14/08/2021 COPD exacerbations: Clinical manifestations and evaluation - UpToDate

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COPD exacerbations: Clinical manifestations and

evaluation
Author: James K Stoller, MD, MS
Section Editor: Peter J Barnes, DM, DSc, FRCP, FRS
Deputy Editor: Helen Hollingsworth, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2021. | This topic last updated: Jan 14, 2021.

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" and "Stable COPD: Overview of management" and
"COPD exacerbations: Management" and "COPD exacerbations: Prognosis, discharge
planning, and prevention".)

EPIDEMIOLOGY

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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:

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● 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 '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.

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● 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] are associated with an increase in hospitalization and
mortality in COPD [26].

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 [1,27].

The relationship between COPD exacerbation and pulmonary embolism was illustrated by a
meta-analysis of five observational studies [28]. 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.

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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 [1,29]. 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

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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".)

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● 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 "Diagnosis of
seasonal influenza in adults", section on 'Laboratory tests'.)

● 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. (See "Clinical evaluation and diagnostic
testing for community-acquired pneumonia in adults", section on 'Other respiratory
viruses'.)

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

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of medication needed to treat the exacerbation [1], but other classifications use a symptom-
based severity metric [29]:

● 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 [1,30,31]. 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
[30]. 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".)

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● 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 "Overview of 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 [27,28,32-34]. The frequency of pulmonary
embolism among patients admitted to the hospital with an exacerbation of COPD varies
across studies, with a systematic review (7 studies, 880 patients) finding a pooled
prevalence of 16 percent [34]. 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 [35]. 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".)

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SUMMARY AND RECOMMENDATIONS

● A rapid overview for the evaluation and management of severe exacerbations of chronic
obstructive pulmonary disease (COPD) in the emergency department is provided in the
table ( table 1).

● 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 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'.)

● 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. (See 'Risk factors'
above.)

● 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.)

● 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 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.)

● For patients who require emergency department care, the evaluation should generally
include a pulse oxygen saturation, chest radiograph, complete blood count and

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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.)

● 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.)

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25. de Miguel-Díez J, Hernández-Vázquez J, López-de-Andrés A, et al. Analysis of

environmental risk factors for chronic obstructive pulmonary disease exacerbation: A
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26. Li MH, Fan LC, Mao B, et al. Short-term Exposure to Ambient Fine Particulate Matter
Increases Hospitalizations and Mortality in COPD: A Systematic Review and Meta-
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27. Tillie-Leblond I, Marquette CH, Perez T, et al. Pulmonary embolism in patients with
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28. Rizkallah J, Man SFP, Sin DD. Prevalence of pulmonary embolism in acute exacerbations
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GRAPHICS

Rapid overview: Initial emergency management of severe COPD exacerbations

Clinical features

Features of COPD exacerbation: Diffuse wheezing, distant breath sounds, barrel-shaped chest, tachypnea, tachycardia,
smoking >20 pack years

Features of severe respiratory insufficiency: Use of accessory muscles; brief, fragmented speech; inability to lie supine;
profound diaphoresis; agitation; asynchrony between chest and abdominal motion with respiration; failure to improve
with initial emergency treatment

Features of impending respiratory arrest: Inability to maintain respiratory effort, cyanosis, hemodynamic instability, and
depressed mental status

Features of cor pulmonale: Jugular venous distension, prominent left parasternal heave, peripheral edema

COPD exacerbations are most often precipitated by infection (viral or bacterial)

Severe respiratory distress in a patient with known or presumed COPD can be due to an exacerbation of COPD or a
comorbid process, such as acute coronary syndrome, decompensated heart failure, pulmonary embolism, pneumonia,
pneumothorax, sepsis

Management

Assess patient's airway, breathing, and circulation; secure as necessary

Provide supplemental oxygen to target a pulse oxygen saturation of 88 to 92% or PaO 2 of 60 to 70 mmHg (7.98 to 9.31
kPa); Venturi mask can be useful for titrating FiO 2 ; high FiO 2 usually not needed and can contribute to hypercapnia (high
FiO 2 requirement should prompt consideration of alternative diagnosis [eg, PE])

Determine patient preferences regarding intubation based on direct questioning or advance directive whenever possible

Provide combination of aggressive bronchodilator therapy and ventilatory support (NIV or invasive ventilation)

Noninvasive ventilation (NIV): Appropriate for the majority of patients with severe exacerbations of COPD unless
immediate intubation is needed or NIV is otherwise contraindicated

Contraindications to NIV include: Severely impaired consciousness, inability to clear secretions or protect airway, high
aspiration risk

Initial settings for bilevel NIV: 8 cm H 2 O inspiratory pressure (may increase up to 15 cm H 2 O if needed to aid ventilation);
3 cm H 2 O expiratory pressure

Administer bronchodilators via nebulizer or MDI: Nebulizer usually requires interruption of NIV; MDIs can be delivered in
line using adaptor (see dosing below)

Obtain ABG after two hours of NIV and compare with baseline: Worsening or unimproved gas exchange and pH <7.25 are
indications for invasive ventilation

Tracheal intubation and mechanical ventilation: Indicated for patients with acute respiratory failure, hemodynamic
instability (eg, heart rate <50/minute, uncontrolled arrhythmia) and those in whom NIV is contraindicated or who fail to
improve with NIV and aggressive pharmacotherapy

Rapid sequence induction (eg, etomidate, ketamine, or propofol)

Intubate with #8 endotracheal tube (8 mm internal diameter) or larger, if possible

Initial ventilator settings aim to maintain adequate oxygenation and ventilation while minimizing elevated airway
pressures: SIMV, tidal volume 6 to 8 mL/kg, respiratory rate 10 to 12/minute, inspiratory flow rate 60 to 80 L/min (increase
if needed to enable longer expiratory phase), PEEP 5 cm H 2 O. May need to tolerate elevated PaCO 2 to avoid barotrauma
(ie, permissive hypercapnia). In patients with chronic hypercapnia, aim for PaCO 2 close to baseline.

Administer inhaled bronchodilator therapy: Usually via MDI with in-line adaptor (see dosing below)

Diagnostic testing

Assess oxygen saturation with continuous pulse oximetry

Obtain ABG in all patients with severe COPD exacerbation

ETCO 2 monitoring (capnography) has only moderate correlation with arterial PaCO 2 in COPD exacerbations

Do not assess peak expiratory flow or spirometry in acute severe COPD exacerbations as results are not accurate

Obtain portable chest radiograph: Look for signs of pneumonia, acute heart failure, pneumothorax

Obtain complete blood count, electrolytes (Na+, K+, Cl–, HCO3–), BUN, and creatinine; also obtain cardiac troponin, BNP, or
NT-proBNP, if diagnosis is uncertain

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Test for influenza infection during influenza season*

Obtain ECG: Look for arrhythmia, ischemia, cor pulmonale

Pharmacotherapy

Inhaled beta agonist: Albuterol 2.5 mg diluted to 3 mL via nebulizer or 4 to 8 inhalations from MDI every hour, or more
frequently if needed

Short-acting muscarinic antagonist (anticholinergic agent): Ipratropium 500 micrograms via nebulizer or 2 to 4 inhalations
from MDI every four hours

Intravenous glucocorticoid (eg, methylprednisolone 60 mg to 125 mg IV, repeat every 6 to 12 hours)

Antibiotic therapy*: Appropriate for majority of severe COPD exacerbations; select antibiotic based on likelihood of
particular pathogens (eg, Pseudomonas risk factors ¶, prior sputum cultures, local patterns of resistance)

No Pseudomonas risk factor(s) ¶: Ceftriaxone 1 to 2 grams IV, OR cefotaxime 1 to 2 grams IV, OR levofloxacin 500 mg
IV or orally, OR moxifloxacin 400 mg IV or orally

Pseudomonas risk factor(s) ¶: Piperacillin-tazobactam 4.5 grams IV, OR cefepime 2 grams IV, OR ceftazidime 2 grams
IV

Antiviral therapy (influenza suspected)*: Oseltamivir 75 mg orally every 12 hours OR peramivir 600 mg IV once (for
patients unable to take oral medication)

Monitoring

Perform continual monitoring of oxygen saturation, blood pressure, heart rate, respiratory rate

Close monitoring of respiratory status

Continuous ECG monitoring

Monitor blood glucose

Disposition

Criteria for ICU admission include:

Patients with high-risk comorbidities (pneumonia, cardiac arrhythmia, heart failure, diabetes mellitus, renal failure,
liver failure)

Continued need for NIV or invasive ventilation

Hemodynamic instability

Need for frequent nebulizer treatments or monitoring

COPD: chronic obstructive pulmonary disease; PaO 2 : arterial tension of oxygen; FiO 2 : fraction of inspired oxygen; PE: pulmonary
embolism; NIV: noninvasive ventilation; MDI: metered dose inhaler; ABG: arterial blood gas; SIMV: synchronized intermittent
mechanical ventilation; PEEP: positive end-expiratory pressure; PaCO 2 : arterial tension of carbon dioxide; ETCO 2 : end-tidal carbon
dioxide; BUN: blood urea nitrogen; BNP: brain natriuretic peptide; NT-ProBNP: N-terminal pro-BNP; ECG: electrocardiogram; IV:
intravenous; ICU: intensive care unit.

* When influenza is suspected, therapy should not be delayed while awaiting results of testing. Doses shown are for patients with
normal renal function. Some agents require dose adjustment for renal impairment; refer to separate UpToDate algorithms of
antibiotic treatment of exacerbations of COPD.

¶ Pseudomonas infection risk factors: Broad spectrum antibiotic use in the past 3 months; chronic colonization or previous isolation
of Pseudomonas aeruginosa from sputum (particularly in past 12 months); very severe underlying COPD (FE V 1 <30 percent
predicted); chronic systemic glucocorticoid use.

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Multidimensional assessment of COPD

GOLD "ABCD" grading: Assessment of symptoms and risk of exacerbations for initiation of COPD
therapy

Assess exacerbation risk: Assess symptoms

Exacerbations/Hospitalizations mMRC* 0 to 1; CAT <10 ¶ mMRC ≥2; CAT ≥10

0 or 1 exacerbations without A B
hospitalization

≥2 exacerbations or ≥1 hospitalization C D
 

GOLD: Severity of airflow limitation (based on postbronchodilator FEV 1 )

Stage Severity FEV 1 (percent predicted)

In patients with FEV 1 /FVC <0.7: Δ

GOLD 1 Mild ≥80

GOLD 2 Moderate 50 to 79

GOLD 3 Severe 30 to 49

GOLD 4 Very severe <30

COPD: chronic obstructive pulmonary disease; GOLD: Global Initiative for Chronic Obstructive Lung Disease; mMRC: modified
Medical Research Council dyspnea scale; CAT: COPD Assessment Test; FEV 1 : forced expiratory volume in one second; FVC: forced
vital capacity.

* mMRC dyspnea scale: Refer to UpToDate graphic.

¶ http://www.catestonline.org.

Δ The GOLD guidelines (www.goldcopd.org) prefer the threshold of <0.7 to the alternative of the fifth percentile lower limit of
normal (LLN) for FEV 1 /FVC.

From the Global Strategy for the Diagnosis, Management and Prevention of COPD 2017, © Global Initiative for Chronic Obstructive Lung
Disease (GOLD), www.goldcopd.org. Adapted with permission. The content within this table is still current as of the 2019 GOLD report.

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Relative frequency of bacterial pathogens isolated from 14 antibiotic comparison trials in

exacerbations of chronic obstructive pulmonary disease*

Pathogen Percentage of bacterial isolates (range)

Haemophilus influenzae 13 to 50

Moraxella catarrhalis 9 to 21

Streptococcus pneumoniae 7 to 26

Pseudomonas aeruginosa 1 to 13

* Enterobacteriaceae have been isolated from the respiratory tract of 3 to 19 percent of patients with chronic obstructive pulmonary
disease (COPD) exacerbations and Staphylococcus aureus has been isolated from the respiratory tract of 1 to 20 percent of patients
with COPD exacerbations, but their pathogenic significance in this setting has not been defined. Haemophilus parainfluenzae has
been isolated from the respiratory tract of 2 to 32 percent of patients with COPD exacerbations, but these organisms are unlikely to
cause COPD exacerbations.

Modified with permission from the American Thoracic Society. Copyright © 2004 American Thoracic Society. Sethi S. Bacteria in
exacerbations of chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society 2004; 1:109. Official Journal of the
American Thoracic Society.

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Risk factors for poor outcomes in patients with acute COPD exacerbations

Comorbid conditions (especially heart failure or ischemic heart disease)

Severe underlying COPD (eg, FEV 1 <50%)

Frequent exacerbations of COPD (ie, ≥2 exacerbations per year)

Hospitalization for an exacerbation within the past 3 months

Receipt of continuous supplemental oxygen

Age ≥65 years*

Patients with greater underlying COPD severity are at higher risk for poor outcomes if initial antibiotic therapy is
inadequate. We thus use a broader empiric regimen for such patients.

COPD: chronic obstructive pulmonary disease; FEV 1 : forced expiratory volume in 1 second.

* Older age (eg, age ≥65 years) is also associated with poorer outcomes and/or risk of infection with drug-resistant pathogens.
While not a strict indication for broadening antibiotic therapy, we consider older age as additive to the risk factors listed above.

References:
1. Balter MS, La Forge J, Low DE, et al. Canadian guidelines for the management of acute exacerbations of chronic bronchitis. Can
Respir J 2003; 10 Suppl B:3B.
2. Miravitlles M, Murio C, Guerrero T. Factors associated with relapse after ambulatory treatment of acute exacerbations of chronic
bronchitis. DAFNE Study Group. Eur Respir J 2001; 17:928.
3. Wilson R, Jones P, Schaberg T, et al. Antibiotic treatment and factors influencing short and long term outcomes of acute
exacerbations of chronic bronchitis. Thorax 2006; 61:337.
4. Garcia-Vidal C, Almagro P, Romaní V, et al. Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation: a prospective
study. Eur Respir J 2009; 34:1072.
5. Parameswaran GI, Sethi S. Pseudomonas infection in chronic obstructive pulmonary disease. Future Microbiol 2012; 7:1129.

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Risk factors for infection with Pseudomonas aeruginosa in patients with acute COPD
exacerbations

Chronic colonization or previous isolation of Pseudomonas aeruginosa from sputum (particularly in the past 12 months)

Very severe COPD (FEV 1 <30% predicted)

Bronchiectasis on chest imaging

Broad-spectrum antibiotic use within the past 3 months

Chronic systemic glucocorticoid use

COPD: chronic obstructive pulmonary disease; FEV 1 : forced expiratory volume in 1 second.

References:
1. Garcia-Vidal C, Almagro P, Romaní V, et al. Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation: a prospective
study. Eur Respir J 2009; 34:1072.
2. Parameswaran GI, Sethi S. Pseudomonas infection in chronic obstructive pulmonary disease. Future Microbiol 2012; 7:1129.
3. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary disease:
characterization and risk factors. BMC Pulm Med 2014; 14:103.
4. Boixeda R, Almagro P, Díez-Manglano J, et al. Bacterial flora in the sputum and comorbidity in patients with acute exacerbations of
COPD. Int J Chron Obstruct Pulmon Dis 2015; 10:2581.

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Contributor Disclosures
James K Stoller, MD, MS Grant/Research/Clinical Trial Support: Alpha-1 Foundation [Alpha-1
antitrypsin detection]; Dicerna Pharmaceuticals [Alpha-1 antitrypsin deficiency]. Consultant/Advisory
Boards: CSL Behring [Alpha-1 antitrypsin detection]; Grifols [Alpha-1 antitrypsin detection]; Takeda
[Alpha-1 antitrypsin detection]; Arrowhead Pharmaceuticals [Alpha-1 antitrypsin deficiency]; Vertex
[Alpha-1 antitrypsin deficiency]; Inhibrx [Alpha-1 antitrypsin deficiency]; 23andMe [Alpha-1 antitrypsin
deficiency]; Alpha-1 Foundation [Member, Board of Directors]; American Respiratory Care Foundation
[Member, Board of Directors]; Insmed. Peter J Barnes, DM, DSc, FRCP, FRS Grant/Research/Clinical
Trial Support: AstraZeneca [Asthma, COPD]; Novartis [COPD]; Boehringer [COPD]; Chiesi [Asthma,
COPD]. Consultant/Advisory Board: AstraZeneca [Asthma, COPD]; Novartis [COPD]; Boehringer [COPD];
Teva [COPD]; Pieris [Asthma]. Speaker's Bureau: AstraZeneca [Asthma]; Novartis [COPD]; Boehringer
[COPD]; Chiesi [Asthma]. Helen Hollingsworth, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

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