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Recentadvancesinthe Managementofacute Exacerbationsofchronic Obstructivepulmonarydisease
Recentadvancesinthe Managementofacute Exacerbationsofchronic Obstructivepulmonarydisease
Management of Acute
E x a c e r b a t i o n s o f C h ro n i c
O b s t r u c t i v e Pu l m o n a r y D i s e a s e
Stacey-Ann Whittaker Brown, MD, MPH*,
Sidney Braman, MD, Master FCCP
KEYWORDS
COPD exacerbation Assessment Risk factors Prevention
KEY POINTS
AECOPD usually results from viral or bacterial respiratory infections, but may also result
from exposure to environmental pollution.
Treatment of patients admitted with AECOPD involves antibiotics in select patients with
increased sputum volume or purulence, corticosteroids, and short-acting bronchodilator
therapy.
Noninvasive positive pressure ventilation is recommended as first-line treatment of pa-
tients presenting with acute or acute-on-chronic hypercapnic respiratory failure if no con-
traindications exist. It is also beneficial in the postexacerbation period in patients with
persistent hypercapnia.
The following interventions are associated with reduced exacerbations or mortality: long-
term oxygen therapy or NIPPV based on physiologic parameters, smoking cessation
counseling, pharmacologic therapies including long-acting bronchodilators and inhaled
corticosteroids, antibiotic therapy or selective phosphodiesterase-4 inhibitor use in those
with frequent or history of severe exacerbations, and vaccination.
Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount
Sinai, One Gustave L. Levy Place, Box 1232, New York, NY 10029, USA
* Corresponding author.
E-mail address: stacey-ann.brown@mountsinai.org
Fig. 1. The GOLD assessment for COPD. A patient with COPD with a post-bronchodilator
FEV1 of 40% who was very symptomatic (CAT score 5 15) and only one exacerbation in
the past year (without hospitalization) is GOLD stage 3, group B. Management is deter-
mined by ABCD group, not spirometric stage. CAT, COPD assessment test; mMRC, modified
British Medical Research Council Questionnaire. (Adapted from Global Strategy for the
Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease 2020
Report. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Available at:
https://goldcopd.org/wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.0wms.pdf. Ac-
cessed Feb 7 2020; with permission.)
Management of Acute Exacerbations of COPD 617
CAUSES
Viral Infections
Viral infections account for 43% of exacerbations.8 Exacerbations triggered by respi-
ratory viral infections are more severe, have longer recovery times, are associated with
higher levels of inflammatory markers, and are more likely to result in hospital readmis-
sion.9,10 The most frequently detected viral species are11
Human rhinovirus (16%)
Respiratory syncytial virus (10%)
Influenza (7%)
Coronavirus (4%)
Adenovirus (2%)
Human metapneumovirus (2%)
Since the introduction of influenza immunization, this virus has become a less prom-
inent cause of exacerbation, although it is still likely to be an important factor at times
of epidemics.
Bacterial Infections
The precise role of bacteria during COPD exacerbations has been difficult to
assess as a result of airway bacterial colonization. Wang and colleagues12 have
discussed an important paradox in COPD: despite the accumulation of leukocytes
in the airways with increasing disease severity, there is still a major failure to
adequately control and eradicate respiratory pathogens. Nearly 50% of patients
with COPD are colonized with pathogenic bacteria, such as Haemophilus influen-
zae, Streptococcus pneumoniae, and Moraxella catarrhalis.10,12–14 AECOPD
complicated by bacterial infection enhances neutrophilic inflammation and this re-
sults in increased levels of neutrophil elastase, tumor necrosis factor-a, and
interleukin-8; the elastase produced by neutrophils inhibits tracheobronchial ciliary
function, and contributes to impaired bacterial clearance.15,16 In addition, second-
ary bacterial infection following viral infection is common and accounts for one-
quarter of infective exacerbations.17
Environmental Pollution
AECOPD has been associated with increased concentrations of ambient air pollut-
ants, such as fine particulate matter with a diameter of less than 2.5 mm nitric oxide,
and sulfur dioxide,18 and is seen mainly in large industrial cities. Numerous personal
devices have recently been developed to help patients with COPD or other respiratory
diseases monitor ambient air pollution and prevent air-pollution-related COPD
exacerbations.19
Assessment
COPD frequently coexists with other medical conditions.23 Decompensated heart fail-
ure, ischemic heart disease, and thromboembolism may mimic an AECOPD. Outlined
in Box 1 are the recommended tests in the initial evaluation of an AECOPD presenting
to the emergency room.
Chest radiography is recommended because there are substantial rates of abnor-
malities in chest radiography among patients with an AECOPD; one study reported
chest radiograph findings prompted change in management in 24% of patients.24 In
addition to unsuspected pulmonary infiltrates, new lung masses, pneumothorax,
and evidence of pulmonary edema can be seen.25
Another useful technique to evaluate the cause of acute dyspnea in the emergency
setting is lung ultrasound, which can distinguish pulmonary edema from an AECOPD.
The bedside recognition of diffuse sonographic vertical artifacts called comet tail or B
lines suggests the presence of pulmonary edema.26
The prevalence of pulmonary embolism in patients hospitalized with an AECOPD
has been reported to be 25%.27 Notably, this study excluded those with antecedent
signs of infection, so was limited to unexplained AECOPD.28 These patients more
frequently exhibit signs of cardiac failure and pleurisy. A higher vigilance for pulmonary
embolism and testing with computed tomography angiography should be considered
in this group.
Box 1
Initial studies for confirmed or suspected cases of the acute exacerbation of chronic
obstructive pulmonary disease
Finally, misdiagnosis of COPD has been reported to exceed 25%29 and is a result of
underuse of spirometry in the primary care setting. Therefore, for patients who have
never had spirometry (or for whom records are not attainable), inpatient spirometry
once clinically stabilized may be performed unless contraindications exist.
INPATIENT MANAGEMENT
Antibiotics
For the subset of COPD exacerbations with increased cough and sputum purulence,
antibiotics have been shown to reduce the risk of short-term mortality by 77%,
decrease the risk of treatment failure by 53%, with a small increase in the risk of diar-
rhea.34 However, the benefit is less clear when including trials that did not require pu-
rulent sputum as an inclusion criteria; a recent meta-analysis found no effect on
mortality, treatment failure, or length of stay on inpatients not admitted to an intensive
care unit.35
Therefore, antibiotic therapy is recommended for the following patients1:
Those with all three of the following:
Increased sputum volume
Sputum purulence
Dyspnea
Or
Those with two signs including sputum purulence or
If mechanical ventilation is required
The duration of antibiotics should not exceed 5 to 7 days and oral antibiotics are
preferred.
Biomarkers for active pulmonary bacterial infection are an area of active research.
Point-of-care testing of C-reactive protein may be a way to reduce unnecessary use
of antibiotics without harming patients who have an AECOPD. Studies suggest that
antibiotics are most beneficial when the C-reactive protein level is greater than or
equal to 40 mg/L.36,37
Similarly, treatment guided by procalcitonin, a sensitive biomarker of bacterial infec-
tion, has been studied in hospitalized patients with AECOPD.38 Procalcitonin-guided
therapy was poorly adopted by providers and was not associated with a decrease in
total antibiotic days provided; however, a low procalcitonin level was associated with
a 25.5% decrease in intravenous antibiotics, suggesting increased comfort stepping
down from intravenous to oral therapy.38
Sputum cultures are not required unless patients display evidence of pneumonia;
require invasive mechanical ventilation; have severe airflow obstruction; or have
frequent exacerbations with antibiotic use, which increases the risk of resistant
organisms.
Management of Acute Exacerbations of COPD 621
Corticosteroid Therapy
Systemic corticosteroids are recommended for all patients hospitalized for an
AECOPD.1,23 A meta-analysis demonstrated that compared with placebo, systemic
corticosteroids reduced the risk of treatment failure and length of stay while improving
FEV1; however, adverse events were common, occurring in one in six people
treated.39 There is no difference in outcomes when comparing oral versus parental
treatment or longer versus shorter duration.40 Therefore, for patients admitted to a
general ward, an oral dose of 40 mg daily or steroid equivalent for 5 days is preferred
unless contraindication to oral feeding exists. Since the implementation of shorter
courses of steroids in 2014, there has been a significant decrease in pneumonia ad-
missions and all-cause mortality, although the causal nature of this relationship is
not established.41
There is evidence that blood eosinophil levels may be used to guide treatment with
corticosteroids; a randomized controlled trial found that patients treated with
eosinophil-guided therapy were less likely to receive corticosteroids and there was
no significant difference in quality of life.42 Patients with low eosinophil counts had
greater treatment failure rates with prednisone therapy. More studies are needed to
determine the safety of eosinophil-guided therapy.
and symptoms may not recover to baseline values at 3 months.21 Longer symptom
duration has been linked to poor health status and a shorter time until the next
exacerbation.49
Prognosis
The risk of readmission has been reported as 60%50 and the risk of death 23% in the
year following a hospitalization for AECOPD.51 Long-term use of oral corticosteroids,
higher PaCO2, and older age were identified as risk factors associated with higher
mortality.51
PREVENTATIVE STRATEGIES
Discharge care bundles have been studied as a means to ensure the delivery of
optimal care.23 Clinical trials have shown mixed results because significant heteroge-
neity exists in the components of the bundled intervention.52 Therefore, although
implementation of interventions known to reduce exacerbations is recommended,
their combined effectiveness in the form of distinct bundles remains an active area
of study. Outlined in Table 1 and discussed next are interventions known to reduce
the risk of future exacerbations.
Pharmacologic Therapy
Initial inhaler therapy
Long-acting bronchodilator therapy is recommended by all expert groups for the pre-
vention of COPD exacerbations,1,53,54 and should be prescribed on discharge.
For patients who have not been on therapy beforehand, initiation of a long-acting
muscarinic agent (LAMA) is recommended. Previous studies have shown increased
efficacy in LAMAs in reducing exacerbations compared with long-acting b-agonists
(LABAs).55,56
For patients who are highly symptomatic at baseline, initial therapy with combined
LAMA/LABA has been shown to improve dyspnea relative to LAMA monotherapy, with
an unclear benefit on exacerbations.57 Consequently, LAMA/LABA therapy may be
considered as first-line.
Inhaled corticosteroids are beneficial for patients with COPD who have a history of
asthma or atopy, peripheral eosinophilia, or frequent exacerbations.1 For hospitalized
patients who have peripheral eosinophilia (absolute eosinophilic count exceeding
Table 1
Preventive strategies to reduce the frequency of AECOPD
Category Intervention
Pharmacologic therapy Long-acting bronchodilators
Inhaled corticosteroids
Macrolide therapy
Phosphodiesterase-4 inhibitor
Nonpharmacologic therapy Smoking cessation
Influenza and pneumococcal vaccination
Supplemental oxygen
Pulmonary rehabilitation
Noninvasive positive pressure ventilation
Self-management
Palliative care
Management of Acute Exacerbations of COPD 623
Dose escalation
Dose escalation according to the GOLD guidelines is provided in Fig. 2. For patients
previously on maximal inhaler therapy before admission, addition of a standing macro-
lide or phosphodiesterase-4 inhibitor should be considered. The use of long-term oral
corticosteroid is no longer recommended in patients with COPD, and has been asso-
ciated with increased mortality.59
Macrolide therapy
Azithromycin has been shown to decrease exacerbations in patients with frequent ex-
acerbations.60 The greatest benefit was seen in those with better lung function, and in
those who were not current smokers.61 Maintenance azithromycin treatment is
Fig. 2. Dose escalation of inhaler therapy after an exacerbation of chronic obstructive pul-
monary disease. ICS, inhaled corticosteroid. a LABA/ICS is considered in patients with
elevated peripheral eosinophil counts (>100 cells/mL). b In patients with low peripheral
eosinophil counts (<100 cells/mL), escalation from LAMA/LABA with addition of azithromycin
or roflumilast should be considered. (Adapted from Global Strategy for the Diagnosis, Man-
agement, and Prevention of Chronic Obstructive Pulmonary Disease 2020 Report. Global
Initiative for Chronic Obstructive Lung Disease (GOLD). Available at: https://goldcopd.org/
wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.0wms.pdf. Accessed Feb 7 2020;
with permission.)
624 Whittaker Brown & Braman
associated with a small increase in hearing loss60; however, long-term side effects,
such as cardiovascular events and bacterial resistance, are unknown.
Phosphodiesterase inhibition
Roflumilast is a phosphodiesterase-4 inhibitor that reduces airway inflammation and
has been shown to reduce exacerbations and improve lung function in patients with
an FEV1 less than 50% and history of chronic bronchitis.62,63 Side effects include
weight loss and diarrhea, and caution should be used in patients with depression or
suicidality.
Smoking Cessation
Smoking cessation is one of the most cost-effective interventions in the management
of COPD and reduces symptom burden, mortality, exacerbation rates, and lung func-
tion decline.53,64 A combination of pharmacologic interventions and behavioral strate-
gies is recommended. A meta-analysis of smoking cessation interventions found that
any counseling resulted in a modest increase in smoking cessation. There was no
additional benefit in higher intensity versus lower intensity counseling.65
Vaccines
Influenza vaccination has been shown to reduce COPD exacerbations on meta-
analysis of 11 studies.66 The role of pneumococcal vaccination in reducing exacerba-
tions has not been clearly demonstrated. There was no benefit of pneumococcal
vaccination on pneumonia incidence, acute exacerbations, hospital admissions, or
emergency department visits on meta-analysis.67 However, combining both influenza
vaccines resulted in fewer exacerbations related to respiratory infections,68 and both
vaccinations are recommended.
Oxygen
LTOT is indicated in patients with:
Resting hypoxemia (PaO2 <55 mm Hg or oxygen saturation <89%), or
PaO2 between 55 and 60 mm Hg with cor pulmonale and erythrocytosis
(hematocrit >50%)
LTOT in this population has been shown to reduce mortality in COPD.69,70 There
was no additional benefit in prescribing LTOT to patients with mild to moderate exer-
tional hypoxemia (ie, with resting saturation between 89% and 93%, and moderate
desaturation to 80% with exertion).71 If patients are prescribed oxygen on discharge
after an AECOPD, continued need should be evaluated in 60 to 90 days.
Pulmonary Rehabilitation
Pulmonary rehabilitation is a comprehensive program of supervised exercise training
and behavioral therapy, including breathing exercises, smoking cessation counseling,
and self-management. It has been shown to reduce hospital readmissions by 66% if
initiated within 3 weeks of discharge.1 It is associated with improved health-related
quality of life and exercise capacity.
The maximal benefit has been seen in trials where the intervention is initiated in the
postexacerbation period.72 A randomized controlled trial showed an increase toward
1-year mortality when pulmonary rehabilitation was initiated as an inpatient compared
with usual care,73 perhaps a result of underuse of posthospital pulmonary rehabilita-
tion. Home-based programs have shown similar efficacy to center-based
Management of Acute Exacerbations of COPD 625
Self-Management Strategies
Self-management strategies empower patients to adapt behaviors and skills to
manage their COPD, reduces respiratory-related exacerbations, and improves exer-
cise performance and disease literacy.78 Important self-management domains in
the periexacerbation period include: ensuring compliance with therapy, smoking
cessation, vaccination, physical activity and exercise training, and pulmonary rehabil-
itation.79 Avoiding stimuli for recurrent exacerbations and awareness of declining
symptoms should be highlighted.
Palliative Care
Despite high symptom burden, palliative care remains underused in patients with se-
vere COPD.80 Early palliative counseling for highly symptomatic patients, independent
of prognosis, has been shown to be beneficial when the following themes were
addressed81:
Emotional symptoms
Respiratory symptoms
Illness understanding
Prognostic awareness
Coping with COPD
In addition, advanced care planning and establishing patients’ preferences
regarding end-of-life care in the event of further clinical deterioration is prudent.
Hospice referral is appropriate in patients with advanced COPD and limited life ex-
pectancy. Patients with advanced COPD without significant life-limiting comorbidities
should undergo a thorough outpatient prognostic assessment; pulmonary rehabilita-
tion and consideration of advanced therapies beyond the scope of this article,
including lung transplantation or lung volume reduction surgery, should be discussed
before hospice referral.
SUMMARY
structured care bundles have not been shown to be efficacious, individual compo-
nents of smoking cessation, early referral to pulmonary rehabilitation, optimal inhaler
therapy, advanced oral therapies including chronic antibiotic or phosphodiesterase
therapy, and vaccinations improve outcomes in patients with COPD. Lastly, because
breathlessness is one of the most distressing symptoms a human can experience it is
equally important to provide palliation. Despite the poor prognosis of AECOPD, pa-
tients are empowered through self-management programs in their battle against
this lethal disease.
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