COPD exacerbations: Prognosis, discharge planning, and prevention

INTRODUCTION — An exacerbation of chronic obstructive pulmonary disease (COPD) is defined as "an event characterized by dyspnea and/or cough and sputum that worsens over ≤14 days, which may be accompanied by tachypnea and/or tachycardia and is often associated with increased local and systemic inflammation caused by airway infection, pollution, or other insult to the airways" by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), a report produced by the National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO) [1,2]. This generally includes an acute change in one or more of the following cardinal symptoms:

●Cough increases in frequency and severity

●Sputum production increases in volume and/or changes character

●Dyspnea increases

The prognosis after a COPD exacerbation and strategies for prevention of future exacerbations will be discussed here. The risk factors, clinical manifestations, diagnosis, and management of COPD exacerbations are discussed separately. (See "COPD exacerbations: Clinical manifestations and evaluation" and "COPD exacerbations: Management" and "Management of infection in exacerbations of chronic obstructive pulmonary disease".)

PROGNOSIS AFTER AN EXACERBATION — Exacerbations of COPD are associated with increased morbidity and mortality [1,3-5]. Individuals who have experienced a single moderate COPD exacerbation, compared with those without exacerbation, have an increased risk of respiratory and all-cause mortality (hazard ratios 2.98 [95% CI 1.14-7.83] and 1.34 [95% CI 0.79-2.29], respectively) [4].

A number of factors influence mortality following hospital discharge after an exacerbation of COPD, including older age, the severity of the underlying COPD, requirement for long-term oxygen at discharge, presence of comorbidities (eg, cardiovascular disease or lung cancer), and the presence of Pseudomonas aeruginosa in the patient's sputum, as described in the following studies [6-14]:

●For patients hospitalized with a COPD exacerbation, in-hospital mortality ranges from three to nine percent [12-14]. In a separate study of patients who required noninvasive ventilation, in-hospital mortality was 11 percent [15].

●In a study of 260 patients admitted with a COPD exacerbation, the one year mortality was 28 percent [9]. Independent risk factors for mortality were age, male sex, prior hospitalization for COPD, arterial tension of carbon dioxide (PaCO₂) ≥45 mmHg (6 kPa), and blood urea >8 mmol/L (BUN 22 mg/dL).

●Patients hospitalized for a COPD exacerbation who have Pseudomonas aeruginosa in their sputum have a higher risk of mortality at three years than those without (59 versus 35 percent; HR 2.33, 95% CI 1.29-3.86), independent of age, comorbidity, or COPD severity [10].

Even if the COPD exacerbation resolves, many patients never return to their baseline level of health [5].

COMPREHENSIVE DISCHARGE PLANNING — For patients who have required hospitalization for a COPD exacerbation, formal criteria for discharge and a comprehensive discharge plan may help to reduce readmissions and recurrent exacerbations, although supportive data are mixed [1,16-18]. Nonetheless, the following discharge planning steps appear sensible and are consistent with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy [1]. (See "Hospital discharge and readmission".)

Criteria for discharge — Criteria for discharge generally depend on sufficient improvement in the manifestations of COPD such that the patient’s condition has stabilized, and frequent nebulizer treatments are no longer required. If the patient is near their prehospital baseline, discharge to home is likely appropriate. However, some patients no longer require hospital-level care but are unable to manage at home due to frailty or severe exercise intolerance; for these patients, a period of inpatient rehabilitation may be more suitable. Patients requiring nocturnal noninvasive ventilation may benefit from a rehabilitation hospital stay. (See "Hospital discharge and readmission", section on 'Determining the post-discharge site of care'.)

When deciding whether a patient can be discharged to home, the patient’s ability to manage activities of daily living (ADLs) at home should be assessed along with the need for assistive devices such as a walker, elevated toilet seat, bedside commode, or shower chair. (See "Comprehensive geriatric assessment", section on 'Activities of daily living'.)

Discharge to home checklist — A number of issues pertaining to COPD exacerbations in particular and hospitalizations in general must be assessed as part of discharge planning, such as: the transition from hospital to home (eg, oxygen en route, stairs to climb), the patient’s ability to obtain and self-administer medications, meal preparation and self-feeding, and the need for visiting nurse, in-home services, and hospice.

A checklist can ensure that important steps to enable a smooth transition to home are not overlooked. Checklists may be general (table 1) or specific to COPD (form 1). Components that are thought to improve discharge success include the following [1]:

●Explain diagnosis and planned postdischarge therapy with patient/caregiver; ensure understanding and agreement with the regimen

●Review with patient the technique(s) of all inhaler devices that will be used at discharge and assess their technique

●Review management plans for comorbidities (eg, heart failure, coronary heart disease, arrhythmia, lung cancer screening, sleep-related breathing disorders, metabolic syndrome, anxiety, depression)

●Ensure that patient understands written and verbal directions for withdrawal of acute medications (eg, antibiotics, systemic glucocorticoids) used to treat exacerbation

●Confirm that patient has received appropriate vaccinations for seasonal influenza, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and S. pneumococcus (See "Pneumococcal vaccination in adults" and "Standard immunizations for children and adolescents: Overview".)

●Provide smoking cessation education and medication to patients who smoke

●Assess need for supplemental oxygen and prescribe if indicated; ensure that supplemental oxygen will be available for transfer to home and in the home before the patient arrives

●Assess need for home nebulizer treatments and arrange for nebulizer if needed

●Arrange for out-patient pulmonary rehabilitation program, as appropriate

●Advise patient regarding any pending test results or planned follow-up testing (eg, lung cancer screening)

●Confirm follow-up visits at approximately one and four weeks, and as indicated

Patients who have a new prescription for long-term oxygen typically need additional instruction on the use of oxygen delivery systems (eg, tanks, concentrators, portable systems) and safe practices regarding oxygen tubing as a tripping hazard and avoiding exposure to open flames (see "Long-term supplemental oxygen therapy" and "Portable oxygen delivery and oxygen conserving devices"). Such patients should be reassessed two to three months after discharge regarding whether supplemental oxygen is still needed and, if so, at what dose.

Palliative care planning — The disease trajectory in COPD is heterogenous and ranges from gradual worsening of exercise tolerance and oxygenation to a sudden and unanticipated end-of-life. Given the difficulties in predicting the clinical course, an exacerbation requiring hospitalization, particularly one requiring intensive care, creates an opportunity to discuss a palliative care consultation. Criteria for considering a palliative care referral are listed in the table (table 2). (See "Palliative care for adults with nonmalignant chronic lung disease", section on 'What are the indications for a palliative care consultation?'.)

The primary care provider or pulmonary specialist can raise the possibility of a palliative care approach and obtain a palliative care consultation, if needed. Important components of palliative care include exploring the patient’s understanding about their illness and prognosis, assessing and managing symptoms, discussing goals of care and advance care planning, coordinating care, and helping to plan end-of-life care, including determining the need and timing of hospice care (table 3). (See "Palliative care for adults with nonmalignant chronic lung disease".)

For patients with advanced COPD, it may be reasonable to discuss hospice care at home. Disease specific guidelines are listed in the table and discussed separately (table 4). (See "Palliative care for adults with nonmalignant chronic lung disease" and "Hospice: Philosophy of care and appropriate utilization in the United States".)

PREVENTION

General measures — Several measures can reduce the frequency of COPD exacerbations including the following [1,19-21]:

•Smoking cessation (see "Overview of smoking cessation management in adults")

•Proper use of medications (including inhaler technique) (table 5 and table 6 and table 7 and table 8) (see "The use of inhaler devices in adults")

•Vaccination against seasonal influenza (see "Seasonal influenza vaccination in adults")

•Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see "COVID-19: Vaccines")

•Pneumococcal vaccination (figure 1) (see "Pneumococcal vaccination in adults")

•Vaccination against respiratory syncytial virus (suspected benefit, which will be revisited as data emerge) (see "Overview of preventive care in adults", section on 'Immunization')

Pulmonary rehabilitation — Pulmonary rehabilitation has a number of benefits; it significantly reduces future hospital admissions and mortality and improves exercise tolerance and quality of life, compared with usual community care [22]. After a COPD exacerbation, we encourage patients to participate in a pulmonary rehabilitation program, if they have not yet done so. The optimal timing for initiating pulmonary rehabilitation after a COPD exacerbation has not been determined and likely needs to be individualized; patients need to have recovered sufficiently to maximize the benefits of exercise training. (See "Pulmonary rehabilitation", section on 'Benefits' and "Pulmonary rehabilitation", section on 'Setting'.)

Physical activity — While pulmonary rehabilitation programs are preferred, if one is not available, physical activity (exercising two to three times per week for 30 minutes to a level that causes mild shortness of breath) may reduce hospitalizations for COPD exacerbations based on observational data [19]. Further study is needed on alternatives to pulmonary rehabilitation programs in under-resourced settings.

Optimizing medications for COPD — A number of medications for COPD reduce the frequency of COPD exacerbations. A personalized approach to medication selection should be based on the patient’s severity of COPD symptoms and exacerbation frequency, noting that certain medications may be of greater benefit for some patients than others [1]. As an example, inhaled glucocorticoids reduce exacerbations in patients with a history of exacerbations but are not likely to be of benefit in patients with low blood eosinophils. (See "Stable COPD: Follow-up pharmacologic management", section on 'Persistent exacerbations with or without dyspnea'.)

The selection among these medications and their efficacy in reducing exacerbations are reviewed separately (algorithm 1 and table 9):

●Long-acting muscarinic antagonists (LAMA). (See "Stable COPD: Initial pharmacologic management", section on 'Long-acting muscarinic antagonists'.)

●Long-acting beta-agonists (LABA). (See "Stable COPD: Initial pharmacologic management", section on 'Long-acting beta-agonists'.)

●LAMA-LABA combination inhalers. (See "Stable COPD: Initial pharmacologic management", section on 'Use of dual bronchodilator therapy'.)

●LABA-glucocorticoid combination inhalers. (See "Stable COPD: Initial pharmacologic management", section on 'Alternative approaches'.)

●LAMA-LABA-glucocorticoid combination inhalers. (See "Stable COPD: Follow-up pharmacologic management".)

●Roflumilast, an oral PDE-4 inhibitor, reduces 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). (See "Management of refractory chronic obstructive pulmonary disease", section on 'Phosphodiesterase-4 inhibitors (Roflumilast)'.)

●Oral thiol derivatives, such as N-acetylcysteine (NAC), erdosteine, and carbocysteine, are used to thin secretions in patients with bothersome sputum production, but studies have not demonstrated a reduction in exacerbations. (See "Role of mucoactive agents and secretion clearance techniques in COPD", section on 'Thiols and thiol derivatives' and "Management of refractory chronic obstructive pulmonary disease", section on 'Mucoactive agents'.)

For patients whose medications are changed during a hospitalization, it is important to reevaluate discharge medications at office visits in the next one to four weeks. This is a good time to consolidate inhaled medications into a single inhaler if possible or to select inhaler devices that use the same technique. The proper technique should be reviewed for every inhaler that the patient is using. If the patient has poor inspiratory flow or is unable to demonstrate proper technique, nebulized medication from the appropriate class can be substituted: LAMAs (revefenacin), LABAs (formoterol and arformoterol), and glucocorticoid (budesonide).

Prophylactic azithromycin — For patients with recurrent exacerbations (≥2 per year) despite optimal therapy (eg, long-acting bronchodilators with or without inhaled glucocorticoids, smoking cessation, vaccinations, and pulmonary rehabilitation), prophylactic azithromycin may reduce the frequency of exacerbations. The dosing, potential adverse effects, and evidence in support of prophylaxis with azithromycin are described separately. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Prophylactic macrolides' and "Management of refractory chronic obstructive pulmonary disease", section on 'Macrolides and other chronic antibiotic therapy'.)

GLP-1 receptor agonists and SGLT-2 inhibitors, for diabetic patients — Glucagon-like peptide 1 (GLP-1) receptor agonists (eg, liraglutide) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors (eg, dapagliflozin) may offer some protection against exacerbations in patients with diabetes and COPD, although further data are needed to confirm these findings.

●In one population-based cohort study of patients with COPD and new initiation of an antihyperglycemic agent, 1252 patients who began GLP-1 receptor agonists and 2956 patients who began SGLT-2 inhibitors were matched with similar patients who received sulfonylureas instead [23]. Compared with patients receiving sulfonylureas, those on GLP-1 receptor agonists were less likely to be hospitalized for COPD exacerbations (3.5 versus 5.0 percent of patients per year [HR 0.7, 95% CI 0.49-0.99]); similar results were seen for those on SGLT-2 inhibitors (2.4 versus 3.9 percent per year [HR 0.62, 95% CI 0.48-0.81]).

●In a separate retrospective database analysis, 1642 patients with COPD initiating new oral agents for DM were evaluated over six months following treatment initiation [24]. The adjusted incidence rates of moderate or severe exacerbations were improved with GLP-1RA inhibitors compared with dipeptidyl peptidase-4 inhibitors (incidence rate ratio [IRR] 0.67, 95% CI 0.49-0.93) or sulfonylureas (IRR 0.49, 95% CI 0.37-0.62); there was no difference compared with SGLT-2 inhibitors.

The mechanism underlying the potential benefits of these agents is unclear. GLP-1 receptor agonists have been shown to reduce inflammation and result in weight loss, with improvements in lung function in small clinical trials [25,26]. SGLT-2 inhibitors decrease endogenous carbon dioxide production via metabolic effects and appear to decrease risk of pneumonia based on meta-analyses of cardiovascular trials [27].

Future trials are needed to determine whether use of GLP-1 receptor agonists or SGLT-2 inhibitors are preferable to other antihyperglycemic agents in patients with DM and risk for COPD exacerbations.

Noninvasive ventilation — For patients who require noninvasive ventilation (NIV) during a hospitalization for a COPD exacerbation and who remain hypercapnic, nocturnal NIV at home significantly reduces the risk of rehospitalization. (See "Nocturnal ventilatory support in COPD".)

Vitamin D supplementation — Adhering to current guidelines regarding vitamin D supplementation in patients with a 25-hydroxyvitamin D level <20 or 30 ng/mL (50 or 75 nmol/L) reduces COPD exacerbations in addition to benefits in reducing falls and fractures (see "Overview of vitamin D"). While randomized trials were conflicting [28-31], a systematic review and meta-analysis used individual patient data from three of the four randomized trials to examine the role of supplementation in patients with 25-hydroxyvitamin D (25[OH]D) levels <25 nmol/L [32].

In the meta-analysis, vitamin D supplementation did not reduce the rate of moderate-to-severe COPD exacerbations overall, but a prespecified subgroup analysis revealed protective effects in patients with a baseline serum 25[OH]D level <10 ng/mL (<25 nmol/L; adjusted rate ratio 0.55, 95% CI 0.36-0.84). The trial that was not included in the analysis had separately found a benefit to vitamin D supplementation in this setting, so its exclusion was unlikely to affect the results. No increase in adverse events was noted with vitamin D supplementation.

The serum 25(OH)D level <10 ng/mL (<25 nmol/L) used as a threshold in the meta-analysis is well below the minimum level of 20 or 30 ng/mL (50 or 75 nmol/L) advised by national and international guidelines to prevent falls and fracture. Estimates of vitamin D requirements to achieve sufficient levels vary and depend in part upon sun exposure. The optimal intake of vitamin D to prevent deficiency is discussed separately. (See "Overview of vitamin D" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Optimal intake to prevent deficiency'.)

Separate studies suggest that vitamin D supplementation prevents acute respiratory tract infections, particularly in patients who are vitamin D deficient, which might contribute to the benefit in preventing COPD exacerbations [33].

INEFFECTIVE INTERVENTIONS

Selective beta-blockers — Preliminary data and a meta-analysis of 15 observational studies suggested that therapy with selective beta-blockers (given for comorbid cardiovascular disease) might reduce COPD exacerbations [34-36]. However, a randomized trial that included 532 patients with COPD and an increased risk of exacerbation (eg, moderate airflow limitation, exacerbation in the previous year, prescribed use of oxygen), but no cardiac indication for beta-blocker therapy, found that extended release metoprolol (25 to 100 mg/day) did not decrease the time to first exacerbation compared with placebo (hazard ratio 1.05, 95% CI 0.84 to 1.32) [37]. The study was stopped early for safety concerns. Metoprolol was associated with an increased risk of an exacerbation leading to hospitalization (hazard ratio 1.91, 95% CI 1.29 to 2.83), although the reason for this increase was unclear. There was no between group difference in forced expiratory volume in one second (FEV₁).

Based on this study, selective beta-blockers do not have a role in prevention of COPD exacerbations but continue to be used for patients with a cardiovascular indication. (See "Management of the patient with COPD and cardiovascular disease".)

Statins — Statins (hydroxymethylglutaryl [HMG] CoA reductase inhibitors) do not diminish COPD exacerbations, although they may have other health benefits. In observational studies of COPD, statins were associated with a reduced rate and severity of exacerbations, rate of hospitalizations, and mortality [38-41]. However, these beneficial effects were not supported in a trial that randomly assigned 885 participants with COPD, but without other indications or contraindications for statin therapy, to simvastatin 40 mg daily or placebo for up to 36 months [42]. Simvastatin did not reduce the rate of exacerbations or the time to first exacerbation. A systematic review found no clear benefit to statins in terms of lung function, exercise capacity, or mortality, but deemed evidence to be low quality [43]. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

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: Pulmonary rehabilitation (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Prognosis after exacerbations – Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased risk of mortality. For patients hospitalized with a COPD exacerbation, in-hospital mortality ranges from 3 to 9 percent and one-year mortality of approximately 25 percent. (See 'Prognosis after an exacerbation' above.)

●General measures – Several general measures can help reduce the frequency of COPD exacerbations, including smoking cessation, pulmonary rehabilitation and increased physical activity, proper use of medications (including correct inhaler technique), and vaccination against seasonal influenza, SARS-CoV-2, and pneumococcus (figure 1). (See 'General measures' above.)

●Pharmacologic interventions – Most medications for COPD reduce the frequency of COPD exacerbations, including long-acting muscarinic antagonists (LAMAs), long-acting beta-agonists (LABAs), inhaled glucocorticoids, and roflumilast. The selection among these medications is based on the patient’s severity of symptoms and risk of exacerbations and is discussed separately. (See 'Optimizing medications for COPD' above.)

•Chronic azithromycin – For patients with recurrent exacerbations (≥2 per year) despite optimal therapy with long-acting bronchodilator and glucocorticoid inhalers, prophylactic azithromycin may also reduce the frequency of exacerbations. (See 'Prophylactic azithromycin' above and "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Prophylactic macrolides' and "Management of refractory chronic obstructive pulmonary disease", section on 'For patients with frequent exacerbations'.)

●Noninvasive ventilation, for hypercapnic patients – For patients who require noninvasive ventilation (NIV) during a hospitalization for a COPD exacerbation and who remain hypercapnic, nocturnal NIV at home significantly reduces the risk of rehospitalization. (See 'Noninvasive ventilation' above and "Nocturnal ventilatory support in COPD".)

●Comprehensive discharge planning – After hospitalization for a COPD exacerbation, formal criteria for discharge and a comprehensive discharge plan may help to reduce readmissions and recurrent exacerbations after hospitalization for a COPD exacerbation (form 1). (See 'Comprehensive discharge planning' above.)