INTRODUCTION — Chronic obstructive pulmonary disease (COPD) is a common condition with an estimated global prevalence of almost 12 percent in adults over age 30 [1-3]. COPD is the fourth leading cause of death among adults worldwide and is expected to become the third leading cause of death by 2020 [2,4-6].
In the majority of patients with COPD, symptoms and exacerbations can be controlled with interventions such as smoking cessation, vaccinations against influenza and pneumococcal infections, pulmonary rehabilitation, and one or more inhaled medications (eg, bronchodilators and glucocorticoids). In a minority of patients, COPD symptoms and exacerbations are persistent despite these interventions. While refractory COPD has not been defined, the context for this diagnostic category is patients with severe, persistent symptoms or high risk for exacerbations in spite of appropriate care, or advanced disease.
The management of refractory COPD will be reviewed here. The clinical manifestations, diagnosis, and management of stable COPD and COPD exacerbations are discussed separately. (See "Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging" and "Stable COPD: Overview of management" and "Stable COPD: Initial pharmacologic management" and "Stable COPD: Follow-up pharmacologic management" and "COPD exacerbations: Management".)
REASSESS COPD — Some patients with COPD have refractory symptoms of dyspnea, exercise limitation, and cough over a period of months or continue to have exacerbations despite therapy with appropriate long-acting muscarinic agent (LAMA, also known as a long-acting anticholinergic agent), long-acting beta agonist, and inhaled glucocorticoid therapies.
In the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification, these patients comprise a small portion of patients in COPD categories B, C, or D [2]. In addition to dyspnea, cough, sputum production, wheezing, and chest tightness, patients with severe and very severe COPD often report fatigue, weight loss, sleep disturbance, and anorexia.
When evaluating such patients, one of the first steps is to confirm proper technique and adherence to prescribed inhalers. (See 'Adherence' below and 'Technique' below.)
We also re-evaluate pulmonary function tests and often obtain a chest radiograph or chest computed tomography (CT) scan. The second two steps help determine whether the degree of airflow limitation has worsened or a new abnormality has developed (eg, impaired gas transfer, pleural effusion, interstitial lung disease, bronchiectasis).
For patients with worsening gas transfer, particularly if it seems out of proportion to the degree of airflow limitation, we often obtain an echocardiogram with Doppler to assess for pulmonary hypertension and high resolution computed tomography (HRCT) to assess the extent and distribution of emphysema and determine whether a new process (eg, interstitial lung disease, lung cancer) has developed. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)
When managing patients with refractory disease, we assess for oxygen desaturation using pulse oximetry at rest and during ambulation. While supplemental oxygen for exertional desaturation has not been conclusively demonstrated to reduce symptoms, enhance function, or improve survival, individual patients may benefit symptomatically. (See "Long-term supplemental oxygen therapy" and "Stable COPD: Overview of management", section on 'Supplemental oxygen'.)
In addition, arterial blood gases are suggested to assess for chronic hypercapnia.
ASSESS FOR COMPLICATING DISEASES — Among patients with COPD, a number of comorbid or concomitant disease processes can contribute to dyspnea and exercise intolerance, including coronary heart disease, heart failure, lung cancer, skeletal muscle dysfunction, anxiety and depression, and chronic nasal/sinus disease. Evaluating for conditions often may reveal additional therapeutic options. We typically obtain an echocardiogram and, depending on the patient’s symptoms and history, may obtain a cardiac stress test. (See "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions" and "Selecting the optimal cardiac stress test".)
Pulmonary cachexia is associated with advanced lung disease and can contribute to peripheral skeletal and respiratory muscle weakness, fatigue, and poor exercise tolerance. Nutritional assessment and supplementation are discussed separately. (See "Malnutrition in advanced lung disease".)
PHARMACOLOGIC AGENTS — For patients who continue to have symptoms or repeated exacerbations of COPD despite therapy with a long-acting muscarinic agent (LAMA), a long-acting beta agonist (LABA), plus an inhaled glucocorticoid (table 1), potential pharmacologic options include optimizing inhaler therapy, a trial of theophylline, and, in patients with recurrent exacerbation, roflumilast or chronic azithromycin.
Optimizing triple inhaler therapy — For patients who have persistent symptoms despite triple inhaler therapy (LAMA, LABA, inhaled glucocorticoid), it is worth reviewing their adherence to therapy and inhaler technique.
Adherence — Adherence to COPD medication regimens is frequently suboptimal, and lower adherence is associated with more frequent hospitalization and greater overall cost [7]. In an administrative claims database study of 14,117 patients with COPD, the proportion of days covered by prescriptions filled was 41 percent [8].
An initial step to assess adherence is asking whether a patient can identify their inhalers from a list or image (table 2 and picture 1 and picture 2 and picture 3) [9]. Barriers to adherence such as complex regimens, lack of confidence about technique, lack of access to medications or expense, stress, depression, and concerns about adverse effects should be explored [10-12].
Technique — Inhaler technique can be challenging, especially as the techniques for using pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs), and soft mist inhalers (SMIs) are quite different. Inhaler technique should be taught to all patients by demonstration to the patient and then demonstration by the patient. The patient’s technique should be reviewed regularly to ensure optimal medication delivery. (See "The use of inhaler devices in adults".)
The techniques for using the various inhalers can be found in the tables and are discussed in greater detail separately (table 3 and table 4 and table 5 and table 6). Videos demonstrating inhaler technique are also available from manufacturers and other sources.
For patients who are unable to achieve adequate technique despite a trial of different devices and a valved holding chamber for metered dose inhalers, an alternative option may be to switch to nebulized medications such as albuterol, arformoterol, levalbuterol, ipratropium, glycopyrrolate, and budesonide, realizing that they may need to be administered more often than the long-acting agents of the same class. While formal study of maintenance dosing in COPD is lacking, budesonide can be administered by nebulizer 0.25 to 1 mg twice daily (off-label), with the higher dose being reserved for patients with concomitant features of COPD and asthma. The LAMA glycopyrrolate (glycopyrronium) is available by nebulization for maintenance treatment in patients with COPD [13-16]. The medication requires a specialized closed nebulizer; the dose is one vial (25 microg) twice daily. (See "Role of muscarinic antagonist therapy in COPD", section on 'Glycopyrronium'.)
Medication selection — The newer LABAs, LAMAs, and inhaled glucocorticoids have not been directly compared within class, so it is not known whether a given patient would derive greater benefit from one agent versus another in the same class.
Medication optimization should take into account variations in medication delivery based on the patient’s ability to use the various inhaler devices. While patients are usually very familiar with pMDIs as they have used them as rescue inhalers, they may have problems with pMDI delivery, especially with hand-breath coordination.
DPIs have the advantage of being breath actuated and thus less subject to problems with actuation-inhalation coordination. On the other hand, DPIs require a threshold inspiratory flow, which patients with advanced COPD may be unable to generate. Alternative choices that are less dependent on inspiratory flow include pMDIs and SMIs.
Theophylline — The oral bronchodilator theophylline is a nonselective phosphodiesterase inhibitor that has a long history of use in COPD based on a rationale that its chemical activities increase levels of cyclic adenosine monophosphate (cAMP), which can lead to bronchodilation, diaphragmatic strengthening, and reductions in dyspnea [17,18]. However, accumulating data do not support a substantial clinical benefit to routine use in COPD.
The question of whether theophylline can reduce COPD exacerbations has also been raised, in part based on information from selective phosphodiesterase inhibitors (see 'Phosphodiesterase-4 inhibitors' below). Theophylline has been shown to enhance histone deacetylase (HDAC) activity, which may facilitate a response to glucocorticoids. However, no data currently demonstrate a specific role for theophylline in exacerbation risk reduction.
For patients with COPD who do not have the option of inhaled long-acting bronchodilators, low dose theophylline can be initiated at a dose of 100 to 300 mg (approximately 10 mg/kg ideal body weight) twice daily and titrated to a serum level in the 5 to 12 mcg/mL range. Low dose theophylline may also be considered in selected COPD patients with continued symptoms, especially dyspnea, in spite of maximal inhaled therapy. However, if a therapeutic response cannot be documented, theophylline should be discontinued.
●Dosing, monitoring, and toxicity – Theophylline has a narrow therapeutic window and multiple adverse effects (eg, headaches, insomnia, nausea, heartburn and seizures). Dosing to higher serum levels of theophylline (12 to 20 mcg/mL) is not recommended due to substantial associated toxicity risk. Lower levels of theophylline (5 to 12 mcg/mL) are currently advised, although adverse effects can still occur within this lower therapeutic range. The use of very low levels of theophylline (1 to 5 mcg/mL) to eliminate a need for therapeutic monitoring has not been shown to be of benefit [19,20].
Dosing of theophylline in COPD can be complex and serum levels can be affected by many factors. Theophylline is metabolized in the liver, and any process that interferes with liver function can rapidly increase theophylline levels. In addition, theophylline clearance decreases with age. Many drugs can alter theophylline metabolism, so awareness of potential interactions is essential. (See "Theophylline poisoning".)
Monitoring of serum levels is essential to avoid toxicity, and peak levels are preferred to trough levels. To properly measure the peak concentration, a blood sample should be obtained 3 to 7 hours after a morning dose of a twice-daily preparation or 8 to 12 hours after a dose of a once daily preparation. Once an appropriate serum level is achieved, subsequent measurements can be made at 6 to 12-month intervals or if the patient’s clinical status or concomitant medications change.
●Efficacy – Despite numerous proposed mechanisms of action and reports of symptomatic benefit (reduced dyspnea, improved exercise tolerance) [17], large clinical trials of low dose theophylline have not found a benefit. It should be remembered that many of the earlier studies supporting these claims used higher dosing levels that do not match current therapeutic dosing recommendations.
•Lung function – In terms of lung function, a meta-analysis of 20 randomized, controlled trials demonstrated that theophylline improved FEV1, forced vital capacity (FVC), and gas exchange compared with placebo [17]. Improvement in exercise performance depended on the method of testing.
•Exacerbation reduction – Randomized trial data do not support a benefit to theophylline for exacerbation reduction using very low doses (serum level 1 to 5 mcg/mL), whether alone or in combination with inhaled or oral glucocorticoids [19-21].
The theophylline and low dose oral corticosteroids (TASCS) trial (1670 participants with moderate to very severe COPD; 1242 completed study) was a multicenter, three-arm comparison of low dose, slow-release theophylline (100 mg twice a day), singly or in combination with oral prednisone (5 mg/day), and dual placebo (with usual care) [20]. Over the 48-week treatment period, theophylline alone or in combination with prednisone did not reduce exacerbation rates, and secondary outcomes of hospitalizations, lung function (FEV1), respiratory quality of life, and COPD Assessment Test (CAT) score were similar among treatment groups. Of note, participants taking LAMAs and LABAs at baseline continued these agents through the study.
A previous trial, the Theophylline With Inhaled Corticosteroids Study (TWICS), compared low-dose theophylline (200 mg once or twice per day; serum level 1 to 5 mcg/mL) with placebo when added to inhaled glucocorticoids in 1536 patients with severe COPD and at least two exacerbations in the previous year [19]. Over a 52-week treatment period, theophylline did not reduce the number of COPD exacerbations requiring oral glucocorticoids and/or antibiotics compared with placebo. Baseline characteristics (eg, greater LABA/LAMA use in the placebo group and lower lung function in the theophylline group) and a high rate of discontinuation of theophylline were thought to explain the apparent lack of benefit from theophylline.
Phosphodiesterase-4 inhibitors — Phosphodiesterase-4 (PDE-4) inhibition decreases inflammation and may promote airway smooth muscle relaxation [22-27]. Roflumilast is an oral, PDE-4 inhibitor that is approved to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of frequent COPD exacerbations (eg, at least two per year or one requiring hospitalization) [28-31]. Roflumilast may further reduce the risk of COPD exacerbations when added to other respiratory medications that have also been shown to reduce exacerbations (eg, LABA/inhaled glucocorticoid combination, LAMA), although the added benefit appears modest. In practice, roflumilast use has generally been limited to COPD patients with continued exacerbations despite maximally tolerated inhaled therapies.
Initiating treatment with roflumilast 250 mcg once daily for four weeks and then increasing to 500 mcg once daily may reduce the rate of treatment discontinuation [32]. However, the lower dose is subtherapeutic and not intended for long-term use. Roflumilast interacts with inducers of CYP3A4 (eg, rifampicin, phenobarbital, carbamazepine) and dual inhibitors of CYP3A4 and CYP1A2 (eg, erythromycin, ketoconazole, cimetidine); concomitant use with the latter will increase roflumilast systemic exposure and may cause adverse effects.
Roflumilast has not been directly compared with azithromycin, a macrolide antibiotic that may have properties beyond those of a simple antimicrobial agent, which has been shown to reduce the frequency of COPD exacerbations in selected COPD patients. When choosing an additional agent for exacerbation reduction in these high-risk COPD patients, the medication choice may be as much dependent on the medication's side effects and contraindications as its efficacy. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Prophylactic macrolides'.)
The effects of PDE-4 inhibitors have been examined in several randomized trials and a meta-analysis [33-38]:
●A systematic review of 42 randomized trials of roflumilast, cilomilast, or tetomilast versus placebo found that treatment with a PDE-4 inhibitor resulted in a small improvement in the FEV1 (49.33 mL, 95% CI 44.17-54.49 mL) and a reduced likelihood of an exacerbation (OR 0.78, 95% CI 0.73-0.84), but had little effect on quality of life [39].
●In a multicenter trial, 1945 patients with COPD, severe airflow obstruction, and at least two exacerbations in the prior year were randomly assigned to roflumilast (500 microg once daily) or placebo for one year [40]. All patients used a combination inhaled glucocorticoid and long acting beta-agonist inhaler in addition to study medication; tiotropium was also allowed. Moderate-to-severe COPD exacerbations were 14 percent lower among those taking roflumilast compared with those taking placebo (rate ratio 0.858, CI 95% 0.740-0.995). Severe exacerbations requiring hospital admission were decreased by 24 percent (rate ratio 0.761, 95% CI 0.604-0.96). However, methodologic concerns, such as high study discontinuation rates and borderline levels of significance, limit the conclusions that can be drawn.
●Roflumilast significantly improved prebronchodilator FEV1 and decreased the rate of moderate to severe exacerbations in a 52 week, randomized trial of 3091 patients with COPD [36]. Compared with placebo, roflumilast decreased exacerbations (17 percent [95%, CI 8-25]).
●In 24 week trials, 933 patients with moderate to severe COPD were randomly assigned to roflumilast plus salmeterol or salmeterol alone and 743 patients were randomly assigned to roflumilast plus tiotropium or tiotropium alone [38]. Roflumilast significantly improved the primary endpoint, the prebronchodilator FEV1, in both trials.
Roflumilast has a limited benefit on lung function. Thus, the medication should be used as a maintenance therapy to prevent exacerbations rather than to improve other COPD outcomes [2].
The US Food and Drug Administration has added a warning that roflumilast may be associated with an increase in adverse psychiatric reactions and should be used with caution in patients with a history of depression. Other adverse effects include insomnia, diarrhea, nausea, vomiting, weight loss, and dyspepsia.
Chronic antibiotic therapy — Chronic antibiotic therapy is not indicated for the majority of patients with stable COPD (eg, emphysema, chronic bronchitis). However, certain antibiotics, macrolides in particular, may have antiinflammatory effects in addition to their antibiotic effect [41,42]. For patients who continue to have frequent exacerbations despite optimal therapy for COPD with bronchodilators and antiinflammatory agents, we suggest antibiotic prophylaxis with azithromycin. The rationale for azithromycin prophylaxis is discussed separately. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Prevention'.)
Azithromycin, 250 mg daily or 500 mg three times per week, reduces exacerbations in patients prone to exacerbations [2,43]. A lower dose of 250 mg three times per week is sometimes used to reduce adverse effects, but has not been rigorously tested for its ability to reduce exacerbations. Azithromycin should be avoided in patients with a long QT interval. Hearing should be assessed periodically as macrolides have been associated with hearing loss in clinical trials. The trials of macrolide prophylaxis are discussed in greater detail separately. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Prophylactic macrolides'.)
Patients whose COPD is associated with bronchiectasis may benefit from chronic antibiotic therapy. The treatment of bronchiectasis is discussed separately. (See "Bronchiectasis in adults: Treatment of acute exacerbations and advanced disease".)
Nonimmunized patients with COPD who are at high risk for contracting influenza and/or have early symptoms of acute influenza infection may benefit from antiviral therapy. (See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention" and "Seasonal influenza in nonpregnant adults: Treatment".)
Rarely used medications — Oral mucolytic agents and chronic systemic glucocorticoids are rarely used in patients with refractory COPD due to lack of evidence of efficacy.
Mucoactive agents — Thick, tenacious secretions can be a major problem in patients with COPD, but there is little evidence that thinning or increasing the clearance rate of secretions induces clinical improvement. While some evidence supports a modest benefit from oral thiol derivatives, other mucoactive agents, such as oral expectorants, iodine preparations, inhaled dornase alfa (DNase), hydration, and inhaled hypertonic saline, are not accepted as routine care for patients with stable COPD. There are no data to support mucolytic agents in patients with COPD refractory to triple inhaler therapy. (See "Role of mucoactive agents and secretion clearance techniques in COPD".)
Thiol derivatives such as N-acetylcysteine (NAC), erdosteine and carbocysteine, are mucolytic agents designed to sever disulfide bonds of mucoproteins and DNA, possibly leading to reduced mucus viscosity. NAC also have antioxidant effects. For patients with bothersome sputum production that is refractory to smoking cessation, routine therapies for COPD, and a course of antibiotics (when indicated), an oral thiol preparation (eg, N-acetyl cysteine [NAC], 600 mg twice daily) can be initiated on a trial basis and continued if there is symptomatic improvement. This suggestion is based on a large multicenter trial (PANTHEON) of 964 patients with moderate to severe COPD (mean FEV1 49 percent of predicted) that found a reduction in exacerbations with NAC (600 mg tablets twice daily) compared with placebo [44]. However, methodologic issues, such as a high drop-out rate, exclusion of oxygen-requiring patients, and the use of a large portion of nonsmokers, limit the conclusions that can be drawn from this study. Furthermore, other studies of oral NAC as mucolytic/antioxidant therapy for COPD have yielded conflicting results and a systematic review concluded that evidence was insufficient to recommend this agent in COPD [45,46]. (See "Role of mucoactive agents and secretion clearance techniques in COPD", section on 'N-acetylcysteine (NAC)'.)
The use of inhaled NAC has no effect on sputum volume, can induce significant bronchoconstriction, and should not be a part of routine COPD management. Other oral thiol mucolytics, erdosteine and carbocysteine, available in some countries outside the United States are of limited benefit. (See "Role of mucoactive agents and secretion clearance techniques in COPD", section on 'Thiols and thiol derivatives'.)
Oral expectorants, such as guaifenesin, bromhexine, ipecac, and iodine preparations have limited clinical benefits in COPD and may have substantial adverse effects. Their use in COPD is not recommended. (See "Role of mucoactive agents and secretion clearance techniques in COPD", section on 'Oral expectorants' and "Role of mucoactive agents and secretion clearance techniques in COPD", section on 'Iodide preparations'.)
DNase, exogenous surfactant, various proteolytic agents, and various detergents have not been adequately studied in COPD and are not recommended for routine use. (See "Role of mucoactive agents and secretion clearance techniques in COPD", section on 'Experimental mucoactive agents'.)
Increasing fluid intake to reduce sputum viscosity is of no value unless a patient is hypovolemic. Nebulized water or hypertonic saline is without documented benefit in COPD and may irritate the airways and induce bronchospasm. On the other hand, hypertonic saline may be of benefit in patients with concurrent bronchiectasis. (See "Role of mucoactive agents and secretion clearance techniques in COPD", section on 'Hydration' and "Role of mucoactive agents and secretion clearance techniques in COPD", section on 'Hypertonic saline'.)
Systemic glucocorticoids — Systemic glucocorticoids have long been used to treat exacerbations in patients with COPD, but are only rarely indicated for chronic use. The adverse effects of long-term use of systemic glucocorticoids are substantial and include a potential increase in morbidity and mortality in COPD [47,48]. The role of systemic glucocorticoids in the treatment of acute exacerbations of COPD is discussed in more detail separately. (See "COPD exacerbations: Management".)
In brief, long-term systemic glucocorticoids are not recommended, even for severe COPD, because of the significant side effects and evidence of increased morbidity and mortality with this therapy [47-49]. In the uncommon circumstance when discontinuing systemic glucocorticoids after a COPD exacerbation is repeatedly met with recurrent symptoms, systemic glucocorticoids should be reduced to the lowest dose possible. Objective measures of improvement (eg, spirometry, walk test) must be used to justify ongoing therapy, as emotional and euphoric effects of systemic glucocorticoids can cloud a patient's perception of benefit. (See "Major side effects of systemic glucocorticoids".)
SUPPORTIVE MEASURES FOR ADVANCED COPD — Select patients with severe COPD may benefit from supplemental oxygen, improved nutrition, and nocturnal noninvasive ventilatory support.
General — Routine supportive measures for COPD, including cigarette smoking cessation, vaccination against influenza and pneumococcus (table 7), supplemental oxygen for severe hypoxemia, and pulmonary rehabilitation, are cornerstones to the management of COPD and are discussed separately. (See "Pulmonary rehabilitation" and "Long-term supplemental oxygen therapy" and "Stable COPD: Overview of management", section on 'Smoking cessation' and "Stable COPD: Overview of management", section on 'Vaccination'.)
Oxygen — Long-term supplemental oxygen therapy is recommended for persistent chronic hypoxemia (arterial oxygen tension [PaO2] ≤55 mmHg or pulse oxygen saturation [SpO2] ≤88 percent) to improve survival. It is less clear whether supplemental oxygen therapy will reduce dyspnea in patients with mild to moderate hypoxemia. These issues are discussed separately. (See "Long-term supplemental oxygen therapy" and "Stable COPD: Overview of management", section on 'Supplemental oxygen'.)
Nutrition — The presence of pulmonary cachexia has traditionally been determined by a weight <90 percent of ideal body weight (calculator 1) or a body mass index (BMI) ≤20 (calculator 2). More than 30 percent of patients with severe COPD have protein-calorie malnutrition, which is associated with increased mortality, impaired respiratory muscle function, and diminished immune competence. Nutritional interventions that may be of benefit in such patients are discussed separately. (See "Malnutrition in advanced lung disease".)
Oxidative damage due to oxidant-antioxidant imbalance has been proposed as a contributor to COPD. Thus, it has been hypothesized that antioxidants may prevent disease progression. However, controlled clinical trials are needed before antioxidant vitamins can be recommended for the routine management of patients with stable COPD.
Nocturnal noninvasive ventilation — Noninvasive ventilatory support is sometimes useful in patients with chronic respiratory failure due to COPD manifest by daytime hypercapnia and nocturnal hypoxemia not due to obstructive sleep apnea and not responsive to supplemental oxygen during sleep, especially those who derived benefit from noninvasive ventilation during an exacerbation of COPD. (See "Nocturnal ventilatory support in COPD".)
SURGICAL AND BRONCHOSCOPIC INTERVENTIONS — Carefully selected patients with advanced COPD and refractory dyspnea may benefit from an intervention, such as lung volume reduction surgery (LVRS), bronchoscopic lung volume reduction (LVR) using endobronchial valves, or lung transplantation [50]. Bronchoscopic LVR is nonsurgical.
Lung volume reduction surgery — LVRS entails wedge excisions of emphysematous tissue to remove poorly functioning lung tissue and reduce hyperinflation. It is generally reserved for patients with severe dyspnea due to COPD despite optimal medical therapy, pulmonary rehabilitation, longer than six months of smoking cessation, and a diffusing capacity for carbon monoxide (DLCO) that is not less than 20 percent predicted and forced expiratory volume in one second (FEV1) of not less than 20 percent predicted. (See "Lung volume reduction surgery in COPD".)
The benefits of LVRS were assessed in the National Emphysema Treatment Trial (NETT), which enrolled 1218 patients with severe emphysema and compared LVRS to maximal medical therapy [51]. Following a baseline assessment, the patients underwent six to ten weeks of mandatory pulmonary rehabilitation and were then randomly assigned to LVRS or continued medical therapy. The efficacy of LVRS varied among patient groups, but there was an overall survival advantage that was most marked in patients with upper lobe emphysema and low exercise capacity. A marked increase in early mortality was noted in patients with an FEV1 <20 percent predicted and either a DLCO <20 percent predicted or non-upper lobe emphysema on chest CT; such patients are not candidates for LVRS [52].
LVRS appears less promising for patients with COPD due to severe deficiency of alpha-1 antitrypsin (AAT) deficiency, than for those without AAT deficiency. (See "Treatment of alpha-1 antitrypsin deficiency", section on 'Lung volume reduction surgery'.)
Bronchoscopic LVR — A number of techniques have been proposed for bronchoscopic LVR, including endobronchial placement of one-way valves, plugs and blockers, endobronchial instillation of biologic sealants, thermal airway ablation, and airway stents for decompression of bullae. These are described separately. (See "Bronchoscopic treatment of emphysema".)
Endobronchial valves — Endobronchial valves (EBVs) are placed in the most diseased lung regions with a goal of inducing atelectasis of the most emphysematous lung (picture 4 and picture 5 and picture 6). Specific assessment using high resolution computed tomography (HRCT) or other methods is needed to ensure that there is little to no collateral ventilation in that region prior to placement of EBVs. The technique for placement of EBVs is discussed separately. (See "Bronchoscopic treatment of emphysema", section on 'Endobronchial valves'.)
For patients with hyperinflation due to severe emphysema who remain symptomatic despite optimal medical therapy and pulmonary rehabilitation (table 8), we suggest placement of EBV in the lung region with the most emphysematous destruction and little to no collateral ventilation. EBV placement is supported by guidance from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and National Institute for Health and Care Excellence (NICE) for selected patients with hyperinflation associated with severe emphysema [2,53,54]. Zephyr duckbill-shaped EBV and Spiration umbrella-shaped EBVs are approved for placement in selected patients in the USA [55]. As placement of EBVs require specialized training and equipment and carries a high risk of pneumothorax, continuing current therapy is a reasonable alternative. Selection between types of EBV is based on local expertise and preferences; there is insufficient evidence to guide selection of one EBV over another.
●Efficacy of Zephyr (duckbill) EBV – Several randomized trials and a multicenter registry have reported modest improvements in symptoms and lung function after placement of Zephyr (duckbill) EBVs [56-67]. The two largest trials provide support for the use of that technology:
•In the LIBERATE trial, 190 subjects with severe heterogeneous emphysema and little or no collateral ventilation in the target lung (based on Chartis assessment) were randomly assigned to Zephyr valve placement or standard of care (SOC) [66]. At 12 months, 48 percent of participants receiving EBV treatment and 17 percent of those receiving SOC had an improvement in FEV1 ≥15 percent. Between group differences in FEV1, 6MWD, dyspnea, and quality of life were all significant. Pneumothoraces developed in 26 percent of the EBV group; four deaths occurred in the first three months in the EBV group.
•A separate multicenter trial (TRANSFORM) randomly assigned 97 patients with severe heterogeneous emphysema without collateral ventilation to receive Zephyr EBV or standard of care (2:1 ratio) [67]. Almost 90 percent of participants in the EBV group had a target lobe volume reduction ≥350 mL (mean 1.09 ±0.62 L). At six months, the between group difference in residual volume was -700 mL, 6MWD was +78.7 m, and modified Medical Research Council dyspnea score was -0.6 points. The improvement in quality of life was slightly greater in the EBV group. The most common adverse event was pneumothorax, which occurred in 29 percent of EBV patients.
●Efficacy of Spiration (umbrella) EBV – A systematic review and meta-analysis of four trials (629 participants) provide support for use of the Spiration EBV for severe emphysema based on improvement in FEV1 (0.12 L; 95% CI 0.09-0.015), SGRQ quality of life (-12.27 points; 95% CI -15.84 to -8.70), and the mMRC dyspnea scale (-0.54 [95% CI -0.74 to -0.33]) in participants with intact fissures, but not in the overall treatment group (included patients without intact fissures) [68]. No improvement was noted in the six-minute walk distance (6MWD). The relative risk of mortality was 2.54 (95% CI 0.81-7.96) and for an exacerbation of COPD 1.68 (95% CI 1.04-2.70).
Placement of endobronchial valves does not preclude subsequent LVRS or lung transplant.
Lung transplantation — The decision to proceed with lung transplantation for severe COPD is complex. Ample evidence suggests that functional capacity is improved following the procedure. Data from the International Society for Heart and Lung Transplantation (ISHLT) registry show a median survival of 7.1 years for patients who undergo lung transplantation for COPD [69]. In a separate study of 342 Swedish patients (128 alpha-1 antitrypsin deficient [AATD] and 214 non-AATD) receiving lung transplants for advanced COPD, those without AATD had a shorter survival time than those with AAT deficiency, 6 years (95% CI: 5.0-8.8) versus 12 years (95% CI: 9.6-13.5) [70]. A survival benefit to lung transplantation was demonstrated in a retrospective study of 54 consecutive patients with COPD, particularly those with a BODE score ≥7 (calculator 3) [71]. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection".)
It is important to define disease severity as precisely as possible in order to determine which patients have the most urgent need for lung transplantation and are likely to have the longest survival after transplantation [72]. Guidelines for timing a referral for a transplant evaluation for patients with COPD and emphysema due to alpha-1 antitrypsin deficiency include the following [73]:
●Progressive disease despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy
●Patient is not a candidate for surgical or endoscopic LVRS
●BODE index 5 to 6 (calculator 3)
●Post-bronchodilator FEV1 <25 percent of predicted
●Resting hypoxemia, defined as arterial oxygen tension (PaO2) <60 mmHg (8 kPa)
●Hypercapnia, defined as carbon dioxide tension (PaCO2) >50 mmHg (6.6 kPa)
The following are suggested criteria for placing a patient with COPD on the transplant list (presence of one criterion is sufficient) [73]:
●BODE index ≥7 (calculator 3)
●FEV1 <15 to 20 percent of predicted
●Three or more severe exacerbations (hospitalizations) in the preceding year
●One severe exacerbation with acute hypercapnic respiratory failure
●Moderate to severe pulmonary hypertension
PALLIATIVE CARE IN COPD — Palliative care aims to relieve suffering at all stages of disease and is not limited to end of life care. For patients with advanced or refractory COPD, it is appropriate to have ongoing discussions with patients and their families about their understanding of their disease and prognosis, persistent symptoms and overall symptom burden, values and preferences regarding life-prolonging therapies, and needs regarding coordination of care (table 9). (See "Palliative care for adults with nonmalignant chronic lung disease".)
Symptom management and goals of care — Patients with advanced lung disease are frequently troubled by dyspnea, but are also prone to other symptoms that may benefit from palliative care, such as cough, sputum production, anxiety, depression, fatigue, insomnia, muscle weakness, and pain. A multidisciplinary approach is helpful to assess the presence, intensity, and functional impact of these symptoms and to help ameliorate the symptoms. The palliative care of patients with chronic lung disease and the evaluation and management of associated symptoms are discussed separately. (See "Palliative care for adults with nonmalignant chronic lung disease" and "Assessment and management of dyspnea in palliative care" and "Palliative care: Overview of cough, stridor, and hemoptysis in adults".)
●Dyspnea – General steps to ameliorate the experience of dyspnea are listed in the table (table 10). Nonpharmacologic interventions may include pulmonary rehabilitation (eg, exercise training, pursed-lip breathing and other breathing strategies), ergonomics, and accommodation strategies (eg, relaxation, modification of activity level, use of a fan to blow air on the face). Opiates may be of benefit for relief of dyspnea in selected patients, such as those with dyspnea unresponsive to the conventional approaches described above. Careful monitoring and individual dose titration are vital to avoid respiratory depression and other side effects. These and other management strategies for dyspnea are discussed separately. (See "Assessment and management of dyspnea in palliative care".)
●Anxiety and depression – Anxiety and depression are often intertwined with the experience of dyspnea, and attempts to characterize which symptom is the dominant or primary problem for an individual patient can be difficult. Indeed, hyperventilation from anxiety can often accentuate and occasionally overwhelm patients with dyspnea. Psychoactive agents and cognitive behavioral therapy can be helpful in selected patients with anxiety or depression [74-77]. Respiratory stimulants are not beneficial to these patients and can often accentuate dyspnea, even in those with hypercapnic COPD.
Advance care planning — Advance care planning (ACP), defined as "planning for and about preference-sensitive decisions often arising at the end-of-life," is an ongoing process in which patients, their families, and their healthcare providers reflect on the patient’s goals, values, and beliefs, and use this information to inform current and future medical care in the context of care that is medically reasonable and appropriate. In an ideal ACP discussion, the clinicians, patient, and his or her loved ones think through particular approaches to follow if (or when) the patient’s health declines. (See "Palliative care for adults with nonmalignant chronic lung disease", section on 'Advance care planning' and "Advance care planning and advance directives".)
Hospice and end-of-life care — Patients with advanced COPD may also benefit from hospice care (table 11). The term hospice is used to describe a model of palliative care that is offered to patients with a terminal disease who are at the end of life (generally with an estimated life expectancy of six months or less) when curative or life-prolonging therapy is no longer the focus of treatment. (See "Palliative care for adults with nonmalignant chronic lung disease", section on 'End-of-life care' and "Hospice: Philosophy of care and appropriate utilization in the United States" and "Palliative care: The last hours and days of life".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease" and "Society guideline links: Pulmonary rehabilitation".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Chronic obstructive pulmonary disease (COPD) (The Basics)" and "Patient education: Medicines for chronic obstructive pulmonary disease (COPD) (The Basics)" and "Patient education: Shortness of breath (dyspnea) (The Basics)" and "Patient education: Medical care during advanced illness (The Basics)" and "Patient education: Advance directives (The Basics)" and "Patient education: Inhaled corticosteroid medicines (The Basics)" and "Patient education: Pulmonary rehabilitation (The Basics)")
●Beyond the Basics topics (see "Patient education: Chronic obstructive pulmonary disease (COPD) (Beyond the Basics)" and "Patient education: Chronic obstructive pulmonary disease (COPD) treatments (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●In the majority of patients with chronic obstructive pulmonary disease (COPD), symptoms and exacerbations can be controlled with interventions such as smoking cessation, vaccinations against influenza and pneumococcal infections, pulmonary rehabilitation, and one or more inhaled medications. (See 'Introduction' above and "Stable COPD: Initial pharmacologic management".)
●In a minority of patients with COPD, symptoms and exacerbations are persistent despite therapy with a long-acting muscarinic agent (LAMA, also known as a long-acting anticholinergic agent), a long-acting beta agonist (LABA), and inhaled glucocorticoid. (See 'Introduction' above.)
●When evaluating such patients, the first steps include confirming smoking cessation, proper inhaler technique, and adherence to prescribed inhalers, assessing severity of airflow limitation with pulmonary function testing, and obtaining a chest radiograph. Depending on the results, further evaluation may include Doppler echocardiogram and/or high resolution computed tomography. (See 'Reassess COPD' above.)
●A number of common comorbidities of COPD can contribute to dyspnea and exercise intolerance, including coronary heart disease, heart failure, metabolic syndrome, lung cancer, skeletal muscle dysfunction, anxiety, and depression. Evaluating for comorbid conditions (eg, echocardiogram, pharmacologic stress test) may reveal additional therapeutic options. (See 'Assess for complicating diseases' above.)
●For patients who have persistent symptoms despite triple inhaler therapy (LAMA, LABA, inhaled glucocorticoid), it is worth reviewing their adherence to therapy and inhaler technique. (See 'Optimizing triple inhaler therapy' above.)
●For patients with persistent dyspnea despite optimal inhaled therapy, we suggest a trial of low-dose theophylline (serum level 5 to 12 mcg/mL) (Grade 2C), as this may improve exercise tolerance. The exact mechanism is unclear. Caution is advised as theophylline has more adverse effects than inhaled bronchodilators and a number of medication interactions. Dosing and monitoring are presented above. Theophylline at a lower dose (serum level 1 to 5 mcg/mL) is not indicated in COPD. (See 'Theophylline' above.)
●For patients with recurrent exacerbations (eg, at least two per year or one requiring hospitalization) despite triple inhalers, we suggest either the phosphodiesterase-4 inhibitor roflumilast or chronic azithromycin therapy (Grade 2C). The choice between these medications is largely based on anticipated adverse effects as they have not been directly compared. (See 'Pharmacologic agents' above.)
•Roflumilast should be avoided in patients with hepatic impairment (Child-Pugh class B or C) or a history of moderate or severe depression. Potential medication interactions should be assessed. (See 'Phosphodiesterase-4 inhibitors' above.)
•Azithromycin can be given as 250 mg daily or 500 mg three times a week. A lower dose of 250 mg three times per week may be used to reduce adverse effects, although this dose is less well studied. Azithromycin should be avoided in patients with a long QT interval or if there are major concerns about hearing loss. (See 'Chronic antibiotic therapy' above.)
●For patients with hyperinflation due to severe emphysema who remain symptomatic despite optimal medical therapy and pulmonary rehabilitation (table 8), we suggest placement of endobronchial valves in the lung region with the most emphysematous destruction and little to no collateral ventilation (Grade 2C). As placement of endobronchial valves requires specialized training and equipment and carries a high risk of pneumothorax, continuing current therapy is a reasonable alternative. (See 'Bronchoscopic LVR' above.)
●Patients who continue to have significant symptoms despite the above interventions may be considered for surgical therapy, such as lung volume reduction or lung transplantation. (See 'Surgical and bronchoscopic interventions' above.)
