Management of refractory chronic obstructive pulmonary disease

INTRODUCTION — Chronic obstructive pulmonary disease (COPD) is a common condition with an estimated global prevalence of almost 12 percent in adults over age 30 years [1-3]. Prior to the onset of the COVID-19 (coronavirus disease 2019) pandemic, COPD was the third leading cause of death worldwide [4].

For most patients with less severe 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 (ie, bronchodilators and glucocorticoids). As the disease progresses, COPD symptoms and exacerbations may be persistent despite these interventions. While refractory COPD has not been formally defined, the context for this diagnostic category is patients with severe, persistent symptoms or frequent exacerbations despite appropriate care.

The management of refractory COPD will be reviewed here. The clinical manifestations, diagnosis, and management of nonrefractory COPD and of COPD exacerbations are discussed separately. (See "Chronic obstructive pulmonary disease: 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".)

ASSESSMENT OF THE PATIENT WITH REFRACTORY COPD — Some patients with COPD continue to have refractory dyspnea and limitations to activity. Others may have continued cough and sputum or recurring exacerbations despite therapy with long-acting muscarinic antagonist (LAMA, also known as a long-acting anticholinergic agent), long-acting beta-agonist (LABA), and inhaled corticosteroid (ICS; aka inhaled glucocorticoid) therapies. In addition to pulmonary symptoms, these patients may also report fatigue, weight loss, sleep disturbance, and anorexia.

Given their high burden of disease and frequent contributing comorbidities, patients with refractory COPD benefit from a comprehensive reassessment of their symptoms and disease burden, as outlined below.

Evaluation of dyspnea, exacerbation history, and other symptoms and signs — The Global Initiative Chronic Obstructive Lung Disease (GOLD) report uses the core metrics of quantified dyspnea/health status and frequency and severity of exacerbations to categorize patients for both initial and follow-up management [2]. We continue to find it helpful in refractory patients to evaluate dyspnea and exercise tolerance using validated instruments, such as the modified Medical Research Council (mMRC) dyspnea scale (calculator 1) or the COPD Assessment Test (CAT) (calculator 2) [2,5-7]. To assess for interval exacerbation history, we ask patients about periods of increased dyspnea, sputum volume, and sputum purulence, as well as any treatments with antibiotics or oral glucocorticoids for respiratory symptoms. COPD hospitalizations mark severe exacerbations. We also monitor symptoms commonly associated with COPD, such as fatigue and sleep disturbance. For patients we are evaluating for the first time, we also review smoking history, other exposure history, and prior pulmonary function testing (if available) to ensure that patients appropriately carry the diagnosis of COPD. (See "Chronic obstructive pulmonary disease: Diagnosis and staging".)

On physical examination, we assess for use of the accessory respiratory muscles of the neck and shoulder girdle, expiration through pursed lips, cyanosis, asterixis due to severe hypercapnia, and liver enlargement/tenderness or peripheral edema due to right heart failure. A falling body mass index (BMI) is common in severe COPD, but a rising BMI may suggest fluid retention due to right heart failure or comorbid heart failure. If present, decreased mental status could reflect hypercapnia or hypoxemia. Other physical findings, such as digital clubbing, bibasilar fine crackles, and peripheral edema, might suggest a comorbidity or alternate diagnosis.

Patients who primarily report ongoing dyspnea have fewer additional pharmacologic options beyond inhaled therapies but may benefit from invasive approaches and palliative symptom management. In addition, reevaluation for alternative diagnoses, consideration for further pulmonary rehabilitation, and assessment of ongoing home exercise is essential. (See 'For patients with persistent dyspnea without exacerbations' below and 'Lung Volume Reduction, in select patients with dyspnea' below and 'Lung transplantation' below and 'Palliative care measures' below.)

In contrast, patients with frequent exacerbations are more likely to benefit from add-on oral pharmacologic therapies. (See 'For patients with frequent exacerbations' below.)

It must be noted that patients may change their disease pattern over time, so therapeutic approaches may need to shift in order to remain tailored to individual patient needs.

Optimizing inhaled therapies — For patients who have persistent symptoms despite optimized inhaled therapies (LAMA and LABA, with or without ICS), it is critical to review patient inhaler technique, adherence to inhaler therapy, and any adverse effects the patient may be experiencing. This information may prompt changes in inhaled agents used, device type (eg, pressurized metered dose inhaler (pMDI) versus dry powder inhaler (DPI) versus soft mist inhaler (SMI) or nebulizer), or dosing schedule to address these concerns. Inhaler device education and reeducation is essential to successful pharmacologic therapy and should always be considered before other changes in therapy. (See "Stable COPD: Overview of management", section on 'Inhaler technique' and "The use of inhaler devices in adults", section on 'Common problems with inhaler devices'.)

A systematic review of studies of inhaler technique found that on average two-thirds of patients with asthma or COPD made one or more errors in device use [8]. Multiple studies support the need for regimen simplicity and reenforcement of inhaler technique [9,10]. (See "Patient education: Inhaler techniques in adults (Beyond the Basics)" and "The use of inhaler devices in adults".)

Adherence — Adherence to COPD medication regimens is frequently suboptimal, and lower adherence is associated with more frequent hospitalization and greater overall cost [11]. In an administrative claims database study of 14,117 patients with COPD, patients underused their prescribed inhalers by at least 50 percent [12].

An initial step to assess adherence is asking whether a patient can identify their inhalers from a list or image (table 1 and picture 1 and picture 2 and picture 3) [13]. Barriers to adherence should be explored, including complex regimens, lack of confidence about technique, lack of access to medications or expense, stress, depression, and adverse effects [14-16]. (See "The use of inhaler devices in adults", section on 'Poor adherence to inhaler use'.)

Social determinants of health are frequent contributors to poor adherence in the COPD population. Some of these barriers can be explored using standardized questionnaires [17], whereas others may require a more comprehensive approach. (See "The patient’s culture and effective communication".)

Technique — Inhaler technique can be challenging, especially as the techniques for using pMDIs, DPIs, and SMIs are quite different. Inhaler technique should be taught to all patients by demonstration to the patient and then return demonstration by the patient. The patient’s technique should be reviewed regularly to ensure optimal medication delivery. Techniques for using various inhalers can be found in the tables and are also discussed in greater detail separately (table 2 and table 3 and table 4 and table 5). Videos demonstrating inhaler technique are also available from manufacturers and other sources. (See "The use of inhaler devices in adults" and "Patient education: Inhaler techniques in adults (Beyond the Basics)".)

Use of nebulized therapies — 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 maintenance long-acting nebulized medications (eg, arformoterol, budesonide) with short-acting agents as needed.

Some patients may also be able to perform proper technique in the office, but not when they are at the nadir of their dosing or having a mild exacerbation. These patients may benefit from short-acting nebulizers (albuterol, levalbuterol) to facilitate administration of maintenance medications.

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. We typically use 0.5 mg twice daily in patients with exacerbations and the lower dose for patients without exacerbations or with adverse effects of ICS such as thrush, voice changes, or recurrent pneumonia.

The LABAs formoterol and arformoterol and LAMAs revefenacin are available by nebulization for maintenance treatment in patients with COPD [18-22]. Formoterol, and arformoterol use a standard nebulizer at a dose of 15 mcg (one vial) twice daily; revefenacin uses a standard nebulizer with a dose of 175 mcg (one vial) once daily. (See "Stable COPD: Initial pharmacologic management", section on 'Long-acting beta-agonists' and "Role of muscarinic antagonist therapy in COPD", section on 'Revefenacin'.)

Medication selection — There are minimal head-to-head data that directly compare one LABA with another, one LAMA with another, or one ICS with another. Therefore, other differences between inhalers, including patient preference, drive agent selection.

●Delivery mechanism – 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 familiar with pMDIs, which they use as rescue inhalers, they may have problems with pMDI delivery, especially with hand-breath coordination. The use of a spacer or valved holding chamber can increase the bioavailability of the medication and reduce the need for hand-breath coordination but still requires patient training on proper technique.

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.

●Regimen simplicity – For many patients, complex inhaler regimens contribute to mistakes and poor adherence. Frequent problems include misidentification of controller therapies as rescue therapies and omission of nocturnal doses. We prefer to simplify inhaler regimens as much as possible, with once or twice daily single-inhaler triple therapy with LABA, LAMA, and ICS for most patients with refractory disease. The most frequent problems with this approach are insurance approval and poor patient inspiratory flow for activation of DPIs, as covered above.

When single-inhaler therapy is not possible, we strive to minimize the number of inhalers and number of actuations needed to improve ease-of-use and adherence.

●Cost and availability – Due to their status as pharmaceuticals and devices, inhaled medications often remain expensive even off-patent; shortages of certain devices or doses are also common. Prohibitive costs are a frequent contributor to poor patient adherence, but patients are sometimes embarrassed to report these issues to their physicians. Working with the patient's insurance carrier, pharmacist, and pharmaceutical company prescription assistance programs can help determine the most affordable options. In the United States, nebulized medications are sometimes covered under Medicare part B rather than part D; the added complexity of nebulized regimens must be weighed against the decrease in cost that can be derived from this approach. (See 'Use of nebulized therapies' above.)

Pulmonary function testing — For patients with refractory symptoms despite optimized inhaled therapies, we reevaluate air flow, lung volumes, and gas exchange, perform ambulatory pulse oximetry, and measure arterial blood gases at rest. The combination of pulmonary function testing, dyspnea and exacerbation assessment, and physical examination allows a reasonable assessment of disease severity and prognosis. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Assessment of severity and staging' and "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions", section on 'Prognostic factors'.)

Several typical pulmonary function testing patterns can be seen:

●Worsening obstruction without restriction – A falling forced expiratory volume in one second (FEV₁), often accompanied by air-trapping (high residual volume) and hyperinflation (elevated lung volumes at functional residual capacity and total lung capacity), suggests worsening obstruction and progression of COPD.

●New restrictive process – A decrease in lung volumes suggests a restrictive process such as interstitial lung disease, pleural effusion, or malignancy. This finding should prompt evaluation by chest computed tomography (CT). (See 'Imaging' below.)

●Isolated reduction in diffusing capacity (DLCO) – Isolated or worsening gas transfer out of proportion to the degree of airflow limitation is concerning for pulmonary vascular disease or combined pulmonary fibrosis and emphysema. For these patients, we 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) has developed. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults" and "Prognosis and monitoring of idiopathic pulmonary fibrosis", section on 'Combined pulmonary fibrosis and emphysema'.)

●Hypoxemia – Resting or exertional hypoxemia frequently manifest in patients with COPD due to poor matching of ventilation and perfusion with progressive disease. Hypoxemia should prompt discussion of and evaluation for supplemental oxygen. (See 'Oxygen' below and "Stable COPD: Overview of management", section on 'Supplemental oxygen' and "Long-term supplemental oxygen therapy".)

●Hypercapnia – Daytime hypercapnia arises from ventilation/perfusion mismatch and an inability to compensate with increased minute ventilation. Poor compensation arises from progressive air-trapping, malnutrition, and/or respiratory muscle weakness. Patients with daytime hypercapnia (eg, arterial carbon dioxide tension [PaCO₂] ≥52 mmHg) should undergo further counseling and consideration of nocturnal noninvasive ventilation. (See 'Nocturnal noninvasive ventilation' below and "Nocturnal ventilatory support in COPD".)

Imaging — After optimization of the inhaled therapeutic regimen and medication adherence, patients with refractory symptoms of COPD should undergo CT evaluation to assess for comorbid conditions and new disease processes. Possible findings include new interstitial lung disease, new lung cancer, evidence of pulmonary edema, indirect evidence of pulmonary hypertension, central airway obstruction, bronchiectasis, or bronchiolitis. Patients who continue to smoke or have quit smoking within the past 15 years generally qualify for CT screening for lung cancer. (See "High resolution computed tomography of the lungs" and "Screening for lung cancer".)

Given the common cardiac comorbidities of patients with COPD and possible development of cor pulmonale with advanced disease, we typically obtain echocardiography in patients with refractory symptoms. (See "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions" and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)

Other imaging evaluation will depend on individual patient factors.

Evaluating for comorbid diseases — Among patients with COPD, multiple comorbid or concomitant disease processes can contribute to dyspnea and exercise intolerance, including asthma, bronchiectasis, lung cancer, environmental allergies, coronary heart disease, heart failure, pulmonary hypertension, obesity, anemia, gastroesophageal reflux disease, chronic nasal/sinus disease, dysphagia or aspiration, immunodeficiency, sleep-disordered breathing, anxiety and depression, and cognitive impairment. Evaluating for these conditions by thorough history and physical examination often may reveal additional therapeutic options.

For patients without other indications based on history and physical examination, we routinely obtain chest imaging with CT and echocardiogram, as discussed above. We also take a sleep history to evaluate for obstructive sleep apnea (OSA), which can often impact exacerbations via nocturnal reflux aspiration (table 6). In patients whose sleep history suggests possible OSA, further sleep evaluation with polysomnography is appropriate. We also have a low threshold to obtain cardiac stress testing in patients whose dyspnea could be consistent with angina. (See "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions" and "Selecting the optimal cardiac stress test" and "Approach to the patient with suspected angina pectoris", section on 'History' and "Sleep-related breathing disorders in COPD".)

PHYSICAL, NUTRITIONAL, AND RESPIRATORY SUPPORT FOR PATIENTS WITH REFRACTORY COPD — Support and encouragement should be given to help patients with refractory COPD quit smoking, maximize physical fitness, and receive appropriate vaccinations against respiratory infections. Select patients with severe COPD may also benefit from supplemental oxygen, improved nutrition, and nocturnal noninvasive ventilatory support.

General — Routine supportive measures for COPD, including cigarette smoking cessation, vaccination against influenza, pneumococcus, and COVID-19 (table 7), and pulmonary rehabilitation, are cornerstones of COPD management and are discussed separately. (See "Stable COPD: Overview of management", section on 'Smoking cessation' and "Stable COPD: Overview of management", section on 'Vaccination' and "Pulmonary rehabilitation".)

Oxygen — Long-term supplemental oxygen therapy is recommended for persistent chronic hypoxemia (resting arterial oxygen tension [PaO₂] ≤55 mmHg or pulse oxygen saturation [SpO₂] ≤88 percent) to improve survival. Less stringent criteria (PaO₂ ≤59 mmHg or an SpO₂ ≤89 percent) are used if there is evidence of cor pulmonale, right heart failure, or erythrocytosis (hematocrit >55 percent). It is less clear whether supplemental oxygen therapy generally reduces dyspnea and improves exercise tolerance in patients with mild to moderate exertional hypoxemia in the absence of hypoxia at rest. In our experience, some patients do demonstrate improved exercise capability on supplemental oxygen, so we discuss with the patients a trial of supplemental oxygen in the setting of dyspnea and exertional hypoxemia (PaO₂ ≤55 mmHg, SpO₂ ≤88 percent). These issues are discussed in more detail 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 3) or a body mass index (BMI) ≤20 (calculator 4). 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 supplementation and diet modification have shown modest benefit in improving body weight, fat free mass, and exercise performance. In refractory cases, progesterone analogs and anabolic steroids have been used to help achieve weight gain, but they have the potential for adverse effects. Specific nutritional interventions are discussed in more detail separately. (See "Malnutrition in advanced lung disease".)

Nocturnal noninvasive ventilation — Noninvasive ventilatory support may be useful in patients with chronic respiratory failure due to COPD, which manifests with daytime hypercapnia or nocturnal hypoxemia not responsive to supplemental oxygen during sleep. A reasonable threshold for daytime hypercapnia that facilitates insurance coverage is a daytime arterial carbon dioxide tension (PaCO₂) ≥52 mmHg. For patients with more mild hypercapnia, home nocturnal high-flow therapy by nasal cannula may also decrease exacerbation frequency.

A failure of supplemental oxygen on nocturnal oximetry testing is defined by an SpO₂ ≤88 percent for ≥5 minutes despite supplemental oxygen at ≥2 L/min. Most patients with stable disease should be evaluated with polysomnography to exclude sleep apnea, which would be treated differently but may manifest similarly. Initiation in the sleep laboratory or the inpatient setting is helpful for achieving appropriate mask-fit, pressure settings, and patient acceptance of the device. Additional details are discussed separately. (See "Nocturnal ventilatory support in COPD" and "Sleep-related breathing disorders in COPD".)

PHARMACOLOGIC APPROACHES — For patients who have repeated exacerbations of COPD despite optimized therapy with a long-acting muscarinic agent (LAMA), a long-acting beta-agonist (LABA), plus an inhaled glucocorticoid (ICS) (algorithm 1), potential pharmacologic options include roflumilast or chronic azithromycin. For patients with persistent breathlessness, there are few proven pharmacologic therapies available; monitored theophylline and low-dose opiates may be helpful in some patients. Low-dose theophylline, mucolytics, and oral glucocorticoids are sometimes used, but lack of efficacy and adverse effects greatly limit their utility. In our experience, optimizing inhaled bronchodilators and glucocorticoids, assessing and treating comorbidities, and using supportive therapies are often more effective than additional pharmacologic agents in refractory COPD. (See 'Assessment of the patient with refractory COPD' above and 'Physical, nutritional, and respiratory support for patients with refractory COPD' above.)

For patients with frequent exacerbations

Our approach — For patients with recurrent exacerbations (eg, at least two per year or one requiring hospitalization per year) despite optimized inhaled therapies, we suggest either the phosphodiesterase-4 (PDE-4) inhibitor roflumilast or chronic azithromycin (algorithm 2). The choice between these medications is largely based on possible adverse effects (gastrointestinal side effects for roflumilast, long corrected QT interval (QTc) and hearing loss with azithromycin), as these agents have not been directly compared.

In tandem with a trial of azithromycin or roflumilast, patients with frequent exacerbations benefit from careful assessment of exacerbation triggers. These include continued smoking or vaping, other inhalational triggers (dusts, perfumes, molds, pollens), aspiration and reflux aspiration, recurrent sinusitis, and immunodeficiency. In addition to a detailed history, our typical work-up includes a barium swallow, a separate swallow evaluation by a speech and language therapist, and testing for human immunodeficiency virus (HIV) and common variable immunodeficiency. Further evaluation by an allergist, otolaryngologist, or gastrointestinal specialist may be helpful depending on the results.

For the subgroup of patients with recurrent exacerbations, chronic bronchitis, and peripheral eosinophilia >300 eosinophils/microL despite triple therapy and azithromycin and/or roflumilast, dupilumab therapy (off-label) may be helpful in reducing exacerbations and improving airflow obstruction based on one clinical trial [23].

Macrolides and other chronic antibiotic therapy — Azithromycin, 250 mg daily or 500 mg three times per week, reduces exacerbations in patients prone to exacerbations [2,24]. Macrolides may also have anti-inflammatory properties in addition to their direct antimicrobial function [25,26]. 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. The optimal duration of therapy is unclear, but 12-month courses or longer are typical. Other antibiotics are rarely used due to lack of evidence, adverse side effects, lack of efficacy, or to reserve their use for active pulmonary infections. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Prevention'.)

A systematic review of 14 trials evaluating 3932 patients with moderate to severe COPD found that the proportion of patients experiencing ≥1 exacerbation was 47 percent with prophylactic antibiotic use (primarily macrolides) compared with 61 percent with placebo (odds ratio [OR] 0.57, 95% CI 0.42-0.78) [27]. However, in one trial, use of azithromycin did not improve exacerbation rates in current smokers [28].

Chronic azithromycin therapy may lead to adverse effects. It should be avoided in patients with a long QT interval. Macrolides are associated with hearing loss in clinical trials, so hearing should be assessed periodically.

Azithromycin should also be avoided in patients with possible atypical mycobacterial infection based on symptoms or radiologic signs (bronchiectasis, tree in bud, chronic opacities on chest radiograph or CT) until sputum culture or polymerase chain reaction (PCR) testing returns. Positive testing for atypical mycobacterial infection should prompt consideration of treatment with combination antibiotic therapy. Chronic azithromycin can be used after negative sputum testing for mycobacteria. (See "Overview of nontuberculous mycobacterial infections".)

Further efficacy data and additional rationales for 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 also benefit from chronic antibiotic therapy. The treatment of bronchiectasis is discussed elsewhere. (See "Bronchiectasis in adults: Treatment of acute and recurrent exacerbations".)

Nonimmunized patients with COPD who are at high risk for contracting influenza and/or have early symptoms of acute influenza infection may also benefit from antiviral therapy. (See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention" and "Seasonal influenza in nonpregnant adults: Treatment".)

Phosphodiesterase-4 inhibitors (Roflumilast) — Daily treatment with roflumilast, an oral PDE-4 inhibitor, reduces the risk of COPD exacerbations in patients with severe COPD and a history of frequent COPD exacerbations (eg, at least two per year or one requiring hospitalization) [29-32]. PDE-4 inhibition may demonstrate this effect by decreasing airway inflammation and promoting airway smooth muscle relaxation [33-38]. The added benefit of roflumilast therapy on a background of other respiratory medications that reduce exacerbations (eg, LABA/ICS combination, LAMA) appears modest. In practice, this has limited roflumilast use 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 due to gastrointestinal side effects [39]. 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 (table 8).

The effects of PDE-4 inhibitors have been examined in several randomized trials and a meta-analysis [40-45]:

●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 forced expiratory volume in one second (FEV₁) (49 mL, 95% CI 44-54 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 [46].

●In a multicenter trial, 1945 patients with COPD, severe airflow obstruction, and at least two exacerbations in the prior year were randomly assigned to receive roflumilast (500 mcg once daily) or placebo for 52 weeks [47]. All patients used a combination ICS-LABA inhaler in addition to study medication; LAMAs were also allowed. Moderate to severe COPD exacerbations were 14 percent lower among those taking roflumilast compared with those taking placebo (0.81 versus 0.93 exacerbations per year, rate ratio 0.86, CI 95% 0.74-0.99). Severe exacerbations requiring hospital admission were decreased by 24 percent (rate ratio 0.76, 95% CI 0.6-0.96). High study drug discontinuation rates and the borderline significance of the outcomes are limitations of this study.

●Similarly, roflumilast had a modest impact on exacerbation rate compared with placebo (1.14 versus 1.37 exacerbations per year, relative risk reduction 17 percent [95%, CI 8-25]) in two trials (totaling 3091 patients) in COPD patients with frequent exacerbations but not treated with either ICS or LAMAs [43].

These trials indicate that roflumilast has a consistent and limited benefit on lung function alone and a modest impact on exacerbation rates in the setting of inhaled therapies. This has led to the approval and use of roflumilast as add-on maintenance therapy to prevent exacerbations; it is not used for improvement in other COPD outcomes [2]. Post hoc analyses have suggested roflumilast may be particularly helpful in the setting of prior hospitalization for an acute exacerbation [48].

Side effects are frequent with roflumilast. 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.

Frequent exacerbations despite azithromycin or roflumilast — For patients who continue to have frequent exacerbations without improvement despite a one-year trial of azithromycin or roflumilast, we suggest switching to the other agent unless there are contraindications to the alternative therapy (algorithm 2). For the subgroup of patients with chronic bronchitis and peripheral eosinophilia (>300 cells/microL) who have exacerbations despite both inhaled therapies and these oral agents, dupilumab may improve exacerbation rates based on evidence from one clinical trial.

Dupilumab is an IL-4 receptor monoclonal antibody that reduces asthma exacerbations when used as add-on therapy for patients with severe asthma and type-2 (eosinophilic) inflammation. Dupilumab is generally dosed at 600 mg subcutaneously as a loading dose, followed by 300 mg subcutaneously every other week. Adverse effects of dupilumab in asthma patients include injection site reactions (in about 15 percent) and transient eosinophilia, particularly in patients who experienced very high levels of eosinophils at baseline (>500 cells/microL). It is prudent to monitor peripheral eosinophil levels and symptoms of hypereosinophilia (eg, fever, arthralgias, and rash). Hypereosinophilic syndrome and eosinophilic vasculitides have been rarely reported. Further details of dosing and side effects are discussed elsewhere. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-lL-4 receptor alpha subunit antibody (dupilumab)'.)

We assess the response to treatment (eg, exacerbations, symptom control, lung function, adverse effects) after 6 to 12 months. Dupilumab should be discontinued if ineffective. Cost, needle phobia, and logistical barriers may limit the ability to use dupilumab in some patients.

In one trial (BOREAS), 939 patients with COPD, chronic bronchitis, and peripheral eosinophilia (>300 eosinophils/microL) who had recurrent moderate to severe exacerbations despite LAMA, LABA, and ICS therapy were randomly assigned to dupilumab 300 mg subcutaneously every two weeks or placebo [23]. Patients with any current or historical diagnosis of asthma or asthma-COPD overlap (ACO) were excluded. Despite lower exacerbation rates than expected due to the COVID-19 pandemic, dupilumab therapy resulted in reduced exacerbation rates (0.78 per patient/year with dupilumab versus 1.10 per patient/year with placebo; rate ratio 0.70, 95% CI 0.58-0.86). There were also modest improvements in airway obstruction after 52 weeks (prebronchodilator forced expiratory volume in one second [FEV₁] +150 mL with dupilumab versus +70 mL with placebo [difference 80 mL, 95% CI 40-130 mL]). Symptoms clinically improved in the dupilumab group at slightly higher rates than in the placebo group (St. George respiratory questionnaire improvement ≥4 at week 52 in 52 versus 43 percent [odds ratio 1.4, 95% CI 1.1-1.9]). Adverse events were similar or lower in the dupilumab arm; for example, major adverse cardiovascular events occurred in 0.9 percent of the patients in the dupilumab group and in 1.9 percent of those in the placebo group.

These results show a larger and more consistent effect than those seen in trials of anti-IL-5 therapies in COPD. Whether this is due to a larger benefit of targeting the IL-4 and IL-13 pathways or more stringent selection criteria (patients with higher eosinophil levels) in the BOREAS trial remains to be determined. Further work on biologic therapies may expand the indications and therapeutic agents available for patients with refractory COPD. (See "Stable COPD: Follow-up pharmacologic management", section on 'Future directions'.)

More formal evaluation of possible occult triggers (eg, allergy testing or sinus imaging) can also be helpful for these difficult-to-treat patients with persistent exacerbations despite many therapies. Concomitant treatment with combinations of azithromycin, roflumilast, or dupilumab has not been well-studied.

For patients with persistent dyspnea without exacerbations

Our approach — Patients with refractory COPD who experience persistent dyspnea without frequent exacerbations are often good candidates for nonpharmacologic interventions, including evaluation and treatment of comorbidities, pulmonary rehabilitation, bronchoscopic or surgical lung volume reduction, lung transplantation, and palliative therapies. For those who do not want, do not qualify for, or are awaiting more invasive interventions, a trial of theophylline (dosed to trough 5 to 12 mcg/mL) may improve lung function and exercise tolerance; however, its use requires close monitoring due to the narrow therapeutic window of this agent. As part of palliative disease management, opiates can also be helpful for dyspnea in this population (algorithm 3). (See 'Lung Volume Reduction, in select patients with dyspnea' below and 'Palliative care measures' below.)

Patients with severe COPD frequently experience significant exertional dyspnea despite optimized inhaled therapies. This is a natural consequence of the pathophysiology of COPD which can sometimes be mitigated but rarely abolished. We engage these patients in shared decision making around the pursuit of additional therapeutic options. Some patients prefer to manage expectations and make changes to their lifestyle rather than engage in therapies that require extensive monitoring, invasive testing, or extensive interaction with the health care system. For others, dyspnea has an intolerable impact on their quality of life, and they present to specialty care specifically for additional management of this symptom.

For patients pursuing treatment of dyspnea, pulmonary rehabilitation has been shown to be highly effective for improvement in quality of life and exercise tolerance [49] and should be performed prior to additional pharmacologic or surgical interventions.

Theophylline, monitored by drug levels — 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 [50,51]. For patients with COPD who have dyspnea despite maximal inhaled therapy and pulmonary rehabilitation, a trial of low-dose sustained-release theophylline (titrated to a trough serum level 5 to 12 mcg/mL) may improve symptoms. However, if a therapeutic response cannot be documented over four to six weeks, theophylline should be discontinued.

●Dosing, monitoring, and toxicity – Theophylline has a narrow therapeutic window and multiple adverse effects (eg, headaches, insomnia, nausea, heartburn, seizures, and cardiac arrhythmias). Dosing by level (trough 5 to 12 mcg/mL) reduces toxicity, but 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 [52,53]. (See "Theophylline poisoning" and 'Low-dose or unmonitored theophylline' below.)

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, including cytochrome oxidase CYP3A4 inducers and inhibitors (table 8), so awareness of potential interactions is essential. (See "Theophylline poisoning".)

Monitoring of serum levels is essential to avoid toxicity. Peak levels correlate best with toxicity, while trough levels are important for maintaining efficacy. Trials have varied in dosing strategy, but generally aim for trough levels above 5 mcg/mL and avoidance of peak levels greater than 20 mcg/mL. We prefer to check levels near trough, aiming for the lower end of the therapeutic range (5 to 12 mcg/mL). Twice daily dosing of sustained-release tablet formulations is preferred to balance ease of use with reducing differences between peak and trough levels. Capsule formulations (eg, Theo-24) may lead to erratic absorption and "dose-dumping," so are best avoided.

We initiate therapy with dosing at a daily dose of 10 mg/kg ideal body weight per day or 300 mg daily, whichever is lower. Trough levels should initially be checked after three to five days after initiating therapy or after each dose adjustment. Dosing can be increased by 20 percent if subtherapeutic. Elevated levels in the 13 to 20 mcg/mL range require dose reduction of 10 to 20 percent; higher levels should lead to stopping therapy for one day followed by dose reduction of 25 to 30 percent. 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 other medications change.

●Efficacy – A meta-analysis of 20 trials demonstrated that theophylline improved FEV₁, forced vital capacity (FVC), and gas exchange compared with placebo (eg, weighted mean improvement in FEV₁ 100 mL, 95% CI 40-160mL) [50]. However, theophylline did not improve walking distance or breathlessness on a visual analog scale. Many of the earlier studies included used higher dosing levels and did not include modern maximal inhaled therapies, so true efficacy is likely smaller and/or more variable.

Opioid therapy, for palliation — Opioids can provide symptomatic improvement in dyspnea on exercise testing [54] and are sometimes used in selected patients with severe dyspnea unresponsive to other nonpharmacologic and palliative approaches. However, in one placebo-controlled trial of 156 patients with moderate to severe COPD and modified Medical Research Council (mMRC) dyspnea scale scores ≥3 (calculator 1), use of extended-release morphine (8 to 32 mg daily, increased stepwise) had no significant effect on breathlessness intensity or on daily step count but did result in higher discontinuation rates and serious treatment-related adverse events [55]. These findings dampen enthusiasm for use of long-acting opioids except for palliation of highly advanced disease. For COPD patients initiated on opioid therapy, careful monitoring and individual dose titration are vital to avoid respiratory depression and other adverse side effects. These agents should only be used alongside additional palliative care measures. (See 'Palliative care measures' below and "Assessment and management of dyspnea in palliative care".)

The limited role for systemic glucocorticoids in refractory disease — Systemic glucocorticoids have long been used to treat exacerbations in patients with COPD, but they 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 [56,57]. The role of systemic glucocorticoids in the treatment of acute exacerbations of COPD is discussed in more detail separately. (See "COPD exacerbations: Management".)

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 [56-58]. Ongoing glucocorticoid use commonly occurs when discontinuing systemic glucocorticoids after a COPD exacerbation is repeatedly met with recurrent symptoms. In this setting, systemic glucocorticoids should be reduced to the lowest dose possible and other causes of symptoms addressed. Objective measures of improvement (eg, spirometry, walk test) must be used to justify any ongoing therapy, as emotional and euphoric effects of systemic glucocorticoids can cloud a patient's perception of benefit. (See "Major adverse effects of systemic glucocorticoids".)

Agents without clear benefit

Low-dose or unmonitored theophylline — Randomized trial data in patients on background inhaled therapies do not support a benefit to theophylline for exacerbation reduction or lung function improvement using small doses, whether alone or in combination with oral glucocorticoids [52,53,59].

●In one trial (TASCS), 1670 patients with moderate to very severe COPD were assigned to use low-dose, slow-release theophylline (100 mg twice a day), singly or in combination with oral prednisone (5 mg/day), or dual placebo along with usual care [53]. Over the 48-week treatment period, theophylline (alone or in combination with prednisone) did not reduce exacerbation rates. Secondary outcomes of hospitalizations, lung functions (FEV₁), respiratory qualities of life, and COPD Assessment Test (CAT) scores were similar among treatment groups.

●Similarly, another trial (TWICS) compared low-dose theophylline (200 mg once or twice per day; serum level 1 to 5 mcg/mL) with placebo in 1536 patients with severe COPD on ICS who had at least two exacerbations in the previous year [52]. Over a 52-week treatment period, theophylline did not reduce the number of COPD exacerbations or improve lung function compared with placebo.

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 conflicting evidence supports a potential 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 clear data to support mucolytic agents in patients with COPD refractory to triple inhaler therapy. Occasional patients may benefit from a trial of oral N-acetylcysteine (NAC). (See "Role of mucoactive agents and secretion clearance techniques in COPD".)

●Oral N-acetylcysteine – Thiol derivatives such as NAC, erdosteine, and carbocysteine are mucolytic agents designed to sever disulfide bonds of mucoproteins and DNA, possibly leading to reduced mucus viscosity. NAC also has 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, NAC, 600 mg twice daily) can be initiated on a trial basis and continued if there is symptomatic improvement.

One trial (PANTHEON) of 964 patients with moderate to severe COPD (mean FEV₁ 49 percent of predicted) found a reduction in exacerbations with NAC (600 mg tablets twice daily) compared with placebo [60]. However, only approximately 50 percent of patients were receiving inhaled bronchodilators and glucocorticoids and there was a high drop-out rate in the study. Furthermore, other studies of oral NAC as mucolytic/antioxidant therapy for COPD have yielded conflicting results; a systematic review concluded that evidence was insufficient to recommend this agent in COPD [2,61]. (See "Role of mucoactive agents and secretion clearance techniques in COPD", section on 'N-acetylcysteine (NAC)'.)

●Other agents – 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'.)

LUNG VOLUME REDUCTION, IN SELECT PATIENTS WITH DYSPNEA — Carefully selected patients with advanced COPD and refractory dyspnea may benefit from lung volume reduction surgery (LVRS) or nonsurgical bronchoscopic lung volume reduction (LVR) using endobronchial valves (EBVs) [62]. Given the invasive nature of these procedures, risk of complications, and sometimes modest benefit achieved, we reserve these therapies for motivated patients with low qualities of life due to severe dyspnea (usually modified Medical Research Council (mMRC) dyspnea scale score ≥3 (calculator 1)) (algorithm 3).

Rationale — Physiologically, surgical excision or valve-mediated collapse of the most emphysematous lung tissue may lead to decreased hyperinflation, improvement in the mechanical function of the diaphragm and chest wall, increased expiratory airflow, increased cardiac output, and improved ventilation-perfusion matching [63-70]. LVRS modestly improves spirometry, lung volumes, exercise capacity, dyspnea, and quality of life as well as long-term survival among selected patient subgroups [71]. When successful, bronchoscopic LVR has similar physiologic effects accompanied by modest improvements in dyspnea and quality of life [72-74].

However, patients with refractory COPD are often physiologically frail and have multiple comorbidities, increasing the potential for harm from invasive interventions. Careful preprocedural evaluation guides patient selection to increase the chance of benefit and reduce the risk of harm. Additional discussion of the rationale for LVR is covered elsewhere. (See "Lung volume reduction surgery in COPD", section on 'Rationale of LVRS' and "Bronchoscopic treatment of emphysema", section on 'Rationale and patient selection'.)

Periprocedural evaluation

●Timing – Further evaluation is appropriate for patients with a forced expiratory volume in one second (FEV₁) <50 percent predicted, known significant emphysema by pulmonary function tests or imaging, an optimized medication regimen, and persistent limiting breathlessness [75]. Evaluation of exercise capacity should be performed after completion of supervised pulmonary rehabilitation.

●Work-up – Ideal candidates for lung volume reduction have dyspnea associated with significant air-trapping and hyperinflation due to emphysema, moderately (but not severely) reduced exercise capacity and gas exchange, and no cardiac or anesthetic contraindications to undergoing the procedure. Testing typically includes pulmonary function tests, a six-minute walk test, arterial blood gas, electrocardiogram, echocardiogram with measurement of pulmonary artery pressures, and high-resolution computed tomography (HRCT).

CT imaging is critical to measure lobar volumes, determine the amount of emphysematous destruction of each lobe, exclude other important diseases like bronchiectasis, and assess nodules or other findings that may require additional evaluation. For bronchoscopic LVR via endobronchial valve placement, analysis of fissural integrity with CT imaging (eg, StratX or SeleCT) is also required.

Some centers also perform cardiopulmonary exercise testing to further assess cardiac and pulmonary limitations to exercise. (See "Lung volume reduction surgery in COPD", section on 'Evaluation' and "Bronchoscopic treatment of emphysema", section on 'Patient selection'.)

Patient Selection — The following clinical features should be present in patients referred for LVR:

●Persistent dyspnea despite optimized inhaled medical therapies and completion of pulmonary rehabilitation

●Severe obstruction (FEV₁ <50 percent predicted) accompanied by air-trapping (total lung capacity [TLC] >100 percent predicted and residual volume [RV] >150 percent predicted)

●Emphysema-predominant HRCT scan

●No active tobacco smoking

●Body mass index (BMI) <40

●Lack of severe resting hypoxemia or hypercarbia

●Absence of unstable cardiovascular disease

Generally, the selection criteria for LVRS are stricter due to the increased risk of perioperative morbidity after thoracic surgery. Patients with upper lobe-predominant disease and impaired exercise capacity have the most improved outcomes [76,77]. Surgical patients also should be less than 75 years of age, have an FEV₁ and diffusing capacity (DLCO) greater than 20 percent predicted, and have minimal additional comorbid illnesses (table 9). Indications and contraindications to LVRS are discussed in more detail separately. (See "Lung volume reduction surgery in COPD", section on 'Indications' and "Lung volume reduction surgery in COPD", section on 'Contraindications'.)

Selection criteria for endobronchial valve placement are largely similar but with some key differences that broaden the pool of potential candidates (table 10). There are no strict age criteria, and patients with more tenuous lung function (FEV₁ or DLCO 15 to 25 percent predicted) are better able to tolerate the procedure. Bronchoscopic techniques do not require heterogeneous distributions of emphysema or upper lobe-predominant disease; however, EBVs are physiologically more likely to be successful if the lobes with the most severe disease can be targeted. Patients must have minimal collateral circulation (ie, intact major and/or minor fissures) in the targeted lobes. Additional information on selection criteria for EBV placement is discussed elsewhere. (See "Bronchoscopic treatment of emphysema", section on 'Endobronchial valves'.)

Patients with significant collateral circulation of the most affected lobes may be more appropriate for investigational bronchoscopic LVR techniques. (See "Bronchoscopic treatment of emphysema", section on 'Investigational procedures'.)

Choice of procedure — We suggest referral of appropriate patients to a center with expertise in both LVRS and endobronchial valve placement. The most appropriate interventional approach should be guided by a multidisciplinary discussion and will depend upon physiologic and anatomic features, exercise capacity, comorbidities, and patient preference. Based on the data from relevant trials, LVRS likely has larger benefit in the best candidates but comes with higher perioperative risk. Bronchoscopic approaches are safer and available to a broader range of patients but likely provide a more modest benefit.

One small trial (n = 59) randomized COPD patients who met all preprocedure criteria for both unilateral LVRS and EBV placement to one of the two procedures [78]. Although follow-up results were impacted by the COVID-19 pandemic, physiologic outcomes were largely similar between the two groups. However, compared with patients who received EBVs, those who underwent LVRS had a greater improvement in symptoms when measured by the COPD assessment test (CAT; -7 versus -1 points; a six-point difference with 95% CI 2-9). This symptomatic benefit in LVRS patients was clinically relevant (the CAT minimal clinically important difference is 2 points). One-year safety outcomes were similar between the treatment groups. LVRS required a longer initial hospital stay, but EBV occasionally required repeat procedures. There was no perioperative (30-day) mortality in either group; a single death occurred in each arm by 12 months.

Lung volume reduction surgery — LVRS entails wedge excisions of emphysematous tissue to remove poorly functioning lung tissue and reduce hyperinflation. LVRS has shown benefit in terms of dyspnea, exercise capacity, quality of life, and mortality in patients with upper lobe-predominant emphysema and reduced exercise capacity but has shown less benefit or evidence of harm in other patient subgroups [76,77,79]. Additional information on efficacy and on the management of patients undergoing LVRS for COPD is available elsewhere. (See "Lung volume reduction surgery in COPD".)

Bronchoscopic lung volume reduction — 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 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 'Zephyr duckbill valve' and "Bronchoscopic treatment of emphysema", section on 'Spiration umbrella valve'.)

Placement of EBVs does not preclude subsequent LVRS or lung transplant. Additional detailed discussion regarding efficacy, complications, and management of EBVs is available separately. (See "Bronchoscopic treatment of emphysema", section on 'Endobronchial valves'.)

ADDITIONAL OPTIONS FOR PATIENTS WITH REFRACTORY DYSPNEA

Lung transplantation — The decision to proceed with lung transplantation for severe COPD is complex. Interested patients who meet criteria and who do not have relative contraindications should be referred to a transplant center for further evaluation and shared decision making.

Patients who are appropriate for referral should meet all of the following criteria [80]:

●Progressive disease despite maximal treatment including medication, pulmonary rehabilitation, and oxygen therapy

●Patient is not a candidate for surgical or endoscopic lung volume reduction surgery (LVRS); prior LVRS is acceptable [81]

●Body mass index (BMI), airflow obstruction, dyspnea, and exercise capacity (BODE) index score ≥5 (calculator 5)

●Postbronchodilator forced expiratory volume in one second (FEV₁) <25 percent of predicted

●Resting hypoxemia, defined as arterial oxygen tension (PaO₂) <60 mmHg (8 kPa) or hypercapnia, defined as carbon dioxide tension (PaCO₂) >50 mmHg (6.6 kPa)

Relative contraindications include:

●Advanced age (lung transplant is uncommonly performed in recipients over age 70 years)

●BMI >35 or (more commonly in advanced COPD) BMI <16

●Active tobacco use or other substance dependence

●Impaired kidney function (glomerular filtration rate (GFR) <40 mL/min/1.73m²)

●Cirrhosis with synthetic dysfunction or portal hypertension

●Limited functional status (minimally ambulatory)

●Severe coronary or cerebrovascular disease

●Frailty

●Critical illness (mechanical ventilation) at time of initial evaluation

Ample evidence suggests that functional capacity is improved following the procedure [82-86]. Data on survival are more mixed. The International Society for Heart and Lung Transplantation (ISHLT) registry shows a median survival of 7.1 years for patients who undergo lung transplantation for COPD [87]. 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 AATD (six [95% CI, 5.0-8.8] versus twelve years [95% CI, 9.6-13.5]) [88]. In a separate retrospective study of 54 patients, a global survival benefit was seen only in patients with a BODE score ≥7 (calculator 5) [89]. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection".)

Based on these data, 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 [90]. The following are suggested criteria for placing a patient with COPD on the transplant list (presence of one criterion is sufficient) [80]:

●BODE index score ≥7 (calculator 5)

●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

Additional information regarding candidate evaluation for lung transplantation can be found elsewhere. (See "Lung transplantation: General guidelines for recipient selection".)

Palliative care measures — 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 caregivers 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 11). (See "Palliative care for adults with nonmalignant chronic lung disease".)

Symptom management — Patients with advanced lung disease are frequently troubled by dyspnea but are also prone to other symptoms that may benefit from palliative approaches, including 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 them. The palliative care of patients with chronic lung disease and the evaluation and management of associated symptoms are discussed in more detail 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 – There are many techniques helpful for ameliorating dyspnea (table 12). Exercise training, breathing techniques, and accommodation strategies are often particularly helpful in patients with advanced COPD. Selected patients with refractory dyspnea may also benefit from opioid therapy, along with careful monitoring 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. 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 [91-94]. Respiratory stimulants are not beneficial to these patients and can often accentuate dyspnea even in those with hypercapnic COPD.

●Cough – Some patients with COPD have moderate to severe cough that disrupts sleep and other daily activities. While peripherally acting antitussive agents (eg, benzonatate) are sometimes helpful, these patients frequently require centrally acting agents, including opioids or GABA analogs (eg, gabapentin, pregabalin), for relief. (See "Palliative care: Overview of cough, stridor, and hemoptysis in adults".)

Advance care planning — Advance care planning (ACP), defined as "planning for and about preference-sensitive decisions often arising at the end of life," can prevent invasive and unwanted care during severe exacerbations or at the end of life in patients with advanced COPD. The best practices for ACP discussions between patients, their caregivers, and their healthcare providers are discussed elsewhere. (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 13). 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 5^th to 6^th 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 10^th to 12^th 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 COPD (The Basics)" and "Patient education: Shortness of breath (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

●Assessment of the patient with refractory COPD – Symptoms and exacerbations of COPD can usually be controlled with interventions such as smoking cessation, vaccinations against influenza and pneumococcal infections, pulmonary rehabilitation, and one or more inhaled medications. In a minority of patients with COPD, symptoms and exacerbations are persistent despite these interventions. (See 'Introduction' above and "Stable COPD: Initial pharmacologic management".)

•When evaluating patients with refractory symptoms, first steps include quantitative assessment of exacerbation history and symptoms and addressing smoking cessation, proper inhaler technique, and adherence to prescribed inhalers. (See 'Evaluation of dyspnea, exacerbation history, and other symptoms and signs' above and 'Optimizing inhaled therapies' above.)

•If no obvious solutions arise from this initial assessment, we routinely reevaluate air flow, lung volumes, and gas exchange, perform ambulatory pulse oximetry during a six-minute walk test, and perform arterial blood gas testing at rest. Depending on the results, further evaluation typically includes echocardiography and/or high-resolution computed tomography (HRCT). (See 'Pulmonary function testing' above and 'Imaging' above.)

•Common comorbidities of COPD can contribute to dyspnea and exercise intolerance, including coronary heart disease, heart failure, obesity, lung cancer, sleep-disordered breathing, anxiety, and depression. (See 'Evaluating for comorbid diseases' above.)

●Physical, nutritional, and respiratory support – General measures for patients with COPD include smoking cessation, physical fitness including pulmonary rehabilitation, and vaccinations against respiratory infections. Select patients with severe COPD may also benefit from supplemental oxygen, nutritional supplementation, and nocturnal noninvasive ventilatory support. (See "Stable COPD: Overview of management", section on 'General measures for all patients' and 'Physical, nutritional, and respiratory support for patients with refractory COPD' above and "Stable COPD: Overview of management", section on 'Supplemental oxygen' and "Long-term supplemental oxygen therapy" and "Nocturnal ventilatory support in COPD".)

●Patients with recurrent exacerbations – For patients with recurrent exacerbations (eg, at least two per year or one requiring hospitalization) despite triple inhalers, we suggest either the phosphodiesterase-4 (PDE-4) inhibitor roflumilast or chronic azithromycin therapy (Grade 2C) (algorithm 2). The choice between these medications is largely based on anticipated adverse effects, as they have not been directly compared. (See 'For patients with frequent exacerbations' above.)

•Chronic azithromycin is usually given as 250 mg daily or 500 mg three times a week. Azithromycin may be less effective in current smokers and should be avoided in patients with a long QT interval. (See 'Macrolides and other chronic antibiotic therapy' above.)

•Roflumilast maintenance dosing is 500 mcg once daily. 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 (Roflumilast)' above.)

•For patients who do not benefit or have intolerable side effects from a one-year therapeutic trial of one of these oral agents, we suggest discontinuation and a trial of the alternative agent (Grade 2C).

•For the subgroup of patients with recurrent exacerbations (eg, at least two per year or one requiring hospitalization) despite triple inhalers and a trial of azithromycin and/or roflumilast, as well as both chronic bronchitis and peripheral eosinophilia (>300 cells/microL), we suggest a trial of dupilumab (off-label) (Grade 2C) based on evidence of efficacy in a single trial. The usual dose of dupilumab is 300 mg subcutaneously every two weeks. Cost, needle phobia, and logistical barriers may sometimes limit this approach. Patients who do not benefit after 6 to 12 months should not continue dupilumab therapy. (See 'Frequent exacerbations despite azithromycin or roflumilast' above.)

●Patients with dyspnea – For patients with persistent dyspnea despite optimal inhaled therapy, pulmonary rehabilitation is an appropriate first step in management. We subsequently engage in shared decision making about the patient's quality of life, current level of function, feasibility of frequent medical follow-up, and comfort with more intensive medical or interventional therapies (algorithm 3).

For those who wish to pursue more intensive therapies for dyspnea, we support the following strategies:

•For patients with hyperinflation due to severe emphysema who remain symptomatic despite optimal medical therapy and pulmonary rehabilitation (table 9 and table 10), we suggest evaluation at a center with expertise in surgical and bronchoscopic lung volume reduction (Grade 2C). (See 'Lung Volume Reduction, in select patients with dyspnea' above.)

•For patients with poor qualities of life due to dyspnea despite or while awaiting invasive interventions, or who do not qualify for such interventions, we suggest a trial of low-dose theophylline (serum trough level 5 to 12 mcg/mL) (Grade 2C). Caution is advised as theophylline has more adverse effects than inhaled bronchodilators, variable dosing with multiple medication interactions, and the potential for severe toxicity at high levels. Dosing and monitoring are presented above. (See 'Theophylline, monitored by drug levels' above.)

•For patients with dyspnea and advanced or refractory COPD, it is appropriate to pursue advanced care planning (ACP) discussions. Additional palliative approaches can help relieve dyspnea, anxiety, and depression in the setting of advanced lung disease. Low-dose opiates for dyspnea management may be included in these interventions. (See 'Palliative care measures' above.)

●Refractory dyspnea despite the above interventions – Patients who continue to have significant symptoms may be considered for lung transplantation and evaluated for additional palliative care, including hospice. (See 'Additional options for patients with refractory dyspnea' above.)