532862

research-article2014
TAJ0010.1177/2040622314532862Therapeutic Advances in Chronic DiseaseH Qureshi, A Sharafkhaneh

Therapeutic Advances in Chronic Disease Review

Chronic obstructive pulmonary disease

Ther Adv Chronic Dis
2014, Vol. 5(5) 212–227

exacerbations: latest evidence and clinical DOI: 10.1177/

2040622314532862

implications
© The Author(s), 2014.
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Hammad Qureshi, Amir Sharafkhaneh and Nicola A. Hanania

Abstract: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and
mortality worldwide and results in an economic and social burden that is both substantial
and increasing. The natural history of COPD is punctuated by exacerbations which have major
short- and long-term implications on the patient and healthcare system. Evidence-based
guidelines stipulate that early detection and prompt treatment of exacerbations are essential
to ensure optimal outcomes and to reduce the burden of COPD. Several factors can identify
populations at risk of exacerbations. Implementing prevention measures in patients at risk is
a major goal in the management of COPD.

Keywords: bronchodilators, chronic bronchitis, chronic obstructive pulmonary disease,

emphysema, exacerbation, prevention, treatment

Introduction exacerbation as an event in the natural course of Correspondence to:

Nicola A. Hanania, MD, MS
Chronic obstructive pulmonary disease (COPD), the disease that is characterized by a change in the Section of Pulmonary,
a common preventable and treatable disease, is patient’s baseline dyspnea, cough and sputum Critical Care and Sleep
Medicine, Department of
characterized by persistent airflow limitation that that is beyond normal day-to-day variations, is Medicine, Baylor College
is usually progressive and that is caused by an acute in onset and warrants a change in regular of Medicine, 1504 Taub
Loop, Houston, TX 77030,
enhanced chronic inflammatory response in the medication [GOLD, 2011]. USA
airways and the lung to noxious particles or gases hanania@bcm.edu

[GOLD, 2013]. COPD is a major cause of mor- Exacerbations of COPD impose a substantial Hammad Qureshi, MD
Section of Pulmonary,
bidity and mortality worldwide and results in an burden on healthcare systems worldwide; they are Critical Care and Sleep
economic and social burden that is both substan- a major cause of morbidity, mortality and poor Medicine, Department of
Medicine, Baylor College
tial and increasing [Lopez et al. 2006]. COPD health status [Seemungal et al. 1998]. of Medicine, Houston,
prevalence, morbidity and mortality vary across Furthermore, they account for the majority of TX, USA
Amir Sharafkhaneh, MD,
countries. In the USA, COPD affects approxi- hospital admissions. More than 50% of the total PhD
mately 24 million Americans, results in about cost of COPD is accounted for by services related Section of Pulmonary,
Critical Care and Sleep
120,000 deaths a year and is now the third lead- to exacerbations. For instance, in the UK, they Medicine, Medical Care
ing cause of death [Kochanek et al. 2011]. are the most common cause of medical hospital Line, Michael E. DeBaKey
VA Medical Center; and
admission, accounting for 15·9% of hospital Department of Medicine,
The natural history of COPD is punctuated by admissions, at a cost to the National Health Baylor College of
Medicine, Houston, TX,
exacerbations which have major implications on System of over £253 million a year [British USA
the patient and healthcare system. In this review Thoracic Society, 2006].
we provide a concise overview of COPD exacer-
bations and their impact, outlining the population Exacerbations of COPD have short- and long-
at risk, etiology and current management and term clinical implications. The time course of
preventive strategies. recovery of symptoms during an acute exacerba-
tion was evaluated by one study which showed that
in 50% of community-treated exacerbations,
Impact of COPD exacerbations patients recovered to baseline symptoms within
The Global Initiative for Chronic Obstructive 7 days. However, in 14% of these events patients’
Lung Disease (GOLD) defines a COPD symptoms did not return to baseline 35 days

212 http://taj.sagepub.com

following the onset and in some patients symptoms
never returned to the baseline level [Seemungal
et al. 2000].
Recurrent exacerbations are associated with
accelerated decline in lung function that is the
hallmark of COPD. In one study, frequent exacer-
bators had a decline in forced expiratory volume
in 1 s (FEV1) of 40.1 ml/year [95% confidence
interval (CI) 38–42] versus 32.1 ml/year (95% CI
31–33) in those with no or infrequent exacerba-
tions (p < 0.05) [Donaldson et al. 2002]. More
recently, a 3-year longitudinal cohort study dem-
onstrated that exacerbations experienced during
the study were associated with an excess decline
in lung function (FEV1) with a mean loss of 2 ml
per year per exacerbation (p < 0.001) [Vestbo
et al. 2011].
Furthermore, frequent exacerbations are associ-
ated with reduced physical activity [Donaldson
et al. 2005], poorer quality of life and even an
increased risk of death [Soler-Cataluña et al.
2005] (Figure 1).
Population at risk
Table 1 shows risk factors associated with
increased COPD exacerbation. An ‘exacerbator’
phenotype for COPD has recently been described
using data from large COPD cohorts, such as the
COPD Gene study and the Evaluation of COPD
Longitudinally to Identify Predictive Surrogate
Endpoints (ECLIPSE) study. Hurst and col-
leagues demonstrated that COPD exacerbations
are not random events but cluster together in time
such that there is a high-risk period for recurrent
exacerbations in the 8-week period after the initial
exacerbation [Hurst et al. 2009]. Furthermore,
analysis of exacerbations in 2138 patients enrolled
in the ECLIPSE study demonstrated that exacer-
bations were more frequent (two or more) and
more severe (associated with hospitalization) with
increased severity of the disease defined using
spirometry measures. Overall, 22% of patients
with stage II disease, 33% with stage III and 47%
with stage IV had frequent exacerbations in the
first year of follow up. In the same study, the sin-
gle best predictor of exacerbations, across all
GOLD stages, was a past history of exacerbations.
Other predictors included health status, presence
of gastro-esophageal reflux and increased white
blood cells (WBCs) [Hurst and Vestbo, 2010]. In
patients seeking medical care, dyspnea may in
fact be defined as chronic cough and phlegm
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H Qureshi, A Sharafkhaneh et al.
Figure 1. Impact of chronic obstructive pulmonary
disease exacerbations.
production for more than 3 months/year for 2
consecutive years, was associated with worse res-
piratory symptoms and more exacerbations in
patients with COPD [Kim et al. 2011].
Etiology of COPD exacerbation
It is estimated that 70–80% of COPD exacerba-
tions are triggered by viral or bacterial respiratory
infections (Table 2) [Sethi and Murphy, 2008].
The remaining 20–30% are associated with expo-
sure to environmental pollution or have an
unknown etiology [Sapey and Stockley, 2006].
COPD exacerbations may be mimicked by other
medical conditions [Beghé et al. 2013].
Occasionally, the presence of congestive heart
failure and pneumonia may be difficult to distin-
guish from an acute exacerbation because, in
severe disease, the characteristic radiologic fea-
tures of these conditions may be masked.
Moreover, these two conditions as well as other
multiple comorbid conditions may complicate an
exacerbation [Clini et al. 2013; Roca et al 2013].
The patients seeking medical care with symptom
of dyspnea may in fact be related to their multiple
comorbid condition and not necessarily a true
COPD exacerbation. Hence, this should always
be kept in mind when managing these patients
with COPD exacerbations.
Limited studies suggest deep venous thrombosis
and pulmonary embolism are associated with
acute exacerbations [Erelel et al. 2002]. The rela-
tionship between COPD exacerbation and pul-
monary embolism was illustrated by a
meta-analysis of five observational studies
[Rizkallah et al. 2009]. Among the 550 patients
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Therapeutic Advances in Chronic Disease 5(5)

Table 1. Risk factors for chronic obstructive pulmonary disease (COPD) exacerbations [Miravitles et al. 2000;
Niewoehner et al. 2007; Anzueto et al. 2007].
Age Prior use of COPD medications
Severity of airway obstruction Bacterial colonization
Chronic bronchial mucus production Comorbid conditions like cardiovascular disease
Longer duration of COPD Poor health-related quality of life
Productive cough and wheezing Prior history of exacerbations
Antibiotic or systemic steroid use

Table 2. Pathogens responsible for chronic demonstrated elevated levels of interleukin 6, von
obstructive pulmonary disease exacerbations. Willebrand’s factor, D dimer and prothrombin
Microbe Role in fragment 1+2 being surrogate markers for inflam-
exacerbations mation, endothelial damage and clotting activa-
tion respectively during an exacerbation of COPD
Bacteria with a return of these levels to baseline with
Haemophilus influenzae 20–30% recovery [Polosa et al. 2011].
Streptococcus pneumoniae 10–15%
Moraxella catarrhalis 10–15%
Psuedomonas aeruginosa 5–10% Management strategies of COPD
Enterobacteriaceae Undefined exacerbations
H. hemolyticus Undefined The goals of management of COPD exacerbation
H. parainfluenza Undefined are to minimize the impact of the current exacer-
Staphylococcus aureus Undefined bation and prevent the development of subsequent
Viruses exacerbations. Depending on the severity, an exac-
Rhinovirus 10–25% erbation can be managed in an outpatient or inpa-
Parainfluenza virus 5–10% tient setting. Most of the time outpatient therapy is
Influenza virus 5–10% sufficient with pharmacologic therapies, including
Respiratory syncytial virus 5–10% bronchodilators, corticosteroids and antibiotics.
Adenovirus 3–5%
Coronavirus 3–5% Based on available evidence, early detection and
Human metapneumovirus 3–5% aggressive prompt management of exacerbations
Atypical bacteria are warranted to ensure optimal outcome.
Chlamydophilia pneumoniae 3–5%
Unfortunately, many patients with COPD fail to
report their exacerbations to their healthcare pro-
Mycoplasma pneumoniae 1–2%
viders. It is therefore imperative to educate
Fungi
patients about the signs and symptoms of exacer-
Pneumocystis jeroveci Undefined
bations in an attempt to build a self-management
plan that may help them seek advice early in the
having a COPD exacerbation, the prevalence of course of exacerbations [American Thoracic
pulmonary embolism was 20%. The prevalence Society/European Respiratory Society, 2010].
was even higher (25%) among those
hospitalized.
Pharmacological interventions
Several pharmacological interventions outlined
Pathophysiologic consequences of COPD below are used in the management of a COPD
exacerbations exacerbation.
In the past decade, the understanding of COPD
has evolved from a disease limited to the airways Inhaled bronchodilators. Short-acting inhaled β2
to a more complex disease frequently associated agonists (SABAs) and anticholinergic agents
with systemic inflammation and other chronic (short-acting muscarinic antagonists, SAMAs)
comorbidities [Clini et al. 2013]. COPD exacer- remain the mainstay in the treatment of symp-
bation has been associated with a proinflamma- toms and airflow obstruction during exacerba-
tory and prothrombotic state. A recent study tions. SABAs such as albuterol act by increasing

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the concentration of cyclic adenosine monophos-
phate [Johnson and Rennard, 2001], while
SAMAs such as ipratropium bromide are nonse-
lective muscarinic antagonists [McCrory and
Brown, 2002].
There is no evidence of a difference between
classes of short-acting bronchodilators in terms of
improvement in lung function (improvement in
FEV1 range from 150 to 250 ml) at 90 min
[Karpel et al. 1990]. When inhaled, the effects of
SABAs begin within 5 min with maximum peaks
at 30 min. In contrast, ipratropium bromide
begins to take effect after 10–15 min, with a peak
at 30–60 min. The effects of these two classes of
bronchodilators decline after 2–3 h but can last as
long as 4–6 h, depending on their individual
properties.
The efficacy of combinations of short-acting bron-
chodilators remains controversial in the acute
management of COPD. Unlike stable COPD
where the simultaneous concurrent administration
of SABAs and SAMAs has been shown to be more
efficacious than either agent given alone
[COMBIVENT Inhalation Solution Study Group,
1997], a combination of short-acting bronchodila-
tors given sequentially in exacerbations does not
provide additional benefit [Moayeddi et al. 1995;
McCrory and Brown, 2002].
A systematic review of the route of delivery of
short-acting bronchodilators demonstrated no sig-
nificant differences in FEV1 improvement between
the use of handheld metered dose inhaler (MDI)
with a good inhaler technique (with or without a
spacer device) and nebulizers [Turner et al. 1997].
However, nebulizer delivery of short-acting bron-
chodilators is used in very ill patients as the patients
may not be able to use the MDI properly.
The use of long-acting bronchodilators in COPD
has been restricted for maintenance treatment of
stable disease. However, formoterol, a rapid-act-
ing long-acting inhaled β2 agonist (LABA), has
also been proposed for use in a cumulative man-
ner for the management of exacerbations
[Malolepszy et al. 2001]. Despite the fact that
high doses of formoterol are well tolerated, it
remains uncertain whether its use can replace the
need for short-acting agents during
exacerbations.
Antibiotics. More than half of the acute exacerba-
tions of COPD are triggered by bacterial
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H Qureshi, A Sharafkhaneh et al.
infection caused by pathogens that commonly
colonize the respiratory tract, such as Haemophi-
lus influenzae, Streptococcus pneumoniae and
Moraxella catarrhalis [Sethi, 1999]. The use of
antibiotics routinely in treatment of exacerbations
remains unsettled. There is evidence supporting
the use of antibiotics in exacerbations when
patients have clinical signs of a bacterial infection,
for example an increase in sputum production. A
systematic review of the very few available pla-
cebo-controlled studies showed that antibiotics
reduced the risk of short-term mortality by 77%,
treatment failure by 53% and sputum purulence
by 44% [Ram et al. 2006].
A large number of oral antimicrobial agents have
been approved for treating acute COPD exacer-
bations. Treatment is usually empirical and not
based on sputum cultures. Sputum gram stain
provides semiquantitative information on the
number of bacteria in the sputum; culture pro-
vides information only on the identity of the
organisms [Murray and Washington, 1975] and
cannot separate colonization from infection.
The choice of antibiotics is influenced by the
severity of exacerbation, prior use of antibiotics
and systemic steroids, and the presence of under-
lying structural lung disease such as bronchiecta-
sis. For a simple exacerbation in patients who are
not at high risk of resistant organisms, macrolides
or β-lactam agents can be used. However, because
more than 50% of H. influenzae and M. catarrhalis
species are β-lactamase producing, the use of
β-lactam antibiotics should be coupled with
β-lactamase inhibitors. The choice of antibiotics
for treatment of acute exacerbation has recently
been challenged by the rise in prevalence of resist-
ant organisms, especially in patients with severe
exacerbations and those with prior therapy with
antibiotics and oral corticosteroids. In this situa-
tion, broader-spectrum antibiotics such as new
fluoroquinolones that will be effective against
resistant strains of H. influenzae and S. pneumonia
are recommended. In the presence of underlying
structural lung disease such as bronchiectasis,
antibiotics targeting Pseudomonas species should
be considered. If systemic symptoms such as fever
are prominent, the presence of pneumonia should
be ruled out and treatment with a broad-spec-
trum antibiotic is recommended [Celli et al.
2004]. A meta-analysis of the duration of antibi-
otic treatment therapy in an exacerbation of
COPD demonstrated that a short course of anti-
biotic treatment (<5 days) is as effective as the
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Therapeutic Advances in Chronic Disease 5(5)
traditional longer treatment in patients with mild
to moderate exacerbations of CB and COPD.
There has been some recent interest in using
inhaled antibiotics for treatment and prevention
of COPD. However, so far, none of the studies
have led to conclusive evidence to incorporate
them in the guidelines for COPD exacerbation
management. Some data exist regarding the use
of inhaled tobramycin in patients with severe
COPD (GOLD 3–4) who have colonization of
their respiratory tracts with multidrug-resistant
Pseudomonas [Dal Negro et al. 2008]. However,
the study only showed reduction in sputum
inflammatory markers and reduction in colony
counts of the bacteria with no change in other
outcomes.
Corticosteroids. The role of systemic corticoste-
roids in the treatment of exacerbations also
remains contentious. There is no strong evidence
to guide appropriate patient selection, route of
administration or duration of treatment. Systemic
corticosteroids reduce recovery time and treat-
ment failures when used to treat acute exacerba-
tions [Albert et al. 1980; Niewoehner et al. 1999].
The optimal dose and duration of therapy with
corticosteroids has not been well established.
GOLD guidelines recommended a dose of 30–40
mg prednisolone equivalent per day, preferably by
the oral route, for 10–14 days. In a randomized
controlled trial of a 9-day tapering dose of oral
prednisone versus placebo in COPD exacerba-
tion, a more rapid improvement in FEV1 and in
moderate hypoxemia (on days 3 and 10 compared
with day 1) were observed in the treatment group
compared with the placebo group [Thompson
et al. 1996]. Similarly, a 10-day course of 40 mg
of oral prednisone versus placebo reduced the
overall relapse rate at 30 days (27% versus 43%
with number needed to treat of 6), improved
post-bronchodilator FEV1 (34% versus 15% and
300 ml versus 160 ml) and breathlessness, but did
not affect hospital admission rate and mortality.
The insomnia group reported more insomnia,
increased appetite and weight gain and increased
trend towards higher incidence of depression and
anxiety [Aaron et al. 2003].
In the largest inpatient study of COPD exacerba-
tion to date [Niewoehner et al. 1999], patients
received either 125 mg intravenous methylpredni-
solone four times daily for 3 days followed by 2 or
8 weeks of a tapering dose of oral prednisone
(starting with 60 mg once daily) or placebo. The
216
steroid groups had a significantly lower treatment
failure rate compared with the placebo group on
days 30 (33% versus 23%) and day 90 (48% versus
37%) but not at 6 months. The length of hospital
stay was shortened by 1 day and FEV1 improved
more rapidly in the steroid group (by approxi-
mately 100 ml) from day 1 but did not differ at 2
weeks. Adverse events were more noticeable in
the steroid treated groups (67% patients had dia-
betes), including hyperglycemia requiring treat-
ment (15%) and a higher proportion of secondary
infection in the group treated for 8 weeks. The
duration of steroid treatment (2 versus 8 weeks)
did not influence these outcomes.
The role of inhaled corticosteroids (ICS) in the
treatment of acute COPD exacerbation is even less
defined. A recent randomized controlled trial in
inpatients [Maltais et al. 2002] compared nebu-
lized budesonide 0.5 mg/ml (2 mg four times daily
for 3 days followed by 2 mg per day for 7 days)
with oral prednisolone (30 mg twice daily for 3
days followed by 40 mg once daily for 7 days) and
with placebo in patients with severe COPD hospi-
talized for moderate to severe exacerbations. The
ICS group showed the same improvement in FEV1
compared with the oral prednisolone group. The
duration of hospitalization was also similar, with
the oral steroids group having more hyperglycemic
events. Another randomized trial examining outpa-
tient therapy for COPD exacerbation compared
inhaled budesonide/formoterol with prednisolone
plus formoterol and demonstrated similar improve-
ment in FEV1 and no differences in symptoms,
quality of life, treatment failures, and the need for
reliever medication in the follow-up period between
the two groups [Ställberg et al. 2009].
No clinical, biochemical or functional markers can
clearly identify patients who will respond better to
corticosteroid treatment. Although no effects on
airway cytokines have been demonstrated in
patients with stable COPD [Keatings et al. 1997],
two studies have reported reductions in airway
eosinophilic inflammatory markers [Brightling
et al. 2000] and in serum C-reactive protein after
2 weeks of treatment with oral steroids [Sin et al.
2004]. An increased number of eosinophils have
been found in patients with mild to moderate
COPD exacerbations [Saetta et al. 1994].
Oxygen. Oxygen therapy is of beneficial value in
acute COPD exacerbation as patients are often
hypoxemic. The primary objective is to treat hypox-
emia without increasing ventilation/perfusion
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mismatch which may occur in patients with chronic
hypoxemia when they receive high amounts of oxy-
gen. During a severe exacerbation, arterial blood
gases should be monitored for arterial oxygen and
carbon dioxide tension and pH. Oxygen saturation
should be monitored for trending and adjusting
oxygen settings. The goal of inpatient oxygen ther-
apy is to maintain a partial pressure of arterial oxy-
gen (PaO2) of 60 mmHg or oxygen saturation of
90% in order to prevent tissue hypoxia and pre-
serve cellular oxygenation. Increasing PaO2 to val-
ues much greater than 60 mmHg confers little
added benefit and may increase the risk of carbon
dioxide retention, which may lead to acute hyper-
capnic respiratory failure [Celli et al. 2004].
Methylxanthines. Intravenous methylxanthines
(theophylline or aminophylline) are considered
second-line therapy, only to be used in selected
cases when there is insufficient response to short-
acting bronchodilators [Mahon et al. 1999]. Side
effects of methylxanthines are significant and
their beneficial effects in terms of lung function
and clinical endpoints are modest and inconsis-
tent [Barr et al. 2003]. In general it is not advised
that these agents be used in the early treatment of
exacerbations.
Mucolytic agents. The use of mucolytics and anti-
oxidant agents (ambroxol, erdosteine, carbocyste-
ine, iodinated glycerol) was investigated in numerous
studies with controversial results. Although a few
patients with viscous sputum may benefit from
mucolytics, the overall benefit seems to be very
small; therefore, the widespread use of these agents
is not recommended at the present time.
Adjunct therapies. Depending on the clinical
condition of the patient, appropriate hydration
with special attention to the administration of
diuretics, anticoagulants, treatment of comorbidi-
ties and nutritional aspects should be considered.
At all times, healthcare providers should strongly
enforce stringent measures against active ciga-
rette smoking. Use of medications that have seda-
tive effects on the sensorium like narcotics,
benzodiazepines and other sedative hypnotics
should be restricted and these medications if
needed should be used with extreme caution.
Nonpharmacological interventions
Chest physical therapy. Chest percussion therapy
initially was thought to augment the sputum
clearance and improve respiratory symptoms of
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H Qureshi, A Sharafkhaneh et al.
patients admitted with COPD exacerbation.
Although the use of this modality is very benefi-
cial in patients with bronchiectasis and cystic
fibrosis, its use in COPD exacerbations remains
of questionable benefit and currently is not rec-
ommended by GOLD guidelines of COPD
management.
Ventilatory support. The primary therapeutic goal
of ventilatory support in patients with exacerba-
tions with acute respiratory failure is to decrease
both mortality and morbidity and to relieve symp-
toms, despite optimal medical treatment.
Mechanical ventilation can be delivered noninva-
sively or invasively (conventionally) using differ-
ent modes that are, in essence, positive pressure
devices (negative ventilation is currently not rec-
ommended) for noninvasive ventilation using
either a nasal or facial mask, or via an endotra-
cheal tube or a tracheostomy for invasive
ventilation.
A major advance in the treatment of acute exacer-
bations of COPD has been the implementation of
noninvasive positive pressure ventilation (NIV).
NIV has been shown to improve acute respiratory
acidosis (increases pH and decreases partial pres-
sure of arterial carbon dioxide), decrease respira-
tory rate, work of breathing, severity of
breathlessness, complications such as ventilator
associated pneumonia and length of stay.
Not only can intubations be avoided, but mortal-
ity for severe COPD exacerbations is also sub-
stantially reduced. A recent randomized trial
testing the benefit of a helium–oxygen mixture for
use in noninvasive ventilatory support in COPD
exacerbations did not show superiority [Maggiore
et al. 2010].
It is common practice for this form of ventilatory
support to be provided in an intensive care unit
setting with trained staff. There are several con-
traindications to its use, including respiratory
arrest, cardiac instability, high aspiration risk and
inability to fit the device securely. If contraindica-
tions are present or if noninvasive ventilation is
inadequate, patients may require intubation and
invasive mechanical ventilatory support. Detailed
discussion of invasive mechanical ventilation in
the management of COPD exacerbation is
beyond the scope of this review. However, impor-
tant consideration to avoid hyperinflation to avoid
barotrauma and volutrauma should be imple-
mented. This can be achieved by properly sedat-
ing the intubated patient and implementing
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Therapeutic Advances in Chronic Disease 5(5)
controlled hypoventilation awaiting the effects of
other treatments to reduce airway obstruction.
Weaning patients from the ventilator can be a very
difficult and prolonged process and the best
method (pressure support of T-piece trial)
remains a matter of debate. In patients with
COPD in whom extubation fails, NIV facilitates
weaning, prevents reintubation and reduces mor-
tality [Esteban et al. 1995]. Early NIV after extu-
bation reduces the risk of respiratory failure and
lowers 90-day mortality in patients with hyper-
capnia during a spontaneous breathing trial
[Ferrer et al. 2009].
Hospital discharge and follow up
Insufficient clinical data exist to establish the
optimal duration of hospitalization in individual
patients with an exacerbation of COPD, although
units with more respiratory consultants and bet-
ter organized care have lower mortality and
reduced length of hospital stay following admis-
sion for an exacerbation [Price et al. 2006]. In the
hospital, prior to discharge, patients should start
optimum therapy for COPD, which will include
long-acting bronchodilators, with or without ICS.
Follow up after discharge should include coun-
seling for smoking cessation, monitoring of the
inhaler technique and effectiveness of medica-
tions, and monitoring changes in spirometric
parameters [Gravil et al. 1998].
Preventive strategies of COPD exacerbations
The significant impact of COPD exacerbation on
both clinical outcomes and financial burden
makes it imperative for clinicians to try to prevent
these exacerbations from occurring. Current
guidelines stipulate that prevention of exacerba-
tion is a major goal in management. Many
modalities, both pharmacological and nonphar-
macological, have been proposed to prevent exac-
erbations (Table 3). We provide a detail account
of these modalities below.
Nonpharmacological strategies
Smoking cessation. Smoking cessation is the
intervention with the greatest capacity to influ-
ence the natural history of COPD. Evaluation of
the smoking cessation component in a lung heath
study indicates that if effective resources and time
are dedicated to smoking cessation, 25% long-
term quit rates can be achieved [Anthonisen et al.
218
1994]. A study conducted among 23,497 Veter-
ans in the USA demonstrated that smoking cessa-
tion is associated with a reduced risk of COPD
exacerbations and the magnitude of the reduced
risk was dependent on duration of abstinence [Au
et al. 2009]. A systemic review of all the available
literature supports the conclusion that, even in
severe COPD, smoking cessation slows the accel-
erated rate of lung function decline and improves
survival compared with continued smoking [God-
tfredsen et al. 2008]. A recent study looking at the
cost effectiveness of a smoking cessation program
showed that a high-intensity smoking cessation
program was associated with a lower average
number of exacerbations (0.38 versus 0.60) and
hospital days (0.39 versus 1) per patient and a
higher number of quitters (20 versus 9) at lower
total costs [Christenhusz et al. 2012].
Vaccines. Several studies evaluated the use of
influenza and pneumococcal vaccination, which
are now routinely recommended for all patients
with COPD of significant severity [Wongsura-
kiat et al. 2004; Wang et al 2007]. One study
that reviewed the outcome of influenza vaccina-
tion in a cohort of older patients with chronic
lung disease demonstrated that influenza vac-
cination is associated with significant health
benefits with fewer outpatient visits, fewer hos-
pitalizations and reduced mortality [Nichol
et al. 1999].
A Cochrane database review of four studies in
patients with COPD showed no evidence of effi-
cacy for injectable antipneumococcal vaccines
[Granger et al. 2006]; however, in another study
of the 23 serotype pneumococcal polysaccharide
vaccine in patients with COPD, Alfageme and
colleagues demonstrated that the vaccine was
effective in the prevention of community-
acquired pneumonia compared with placebo in
patients younger than 65 years or those with
severe airflow obstruction [Alfageme et al.2006].
However, no difference in mortality between the
groups was seen. Larger well designed studies are
needed to examine the effects of pneumococcal
vaccine in patients older than 65 years with
COPD.
Immunostimulatory agents have also been
reported to reduce COPD exacerbation fre-
quency. A study of the immunostimulant OM-85,
a detoxified oral immunoactive bacterial extract,
reported a reduction in the severe complications
of exacerbations and hospital admissions in
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Table 3. Strategies to prevent chronic obstructive pulmonary (COPD) disease exacerbations.
Nonpharmacological
Smoking cessation
Vaccines
Approved
Influenza
Pneumococcal
Experimental
Killed Haemophilus influenzae
NTHi oral immunotherapy
(HI-164OV)
Bacterial lysate
Pulmonary rehabilitation
Disease management programs
ACE, angiotensin-converting enzyme; ICS, inhaled corticosteroid; LABA, long-acting inhaled β2 agonist; LAMA, long-
acting muscarinic antagonist; NTHi, nontypeable Haemophilus influenzae.
patients with COPD, with a follow-up study con-
firming the economic benefits of using this agent
[Collet et al. 1997]. A recent randomized study
demonstrated benefits but the patients had het-
erogeneous pathology [Soler et al. 2007]. A sys-
tematic review of 13 trials involving 2066 patients
reported no consistent evidence of a benefit,
though the agent is currently in use in Europe
[Sprenkle et al. 2005]. Further studies are needed
to understand the mechanisms of action of this
immunostimulant before its role in COPD can
be defined.
Pulmonary rehabilitation. The evidence for the
effectiveness of pulmonary rehabilitation is
very strong, but its impact on exacerbation
rate is less studied than other more direct out-
comes, such as exercise performance and
health status. Conducting such studies now
will be difficult, given the ethics of withhold-
ing rehabilitation for long enough for an exac-
erbation to occur. Respiratory rehabilitation
may improve prognosis in patients with COPD
by addressing relevant risk factors for exacer-
bations, such as low exercise capacity,
decreased anxiety and depression, central
desensitization to dyspnea and reduction in
dynamic hyperinflation.
The most convincing evidence comes from the
prospective randomized control trial conducted
some years ago in South Wales where patients
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H Qureshi, A Sharafkhaneh et al.
Pharmacological
Bronchodilators
LAMAs: tiotoprium
LABAs: salmeterol, formoterol,
Indacaterol
Antioxidants
Carbocisteine
Acetylcysteine
Anti-inflammatory
ICS/LABA
Roflumilast
Antibiotics
Systemic antibiotics
Macrolides, fluoroquinolones
Inhaled antibiotics
Drugs used to treat comorbidities of COPD: statins,
β blockers, ACE inhibitors
who received pulmonary rehabilitation had on
average 10.4 days in hospital compared with
21.0 days in those randomized to receive con-
ventional medical treatment [Griffiths et al.
2000]. Combined analysis of results from six tri-
als including 230 patients indicated that respira-
tory rehabilitation reduced the risk of hospital
admissions (pooled relative risk = 0.26) and
mortality (pooled relative risk = 0.45) [Puhan
et al. 2005].
Disease management programs and patient edu-
cation. Self-management interventions improve
various outcomes for many chronic diseases.
Studies conducted in a COPD population showed
that establishing a simple disease management
program and improving patient education about
COPD exacerbation symptoms and seeking help
early does reduce hospitalizations and emergency
department visits and helps in reducing costs to
the healthcare delivery systems [Bourbeau et al.
2003, 2004; Rice, 2010]. However, controversy
was thrown on the above findings by a recent ran-
domized trial which suggested that implementa-
tion of a home educational and management
program for patients with COPD did not result in
a reduction in admissions for acute exacerbations
of COPD and, unexpectedly, showed increased
overall mortality [Fan et al. 2012]. More studies
are needed to clarify the role of disease manage-
ment and patient education on reduction in
COPD exacerbations.
219
Therapeutic Advances in Chronic Disease 5(5)
Table 4. Comparative data of pharmacologic therapies for reduction in chronic obstructive pulmonary
exacerbation rates [Han and Martinez, 2011].
Drug class
LAMA
LABA
ICS
ICS/LABA combination
PDE4 inhibitors
N acetylcysteine
Antibiotics (moxifloxacin)
ICS, inhaled corticosteroid; LABA, long-acting inhaled β2 agonist; LAMA, long-acting muscarinic antagonist; PDE4, phos-
phodiesterase 4.
Pharmacological strategies
Comparative data of these pharmacologic thera-
pies and their impact on reduction of exacerba-
tion rates is shown in Table 4. A detailed account
of these modalities is discussed below.
Long-acting bronchodilators. With regard to
long-acting muscarinic antagonists (LAMAs),
the use of the long-acting anticholinergic, tiotro-
pium, has demonstrated a significant effect on
reduction in COPD exacerbations. Understand-
ing the Potential Long-Term Impacts on Func-
tion with Tiotropium (UPLIFT) Trial, which
included a total of 5993 patients, 2987 in the
tiotropium group and 3006 in the placebo group,
showed that tiotropium was associated with a
reduction in the mean number of exacerbations
of 14% (p < 0.001) during the 4-year period
[Tashkin et al. 2008]. The recently published
Prevention of Exacerbations with Tiotropium
POET-COPD trial, a 1-year, randomized, dou-
ble-blind, double-dummy, parallel-group trial,
compared the effect of treatment with 18 μg of
tiotropium once daily with that of 50 μg salme-
terol twice daily on the incidence of moderate or
severe exacerbations in patients with moderate
to very severe COPD and a history of exacerba-
tions in the preceding year. The trial demon-
strated superiority of tiotropium to salmeterol in
prolonging time to first exacerbation [Vogel-
meier et al. 2011].
The role of other long-acting anticholinergic
agents (some of which are still in clinical develop-
ment) such as aclidinium bromide, glycopyrro-
nium and umeclidinium in the prevention of
COPD exacerbations has not yet been well
defined.
220
Reduction in exacerbation rates
14% reduction [Tashkin et al. 2008]
15% reduction [Calverley et al. 2007]
25% reduction [Burge et al. 2000]
26–35% reduction [Calverley et al. 2007; Anzueto
et al. 2009]
17% reduction [Calverley et al. 2009]
25% reduction [Gerrits et al. 2003]
20% reduction [Sethi et al. 2010]
With regard to LABAs, the use of salmeterol, for-
moterol and indacaterol in the maintenance treat-
ment of COPD has been shown to reduce COPD
exacerbations. A recent meta-analysis reviewed
17 randomized trials to assess the effect of LABA
on COPD exacerbations [Wang et al. 2012].
Salmeterol, formoterol and indacaterol signifi-
cantly reduced COPD exacerbations compared
with placebo. Salmeterol significantly reduced
COPD exacerbations with both study arms
exposed or not exposed to ICS. The summary
ORs were 0·79 (95% CI 0·67–0·92; p < 0·01) and
0·80 (95% CI 0·65–0·99; p = 0·04).
Compared with twice-daily LABAs, new LABAs
with ultra-long duration (ultra LABAs) could
provide improvements in efficacy and compliance
with fast onset of action, 24 h bronchodilation
and a good safety profile. Several novel ultra
LABAs showing once-daily delivery profiles are in
development. The only licensed ultra LABA at
this time is indacaterol. As more drugs get devel-
oped in this class and more safety and long-term
data are available, their use in the management of
COPD will increase [Malerba et al. 2012].
With regard to LABA/LAMA combinations, sev-
eral of these are under development for mainte-
nance therapy of COPD, including indacaterol/
glycopyrronium, formoterol/aclidinium, vilanterol/
umeclidinium and olodaterol/tiotropium. The role
of these agents in the prevention of COPD exacer-
bation has not been well defined and need to be
examined.
Inhaled corticosteroids. ICS have consistently
resulted in about a 25% reduction in exacerbation
frequency and are recommended in the GOLD
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guidelines for this purpose. The Inhaled Steroid in
Obstructive Lung Disease in Europe (ISOLDE)
trial studied the long-term effects of fluticasone on
exacerbations in 751 patients with COPD. The
median exacerbation rate was reduced by 25%
from 1.32 a year on placebo to 0.99 a year with
fluticasone propionate (p = 0.026) [Burge et al.
2000]. However, current guidelines do not recom-
mend the use of ICS as standalone agents in the
maintenance therapy of COPD as their effect is sig-
nificantly improved when combined with a LABA.
ICS/LABA combination. Results from the TORCH
study showed that all active treatments were sig-
nificantly superior to placebo in decreasing the risk
of moderate to severe exacerbations, and exacerba-
tions requiring systemic steroids (all p < 0.05).
Combination treatment and salmeterol were also
significantly superior to placebo in decreasing the
risk for exacerbations requiring hospitalization
(both p < 0.05) [Calverley et al. 2007].
A study by Anzueto and colleagues comparing the
effects of combination therapy of fluticasone pro-
pionate/salmeterol 250/50 µg versus salmeterol
alone [Anzueto et al. 2009] demonstrated a statis-
tically significant reduction in moderate/severe
exacerbations, rescue albuterol use, night-time
awakenings and dyspnea scores, supporting the
use of combination therapies for COPD for pre-
vention of exacerbations.
A recently published randomized, double-blind,
double-dummy, parallel-group, 12-month multi-
center study evaluated the effect of budesonide/
formoterol pressurized MDI on COPD exacerba-
tions. Both doses of budesonide/formoterol 320/9
and 160/9 reduced exacerbation rates (number
per patient-treatment year) by 34.6% and 25.9%
respectively versus formoterol (p ≤ 0.002)
[Sharafkhaneh et al. 2012].
A review of four clinical trials assessing combina-
tion therapy with budesonide and formoterol
indicates that in patients with moderate or severe
COPD who have a history of a COPD exacerba-
tion, combination therapy improves various
COPD-related outcomes, including lung function
and health-related quality of life, and reduces the
incidence of exacerbations compared with the
individual components alone or placebo
[Sharafkhaneh and Mattewal, 2010].
A recent publication of two replicate double-blind
parallel-group 1-year trials looking at the addition
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H Qureshi, A Sharafkhaneh et al.
of fluticasone furoate to vilanterol showed that
the addition of an ICS to vilanterol was associated
with a decreased rate of moderate and severe
exacerbations of COPD but was also associated
with an increased pneumonia risk [Dransfield
et al. 2013].
Phosphodiesterase 4 inhibitors. Although theoph-
ylline remains the most widely used nonspecific
phosphodiesterase inhibitor, data about its effects
on exacerbations are lacking and the situation is
scarcely better for the more specific phosphodies-
terase 4 inhibitors. These drugs have many attrac-
tive pharmacological properties which might
potentially reduce the patient’s likelihood of exac-
erbating but, to date, there are few published data
to support this action. Cilomilast has been stud-
ied in several unpublished clinical trials which can
be accessed via the US Food and Drug Adminis-
tration website (http://www.fda.gov). Overall
there was a small (32 ml) improvement in lung
function with the drug and no effect on exacerba-
tion rates compared with placebo.
More recently a different drug in this class, roflu-
milast, has been shown to reduce the overall rate
of moderate/severe exacerbation rates over 1 year
of treatment in subjects with severe COPD, CB
and a history of previous exacerbation. This was
accompanied by improvements in FEV1 with an
acceptable side-effect profile [Calverley et al.
2009].
Antioxidants and mucolytic agents. Carbocisteine,
a mucolytic agent with anti-inflammatory and
antioxidant properties, was studied in the PEACE
trial for the effect on COPD exacerbations. The
study demonstrated a significant decrease in the
treatment arm. The 1-year cumulative number of
exacerbations was 325 in the carbocisteine group
and 439 in the placebo group (p = 0.004) [Zheng
et al. 2008].
N acetylcysteine (NAC) has been shown in vivo
to have a significant antioxidant effect and this
provides a biologically attractive mechanism for
exacerbation prevention in COPD. A systematic
review of the existing evidence suggested that
NAC would have an important effect on exacer-
bation prevention [Gerrits et al. 2003]. But a well
performed prospective randomized control trial
(BRONCHUS) conducted over 3 years in 523
patients which found that the exacerbation rate in
those randomized to NAC was no different from
that in the placebo group [Decramer et al. 2005].
221
Therapeutic Advances in Chronic Disease 5(5)
A subgroup analysis suggested that patients who
were not receiving concomitant ICS had fewer
exacerbations if they were randomized to NAC
(0.76 versus 1.11 moderate or severe exacerba-
tions per year), but this conclusion requires pro-
spective confirmation.
A recent 1-year double-blind placebo-controlled
trial in Hong Kong showed significant improve-
ment in forced expiratory flow (25% to 75%), a
significant reduction in exacerbation frequency
(0.96 versus 1.71 times/year) and a tendency
towards reduction in admission rate (0.5 versus
0.8 times/year) with NAC versus placebo [Tse
et al. 2013].
Antibiotics. An alternative approach to preventing
infectious exacerbations of COPD is the use of
antibiotics in a prophylactic manner. Among the
antibiotic classes, macrolides (including erythro-
mycin, azithromycin and clarithromycin) are
especially attractive as prophylactic antibiotics in
COPD. In addition to their direct antibacterial
effects, they have also been shown to have poten-
tially beneficial immunomodulatory and anti-
inflammatory effects. Albert and colleagues report
a major study with daily azithromycin for the pre-
vention of exacerbations. In this multicenter, pro-
spective, placebo-controlled, double-blind,
randomized trial, the authors examined the use of
azithromycin in 570 subjects with COPD com-
pared with placebo in 572 subjects with similar
severity of COPD. The median time to the first
exacerbation was 266 days in the azithromycin
group versus 174 days in the placebo group, which
was significantly different. The authors also noted
an exacerbation frequency of 1.48 exacerbations
per patient year in the group receiving azithromy-
cin versus 1.83 exacerbations per patient year in
the placebo group, with a hazard ratio of 0.73.
Patients with COPD with two or more exacerba-
tions a year in spite of appropriate standard ther-
apy are potential candidates for this therapeutic
approach. However, optimal duration and dosing
of macrolide prophylaxis for exacerbation remains
uncertain [Albert et al. 2011].
In another recent study (PULSE) by Sethi and
colleagues, the effect of pulsed therapy with moxi-
floxacin 400 mg daily for 5 days and repeated
every 8 weeks for a total of six courses showed a
statistical reduction in odds of an exacerbation by
20% and a 44% reduction in patients who exhib-
ited purulent sputum at baseline [Sethi et al
2010]. Though PULSE demonstrates that
222
intermittent treatment with moxifloxacin is an
effective option for preventing acute exacerba-
tions in patients with COPD, further studies are
required to determine the optimal patient popula-
tion as well as dosing regimen and therapy dura-
tion for this approach.
The above studies have also sparked interest in
potentially using antibiotics via inhalation to
reduce exacerbation risk. Several studies are
ongoing to examine the effects of inhaled antibi-
otics in the prevention of COPD exacerbations.
Vitamin D. A recent randomized trial looking at
the effect of vitamin D supplementation in
patients with COPD did not show a statistically
significant reduction in exacerbation rates
[Lehouck et al. 2012]. A subgroup of patients
with very low vitamin D levels did show some
reduction in COPD exacerbation rates but fur-
ther studies are needed to establish guideline for
vitamin supplementation to reduce exacerbation
rates.
Effect of cardiovascular drugs on COPD exacerba-
tions. Multiple observational studies examined
the effects of statins/β blockers and angiotensin-
converting enzyme (ACE) inhibitors on preven-
tion of exacerbations of COPD. There is evidence
from observational studies and one randomized
controlled trial that statins may reduce morbidity
and mortality in patients with COPD [Dobler
et al. 2009]. To clarify the effect of statins on
COPD, a large prospective randomized con-
trolled trial (STATCOPE) is underway and
results are pending [ClinicalTrials.gov identifier:
NCT01061671].
Multiple studies have shown a beneficial effect of β
blockers on reducing the rate of COPD exacerba-
tions, which was contrary to prevailing thought
that β blockers may be harmful in COPD. Recent
data show a reduction in mortality in patients with
COPD exacerbations with β blockers, possibly due
to dual cardiopulmonary protective properties
[Short et al. 2011; Rutten et al. 2010]. These find-
ings need further exploration in prospective trials.
Conclusion
COPD exacerbations are often triggered by airway
infection and are an important cause of morbidity,
impairment of health status and mortality. One of
the main goals of management of COPD is to reduce
the morbidity associated with exacerbations and
http://taj.sagepub.com

thus improve the quality of life of patients with this
disabling condition. Although many pharmacologi-
cal and nonpharmacological interventions are avail-
able to prevent exacerbations, the degree of reduction
of exacerbation frequency by such interventions is
still restricted, underlining the need for novel inter-
ventions to be developed and studied in well designed
and adequately powered randomized trials.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest in
preparing this article.
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