carbon monoxide, hypoxaemia and alveolar hypoventilation. Though FEV 1 does not consistently predict disability or mortality among COPD patients, it helps in guiding therapy. 21 Spirometry is to be performed in all patients at risk to find out asymptomatic airflow limitation. It is advocated to perform spirometry annually in patients with established disease, as it helps in the assessment of clinical status and response to therapy. Inspiratory capacity (IC) is a surrogate for lung hyperinflation that is easily obtained through spirometry. The ratio of inspiratory capacity to total lung capacity helps in accurate assessment of COPD than FEV 1. It is likely to reflect the functional response and improvement of symptoms and exercise tolerance induced by bronchodilators in COPD. 22 The patients become symptomatic only after substantial reduction of lung functions. An airflow limitation in COPD is characterised by an FEV 1 value less than 80% of the predicted and a FEV 1 /FVC ratio of less than Often it is considered that there is limitation to evaluate severity of COPD based on lung function. Traditional measurement of lung functions does not evaluate the systemic effects of COPD. There is a constant search to find newer markers to assess the disease. A multi-dimensional grading system, the BODE index (Body mass index, degree of airflow obstruction, a modified MRC dyspnoea scale, and exercise capacity based on 6-minute walking test) appears to predict better than FEV 1 of the risk of hospitalisation and death among patients with COPD. 23 The sum of components provides a score from 0 to 10. The index is widely applicable, simple and requires no special equipment. Increase in serum C-reactive protein in COPD is related to the presence of co-morbidities. It decreases following administration of steroids. 24 Risk Factors Tobacco smoking, both active and passive, forms the most important risk factor for COPD. It acts through the generation of oxidative stress and/or reduction of antioxidant capacity. Not all smokers develop COPD, suggesting that genetic factors may be involved. Indoor air pollution is another risk factor. It includes emission from combustion-generated products, such as biomass fuels and fossil fuels used for cooking and heating, exposure to biomass pollution from firewood and smoke from burning cow-dung cakes, haystacks, woodchips, crop residues and agricultural wastes in illventilated kitchen, and exposure to occupational dusts and chemicals. Alpha-1 antitrypsin deficiency (PiZZ) is a well documented genetic risk factor, and the condition makes an early onset, usually younger than 40 years. Treatment of Patients with Stable COPD The deterioration of lung function, and progressive downhill course of COPD should be prevented by smoking cessation, by control of atmospheric pollution, and by treatment mainly directed to reduce airway obstruction and its physiologic consequences. The goals of therapy for COPD are to prevent disease progression, to relieve symptoms, improve health status, prevent and treat complications and exacerbations, reduce morbidity and prevent or minimise adverse effects from treatment. 18 Though COPD is predominantly a disorder of respiratory system, it produces significant systemic consequences. Existing therapies for COPD are grossly inadequate. None has been shown to slow the relentless progression of the disease. The drugs and supplemental therapies are used in a step-wise manner as the disease progresses. Smoking Cessation All patients with COPD regardless of severity should stop smoking or remain abstinent. The former is advocated for active smokers and the latter for former smokers. All persons regardless of smoking status show a decline in FEV 1, starting around 30 years of age. It exhibits an accelerated decline in patients with COPD. The normal rate of approximately 30 ml per year becomes nearly 60 ml per year. 25 Thus, the patients with COPD who continues to smoke loses lung function twice the rate of a non-smoker. Following quitting smoking the decline in lung function slows and returns to about the rate of decline of a non-smoker. Smoking cessation is the single most important intervention to slow the rate of decline in lung function. 26 Step-wise Treatment It has been recommended to manage patients of COPD in a step-wise manner by addition of medication (bronchodilators) with increasing severity and worsening of symptoms. 2 Inhaled Bronchodilators Inhaled bronchodilators form the cornerstone of pharmacotherapy for COPD patients. These agents help in relief of symptoms, decrease exacerbations of disease,

5 2008; Vol. 50 The Indian Journal of Chest Diseases & Allied Sciences 83 improvement in airflow and hyperinflation, thus a decrease in the work of breathing and improved exercise tolerance and improved quality of life. Such a therapy is also recommended for patients with intermittent symptoms. It must be noted that symptomatic improvement is not always reflected by changes in FEV 1 and FVC. The drug administered through aerosol gets retained in the airway and causes bronchodilatation and it is not dependent on its plasma levels. Inhaled bronchodilators are grouped into two types (short-acting and long-acting) based on the mechanism or duration of action. Patients with stage I COPD may not exhibit any respiratory symptoms. However, when respiratory symptoms are present, short-acting bronchodilators (salbutamol and ipratropium) are to be prescribed to reduce symptoms and to improve exercise tolerance. It must be noted that the agents do not modify the clinical course, the rate of decline in pulmonary function or survival in patients with COPD. 27 Patients with stage II (moderate COPD), stage III (severe COPD) and stage IV (very severe COPD) disease are to be prescribed longacting bronchodilators. Short-acting bronchodilators (SABA). Selective beta-adrenergic receptor agonists combine with beta-2 receptors on bronchial smooth muscle to increase production of cyclic adenosine monophosphate (camp) and cause bronchodilatation. Anti-cholinergics compete with acetylcholine for the muscarine receptors in the smooth muscle of the bronchial passages and mucus glands. Salbutamol (Beta-2 agonist) and ipratropium (anticholinergic agent) are equally effective bronchodilators and can be used interchangeably in the treatment of mild disease as the first step. 26 The effect of short-acting β 2 -agonists is felt immediately (<10 minutes) after inhalation, reach at peak in 30 to 60 minutes and disappears in 4-6 hours. Two puffs of salbutamol (each puff of 90 micrograms) have to be taken through a metered dose inhaler (MDI) every four hours. Ipratropium is as effective as β 2 - agonists in patients with stable COPD. It has a slower onset of action taking minutes to cause bronchodilation but the maximal effect is noted two hours after its administration. The total duration of action is for four to six hours. Two puffs (each puff of 18 micrograms) has to be taken through MDI every four hours. It is topically active and there is no significant absorption from the oropharynx and airways. Salbutamol can be administered orally in a dose of 2-4 mg three or four times a day in patients who cannot take the drug by aerosol route. Other oral preparations are orciprenaline (10-20 mg) and terbutaline ( mg). The oral preparations on administration show their effect in 15 to 30 minutes, reaching a peak in one to three hours. The dose used in oral preparations is much higher than that used in aerosol. The bronchodilator effect depends on the plasma concentration achieved. Unlike aerosol which produces dilatation of central airways preferentially, the oral preparation causes dilatation of central and peripheral airways. Long-acting bronchodilators (LABA). Patients with stage II, III and IV COPD are to be given one or more long-acting bronchodilators regularly to produce optimal effect, in addition to the short-acting bronchodilators. There is no difference in action between longacting anticholinergic agent (tiotropium bromide) and β 2 -agonist (formotereol fumarate, and salmeterol ximafoate). 28 The duration of action of tiotropium is less than 24 hours with one inhalation of 18 micrograms given through dry powder inhaler (DPI). The duration of action of formotereol lasts 8 to 12 hours with two puffs (each with a dose of 12 micrograms) given twice a day through DPI. Salmeterol has also similar duration of action with two puffs of 90 micrograms given twice a day through DPI. The combination of a short-acting anticholinergic with a long-acting β-agonist or the combination of a long-acting anticholinergic with a short- or long-acting β-agonist appear to improve lung functions and it may be used for patients in whom a single inhaled bronchodilator has failed to provide adequate relief of symptoms. 29 A combination of bronchodilators with different mechanisms of action will give greater bronchodilatation than either drug administered singly. One of the widely used combination schedules for treatment of COPD is a short-acting anticholinergic (ipratropium) plus a short-acting β-agonist (salbutamol, SABA). However, ipratropium bromide can be used as long-term maintenance therapy for patients having COPD. Its use is associated with significant improvements in FEV 1 and FVC from baseline. It has to be administered four times a day, as it has a shortduration of action of four to six hours. A long-acting oral, beta adrenergic agonist, bambuterol may be given orally in a dose of mg a day. The duration of its action lasts for 24 hours. Long-acting β 2 -agonists improve health-related quality of life but not the mortality. Tiotropium bromide administered as a single daily dose of 18 mcg has exhibited greater mean change in FEV 1 and relief in symptoms for 24 hours compared with patients receiving ipratropium. 30 A meta-analysis involving 3574 patients with moderate-to-severe COPD has shown that tiotropium bromide reduces acute exacerbations compared with either placebo or ipratropium. 29,30 Another analysis of two randomised, double-blind, placebo-controlled trials of one year and six months duration in 921 and 623 patients respectively has shown a significantly greater FEV 1 response at trough (FEV 1 found immediately prior to the next scheduled dose of bronchodilator) of significantly less dyspnoea compared with those receiving placebo Long-acting inhaled bronchodilators are not suitable

6 84 Recent Advances in COPD Assessment and Management P.S. Shankar for the treatment of acute symptoms. Therefore, shortacting bronchodilators are indicated for relief of acute symptoms. The residual airway patency is essentially controlled by parasympathetic innervation of the smooth muscles surrounding bronchioles and by the secretion of the broncho-constricting mediators. Acetylcholine released from the peribronchial ganglion cells of the vagus nerve, interacts with three muscarine cholinergic receptors on the airways and mucus-secreting glands. There is constriction of airway smooth muscles and increased secretion from the glands, resulting in narrowed caliber of the airway. The negative feedback mechanism protects the lung from excessive bronchoconstriction. A greater amount of secretion of acetylcholine results in activation of M2 muscarine receptors, causing an inhibition of further release of acetylcholine. An ideal agent that prevents acetylcholine-induced bronchoconstriction should be able to interrupt the mechanism by blocking in M3 receptors found in the airways of patients with COPD. 29 All studies have shown a decreased frequency of exacerbation of COPD while on tiotropium. The longacting β 2 -agonists (formotereol and salmeterol) when administered twice a day have shown improvements in pulmonary functions in patients with COPD. 35 Methyl xanthines. Methyl xanthine derivatives are moderately powerful bronchodilators. Theophylline, given orally in a dose of mg a day, reduces dyspnoea in some patients by improving contractility and endurance of fatigued diaphragm in a setting of hypoxaemia and myocardial contractility. Theophylline can be added to inhaled bronchodilator therapy to obtain additional improvement in lung functions and symptomatology. Theophylline has significant antiinflammatory effects in COPD at lower plasma concentrations. It activates histone deacetylases which in turn enhances the anti-inflammatory effect of corticosteroids. 36 Phosphodiesterase-4 inhibitors. Phosphodiesterases (PDEs) are intracellular enzymes that inactivate camp. Methyl xanthines are non-selective phosphodiesterase inhibitors. The PDE-4 sub type is the predominant isoenzyme found in inflammatory cells and it specifically targets camp. Cilomilast, a selective PDE-4 inhibitor, administered in a dose of 15 mg twice a day is capable of reducing the inflammatory process in COPD patients, maintain pulmonary functions and reduce the rate of exacerbations. 37, 38 In patients with moderate-tosevere COPD, long-term treatment with 250 µg µg of roflumilast administered orally appears to improve FEV 1, pulmonary functions and reduce the rate of mild exacerbations. 39 However, these agents have a limited therapeutic ratio. Inhaled Corticosteroids Inhaled corticosteroids (ICSs) do not appear to bring about substantial changes in airway inflammation in COPD. Use of inhaled corticosteroids in the treatment of COPD is controversial. Many clinical trials (doubleblind, randomised, placebo-controlled, single/multicentre studies) have been conducted to provide evidence-based clinical data about the usefulness and efficacy of ICS in the management of COPD patients The patients receiving budesonide in The European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOPE) study 40 demonstrated improvement in FEV 1 at the rate of 12 ml per year in the first six months of therapy and it was not sustained later. In the Lung-Heart Study II, 42 though there was no significant difference in mean declines in FEV 1 for the triamcinolone and placebo groups, patients with severity COPD showed a modest improvement in dyspnoea and the onset of severe symptoms. Further, the steroid group had an increased risk for the development of osteoporosis. 44 In the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study, 43 though there was no significant difference in FEV 1 between steroid and placebo group, there was a 100 ml increase in FEV 1 after three to six months of therapy and it was maintained over the three-year period, and exhibited decreased rate of exacerbations. The meta-analysis of six randomised, double-blind, placebo-controlled trials that assessed the long-term effects of inhaled corticosteroids on patents with COPD have shown that inhaled corticosteroids did not have significant effect on FEV A trial of high-dose inhaled corticosteroids can be used in those patients of COPD who remain symptomatic and continue to have frequent exacerbations despite maximal bronchodilatation with inhaled bronchodilators. During acute exacerbations of COPD, systemic corticosteroids may be administered for a short period of time. Prednisolone may be given in a dose of 30 to 40 mg daily for days along with bronchodilator. However, this view has not found support from the GOLD consensus workshop. 2 Inhaled corticosteroids can be recommended for patients with moderate-to-severe airflow limitation who have persistent symptoms despite optimal bronchodilator therapy as they appear to provide some clinical benefit to COPD patients. Combination of inhaled corticosteroids (fluticasone, budesonide) and longacting beta-agonists (salmeterol, formotereol) has shown to be superior to either drug alone with regard to lung function and frequency of exacerbations. 45, 46 The treatment should not be persisted if there is no substantial clinical or physiological improvement. It is advisable to assess the spirometric response to a trial of oral corticosteroids in order to identify patients who respond to inhaled corticosteroids. 46 Though it helps in detection of co-existent asthma, it is a poor predictor of the response to inhaled corticosteroids among patients with COPD. Oral corticosteroids are not advocated in the routine management of stable COPD.

7 2008; Vol. 50 The Indian Journal of Chest Diseases & Allied Sciences 85 GOLD states that regular treatment with ICS alone or in combination with inhaled long-acting beta-agonists should be prescribed only to patients with severe COPD (FEV 1 <50% of the predicted) and repeated exacerbations requiring treatment with antibiotics and/ or oral corticosteroids. 2 An inhaled corticosteroid (fluticasone propionate) plus a long-acting beta-agonist 45, 46 (salmeterol) is a frequently prescribed combination. Calverley and colleagues for the Towards a Revolution in COPD Health ( TORCH ) 47, conducted a randomised, double-blind, placebo-controlled trial involving 6112 patients of COPD in 444 centres in 42 countries, comparing salmeterol at a dose of 50 mg plus fluticasone proprionate at a dose of 500 mg twice daily as a combination regimen administered with a single inhaler, with placebo, salmeterol alone or fluticasone proprionate alone over a period of three years. There were 875 deaths within three years after the start of the study treatment. The proportion of deaths from any cause at three years were 12.6% in the combination therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group and 16.0% in the fluticasone group. The absolute risk reduction for death in the combination therapy group as compared with the placebo group was 2.6 percent. The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo. As compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values for all comparison with placebo. The combination therapy though shows symptomatic and functional improvement, it may not have any effect on survival. Pneumonia was noted as an adverse event among patients receiving medications containing fluticasone propionate. Antibiotics Antibiotics are to be given during infective exacerbations. Quite often, patients show improvement on empiric therapy for 10 days with amoxicillin, doxycyclin, or trimethoprime-sulphamethoxazole. Prophylactic therapy with antibiotics, however, does not prevent the occurrence of infection. New Drugs Mediator antagonists. A variety of inflammatory mediators participate in the chronic inflammation and structural alterations noted in COPD. As neutrophils are the predominant cells involved in the inflammatory process of COPD, the treatment strategy is to antagonise the mediators involved in recruitment and activation of neutrophils. The inflammatory cells play a dominant role in airway and lung damage in patients with COPD. The inflammatory process causes airflow limitation in the small airways and surrounding parenchyma of the lung. However, in the presence of a multitude of mediators blocking a single mediator may not be able to exhibit clinical benefit. Tumour-necrosis factor takes part in the pathogenesis of COPD. Its amount is raised both in the sputum and in circulation. Infliximab, a chimeric monoclonal antibody that neutralises the biologic activities of TNF-α has been used in patients with COPD. However, it has failed to produce clinically beneficial effects in patients with mild-to-moderate COPD. 48 Long-term administration may induce development of blocking antibodies. Tumour-necrosis factor-α converting enzyme (TACE) is necessary for the release of soluble TNF-α. An agent that acts as TACE inhibitor may be useful in lowering the level of TNF-α. 49 Antioxidants. There is an increased oxidative stress in COPD patients which is more evident during acute exacerbations. As the reactive oxygen species are responsible for such a complication, antioxidants are likely to counter the effects. N-acetyl cysteine provides cysteine for an increased production of glutathione, which has an antioxidant effect. 50 N-acetyl cysteine is able to reduce exacerbations to some extent. Retinoic acid. Animal experiments have shown retinoic acid induces alveolar regeneration. Retinoids are being tried in patients with emphysema with a hope that alveolar regeneration may help in repair of emphysematous lesions in humans. 51 Extrapulmonary Effects Weight loss and skeletal muscle dysfunction limit the exercise capacity of patients with COPD. There appears improvement in prognosis in patients with COPD if they regain their body weight. No specific therapy has been formulated as the pathogenesis of the systemic effects of COPD has not yet well understood. Physical rehabilitation and domiciliary oxygen therapy is advocated to overcome sedentary life and tissue hypoxia. A low dose of inhaled steroids is potentially beneficial due to its anti-inflammatory effect. 52 Nutritional supplementation is necessary. Supplemental Therapy Pulmonary rehabilitation. Patients with moderate-tovery severe COPD are likely to benefit by participating in a pulmonary rehabilitation programme. These programmes consisting of chest physical therapy, breathing retraining, energy conservation, adequate nutrition, respiratory muscle training, improve health status, quality of life, reduces dyspnoea and exercise tolerance. It is appropriate for the patients with clinically significant exertional dyspnoea. The patients are instructed to breathe-in through their nose and breath-out twice as long as they breathin. The lips should be kept firmly together except the centre. While exhaling air, it should be blown-out slowly in a firm steady stream through the centre of lips.

8 86 Recent Advances in COPD Assessment and Management P.S. Shankar Among exercises, diaphragmatic breathing and pursedlip breathing are commonly employed. Breathing exercises increase the strength and co-ordination of breathing muscle. Deep breathing helps in opening poorly ventilated areas. The diaphragm and abdominal muscles should play an active part. They allow the abdomen to protrude during inspiration causing a greater descent of the diaphragm. After deep inspiration, the patient has to exhale slowly to prevent collapse of airways. Supplemental oxygen. Supplemental oxygen is beneficial for survival in COPD patients, especially during acute hypoxic exacerbations. Hypoxaemia develops as a result of a worsening ventilationperfusion inequality. An arterial oxygen tension (PaO 2 ) of 60 mm Hg without respiratory acidosis can be achieved with low fractional inspired oxygen concentration. Nasal supplementation with two litres oxygen per minute will help in attaining adequate arterial oxygenation. The patients with severe COPD having FEV 1 of less than 30% of predicted value are to be screened for the need for supplemental oxygen. The survival benefit is obtained only with the use of supplemental oxygen for more than 15 to 18 hours per day. The qualifying criteria to initiate home oxygen therapy include at least one of the given in table 3. Tablel 3. Criteria to initiate oxygen therapy at home Resting pulse oximetry of 88% or less Exercise pulse oximetry that falls by at least 4% and is 88% or less resting Partial pressure of arterial oxygen (PaO 2 ) of less than 55 mmhg or lower or resting PaO 2 of less than 60 mmhg with evidence of pulmonary hypertension Peripheral oedema (suggesting congestive heart failure) or polycythaemia (with a haematocrit value greater than 55%) Supplemental oxygen should be adjusted to maintain an oxygen saturation of at least 90% at all times. Pulse oximetry and oxygen titration should be performed at rest, on exertion and during sleep. In advanced disease, there is occurrence of hypoxaemia and hypercapnia. The latter occurs from hypoventilation, increased dead-space ventilation, and increased work of breathing with enhanced production of carbon dioxide. Ventilation-perfusion mismatch and alveolar hypoventilation aggravate hypoxaemia. Some patients with alveolar hypoventilation are benefited by inhaled bronchodilators as these help in reducing the work of breathing and improve gas exchange. Noninvasive positive-pressure ventilation, in addition to supplemental oxygen, may show improvement in dyspnoea and quality of life. But the improvement in arterial carbon dioxide levels is quite small. 53 Heliox Exertional dyspnoea leads to reduction in daily activities. Reduction of dyspnoea forms an important therapeutic intervention especially in patients with more severe COPD. Physical training and ambulatory oxygen therapy help in reducing exertional dyspnoea. Effects of helium and oxygen (heliox) mixture has been tried to determine its effects on exercise capacity in severe COPD. 54 Nitrogen in inspired air is replaced with lower density helium. It reduces turbulent flow of resistance in the airway leading to improved ventilation and gas exchange. Reducing inspired gas density can improve exercise performance in COPD as much as increasing inspired oxygen. The effects can be combined as Heliox28 (72% helium/28% oxygen) to get benefit in patients with more severe airflow obstruction. 56 Heliox mixture is recommended as an adjunct to pulmonary rehabilitation programme with severe COPD who are still disabled by dyspnoea and are unable to achieve full benefits of training despite pharmacologic treatment and ambulatory oxygen therapy. 55 Surgery Lung Volume Reduction Surgery (LVRS) Patients with very severe COPD may benefit from surgical intervention that involves removal of the most damaged areas of the lung. Lung volume reduction surgery reduces hyperinflation, and it should be considered in patients with severe upper-lobe emphysema and reduced exercise-tolerance despite improvement with medical therapy alone. Three clinical trials involving 1321 patients have shown that LVRS improves health-related quality of life and exercise capacity in patients who have an FEV 1 of less than 30% of the predicted. 56 Lung Transplantation Single-lung transplantation is used as a potential surgical intervention for patients with very severe COPD who do not have significant co-morbid conditions. It does not prolong life, but has the potentiality for significant improvment in the quality of life in patients of COPD who exhibit an extremely limited functional status due to dyspnoea with minimal exertion. Lung transplantation can be considered for patients with end-stage emphysema who have an FEV 1 of less than 25% of the predicted value after a bronchodilator, and who have complications such as pulmonary hypertension, marked hypoxaemia, and hypercapnia. 57 The lung implanted in COPD patients is smaller than the larger diseased lung. Following transplantation, the over-inflated chest cavity decreases in size as air-trapping does not exist. CONCLUSIONS The understanding of the pathogenesis and

9 2008; Vol. 50 The Indian Journal of Chest Diseases & Allied Sciences 87 pathophysiology of chronic obstructive pulmonary disease (COPD) have presented a number of novel therapeutic opportunities. The management guidelines include assessment and monitoring of the disease, reduction of risk factors and treatment of patients with stable COPD and with those exhibiting infective exacerbations. The diagnosis, though suggested by symptoms, is to be confirmed by spirometry. The airflow limitation is not fully reversible. The severity of the disease is based on the measurements of airflow limitation during forced expiration. The deterioration of lung functions, and progressive downhill course of COPD should be prevented by smoking cessation, by controlling atmospheric pollution, and by treatment directed to reduce airway obstruction and reduction of its pathologic consequences. The drugs are administered in a step-wise manner. Beta-2 adrenergic receptor agonists and anti-cholinergic drugs are the mainstay of the therapy for many patients of COPD. Both short-acting and long-acting preparations are used. The future treatment of patients of COPD involves more extensive use of combination of short- and long-acting bronchodilators. Methyl xanthine and cilomilast are other agents used in its management. Inhaled corticosteroids are to be used in selected patients. Antibiotics and oxygen therapy are necessary in the management of acute exacerbations of COPD. In hypoxaemic patients with stable chronic COPD, longterm oxygen therapy improves neuropsychiatric functions and reduces mortality. These patients need pulmonary rehabilitation to return to the highest possible functional capacity. Lung-volume reduction surgery and the lung transplantation are the two surgical procedures available for selected cases. There are no current therapies that reduce the inevitable progression of COPD. 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