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Ther Adv Chronic Dis
2014, Vol. 5(5) 212 –227
DOI: 10.1177/ 
2040622314532862
© The Author(s), 2014. 
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Therapeutic Advances in Chronic Disease
Introduction
Chronic obstructive pulmonary disease (COPD), 
a common preventable and treatable disease, is 
characterized by persistent airflow limitation that 
is usually progressive and that is caused by an 
enhanced chronic inflammatory response in the 
airways and the lung to noxious particles or gases 
[GOLD, 2013]. COPD is a major cause of mor-
bidity and mortality worldwide and results in an 
economic and social burden that is both substan-
tial and increasing [Lopez et  al. 2006]. COPD 
prevalence, morbidity and mortality vary across 
countries. In the USA, COPD affects approxi-
mately 24 million Americans, results in about 
120,000 deaths a year and is now the third lead-
ing cause of death [Kochanek et al. 2011].
The natural history of COPD is punctuated by 
exacerbations which have major implications on 
the patient and healthcare system. In this review 
we provide a concise overview of COPD exacer-
bations and their impact, outlining the population 
at risk, etiology and current management and 
preventive strategies.
Impact of COPD exacerbations
The Global Initiative for Chronic Obstructive 
Lung Disease (GOLD) defines a COPD 
exacerbation as an event in the natural course of 
the disease that is characterized by a change in the 
patient’s baseline dyspnea, cough and sputum 
that is beyond normal day-to-day variations, is 
acute in onset and warrants a change in regular 
medication [GOLD, 2011].
Exacerbations of COPD impose a substantial 
burden on healthcare systems worldwide; they are 
a major cause of morbidity, mortality and poor 
health status [Seemungal et  al. 1998]. 
Furthermore, they account for the majority of 
hospital admissions. More than 50% of the total 
cost of COPD is accounted for by services related 
to exacerbations. For instance, in the UK, they 
are the most common cause of medical hospital 
admission, accounting for 15·9% of hospital 
admissions, at a cost to the National Health 
System of over £253 million a year [British 
Thoracic Society, 2006].
Exacerbations of COPD have short- and long-
term clinical implications. The time course of 
recovery of symptoms during an acute exacerba-
tion was evaluated by one study which showed that 
in 50% of community-treated exacerbations, 
patients recovered to baseline symptoms within 
7 days. However, in 14% of these events patients’ 
symptoms did not return to baseline 35 days 
Chronic obstructive pulmonary disease 
exacerbations: latest evidence and clinical 
implications
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
Correspondence to: 
Nicola A. Hanania, MD, MS 
Section of Pulmonary, 
Critical Care and Sleep 
Medicine, Department of 
Medicine, Baylor College 
of Medicine, 1504 Taub 
Loop, Houston, TX 77030, 
USA 
hanania@bcm.edu
Hammad Qureshi, MD 
Section of Pulmonary, 
Critical Care and Sleep 
Medicine, Department of 
Medicine, Baylor College 
of Medicine, Houston, 
TX, USA
Amir Sharafkhaneh, MD, 
PhD 
Section of Pulmonary, 
Critical Care and Sleep 
Medicine, Medical Care 
Line, Michael E. DeBaKey 
VA Medical Center; and 
Department of Medicine, 
Baylor College of 
Medicine, Houston, TX, 
USA
532862 TAJ0010.1177/2040622314532862Therapeutic Advances in Chronic DiseaseH Qureshi, A Sharafkhaneh
research-article2014
Review
H Qureshi, A Sharafkhaneh et al.
http://taj.sagepub.com 213
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 
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 relatedto 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 
Figure 1. Impact of chronic obstructive pulmonary 
disease exacerbations.
Therapeutic Advances in Chronic Disease 5(5)
214 http://taj.sagepub.com
having a COPD exacerbation, the prevalence of 
pulmonary embolism was 20%. The prevalence 
was even higher (25%) among those 
hospitalized.
Pathophysiologic consequences of COPD 
exacerbations
In the past decade, the understanding of COPD 
has evolved from a disease limited to the airways 
to a more complex disease frequently associated 
with systemic inflammation and other chronic 
comorbidities [Clini et al. 2013]. COPD exacer-
bation has been associated with a proinflamma-
tory and prothrombotic state. A recent study 
demonstrated elevated levels of interleukin 6, von 
Willebrand’s factor, D dimer and prothrombin 
fragment 1+2 being surrogate markers for inflam-
mation, endothelial damage and clotting activa-
tion respectively during an exacerbation of COPD 
with a return of these levels to baseline with 
recovery [Polosa et al. 2011].
Management strategies of COPD 
exacerbations
The goals of management of COPD exacerbation 
are to minimize the impact of the current exacer-
bation and prevent the development of subsequent 
exacerbations. Depending on the severity, an exac-
erbation can be managed in an outpatient or inpa-
tient setting. Most of the time outpatient therapy is 
sufficient with pharmacologic therapies, including 
bronchodilators, corticosteroids and antibiotics.
Based on available evidence, early detection and 
aggressive prompt management of exacerbations 
are warranted to ensure optimal outcome. 
Unfortunately, many patients with COPD fail to 
report their exacerbations to their healthcare pro-
viders. It is therefore imperative to educate 
patients about the signs and symptoms of exacer-
bations in an attempt to build a self-management 
plan that may help them seek advice early in the 
course of exacerbations [American Thoracic 
Society/European Respiratory Society, 2010].
Pharmacological interventions
Several pharmacological interventions outlined 
below are used in the management of a COPD 
exacerbation.
Inhaled bronchodilators. Short-acting inhaled β2 
agonists (SABAs) and anticholinergic agents 
(short-acting muscarinic antagonists, SAMAs) 
remain the mainstay in the treatment of symp-
toms and airflow obstruction during exacerba-
tions. SABAs such as albuterol act by increasing 
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 
obstructive pulmonary disease exacerbations.
Microbe Role in 
exacerbations
Bacteria
 Haemophilus influenzae 20–30%
 Streptococcus pneumoniae 10–15%
 Moraxella catarrhalis 10–15%
 Psuedomonas aeruginosa 5–10%
 Enterobacteriaceae Undefined
 H. hemolyticus Undefined
 H. parainfluenza Undefined
 Staphylococcus aureus Undefined
Viruses
 Rhinovirus 10–25%
 Parainfluenza virus 5–10%
 Influenza virus 5–10%
 Respiratory syncytial virus 5–10%
 Adenovirus 3–5%
 Coronavirus 3–5%
 Human metapneumovirus 3–5%
Atypical bacteria
 Chlamydophilia pneumoniae 3–5%
 Mycoplasma pneumoniae 1–2%
Fungi 
 Pneumocystis jeroveci Undefined
H Qureshi, A Sharafkhaneh et al.
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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 
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, becausemore 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 
Therapeutic Advances in Chronic Disease 5(5)
216 http://taj.sagepub.com
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 
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 
H Qureshi, A Sharafkhaneh et al.
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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 widespreaduse 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 
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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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. 
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 bacterialextract, 
reported a reduction in the severe complications 
of exacerbations and hospital admissions in 
H Qureshi, A Sharafkhaneh et al.
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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 
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.
Table 3. Strategies to prevent chronic obstructive pulmonary (COPD) disease exacerbations.
Nonpharmacological Pharmacological
Smoking cessation
Vaccines
 Approved
 Influenza
 Pneumococcal
 Experimental
 Killed Haemophilus influenzae
 NTHi oral immunotherapy
 (HI-164OV)
 Bacterial lysate
Bronchodilators
 LAMAs: tiotoprium
 LABAs: salmeterol, formoterol, 
 Indacaterol
Antioxidants
 Carbocisteine
 Acetylcysteine
Anti-inflammatory
 ICS/LABA
 Roflumilast
Pulmonary rehabilitation
Disease management programs
Antibiotics
 Systemic antibiotics
 Macrolides, fluoroquinolones
 Inhaled antibiotics
Drugs used to treat comorbidities of COPD: statins, 
β blockers, ACE inhibitors
ACE, angiotensin-converting enzyme; ICS, inhaled corticosteroid; LABA, long-acting inhaled β2 agonist; LAMA, long-
acting muscarinic antagonist; NTHi, nontypeable Haemophilus influenzae.
Therapeutic Advances in Chronic Disease 5(5)
220 http://taj.sagepub.com
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.
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 
Table 4. Comparative data of pharmacologic therapies for reduction in chronic obstructive pulmonary 
exacerbation rates [Han and Martinez, 2011].
Drug class Reduction in exacerbation rates
LAMA 14% reduction [Tashkin et al. 2008]
LABA 15% reduction [Calverley et al. 2007]
ICS 25% reduction [Burge et al. 2000]
ICS/LABA combination 26–35% reduction [Calverley et al. 2007; Anzueto 
et al. 2009]
PDE4 inhibitors 17% reduction [Calverley et al. 2009]
N acetylcysteine 25% reduction [Gerrits et al. 2003]
Antibiotics (moxifloxacin) 20% reduction [Sethi et al. 2010]
ICS, inhaled corticosteroid; LABA, long-acting inhaled β2 agonist; LAMA, long-acting muscarinic antagonist; PDE4, phos-
phodiesterase 4.
H Qureshi,A Sharafkhaneh et al.
http://taj.sagepub.com 221
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 
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]. 
Therapeutic Advances in Chronic Disease 5(5)
222 http://taj.sagepub.com
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 
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 
H Qureshi, A Sharafkhaneh et al.
http://taj.sagepub.com 223
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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