INTRODUCTION — 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), defines an exacerbation of chronic obstructive pulmonary disease (COPD) as "an acute event characterized by a worsening of the patient's respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication" [1]. 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 clinical manifestations and evaluation of patients with exacerbations of COPD are discussed in detail here. A table to assist with emergency management of severe acute exacerbations of COPD is provided (table 1). The diagnosis and treatment of stable COPD and the treatment, risk factors, prognosis, and prevention of exacerbations of COPD are discussed separately.
●(See "Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging".)
●(See "Stable COPD: Overview of management".)
●(See "COPD exacerbations: Management".)
●(See "COPD exacerbations: Prognosis, discharge planning, and prevention".)
EPIDEMIOLOGY — Among patients with COPD, the frequency of exacerbation varies with the severity of disease, and some patients have more frequent exacerbations than others independent of other measures of disease severity [1,2].
●Among almost 100,000 patients with COPD, the number of exacerbations in a baseline year of observation predicted the rate over the subsequent 10 years [3]. Approximately, 25 percent did not have an exacerbation; those with one baseline exacerbation were likely to have another (hazard ratio [HR] 1.71, 95% CI 1.66-1.77); and those with ≥5 events were even more likely to have future events (HR 3.41, 95% CI 3.27-3.56).
●A study of Medicare beneficiaries found a 64 percent readmission rate after a discharge for a COPD exacerbation [4].
●In a survey that included over 4000 respondents with COPD, approximately 10 to 25 percent needed an emergency room evaluation for COPD and 5 to 10 percent required hospitalization [5].
●In a separate survey of more than 1000 patients, 21 percent of those who reported a COPD exacerbation required hospitalization [6].
RISK FACTORS AND TRIGGERS
Risk factors — According to observational studies, the risk of developing an exacerbation of COPD correlates with the following features [7-12]:
●Advanced age
●Productive cough
●Longer duration of COPD
●History of antibiotic therapy
●COPD-related hospitalization within the previous year
●Chronic mucous hypersecretion
●Peripheral blood eosinophil count >0.34 x 109 cells/L (340 cells/microL)
●Theophylline therapy
●Presence of one or more comorbidities (eg, ischemic heart disease, heart failure, or diabetes mellitus)
Women are slightly more likely to experience a COPD exacerbation than men [12,13]. In general, worsening airflow limitation (lower forced expiratory volume in one second [FEV1]) is associated with an increasing risk of COPD exacerbation, although airflow limitation alone does not provide a good assessment of exacerbation risk [1].
Other potential contributors to an increased risk of exacerbations include the following:
●Severity of COPD and history of prior exacerbations – In the prospective Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, 2138 patients with moderate to severe COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 2, 3, or 4 (table 2)) were followed for three years [14]. The single best predictor of exacerbations was a history of prior exacerbations, regardless of COPD severity [3].
The GOLD guidelines suggest using a combination of an individual's FEV1, history of exacerbations, history of hospitalization for exacerbation, and symptoms to assess the exacerbation risk [1]. The number of exacerbations in the previous 12 months is stratified: A history of zero or one exacerbation suggests a low future risk of exacerbations, while two or more suggest a high future risk [1]. The severity of lung function impairment is stratified based on the postbronchodilator FEV1, using the GOLD classification of airflow limitation (table 2). These components are combined as follows:
•Low risk: Typically GOLD 1 or 2 (mild to moderate airflow limitation) and/or 0 to 1 exacerbation per year, no hospitalization due to an exacerbation
•High risk: Typically GOLD 3 or 4 (severe or very severe airflow limitation) and/or ≥2 exacerbations per year or ≥1 hospitalization due to an exacerbation
The full COPD staging system used in the GOLD guidelines incorporates information about the severity of symptoms (based on instruments such as the COPD Assessment Test [CAT] and the modified Medical Research Council Dyspnea Scale), the degree of airflow limitation (based on the FEV1), and the frequency of prior COPD exacerbations and is discussed separately [1]. (See "Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging", section on 'Assessment of severity and staging'.)
●Gastroesophageal reflux disease – Gastroesophageal reflux disease (GERD) may be an additional risk factor for COPD exacerbations [15,16]. In the ECLIPSE study noted above, the occurrence of two or more exacerbations in a year was associated with a history of GERD or heartburn [14]. A similar observation was made in a case-control study that assessed the presence of GERD symptoms and frequency of COPD exacerbations in 80 patients with COPD. The presence of GERD symptoms was associated with an increased risk of COPD exacerbations (RR 6.55, 95% CI 1.86-23.11) [15]. However, in an observational study of 638 patients with stable COPD, therapy with proton pump inhibitors did not decrease the risk for severe exacerbations [17]. Additional studies are needed to determine whether GERD contributes to the development of COPD exacerbations.
●Pulmonary hypertension – Secondary pulmonary hypertension may be an additional risk factor for COPD exacerbations, possibly as an indicator of disease severity. In a follow-up to the ECLIPSE study, chest computed tomography scans were used to compute the ratio of the diameter of the pulmonary artery to the diameter of the aorta (PA:A ratio) [18]. In the study, a PA:A ratio greater than 1 was an independent risk factor for a future severe exacerbation (OR 3.44, 95% CI 2.78-4.25). Notably, a PA:A ratio >1 suggests the presence of pulmonary hypertension, although it does not clarify the cause of pulmonary hypertension (eg, hypoxemia due to COPD or other lung disease, left heart failure, sleep apnea). The clinical usefulness of this observation in terms of treatment decisions is unclear.
Triggers — Respiratory infections, most commonly viral (eg, rhinovirus) or bacterial, are estimated to trigger approximately 70 percent of COPD exacerbations (table 3) [1,19]; atypical bacteria are a relatively uncommon cause [20,21]. The remaining 30 percent are due to environmental pollution, pulmonary embolism, or have an unknown etiology [1,22-24]. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease".)
In a database study, hospitalizations for COPD exacerbation were associated with exposure to poor outdoor air quality, such as higher levels of ozone, carbon monoxide, particulate matter (up to 10 microns), and nitrogen dioxide [25]. Increased ambient levels of fine particulate matter (≤2.5 microns, aka PM2.5) are associated with an increase in hospitalization and mortality in COPD [26]. In a trial of 116 patients with COPD and exposure to poor air quality at home (PM2.5 >10 mcg/m3), use of indoor air filters versus sham air filters resulted in a dose-dependent improvement in respiratory symptoms and risk of moderate exacerbations [27].
As dyspnea and cough are nonspecific symptoms, COPD exacerbations of unknown etiology may be actually related to other medical conditions, such as myocardial ischemia, heart failure, aspiration, or pulmonary embolism [1,28].
The relationship between COPD exacerbation and pulmonary embolism was illustrated by a meta-analysis of five observational studies [29]. Among the 550 patients having a COPD exacerbation, the prevalence of pulmonary embolism was 20 percent. The prevalence was even higher (25 percent) among those hospitalized. An important limitation of the meta-analysis was its inability to determine whether the pulmonary embolism was the cause of the COPD exacerbation, a result of the COPD exacerbation, or a mere bystander.
CLINICAL MANIFESTATIONS — The clinical manifestations of exacerbations of COPD range from a mild increase in dyspnea, cough that is productive or nonproductive to respiratory failure with acute respiratory acidosis and/or hypoxemia.
Medical history — By definition, patients present with the acute onset or worsening of respiratory symptoms, such as dyspnea, cough, and/or sputum production, over several hours to days [1,30]. These symptoms should be characterized further in terms of the following features:
●Time course of the symptoms
●Comparison to baseline level of symptoms
●Severity of respiratory compromise (eg, dyspnea at rest, dyspnea climbing stairs)
●Delineation of sputum characteristics (eg, amount, color, purulence, blood)
●Use of home oxygen now or in the past
Associated features that might suggest an alternate diagnosis or comorbidity include:
●Constitutional symptoms (eg, fever, chills, night sweats)
●Chest pain, chest pressure, peripheral edema, or palpitations
●Risk factors for coronary disease
●Risk factors for thromboembolic disease
●Upper respiratory symptoms that might suggest a viral respiratory infection or exposure to anyone with influenza
Patients should be asked if they currently smoke cigarettes or use vaping products. The past history of exacerbations should be ascertained: number of prior exacerbations, courses of systemic glucocorticoids, antibiotic therapy in the preceding three months, prior exacerbations requiring hospitalization or ventilatory support, and response to therapy of previous exacerbations.
Physical examination — Physical findings associated with an exacerbation of COPD often include wheezing and tachypnea and may include features of respiratory compromise such as difficulty speaking due to respiratory effort, use of accessory respiratory muscles, and paradoxical chest wall/abdominal movements (asynchrony between chest and abdominal motion with respiration).
If present, decreased mental status could reflect hypercapnia or hypoxemia and asterixis could indicate hypercapnia.
Attention should also be paid to other physical findings, such as fever, hypotension, bibasilar fine crackles and peripheral edema, which might suggest a comorbidity or alternate diagnosis.
EVALUATION AND DIAGNOSIS — The goals of the evaluation of a suspected exacerbation of COPD are to confirm the diagnosis, identify the cause (when possible), assess the severity of respiratory impairment and contribution from comorbidities, and exclude alternate diagnostic possibilities. A rapid overview for the evaluation and management of severe exacerbations of COPD is provided in the table (table 1).
Initial evaluation — The choice of specific tests is guided by the severity of the exacerbation and the particular associated clinical findings. (See 'Clinical manifestations' above.)
For patients with a mild exacerbation (absence of resting dyspnea or respiratory distress, preserved ability to perform activities of daily living), who do not require emergency department treatment, the evaluation may be limited to clinical assessment and possibly pulse oxygen saturation.
For patients who require emergency department care, the evaluation should generally include the following (table 1):
●Assessment of pulse oxygen saturation
●A chest radiograph to exclude pneumonia, pneumothorax, pulmonary edema, pleural effusion
●Laboratory studies (eg, complete blood count and differential, serum electrolytes and glucose)
●Arterial blood gas analysis is obtained if acute or acute-on-chronic respiratory acidosis is suspected or if ventilatory support is anticipated. Concern about acute-on-chronic hypercapnia might be prompted by a history of prior elevation in arterial tension of carbon dioxide (PaCO2), an elevated serum bicarbonate (perhaps reflecting compensation for chronic hypercapnia), or the presence of severe airflow obstruction (eg, forced expiratory volume in one second [FEV1] <50 percent of predicted)
We do not use procalcitonin or C-reactive protein to determine the need for antibiotics in COPD exacerbations, as study results do not clearly and consistently demonstrate that either assay adds value to clinical judgment alone. (See "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease", section on 'Procalcitonin and C-reactive protein'.)
Additional testing — Additional tests are largely used to exclude processes in the differential diagnosis and are obtained depending on the degree of diagnostic uncertainty following clinical evaluation and initial testing.
●Electrocardiogram and blood cardiac troponins are obtained to evaluate tachycardia and/or potential myocardial ischemia. (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department".)
●Plasma brain natriuretic peptide (BNP) or NT-proBNP can help to exclude heart failure, as indicated by features such as crackles on chest auscultation, peripheral edema, suggestive chest radiographic findings (eg, vascular congestion, pleural effusion). If the clinical picture is unclear, an echocardiogram should be obtained. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults".)
●D-dimer to assess for thromboembolic disease if the patient has risk factors for thromboembolism. (See 'Differential diagnosis' below and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)
●Sputum Gram stain and culture are not obtained for most exacerbations of COPD. However, sputum Gram stain and culture can be useful in patients at risk for a poor outcome or increased risk of infection with Pseudomonas (table 4 and table 5). Sputum culture may be helpful in patients who are strongly suspected of having a bacterial infection but fail to respond to initial antibiotic therapy. (See "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease", section on 'When to obtain sputum studies'.)
●Influenza testing is appropriate during influenza season or in patients with features of influenza (eg, acute onset of fever, myalgias, coryza during an influenza outbreak). Rapid antigen testing and direct or indirect immunofluorescence antibody staining tests are useful screening tests for influenza infection but have limited sensitivity; polymerase chain reaction (PCR)-based testing is more sensitive and specific. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)
●COVID-19 – Test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease 2019 (COVID-19) pandemic. (See "COVID-19: Diagnosis".)
●Respiratory virus panel in selected patients – The majority of COPD exacerbations are caused by viral infections, predominantly adenovirus. While not necessary in most patients, PCR diagnostic panels can detect multiple respiratory viruses simultaneously (eg, influenza, adenovirus, parainfluenza virus, respiratory syncytial virus, human metapneumovirus, coronavirus, and rhinovirus). These studies are more frequently obtained in patients with community-acquired pneumonia, and the exact indications for their use in COPD exacerbations are not clear.
Severity of exacerbation — The classification of exacerbation severity described in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) is largely based on the amount of medication needed to treat the exacerbation [1], but other classifications use a symptom-based severity metric [30]:
●Mild – Only one of three cardinal symptoms (increased dyspnea, increased sputum volume, or increased sputum purulence) are present. Treatment with short-acting bronchodilators is sufficient.
●Moderate – At least two of three cardinal symptoms (increased dyspnea, increased sputum volume, or increased sputum purulence) are present. Treatment includes short-acting bronchodilators plus antibiotics and/or oral glucocorticoids
●Severe – Patient requires emergency room treatment or hospitalization for severe symptoms (eg, sudden worsening of dyspnea, high respiratory rate, decreased oxygen saturation, confusion, drowsiness), insufficient response to initial short-acting bronchodilators, and presence of all three cardinal symptoms. Treatment includes short-acting bronchodilators, antibiotics, and oral or intravenous glucocorticoids. Severe exacerbations may be associated with respiratory failure and require noninvasive or invasive ventilation.
DIFFERENTIAL DIAGNOSIS — Patients with COPD who present to the hospital with acute worsening of dyspnea should be evaluated for potential alternative diagnoses, such as heart failure, cardiac arrhythmia, pneumonia, pulmonary embolism, and pneumothorax [1,31,32]. A chest radiograph will differentiate among several of these possibilities (eg, heart failure, pneumonia, pneumothorax); a clear chest radiograph may be a clue to pulmonary embolism, especially when dyspnea and hypoxemia are more prominent than cough or sputum production.
The importance of considering these alternate diagnoses was illustrated in an autopsy study of 43 patients with COPD who died within 24 hours of admission for a COPD exacerbation [31]. The primary causes of death were heart failure, pneumonia, pulmonary thromboembolism, and COPD in 37, 28, 21, and 14 percent, respectively.
●Heart failure – Acute decompensated heart failure (ADHF) is characterized by the development of acute dyspnea associated with elevated intracardiac filling pressures with or without pulmonary edema. HF may be new or an exacerbation of chronic disease. The diagnosis of ADHF is a clinical diagnosis based upon the presence of a constellation of symptoms and signs of HF. While test results (eg, natriuretic peptide level, chest radiograph, echocardiogram) are often supportive, the diagnosis cannot be based on a single test. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults".)
●Cardiac arrhythmias – Cardiac arrhythmias, such as atrial fibrillation, are frequent in patients with COPD, and may be a trigger or consequence of COPD exacerbation [1]. A bedside electrocardiogram can be diagnostic. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".)
●Pneumonia – Pneumonia can present with acute shortness of breath, hypoxemia, and an inconclusive pulmonary examination. Chest radiograph findings may differ, but some cases of bibasilar pneumonia may be similar to HF, although evidence of upper zone redistribution is not present with pneumonia. Fever and leukocytosis may suggest an infectious process. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)
●Pneumothorax – COPD is a risk factor for pneumothorax. Worsening dyspnea can be due to either a COPD exacerbation or pneumothorax, but acute pleuritic chest pain would be more suggestive of pneumothorax while increased volume of sputum and sputum purulence would suggest a COPD exacerbation. A pneumothorax is usually apparent on conventional chest radiograph or thoracic ultrasound, although bullous emphysema can mimic a pneumothorax and necessitate a chest computed tomography (CT) scan for differentiation. (See "Clinical presentation and diagnosis of pneumothorax".)
●Pulmonary embolism – The sudden onset of symptoms such as dyspnea, pleuritic chest pain, and cough may be caused by a pulmonary embolism. The suspicion for pulmonary embolism rises in the absence of purulent sputum production, history of an upper respiratory infection, or pneumothorax [28,29,33-35]. The frequency of pulmonary embolism among patients admitted to the hospital with an exacerbation of COPD varies across studies [33,34,36,37], with a systematic review (7 studies, 880 patients) finding a pooled prevalence of 16 percent [35]. In a subsequent, prospective study of 740 patients with COPD who were admitted to the hospital with acute worsening of respiratory symptoms, pulmonary embolism was identified in 6 percent in the first 48 hours following with a predetermined algorithm [36]. Depending on the likelihood of pulmonary embolism (eg, Wells score, Modified Geneva score), testing may include a blood D-dimer test, lower extremity compression ultrasonography with Doppler, and CT pulmonary angiogram. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)
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".)
SUMMARY AND RECOMMENDATIONS
●Definition – An exacerbation of COPD is characterized by an acute increase in symptoms beyond normal day-to-day variation that leads to a change in medication. (See "COPD exacerbations: Management", section on 'Introduction'.)
●Risk factors – Risk factors for exacerbations of COPD include advanced age, productive cough, duration of COPD, history of antibiotic therapy, COPD-related hospitalization within the previous year, chronic mucous hypersecretion, blood eosinophil count >0.34 x 109 cells/L (340 cells/microL), and comorbid disease. The single best predictor of exacerbations is a history of prior exacerbations. (See 'Risk factors and triggers' above and "COPD exacerbations: Prognosis, discharge planning, and prevention", section on 'Prognosis after an exacerbation'.)
●Triggers – Respiratory infections are estimated to trigger approximately 70 percent of COPD exacerbations. Viral and bacterial infections are most common; atypical bacterial infection is an uncommon trigger. Other potential triggers include myocardial ischemia, heart failure, aspiration, and pulmonary embolism. (See 'Triggers' above.)
●Clinical manifestations
•Symptoms – The three cardinal symptoms of COPD exacerbation are dyspnea, cough, and/or sputum production; they can occur alone or in combination. Exacerbations typically develop over several hours to days. Symptoms such as fever, chills, night sweats, chest pain, or peripheral edema suggest an alternate or comorbid diagnosis. (See 'Clinical manifestations' above.)
•Physical exam findings – Physical findings associated with an exacerbation of COPD often include wheezing and tachypnea and may include features of respiratory compromise. Patients should be examined for physical findings, such as fever, hypotension, bibasilar fine crackles and peripheral edema, which might suggest a comorbidity or alternate diagnosis. (See 'Physical examination' above.)
●Evaluation – For patients who require emergency department care, the evaluation should generally include a pulse oxygen saturation, chest radiograph, complete blood count and differential, and serum electrolytes and glucose (table 1). Arterial blood gases are obtained when acute or acute-on-chronic hypercapnia is suspected due to prior elevation in arterial tension of carbon dioxide (PaCO2), an elevated serum bicarbonate, or the presence of severe airflow obstruction (eg, FEV1 <50 percent predicted). (See 'Initial evaluation' above.)
●Differential diagnosis – The most common processes in the differential diagnosis of a COPD exacerbation are heart failure, cardiac arrhythmias, pulmonary embolism, pneumonia, and pneumothorax. (See 'Differential diagnosis' above.)
