COPD-Etiopathogenesis and newer management protocols
Chronic obstructive pulmonary disease (COPD) is a disease characterized by accelerated decline in lung function. Ninety percent of COPD is caused by cigarette smoking; however, only 15% to 20% of chronic tobacco smokers develop COPD, thus implicating additional risk factors in COPD susceptibility. COPD tends to occur more frequently in smokers with family members who have airways obstructive disorders such as asthma and COPD. Thus, there is evidence that accelerated decline in lung function that leads to COPD may be caused by host or genetic factors in a susceptible population of individuals who smoke.
COPD is a complex disorder characterized not only by inflammation but also by tissue remodeling. Remodeling is the net result of tissue destruction and repair. The MMPs and cathepsins are important in tissue destruction and are naturally inhibited by the tissue inhibitor of metalloproteases (TIMP).
It has become clear that the inflammatory process increases in intensity as COPD progresses and does not “burn out” as with many other chronic inflammatory diseases. There is a complex remodeling process in the peripheral lung, resulting in parenchymal destruction (emphysema) and fibrosis of airways (chronic obstructive bronchitis). It is presumed that the inflammatory process leads to these structural changes
COPD pathogenesis can be separated into 4 broad categories: (1) inflammation, (2) age-related changes, (3) genetic associations, and (4) possible therapeutic targets. There is substantial overlap among the categories; however, most of the abstracts fit into the inflammation category.
There is increased inflammation in the bronchial epithelium in smokers with COPD. Smokers without obstruction also had increased numbers of CD4+ cells compared with nonsmokers. CD4+ lymphocytes were increased in the airways of smokers with COPD. Several studies focused on the role of matrix metalloproteases (MMP) in COPD. It is found that the number of airways, type II cells, and macrophages that stained positive for MMP-1 was proportional to severity of emphysema in smokers. Cytokines involved in the inflammatory process of COPD are transforming growth factor-beta (TGF-beta), interferon (IFN)-gamma, stromal cell-derived factor (SDF)-1, urotensin-II, and toll like receptor (TLR)-4.
Aging was also associated with spontaneous changes in the lungs consistent with emphysema. These changes were associated with up regulation of several chemokines (Cxc16, Cxc113, and Cxc19), cell surface receptors (Cd3g, Cd3d and Cd79b), and proteases (MMP12 and MMP9). There were several genetic associations hinting at possible candidate genes that may serve to incite, regulate, or amplify the effects of cigarette smoking-induced airway inflammation.
Candidate genes evaluated for association with the presence or severity of COPD included beta-2 adrenergic receptor, thrombospondin, ADAM33, and TGF-beta. A significant association was found between the Gln27 polymorphism and the presence of COPD in the German population. Risk Factors for COPD
¡ Cigarette Smoking
¡ Exposure to particles
¡ Outdoor air pollution
¡ Genes
¡ Lung Growth and Development
¡ Oxidative stress
¡ Gender
¡ Age
¡ Respiratory infections
¡ Socioeconomic status
¡ Nutrition
¡ Co-morbidities
Systemic Features of COPD
¡ Cachexia: loss of fat free mass
¡ Skeletal muscle wasting: apoptosis, disuse atrophy
¡ Osteoporosis
¡ Depression
¡ Normochromic normocytic anemia
¡ Increased risk of cardiovascular disease
Diagnosis of COPD
Key Indicators for Considering a Diagnosis of COPD
Chronic cough:
¡ Present intermittently or every day, often present throughout the day, seldom only nocturnal.
Chronic sputum production
Any pattern of chronic sputum production may indicate COPD.
Dyspnea
¡ Progressive (worsens over time).
¡ Persistent (present every day).
¡ Worse on exercise.
¡ Worse during respiratory infections.
History of exposure to risk factors
¡ Tobacco smoke.
¡ Occupational dusts and chemicals.
¡ Smoke from cooking.
Physical signs
¡ Not specific to the disease and depend on the degree of air flow limitation and hyperinflation
¡ Tachypnoea, purse lip breathing, weight loss, barrel shaped chest, polyphonic wheezes and crackles
¡ Features of pulmonary hypertension and right heart failure
Management
Goals of effective management
¡ Relieve symptoms
¡ Prevent disease progression
¡ Improve exercise tolerance
¡ Improve health status
¡ Prevent and treat complications
¡ Prevent and treat exacerbations
¡ Reduce mortality
Current therapy for chronic obstructive pulmonary disease (COPD) has improved the management of this difficult disease, but there is still a pressing need for new therapeutic approaches, particularly in reducing the progression and mortality of this disease. COPD has now become a much greater drain on health resources than asthma, and exceeds the healthcare spending on asthma by some three-fold in industrialized countries. Since the prevalence of COPD is predicted to increase throughout the world by the next 20 yrs, these costs will escalate further. There is no doubt that the management of COPD has improved considerably with the introduction of more effective treatments and the use of non-pharmacological interventions, such as pulmonary rehabilitation and noninvasive ventilation (NIV).
Smoking cessation
Cigarette smoking is the major cause of COPD in the world and smoking cessation is the only therapeutic intervention so far shown to reduce disease progression. Nicotine addiction/dependence is the major problem and treatment should be directed at dealing with this addictive state. At present, several forms of nicotine replacement therapy and some antidepressant drugs are used, but the efficacy of these therapies is low. The most effective therapy available is the atypical antidepressant bupropion and a short course is an effective adjunct for smoking cessation in patients with COPD. However, the relatively poor long-term quit rate (16% at 6 months) indicates that more effective approaches are needed. The partial nicotine agonists that target the α4β2 nicotinic acetylcholine receptor, such as varenicline, appear to be promising. Another approach which may have long term benefits is the development of a vaccine against nicotine. The vaccine is designed to stimulate the production of antibodies that bind nicotine so that it cannot enter the brain.
Long-acting bronchodilators
COPD guidelines now recommend the use of long-acting bronchodilators as the mainstay of COPD management. The introduction of the long-acting β2-agonists formoterol and salmeterol and the anticholinergic tiotropium bromide have been important advances in the management of COPD.
The overall approach to managing stable COPD should be characterized by a stepwise increase in the treatment, depending on the severity of the disease. None of the existing medications for COPD has been shown to modify the long-term decline in lung function that is the hallmark of this disease. Therefore, pharmacotherapy for COPD is used to decrease symptoms and/or complications. The choice between beta-2 agonist, anticholinergic, theophylline, or combination therapy depends on availability and individual response in terms of symptom relief and side effects.
Regular treatment with long-acting inhaled bronchodilators is more effective and convenient than treatment with short-acting bronchodilators, but more expensive. Combining bronchodilators may improve efficacy and decrease the risk of side effects compared to increasing the dose of a single bronchodilator. Current evidence supports the use of at least one of the two classes of long-acting inhaled bronchodilators as initial maintenance therapy for symptomatic COPD. In patients who do not respond satisfactorily to tiotropium or LABA as the initially prescribed single maintenance agent, GOLD guidelines recommend the addition of the alternate class of long-acting inhaled bronchodilator as the next step. The choice of agents will depend ultimately on how well the patient responds to a trial of the drug in terms of both efficacy and side effects, and patient preference and cost.
Indacaterol, (Ultra LABA) significantly improved lung function compared to placebo at 12 weeks in three phase III studies. When given once daily, it showed clinically relevant 24-hour bronchodilation and the onset of action was within five minutes. In a 52-week study, it increased lung function compared to twice-daily Formeterol from day one through one year of treatment.
Treatment with tiotropium provides clinical efficacy in patients with GOLD stage II disease with all levels of FEV1. Aclidinium, the new long acting anticholinergic, provided clinically significant bronchodilation and improvements in dyspnoea and may be a valuable new treatment for COPD.
Regular treatment with inhaled glucocorticosteroids is appropriate for symptomatic COPD patients with an FEV1 < 50% predicted (Stage III and Stage IV) and repeated exacerbations e.g. 3 in the last three years. Inhaled glucocorticosteroid combined with a long-acting B2-agonist is more effective than the individual components. Chronic treatment with systemic glucocorticoids should be avoided because of an unfavorable benefit-to-risk ratio.
Long Term Oxygen
The long-term administration of oxygen (> 15 hours per day) to patients with chronic respiratory failure has been shown to increase survival.
Avoidance of risk factors
¡ smoking cessation
¡ reduction of indoor pollution
¡ reduction of occupational exposure
Vaccines
¡ Influenza vaccines
¡ Pneumococcal polysaccharide vaccine
Newer Drugs
PDE4 Inhibitors: Inhibit neutrophil chemotaxis, adhesion, degranulation and release of proteases. They also reduce exacerbations; improve lung function and health status. The promising drugs in this group are Cilomilast and Roflumilast.
N Acetyl Cysteine
N-acetyl cysteine (NAC) provides cysteine for enhanced production of the antioxidant glutathione and has antioxidant effects in vitro and in vivo. A systematic review of studies with oral NAC in COPD suggested a small reduction in exacerbations.
Other Targeted Drugs
¡ Neutrophil elastase inhibitors
¡ Cysteine protease inhibitors
¡ MMP inhibitors
¡ EGFR inhibitors
¡ Endothelin antagonists
¡ PDE- inhibitors
¡ TNFa inhibitors
¡ IL-8 antagonists
¡ Mucoregulators
Exacerbations of respiratory symptoms requiring medical intervention are important clinical events in COPD. The most common causes of an exacerbation are infection of the tracheobronchial tree and air pollution, but the cause of about one-third of severe exacerbations cannot be identified. Inhaled bronchodilators (beta2-agonists and/or anticholinergics), theophylline, and systemic, preferably oral, glucocorticoids are effective for the treatment of COPD exacerbations. Patients experiencing COPD exacerbations with clinical signs of airway infection (e.g., increased volume and change of color of sputum, and/or fever) may benefit from antibiotic treatment. Noninvasive intermittent positive pressure ventilation (NIPPV) in exacerbations improves blood gases and pH, reduces in-hospital mortality, decreases the need for invasive mechanical ventilation and intubation, and decreases the length of hospital stay.
Pulmonary Rehabilitation
The principal goals are to
¡ Reduce symptoms
¡ Improve quality of life
¡ Increase physical and emotional participation in everyday activities
¡ Improves exercise capacity
¡ Reduces the perceived intensity of breathlessness
¡ Improves health-related quality of life
¡ Reduces the number of hospitalizations and days in the hospital
¡ Reduces anxiety and depression associated with COPD
Surgical Options
¡ Bullectomy: When a large unilateral bullae which gradually compresses healthy lung, bullectomy is the best option.This can be done by thoracotomy or through thoracoscopy.
¡ LVRS: When bullous lesions are heterogenous and mainly occupying upper lobes lung volume reduction surgery can be undertaken. This removes mostly diseased part of lung allowing remaining part of lung to inflate adequately. This reduces air trapping and dynamic compression. Three methods are available 1) LVRS by thoracotomy 2) LVRS through VATS and 3) LVRS by endobronchial valves.
¡ Lung Transplantation: Lung transplantation should be offered to patients with diffuse disease who have any of the following
¡ FEV1 <20% predicted
¡ Hypercapnia
¡ Associated pulmonary hypertension
¡ Predicted survival of less than the expected post-transplant survival.
Potential lung transplant recipients must be ambulatory and have a preoperative weight of 70-130% of predicted. Candidates should also be motivated, have adequate social support to deal with the rigorous pre- and post-transplant activities, and have undergone a comprehensive preoperative pulmonary rehabilitation program.
Conclusion
COPD is a disease with progressive deterioration in lung function. There is no effective treatment to revert the pathology, but proper drug selection combined with programmed rehabilitation can improve the quality of life in these patients. For this we need advanced care planning (ACP) and proper implementation of treatment strategy.
