Emphysema Treatment & Management
- Author: Kamran Boka, MD, MS; Chief Editor: Zab Mosenifar, MD, FACP, FCCP more...
Once the diagnosis of chronic obstructive pulmonary disease (COPD) is established, the patient should be educated about the disease and should be encouraged to participate actively in therapy. The goal of therapy is to relieve symptoms, prevent disease progression, improve exercise tolerance and health status, prevent and treat complications and exacerbations, and reduce mortality. Treatments should be added in a stepwise fashion to reach these goals.
Smoking cessation is the single most effective therapy for most COPD patients. Studies have shown that a less than 10-minute discussion by a physician can motivate a patient to quit smoking. A smoking cessation plan is an essential part of a comprehensive treatment plan. Although many believe that the success rates for smoking cessation are low because of the addictive potential of nicotine, it is the conditioned response to smoking-associated stimuli, including oral fixation, habit, psychosocial stressors, and forceful promotional campaigns by the tobacco industry, which are more dominant players. The process of smoking cessation must involve multiple interventions. Quitting "cold turkey" has been shown to have the greatest success rate over all other quitting aids.
The transition from smoking to nonsmoking status involves 5 stages. These stages are (1) precontemplation, (2) contemplation, (3) preparation, (4) action, and (5) maintenance. Smoking intervention programs include self-help, group, physician-delivered, workplace, and community programs. Setting a target date to quit may be helpful. Physicians and other health care providers should participate in setting the target date and should follow up with respect to maintenance. Successful cessation programs usually use the following resources and tools:
A target date to quit
Advice for healthy lifestyle changes
Social support systems
Adjuncts to treatment (ie, pharmacological agents)
According to the US Preventive Services Task Force guidelines, clinicians should ask all adults about the use of tobacco products and provide cessation interventions to current users. The guideline engages a “5-A” approach to counseling that includes the following:
Ask about tobacco use.
Advise to quit through personalized messages.
Assess willingness to quit.
Assist with quitting.
Arrange follow-up care and support.
The task force also advises clinicians to ask all pregnant women, regardless of age, about tobacco use. Those who currently smoke should receive pregnancy-tailored counseling supplemented with self-help materials. Brief behavioral counseling and pharmacotherapy are each effective alone, although they are most beneficial when used together.
Supervised use of pharmacologic agents is an important adjunct to self-help and group smoking cessation programs. Nicotine is the ingredient in cigarettes primarily responsible for the addiction of smoking. Withdrawal from nicotine may cause unpleasant adverse effects (ie, anxiety, irritability, difficulty concentrating, anger, fatigue, drowsiness, depression, and sleep disruption). These effects usually occur during the first weeks after quitting smoking. Nicotine replacement therapies after smoking cessation reduce withdrawal symptoms. A person who smokes and who requires the first cigarette within 30 minutes of waking is likely to be highly addicted and would benefit from nicotine replacement therapy. Several nicotine replacement therapies are available.
Nicotine polacrilex is a chewing gum and produces improved quit rates compared to counseling alone. Transdermal nicotine patches are readily available for replacement therapy. Long-term success rates have been 22-42%, compared with 2-25% with placebos. These agents are well tolerated, and the adverse effects are limited to localized skin reactions. The use of an antidepressant medication, bupropion at 150 mg bid has been shown to be effective for smoking cessation and may be used in combination with nicotine replacement therapy.
The most recent drug to receive approval for smoking cessation is varenicline. Varenicline is a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. Its mechanism of action is believed to be binding the nicotinic subtype receptor, producing agonist activity while simultaneously preventing nicotine binding. Varenicline's agonistic activity is significantly lower than nicotine's.
Pharmacologic therapy for emphysema
Bronchodilators are the backbone of any COPD treatment regimen. They work by dilating airways and thereby decreasing airflow resistance. This increases airflow and decreases dynamic hyperinflation. Lack of response of pulmonary function testing should not preclude their use. These drugs provide symptomatic relief but do not alter disease progression or decrease mortality.
The 2 classes of short-acting bronchodilators are beta2-agonists and anticholinergic agents. Beta2-agonists stimulate beta2-adrenergic receptors, increasing cyclic adenosine monophosphate (cAMP) and resulting in bronchodilation. The inhaled route is preferred because it minimizes adverse systemic effects. The adverse effects are predictable and include tachycardia and tremors. Although rare, they may also precipitate a cardiac arrhythmia. Anticholinergic agents block M2 and M3 cholinergic receptors and result in bronchodilation. These agents are poorly absorbed systemically and are relatively safe. Reported adverse effects include dry mouth, metallic taste, and prostatic symptoms.
The initial choice of agent remains in debate. Historically, beta2 agonists were considered first line and anticholinergics added as adjuncts. Not surprisingly, studies have shown combination therapy results in greater bronchodilator response and provides greater relief. Monotherapy with either agent and combination therapy with both are acceptable options. The adverse effect profile may help guide therapy.
If short-acting agents do not provide sufficient relief, patients should be placed on a long-acting bronchodilator. Like the short-acting agents, the choices include long-acting beta agonists or long-acting muscarinic agents. In general, neither agent is preferred over the other. Oral phosphodiesterase inhibitors such as theophylline also provide long-acting bronchodilation, although their use is currently limited.
Long-acting beta-agonists include salmeterol, formoterol, arformoterol, and indacaterol. They all require twice-daily dosing, except for indacaterol, which is administered once daily. Multiple studies have demonstrated the benefit and safety of long-acting beta-agonists. The 2007 Toward a Revolution in COPD Health (TORCH) trial studied salmeterol with and without fluticasone versus placebo over a three-year period. It demonstrated decreased exacerbation rates, improved lung function, and improved quality of life. The TORCH trial showed a trend towards mortality benefit of combination therapy with salmeterol plus fluticasone.
Tiotropium was introduced in 2004 and is the only available long-acting muscarinic agent at this time. Tiotropium has been shown to provide 24-hour bronchodilation and is hence dosed once daily. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial studied the effects of use over a 4-year period. The UPLIFT trial showed improvements in lung function, quality of life, and exacerbations, but it did not show a decrease in the rate of decline of lung function.
Evidence is mounting on the efficacy of tiotropium over long-acting beta-agonists. Two large randomized trials have compared tiotropium, salmeterol, and placebo.[28, 29] Both studies showed greater improvement in lung function, dyspnea, and quality of life in the tiotropium group versus the salmeterol group. The study by Brusasco et al also showed a delay in first exacerbations and fewer exacerbations per year in the tiotropium group.
Phosphodiesterase (PDE) inhibitors increase intracellular cAMP and result in bronchodilation. Theophylline is a nonspecific phosphodiesterase inhibitor and is now limited to use as an adjunctive agent. Theophylline has a narrow therapeutic window, with significant adverse cardiac effects. It is reserved for patients with hard-to-control COPD or for individuals who are not able to use inhaled agents effectively. Roflumilast and cilomilast are second-generation, selective PDE-4 inhibitors. They cause a reduction of the inflammatory process (macrophages and CD8+ lymphocytes) in patients with COPD. Twice-daily dosing has been found to be clinically effective. An FDA advisory panel rejected approval of cilomilast in 2002.
Roflumilast was approved by the FDA in 2011 as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. To analyze the impact of roflumilast on the incidence of COPD exacerbations requiring corticosteroids, Calverley et al performed 2 randomized, double-blind, placebo-controlled multicenter trials. Patients with COPD were randomly assigned to receive roflumilast once daily or placebo for 52 weeks. Both studies revealed increased FEV1 levels in patients who received roflumilast, as compared with patients who received placebo (P < 0.0001). In addition, the rate of COPD exacerbations was reduced by 17% in patients who received roflumilast (P < 0.0003).
Inflammation plays a significant role in the pathogenesis of COPD. Oral and inhaled corticosteroids attempt to temper this inflammation and positively alter the course of disease. The use of oral steroids in the treatment of acute exacerbations is widely accepted and recommended, given their high efficacy. On the other hand, use of oral steroids in the management of stable chronic COPD is not recommended, given their adverse effects. Inhaled corticosteroids, similar to other inhaled agents, are only minimally absorbed and therefore systemic adverse effects are limited. Nonsteroidal antiinflammatory drugs such as cromolyn and nedocromil have not been shown to be efficacious in the treatment of COPD.
Inhaled corticosteroids are widely used in COPD patients despite limited evidence of benefit. Despite the theoretical benefit, the current consensus is that inhaled corticosteroids do not decrease the decline in FEV1. They have, however, been shown to decrease the frequency of exacerbations and improve quality of life for symptomatic patients with an forced expiratory volume in 1 second (FEV1) of less than 50%. Inhaled corticosteroids are not recommended as monotherapy and should be added to a regimen that already includes a long-acting bronchodilator.
Oral steroids have been widely used in the treatment of acute exacerbation of COPD. A meta-analysis concluded that oral or parenteral corticosteroids (1) significantly reduced treatment failure and need for additional medical treatment and (2) increased the rate of improvement in lung function and dyspnea over the first 72 hours. The use of oral steroids in persons with chronic stable COPD is widely discouraged given the adverse effect profile, which includes hypertension, glucose intolerance, osteoporosis, fractures, and cataracts, among others. A Cochrane review showed no benefit at low-dose therapy and short-lived benefit with higher doses (>30 mg of prednisolone).
Debate continues regarding use of inhaled corticosteroids and the risk for pneumonia in patients with COPD. Sin et al analyzed data from 7 large clinical trials (n = 7042) of patients with stable COPD who used inhaled budesonide (n = 3801) or a control regimen (placebo or formoterol alone). No significant difference was recorded for pneumonia occurrence between the budesonide group (3%; n = 122) and the control group (3%; n = 103). Increasing age and decreasing percent of predicted FEV1 were the only variables that were significantly associated with pneumonia occurrence.
In patients with COPD, chronic infection or colonization of the lower airways with S pneumoniae, H influenzae, and/or Moraxella catarrhalis is common. Patients with severe disease have a higher prevalence of Gram-negative organisms such as Pseudomonas. The use of antibiotics for the treatment of acute exacerbations is well supported. The patients who benefited most from antibiotic therapy were those with exacerbations that were characterized by at least 2 of the following: increases in dyspnea, sputum production, and sputum purulence (The Winnipeg criteria). No evidence supports the continuous or prophylactic use of antibiotics to prevent exacerbations.
Viscous lung secretions in patients with COPD consist of mucus-derived glycoproteins and leukocyte-derived DNA. Mucolytic agents reduce sputum viscosity and improve secretion clearance. Although mucolytic agents have been shown to decrease cough and chest discomfort, they have not been shown to improve dyspnea or lung function.
However, in 2009-2010, Chinese investigators designed and implemented a prospective, randomized, double-blind placebo-controlled trial, studying the effects of long-term oral N-acetylcysteine at 600 mg twice daily in subjects with GOLD stage I COPD. They found long-term use (over a year and a half) can actually prevent exacerbations in moderate disease. Interesting enough, exacerbations of COPD were the most significant adverse effect of the trial. The study was published in The Lancet in March of 2014.
Proton pump inhibitors
Sasaki et al conducted a randomized, observer-blind, controlled trial to determine if proton pump inhibitors (PPIs) reduce the incidence of common colds in patients with COPD. Patients (n = 100) were assigned to conventional therapy (control group) or conventional therapy plus PPI (lansoprazole 15 mg/d). The frequency of common colds and COPD exacerbations was measured, and the number of exacerbations per person over 12 months was significantly lower in the PPI group compared with the control group (P < .001). No significant difference in the numbers of common colds was observed between the PPI group and the control group. The authors concluded that although lansoprazole showed a significant decrease in COPD exacerbations, more definitive clinical trials are required.
Chronic hypoxemia may develop in patients with severe stable COPD (GOLD stage IV). Two landmark trials, the British Medical Research Council (MRC) study and the National Heart, Lung, Blood Institute's Nocturnal Oxygen Therapy Trial (NOTT) showed that long-term oxygen therapy improves survival by 2-fold or more in hypoxemic patients with COPD. Hypoxemia was defined as a PaO2 of less than 55 mm Hg or oxygen saturation of less than 90%. Exercise-induced hypoxemia is also an accepted indication for supplemental oxygen because it improves exercise performance.
Oxygen toxicity from high O2 concentrations (FiO2 >60%) is well recognized. Little is known about the long-term effects of low-flow oxygen. The increased survival rate and quality-of-life benefits of long-term oxygen therapy outweigh the possible risks. PaCO2 retention from depression of the hypoxic drive has been overemphasized. PaCO2 retention more likely is a consequence of ventilation/perfusion mismatching than of respiratory center depression. While this complication is not common, it can be avoided by titrating oxygen delivery to maintain the PaO2 at 60-65 mm Hg.
The continuous-flow nasal cannula is the standard means of oxygen delivery for stable hypoxemic patients. The cannula is simple, reliable, and generally well tolerated. Each liter of oxygen flow adds 3-4% to the fraction of inspired oxygen (FIO2). Oxygen-conserving devices function by delivering all of the oxygen during early inhalation. These devices improve the portability of oxygen therapy and reduce the overall costs. Three distinct oxygen-conserving devices are available, and they include reservoir cannulas, demand-pulse delivery devices, and transtracheal oxygen delivery. Although no longer regularly performed I he United States, transtracheal oxygen delivery involves insertion of a catheter percutaneously between the second and third tracheal interspace. Transtracheal oxygen delivery is invasive and requires special training for the physician, patient, and caregiver. The procedure has risks and medical benefits but is of limited applicability.
Infections can lead to COPD exacerbations. Vaccinations are a safe and effective modality to reduced infections in susceptible COPD patients. The pneumococcal vaccine should be offered to all patients older than 65 years or patients of any age who have an FEV1 of less than 40% of predicted. The influenza vaccine should be given annually to all COPD patients.
There is emerging evidence that the current 23-valent pneumococcal vaccine administered to patients with COPD may not be as effective as previously thought; a 2013 Cochrane review suggests the evidence is less clear for routine support of vaccination against all-cause pneumonia.[40, 41] Efficacy was shown in subgroups of patients younger than 65 years with severe airflow obstruction, but not otherwise. The 23-valent vaccine includes serotypes studied to be effective against nearly 72-95% of invasive pneumococcal diseases. A 13-valent vaccine is being studied in Europe with enhanced immunogenicity, and is already approved for children and adults with chronic illnesses older than 50 years. Despite the data discussed here, it should be noted that current guidelines recommend pneumococcal vaccination in patients with emphysema and COPD aged 65 years and older.
The treatment strategies for alpha1-antitrypsin (AAT) deficiency involve reducing the neutrophil elastase burden, primarily by smoking cessation, and augmenting the levels of AAT. Available augmentation strategies include pharmacologic attempts to increase endogenous production of AAT by the liver (ie, danazol, tamoxifen) or administration of purified AAT by periodic intravenous infusion or by inhalation. Tamoxifen can increase endogenous production of AAT to a limited extent, so this may be beneficial in persons with the PIZZ phenotype.
Intravenous augmentation therapy is the only available approach that can increase serum levels to greater than 11 mmol/L, the protective threshold. Studies show that the infusions can maintain levels of more than 11 mmol/L, and replacement is administered weekly (60 mg/kg), biweekly (120 mg/kg), or monthly (250 mg/kg). The ability of intravenous AAT augmentation to alter the clinical course of patients with AAT deficiency has not been demonstrated. Uncontrolled observations of patients suggest that the FEV1 may fall at a slower rate in patients who receive AAT replacement.[7, 43]
Various surgical approaches to improve symptoms and restore function in patients with emphysema have been described. These should be offered to carefully selected patients as they may provide great benefit.
Removal of giant bullae has been a standard approach in selected patients for many years. Bullae can range from a few centimeters to occupying a third of the hemithorax. Giant bullae may compress adjacent lung tissue, reducing the blood flow and ventilation to the relatively healthy lung. Removal of these bullae may result in expansion of compressed lungs and improvement of lung function. Giant bullectomy can produce subjective and objective improvement in selected patients, ie, those who have bullae that occupy at least 30%—and preferably 50%—of the hemithorax that compress adjacent lung, with an FEV1 of less than 50% of predicted and relatively preserved lung function otherwise.
Lung volume reduction surgery
Lung volume reduction surgery (LVRS) attempts to decrease hyperinflation by surgically resecting the most diseased parts of the lung. This improves airflow by increasing the elastic recoil of the remaining lung and the mechanical efficiency of the respiratory muscles to generate expiratory pressures. The National Emphysema Treatment Trial (NETT) compared LVRS with medical management over a 4-year period. Subgroup analysis revealed the greatest benefit was achieved for patients with upper lobe–predominant emphysema and low exercise tolerance. These patients had improvement in mortality, work capacity, and quality of life. LVRS was shown to increase mortality in subjects considered to be high-risk patients (eg, FEV1 < 20% predicted and either DLCO < 20% predicted or homogeneous changes on chest CT scan).
Endobronchial valve placement
Endobronchial valve placement through bronchoscopy is under investigation as an alternative to LVRS. These valves are unidirectional and allow exhalation but do not allow inhalation. This results in a deflated lung distal to the valve. Bronchi are chosen to isolate segments of the lung that show the greatest emphysema and hyperinflation. The benefit, similar to LVRS, is obtained by decreasing the volume of most diseased portions of the lung.
The Endobronchial Valve for Emphysema Palliation Trial (VENT) studied the safety and efficacy of this approach in a nonblinded, prospective, randomized multicenter study. Results showed a modest but significant improvement in both the FEV 1 (relative increase, 6.8%) and 6-minute walk test (relative increase, 19.1 m) in the study group. Analysis revealed that the greatest benefit was obtained by those patients with greater heterogeneity of emphysema and intact interlobar fissures. The study group unfortunately also showed significantly higher rates of COPD exacerbations and hemoptysis.
COPD makes up the largest single category of patients who undergo lung transplantation. Lung transplantation provides improved quality of life and functional capacity but does not result in survival benefit. The lack of survival benefit makes the timing of transplant difficult. The patients selected to receive transplants should have a life expectancy of 2 years or less. Current guidelines by the International Society of Heart and Lung Transplantation recommends referring for transplantation when the BODE index (body mass index, obstruction [FEV1], dyspnea [ie, Medical Research Council Dyspnea Scale], and exercise capacity [ie, 6-min walking distance]) is greater than 5.
Consultation with a pulmonary specialist is recommended.
Inadequate nutritional status associated with low body weight in patients with COPD is associated with impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity, and higher mortality rates. Nutritional support is an important part of their comprehensive care.
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