Clinical implications of
acute exacerbations in COPD
The studies described in this thesis were supported by research grants from
AstraZeneca BV and GlaxoSmithKline BV.
Publication of this thesis was financially supported by AstraZeneca BV,
GlaxoSmithKline BV and Chiesi Pharmaceuticals BV.
© Copyright Karin Groenewegen, 2008
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Clinical implications of
acute exacerbations in COPD
ter verkrijging van de graad van doctor
aan de Universiteit Maastricht
op gezag van
prof. mr. G.P.M.F. Mols, Rector Magnificus,
volgens het besluit van het College van Decanen,
in het openbaar te verdedigen
op woensdag 25 juni 2008 om 14.00 uur
Prof. dr. E.F.M. Wouters
Prof. dr. A. Masclee (voorzitter)
Prof. dr. H.A.M. Kerstjens (Rijksuniversiteit Groningen)
Prof. dr. R. Louis (CHU Sart-Tilman, Liege)
Dr. E. Stobberingh
Dr. G.P.M. ten Velde
Bacterial infections in acute exacerbations
of COPD; a one-year prospective study
Longitudinal follow-up of systemic
inflammation after acute exacerbations
Increased systemic inflammation is a risk
factor for COPD exacerbations
Elevated plasma homocysteine levels in
stable COPD patients
Low serum MBL levels offer no increased
risk for acute exacerbations of COPD
Systemic inflammation in COPD: the role
of acute exacerbations
Mortality and mortality-related factors
after acute exacerbations of COPD
General Discussion and summary
Chronic obstructive pulmonary disease (COPD) is defined according to the
recently updated GOLD guidelines as “a preventable and treatable disease with
some significant extrapulmonary effects that may contribute to the severity
in individual patients. Its pulmonary component is characterized by airflow
limitation that is not fully reversible. The airflow limitation is usually progressive
and associated with an abnormal inflammatory response of the lung to noxious
particles or gases. The chronic airflow limitation characteristic of COPD is caused
by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal
destruction (emphysema), the relative contributions of which vary from person
to person”. The clinical manifestations of COPD include dyspnea, cough,
sputum production and impaired exercise tolerance. The clinical course of COPD
is generally one of gradual progressive impairment, which may eventually lead to
respiratory failure. Periods of relative clinical stability are interrupted by recurrent
exacerbations. An acute worsening of respiratory symptoms is often described as
an exacerbation. The definition of an acute exacerbation of COPD (AECOPD) is
generally based on varying combinations of symptoms as an increase in cough
or sputum production, worsening of dyspnea or changes in sputum purulence.
However, no complete, clear and standardized definition of an exacerbation
currently exists. In 1999 a working definition of an exacerbation was proposed : a
sustained worsening of the patient’s condition, from the stable state and beyond
normal day-to-day variations, that is acute in onset and necessitates a change
in regular medication in a patient with underlying COPD. In the 2006 GOLD
guidelines, acute exacerbations were defined as an event in the natural course
of the disease characterized by a change in the patient’s baseline dyspnoea,
cough, and/or sputum that is beyond day-to-day variations, is acute in onset
and may warrant a change in regular medication in a patient with underlying
COPD. However, these episodes of acute exacerbation can vary considerably
in severity: part of these exacerbations remain unreported while some episodes
are complicated by respiratory failure and require therefore hospital admission.
Rodriguez-Roisin et al suggested to stage COPD exacerbations based on health-
care utilisation. They defined 3 levels of severity: mild, moderate and severe.
During a mild exacerbation, patient has an increased need for medication, which
he/she can manage in their own normal environment. Patients with a moderate
exacerbation have an increased need for medication and need to seek additional
medical assistance; during a severe exacerbation, the patient recognizes obvious
and/or rapid deterioration in condition, requiring hospitalization. However, such
operational definitions of severity of exacerbations are possibly dependent on the
local health care organisation.
On average, patients with COPD have one to four exacerbations a year with
important complications for consumption of health care resources. A prospective
study performed in the United States in 1995, involving more than 1000 adults
admitted to hospital for an acute exacerbation of COPD found the median length
of hospital stay was 9 days and hospital readmissions were very common. In
the Netherlands, more than 50% of direct medical costs are related to hospital
admissions for acute periods of COPD: reductions of the number of exacerbations
may have important implications in direct medical costs. It has been shown that
costs vary considerably with the severity of the exacerbation as well as with the
severity of COPD. Exacerbations are not only important events in the natural
history of COPD because they pose a considerable economic burden but more
importantly because repeated exacerbations of COPD lead to deteriorating health-
related quality of life and when associated with ventilatory failure to premature
death. Exacerbations of COPD are therefore of major importance in terms
of the prolonged detrimental effect on patients. Furthermore the frequency of
exacerbations contributes to the long term decline in lung function in patients with
moderate to severe COPD.
However, largely as a consequence of the demographic developments in the
western world, significant increases in the number of hospitalizations can be
expected as long as no marked changes in the system of health care delivery are
The presently used definition of acute exacerbations of COPD, largely based on
experienced symptomatology by the patient without measurable parameters in
order to define severity or outcome, interferes with a systematic approach of this
acute disease condition as well as development of adequate strategies in order to
prevent or manage this important medical problem.
Risk factors for AECoPD
Despite the clinical impact of AECOPD for the patient and the community, only
limited studies are reported assessing possible risk factors for the development
of AECOPD itself: most studies evaluated factors predicting hospitalization
for acute exacerbation in patients with COPD. In one study, daily wheeze and
bronchitic symptoms contributed to a higher frequency of AECOPD . Another
study reported that the risk of hospitalization was higher in the patients with more
severe airflow limitation. However, others did not find an association between
hospitalization risk and the degree of airflow limitation[10, 11], although there
is growing evidence that exacerbation frequency increases with disease severity.
Frequent past exacerbations as well as quality of life have also been related to a
higher frequency of exacerbations[8, 10]. Regarding physiological parameters, in
one report muscle weakness was associated with high use of health services for
The role of smoking has only been limitedly addressed: smoking habits had no
significant impact on the risk of hospitalization. Among other external factors,
influenza vaccination has been shown to reduce the risk of admission . High
levels of air pollution are also related to a higher risk for admission.
In a small number of chronic hypercapnic patients, Vitacca et al. reported that
basal body weight, the decline in FEV1 and the rate of deterioration of arterial blood
gases were related to the necessity of ICU admission for acute exacerbations.
The same group reported some years later that underlying general condition
manifested by malnutrition and APACHE II score, a widely applied prognostic
score including 12 physiological variables, was an important determinant of
outcome for AECOPD and that flow limitation as assessed by the forced expiratory
manoeuvre provides additional information.
Kessler et al reported data on predictive factors of hospitalization in a series of 64
patients with COPD followed during a period of at least 2.5 years. In this study,
the risk of being hospitalized was significantly increased in patients with a low body
mass index and in patients with a limited 6-min walking distance. But above all,
the risk of hospitalization for acute exacerbation was significantly increased by gas
exchange impairment and pulmonary haemodynamic worsening: by multivariate
analysis only arterial carbon dioxide tension (PaCO2) and mean pulmonary arterial
pressure were independently related to the risk of hospitalization for AECOPD. It
is noteworthy that in this study neither the severity of airways obstruction nor the
degree of hypoxemia was a predictive factor of hospitalization.
In a study by Garcia-Aymerich, the association between modifiable and non-
modifiable potential risk factors of exacerbation and the admission for a COPD
exacerbation was estimated in a case-controlled approach. Among a wide
variety of potential risk factors, it was demonstrated that previous admissions,
lower FEV1 and underprescription of long-term oxygen therapy were independently
associated with a higher risk of admission for COPD exacerbation. A recent study
from the same group demonstrated a lower risk of admission in COPD patients
who perform some level of physical activity.
A recent study reported low BMI, a high number of concomitant diagnoses, a
high number of respiratory medications and a low Baseline Dyspnoea Index
(BDI) as independent risk factors for hospital admission. Furthermore a
number of studies investigated the risk factors for re-admission after an acute
exacerbation of COPD. In a small study, low BMI on admission and weight loss
during hospitalisation were related to an increased risk of re-admission. These
findings were confirmed by a more recent study from Sweden, which found that
weight loss during the follow-up period and low BMI were predictive for new
episodes of exacerbation. A retrospective study conducted in Hong Kong
identified previous hospital admission, total length of stay more than 5 days,
nursing home residency, dependency in self-care, right heart strain on ECG, high
dose of inhalation corticosteroids, and bicarbonate level more than 25 mmol/l as
independent risk factors for hospital readmission. A prospective study from
the Spanish group showed the following risk factors: 3 or more readmissions
for COPD in the year before recruitment, FEV1, pO2, and taking anti-cholinergic
drugs, while a higher level of physical activity was a protective factor for
readmission. Another recent Spanish study found the combination of quality of
life, hospitalization for COPD in the previous year and hypercapnia at discharge as
predictors for readmission. A Swedish group reported that walking distance is
an independent predictor of readmission for acute exacerbations.
Patients that are readmitted also seem to have lower health status and a higher
level of anxiety.
Further research is needed to prevent or relieve exacerbations and to reduce the
risk of hospitalization. Longitudinal studies with optimal phenotyping of patients
are needed to identify disease-related risk factors. The health care system needs to
overcome already identified modifiable care-associated risk factors. At least current
evidence indicates that this phenotyping needs to include the total respiratory
impairment as well as the extrapulmonary characteristics of the disease.
Physiological consequences of AECoPD
Increased sensation of dyspnea is a common and characteristic finding
in AECOPD. Clearly, the sensation of breathlessness is a complex sensory
phenomenon depending on the central processing of both respiratory-related
and non-respiratory neural activity arising from other CNS structures . The
mass, strength, length, coordination and endurance capacity of the respiratory
muscles, the impedance of the ventilatory pump, and gas exchange efficiency are
interdependent factors controlling ventilation and contribute to the sensation of
dyspnea and effort. The quality and quantity of sensory information associated
with dyspnea during AECOPD is poorly documented and generally not considered
in daily clinical practice. However, when it is generally assumed that the load
opposing the muscles during AECOPD is increased, effort as well as dyspnea both
increase. Similar changes in effort and dyspnea can be expected as ventilation
increases or as the respiratory muscles are weakened. Currently available data
from patients requiring mechanical ventilation indicates the presence of increased
central drive, dyspnoea, tachypnoea, reduced tidal volume and development of
hypercapnic respiratory failure, while ventilation/perfusion matching seems to be
relatively preserved[29, 30].
Dynamic hyperinflation (DH) is generally considered as an important factor
of exercise related breathlessness in COPD. Most studies about dynamic
hyperinflation have been performed in patients undergoing mechanical ventilation
for acute respiratory failure as a consequence of AECOPD. As a result of dynamic
hyperinflation, tidal breathing becomes shifted upwards on the pressure-volume
curve, closer to TLC. In this situation, increased pressure must be generated
to maintain tidal volume. Dynamic lung compliance becomes reduced as a result
of the accompanying tachypnoea and reduced inspiratory time and, in conjuction
with the increased airway resistance, contributes importantly to the increased
dynamic respiratory work .
Acute dynamic hyperinflation furthermore shortens the inspiratory muscles,
particularly the diaphragm and causes functional muscle weakness. The
accessory muscles of breathing are maximally recruited and inspiratory threshold
loads increase significantly . This has been suggested to account for nearly 60 % of
the increased static inspiratory work of breathing during an exacerbation.
Two studies have evaluated lung mechanics, including spirometry, inspiratory
capacity and dyspnoea during recovery from an exacerbation[33, 34]. In both
studies, the FEV1/forced vital capacity (FVC) ratio and expiratory flow limitation
changed relatively little throughout the study period. Both studies demonstrated
that changes in lung volume rather than airflow resistance predominated.
Hypoxemia is a common problem in AECOPD. V/Q inequality is the most
important determinant of hypoxemia under these conditions although low mixed
venous oxygen tension (PvO2) is a contributing factor . Lower PvO2 can be
explained by an increased oxygen utilization due to the increased work of breathing
as well as by inadequate cardiac compensating capacity to increase cardiac output.
Oxygen therapy in these conditions may have unintended deleterious effects:
hypercapnia induced by oxygen therapy is a common problem in the management
of AECOPD. The most important mechanisms are a reduction in ventilation
associated with removal of the hypoxic stimulus and increase in the ventilation-
perfusion inequality as a consequence of the hypoxic vasoconstriction. Indeed, an
increased dispersion of blood flow due to release of hypoxic vasoconstriction is
demonstrated after 100% oxygen breathing during AECOPD but is not significantly
different between CO2 retainers and non-CO2-retainers . However, oxygen-
induced hypercapnia was characterised by an overall reduction in ventilation
during oxygen breathing suggesting that a change in ventilatory control is the
major discriminating factor between retainers and non-retainers. In addition,
CO2 retainers manifested a significant increase in true alveolar dead space: this
substantial increase in alveolar dead space clearly leads to more wasted ventilation
and increase in carbon dioxide retention. Increases in physiologic dead space
were previously reported by others[36-38]. Few studies have attempted to relate
the changes in physiology to changes in the inflammatory process. One study
reported an association between serum levels of IL-8 and LTB4 and the magnitude
of dyspnoea, respiratory rate and inspiratory capacity.
However, precise analysis of pathophysiological changes during AECOPD is
scarce, resulting in an imprecise, broad and unfocused treatment strategy in
clinical practice, ignoring the clinically important pathophysiological mechanisms.
An exacerbation of COPD appears to be characterized by increased central drive,
decreased inspiratory capacity and decreased inspiratory muscle force.
Diagnosis and assessment of AECoPD
Diagnosis of AECOPD is still largely based on medical history. The three major
symptoms are increased dyspnea, increased sputum volume and increased
sputum purulence. Exacerbations may also be accompanied by fever,
wheezing, chest tightness and number of non-specific complaints. An increase in
sputum volume and purulence can be indicative for a bacterial cause, as well as a
prior history of chronic sputum production[40, 41].
Medical history can direct the diagnosis to other disease conditions, manifested
by AECOPD related symptoms. Many of these disease conditions are regularly
considered as secondary causes of AECOPD. In fact, these diseases have to be
considered as separate disease entities in order to avoid further confusion and
in order to determine more precisely the pathogenesis and pathophysiology of
Assessment of severity of an AECOPD is based on patient’s medical history before
the exacerbation, symptoms, physical examination, lung function tests, arterial
blood gas measurements, and other laboratory tests[42, 43].
The history of the previous stable condition provides a comparable measure of
the performance of the patient during daily living activities. The duration of the
episode and the progression of symptoms are also important parameters in the
assessment of the severity of the AECOPD. Sleeping and eating difficulties have to
be assessed very carefully. Specific information is also required on the frequency
of attacks and the level of dyspnoea has to be noted. When the patient is unable
to complete one sentence, the AECOPD is considered severe. However, the most
important sign is the change in the alertness of the patient.
Important signs at physical examination are the use of accessory respiratory
muscles, paradoxical chest movements, central cyanosis, oedema, haemodynamic
instability and signs of cor pulmonale. A body temperature >38.5 C, a respiratory
Differential diagnosis of AECOPD
Rib fractures/Chest trauma
Right and/or left heart failure or arrythmias
Inappropriate use of sedatives
Gastro-oesopheagal reflux and/or aspiration
rate> 25 breaths/min and a heart rate > 110 beats> min are arbitrary cut-off points
indicating severe exacerbation .
Available prior measures of lung function and blood gases are extremely useful
for comparison with those during the acute episode. However, admission for an
AECOPD is many times the first time that patients are referred to evaluate their
respiratory condition. During AECOPD even simple lung function tests can be
difficult to perform properly, and their routine use is not recommended according
to the latest GOLD guidelines.
In the hospital, measurement of arterial blood gases is essential to assess the
severity of an exacerbation. Arterial oxygen tension (PaO2) < 8.0 kPa and/ or
an arterial oxygen saturation (SaO2) < 90% when breathing room air indicate
respiratory failure. In addition, a PaO2 < 5.3 kPa, PaCO2 > 8.0 kPa and pH < 7.25 are
generally accepted criteria for ICU admission of AECOPD.
Chest radiographs are useful in identifying alternative diagnoses that can mimic
the symptoms of an exacerbation. However, data on the diagnostic accuracy
of chest x-rays during acute exacerbations are lacking. An ECG may help in the
diagnosis of right heart hypertrophy, arrhytmias or ischemic episodes. Further
technical investigations or imaging techniques have to be considered when other
diagnoses are suspected.
Laboratory investigations can reveal specific abnormalities. Whole blood count
may identify polycythaemia. Sputum stain and culture are useful in identifying
bacterial infections and directing antimicrobial therapy. Biochemical analysis
can reveal electrolyte disturbances contributing to muscle weakness like
hypophophataemia or can be indicative for systemic inflammation as manifested
by increased levels of acute phase proteins like C- reactive protein.
In general, it can be assumed that criteria reflecting the severity of the disease or
of disease related complications as AECOPD are used in order to guide clinical
decision making as to decide if there are indications for hospitalization for these
Medical history and signs of severity of AECOPD
Duration or worsening of new
number of previous episodes
Present treatment regimen
Signs of severity
Use of accessory respiratory muscles
Paradoxical chest wall movements
Worsening or new onset central cyanosis
Development of peripheral oedema
Signs of right heart failure
patients. The GOLD document  identified indications for hospital assessment or
admission for AECOPD.
Remarkably, many of the formulated criteria are related to facilities for health care
delivery or to criteria derived from medical history from the patient and his/her
relatives. Furthermore, growing development of monitoring facilities even at home
will blur the dissociation between hospital managed and home managed acute
Indications for ICU admission of patients with AECOPD are defined more strictly,
as recently summarised in the GOLD document :
Indications for hospital assessment or admission for AECOPD∗
Marked increase in intensity of symptoms such as sudden development of resting
Severe underlying CoPD
onset of new physical signs (eg. cyanosis, peripheral oedema)
Failure of exacerbation to respond to initial medical treatment
newly occurring arrythmias
Insufficient home support
∗Local resources need to be considered
Indications for ICU admission of patients with AECOPD∗
Severe dyspnea that responds inadequately to initial emergency therapy
Change in mental status (confusion, lethargy, coma)
Persistent or worsening hypoxemia (Pao2 < 5.3 kPa, 40 mm Hg), and /or severe/
worsening hypercapnia (pCo2 > 8.0 kPa, 60 mm Hg, and /or severe/worsening
respiratory acidosis (pH < 7.25) despite supplemental oxygen and noninvasive
Failure of exacerbation to respond to initial medical treatment
need for invasive mechanical ventilation
Hemodynamic instability-need for vasopressors
∗Local resources need to be considered
Causal aspects of AECoPD
Bacteria, viruses and environmental agents account for the vast majority of
episodes of exacerbations, although many patients suffer from exacerbations,
where no specific cause can be identified.
The role of bacterial infection in COPD is still a matter of debate despite decades
of investigation. Murphy et al summarised the different obstacles to define the
role of bacteria in COPD in general, and their role in causing exacerbations in
particular. First, the lower airways in COPD patients are colonised by bacteria even
in the absence of symptoms of an exacerbation. Second, patients with COPD as
well as exacerbations of the disease are highly heterogeneous, and, as a result,
bacteria may vary from patient to patient and are likely to play different roles in
different patients. Third, the information obtained from cultures of expectorated
sputum samples is limited since these samples do not reliably reflect conditions
in the lower airways. Fourth, the three bacteria most strongly implicated in causing
exacerbations (non-typeable Haemophilus influenzae, Moraxella catarrhalis, and
Streptococcus pneumoniae) are exclusively human pathogens, limiting the use of
animal models .
Patients with COPD have a number of predisposing factors for bacterial infection,
such as impaired mucociliary clearing and impaired neutrophil function leading to
abnormal inflammatory airway responses[46, 47].
An assessment of the microbiological studies indicates that conventional bacterial
respiratory pathogens are absent in about 50% of acute exacerbations in COPD.
The percentage of positive sputum cultures using protected specimen brushes to
define the microbial flora of the distal airways varies between 50 and 72%[48-50].
Monso et al found positive bacterial cultures in 52% of outpatients with AECOPD.
In that study, only 25% of the outpatients in stable condition had a significant
concentration (> 1000 cfu/ mL) of bacteria recovered by the protected- specimen
brush technique from the lower airways, while 52% of patients with exacerbation
had this amount of bacteria present, suggesting that bacteria are present in the
lower airways during exacerbations in concentrations sufficient to cause invasive
Fagon et al found evidence of bacterial infection in 50% of patients who required
mechanical ventilation . In contrast to these data, Soler et al found 72% of
positive cultures in ventilated patients for AECOPD . In this study , gram-
negative enteric bacteria and Pseudomonas or Stenotrophomonas represented
39% of potential pathogens.
A shift in the type of micro-organism isolated was reported in patients with
more severely compromised lung function [52, 53]. Indeed, both studies
reported in patients with lower FEV1 a higher incidence of Pseudomonas and
Enterobacteriaceae in their sputum. They hypothesized a possible relationship
between the decline in lung function and occurrence of Pseudomonas and other
Gram negative species in sputum.
The hypothesis of an etiological role of bacterial pathogens in AECOPD can be
supported by presence of greater neutrophilic airway inflammation in pathogen-
positive than in pathogen-negative exacerbations. Soler et al reported that the
presence of potentially pathogenic micro-organisms in their study was significantly
associated with higher percentages of neutrophils and TNF-alpha concentration
in broncho-alveolar lavage fluid. Sethi et al tested this hypothesis by comparing
levels of interleukin (IL)-8, tumor necrosis factor (TNFalpha) and neutrophil
elastase (NE) in 81 sputum samples obtained from 45 patients with AECOPD. H.
influenzae exacerbations were associated with significantly higher sputum IL-8,
TNF-alpha, and NE. M. catarrhalis exacerbations demonstrated significantly higher
sputum TNF-alpha and NE when compared to pathogen-negative exacerbations.
H. parainfluenzae-associated exacerbations had an inflammatory profile similar to
pathogen-negative exacerbations. This increased airway inflammation associated
with isolation of H. influenzae and M. catarrhalis supports an etiological role of
those pathogens in AECOPD . Furthermore, bacterial strains of H. influenzae
isolated from patients with acute exacerbation cause more airway inflammation in
a mouse model than bacterial strains from patients isolated when no symptoms
are present . Recently, a number of studies have investigated the role of non-
typeable Haemophilus Influenzae (NTHI) in acute exacerbations. Bandi et al.
found NTHI intracellulary in the lower airways in 87 % of patients with acute
exacerbation, compared to 33 % in stable patients and none in healthy controls,
suggesting a role for intracellular infection by NTHI in the pathogenesis of
Earlier studies of immune response to Haemophilus influenzae after acute
exacerbations of COPD have contradictory results, mostly due to limitation in
study design and a failure to detect strain-specific immune responses. More
recent studies have shown that immune response to bacterial pathogens after
acute exacerbations of COPD is characterized by considerable strain specificity,
suggesting the importance of differentiation among strains of bacterial pathogens
isolated over time from patients with COPD. A longitudinal cohort study in COPD
patients with repeated sputum sampling and molecular strain differentiation
showed that the acquisition of a new bacterial strain (one that the patient had
not been infected with earlier) was associated with significantly increased risk
of exacerbation. Furthermore, it was demonstrated that patients develop a
strain-specific antibody response after acute exacerbations, that has only limited
bactericidal ability for heterologous strains, leaving the patient susceptible to
reinfection by these heterologous strains of H. influenzae.
Although most studies of immune response to respiratory pathogens have focused
on antibody production, lymphocyte proliferative response is also important. Abe
et al. examined the lymphocyte response to OMP (outer membrane protein) P6 of
H. influenzae in COPD patients who had experienced a H. influenzae exacerbation
in the past 12 months, patients without such an exacerbation and healthy controls.
They demonstrated that susceptibility to H. influenzae exacerbation was associated
with a specific decrease in T-lymphocyte proliferation to P6.
Hill et al confirmed that bacterial load and species contribute to airway
inflammation in patients with stable chronic bronchitis . They demonstrated
that airway bacterial load correlated with sputum myeloperoxidase level, an
indirect measure of neutrophil activation and number, with sputum neutrophil
chemoattractants as IL-8 and leukotriene B4 level, with sputum leukocyte elastase
activity as well as with albumin leakage from serum to sputum. Markers of
inflammation increased at bacterial loads of 10*6 to 10*7 colony-forming units per
milliliter and increased progressively with increasing bacterial load. The bacterial
species influenced airway inflammation. Sputum myeloperoxidase activity was
greater in patients colonized with Pseudomonas aeruginosa than in patients
colonized with non-typeable H. influenzae, which in turn was greater than those
colonized with Moraxella catarrhalis.
In contrast, a study of Aaron et al. did not show greater increases in sputum
inflammatory cytokines MPO, TNF-α and IL-8 during exacerbations in patients
with documented bacterial or viral infection compared with patients without
White et al. conducted a longitudinal study of bacterial cultures and sputum
markers of inflammation. After acute exacerbation, the concentration of
sputum MPO and LTB4 was lower in patients in whom bacteria were eradicated
than in those with persistent bacteria, suggesting that resolution of bronchial
inflammation after acute exacerbation is related to bacterial eradication.
Combined assessment of bacterial load and inflammatory profiles in longitudinal
as well in well conducted prospective antibiotic intervention studies may contribute
to unravel the exact role of bacteria in AECOPD and to understand the pattern of
inflammation and spectrum of mediators in exacerbations due to different causal
mechanisms.. Host factors as alterations in the innate immunity are likely to be of
substantial importance, but have not yet been investigated in a systematic manner.
Based on current understanding, bacteria are an important cause of exacerbations
Estimates of the proportion of COPD exacerbations associated with viral infections
range considerably. Based on the highest quality studies the proportion of
exacerbations attributed to viral illness ranges from 18 to 34%. Influenza, para-
influenza, and coronavirus were the most frequent pathogens to be significantly
associated with exacerbations [63, 64]. Interestingly, Smith et al. reported that
Haemophilus influenzae and Streptococcus pneumoniae were isolated more than
twice as often as expected following influenza virus infection .
Greenberg and colleagues recently studied viral etiologies of COPD exacerbations
and found that 27 % of COPD exacerbations were associated with respiratory
viruses, based on viral cultures and serology, whereas in 44 % of acute
respiratory illnesses in control subjects were assciated with viruses. In the patients
with COPD, rhinoviruses accounted for 43 % of the virus infections and were thus
responsible for a total of 12 % of the exacerbations.
The availability of PCR techniques for viral detections allows for a more detailed
investigation of the role of virus in COPD exacerbations. Recent studies have
shown that about 50 % of COPD exacerbation is associated with viral infections,
the majority of which are rhinovirus[66-69]. Rohde et al. showed that viral
respiratory pathogens can be recovered from sputum more often than from nasal
aspirates during exacerbations. The most commonly detected viruses in that
study were picornaviruses (including rhinovirus, 36 %), influenza A (25 %), and
respiratory syncytial virus (RSV, 22%).
In a study by Seemungal et al., rhinovirus was detected by PCR in induced sputum
and nasal aspirates in 23 % of COPD exacerbations. Rhinovirus was associated
with a greater rise in lower airway IL-6 levels and a higher symptom score. The
same authors have shown that respiratory virus infections are associated with
more severe and frequent exacerbations of COPD and may cause chronic infection
in COPD patients. In this study the majority of viruses detected was rhinovirus;
other detected viruses were coronaviruses, influenza A and B, parainfuenza and
Respiratory Syncytial Virus (RSV). Furthermore, a recent study by Wilkinson
showed that persistent detection of this RSV in COPD patients was associated with
greater airway inflammation and more accelerated decline in FEV1.
Interestingly, frequent exacerbators (i.e. those with an exacerbation frequency
greater than the median) experience significantly more common colds than
infrequent exacerbators, whereas the likelihood of an exacerbation during a cold is
unaffected by exacerbation frequency.
A few studies have investigated the effect of interactions between lower airway
bacterial and viral infections. Wilkinson et al. showed that COPD exacerbations
in which both rhinovirus and H. influenzae were present, had higher bacterial
load and higher serum levels of IL-6. In a study by Papi et al, patients with
exacerbations with co-infections had more marked lung function impairment and
longer hospitalisations. In that study, sputum eosinophilia was associated with
Further studies are needed to get information how often bacterial infection
in AECOPD follows an inciting viral infection and what the relation is to the
clinical and inflammatory response in acute exacerbations of COPD. In a study
of viral-induced asthma exacerbations, it was shown that rhinovirus infection of
respiratory epithelial cells increased VCAM-1 surface expression via NF-κB and
GATA-mediated transcriptional upregulation. VCAM-1 and the NF-κB and GATA
transcription families may be potential therapeuric targets for virus induced
Considerable confusion exists in the literature regarding the significance of atypical
pathogens in acute exacerbations of COPD. This is partly due to differences in
the techniques used to detect the presence of atypical infections. When a fourfold
increase in antibody titer or a positive culture or RT-PCR is used, M. Pneumoniae
and Legionella are rare and C. Pneumoniae infection may be involved in up to
9% of COPD exacerbations[64, 75-77]. Moreover, chronic colonization with C.
Pneumoniae may be associated with a higher rate of COPD exacerbations. C.
Pneumonia infection can amplify inflammation in the airways of COPD patients by
stimulating the production and expression of cytokines, chemokines and adhesion
molecules[78, 79]. However, clear evidence showing a direct relationship between
increased inflammation and C. Pneumoniae infection during COPD exacerbations
is yet lacking.
Different studies have reported excess hospitalizations related to air pollution.
These studies indicate that about 5 % of episodes of AECOPD might be related
to air pollution. These effects are demonstrable at pollution levels below current
air-quality standards[80, 81]. In a study in several European cities, different air
pollutants were significantly associated with admissions for COPD independent of
environmental characteristics. In this study, the most consistent effects were
for ozone, but significant effects were also found for SO2, NO2 and measures of
particles (total suspended particles = TSP and black smoke = BS).
Particularly concentrations of particulate matter under 10 microns in diameter
(PM10) are associated with acute admissions for COPD. PM10 has free radical
activity and can enhance inflammatory response in the airways by activating
transcription factors AP-1 and NF-κB and inducing the expression of IL-8,
particularly when airway epithelial cells have been infected with adenovirus.
PM10 may also increase proinflammatory activity in airway epithelial cells via
alteration in the balance between histone acetylation and deacetylation.
Several studies and meta-analyses have shown that exacerbations in severe COPD
are particularly related to ozone (O3)[86, 87].
In patients who were admitted for an acute exacerbation of COPD with unknown
origin, the prevalence of pulmonary embolism was 25 %, according to a recent
study. Malignant disease, history of thrombo-embolism, and a decrease in
PaCO2 from baseline were risk factors for PE in this study.
Local inflammation in AECoPD
In recent years, there is a growing interest in the local as well as systemic
inflammatory consequences of AECOPD. Airway inflammation is presumed to
play an important role in the pathogenesis of worsening of airflow obstruction
seen during acute exacerbations of COPD. Several studies have demonstrated an
increase in local airway inflammation during acute exacerbations.
Saetta et al reported in lobar bronchial biopsies obtained during acute
exacerbations a 30-fold increase in eosinophils during exacerbation than under
baseline conditions. The numbers of neutrophils, T-lymphocytes, VLA-1 positive
cells and TNF-alpha positive cells were also increased during exacerbations.
Eosinophils were also increased in sputum of subjects with exacerbations when
compared with those examined under basal conditions [89, 90]. The study by Zhu
demonstrated that the eosinophilia is associated with increased expression of
CCL5 (also known as RANTES).
There is an upregulation of leucocyte adhesion molecules like E- selectin, which
are involved in the recruitment of cells to inflammatory sites, in the bronchial
mucosa of stable COPD patients, suggesting a role for these molecules in the
pathogenesis of COPD. Also during exacerbations, upregulation of E-selectin
has been found. Others suggested that plasma levels of endothelial adhesion
molecule ICAM-1 are reduced in COPD patients, both in the stable situation
and during exacerbation, indicating some form of epithelial dysfunction in
these patients. Balbi et al  analysed airway inflammation in patients with
and without an exacerbation of bronchitis using BAL. Compared with patients
under baseline conditions, chronic bronchitis patients with an exacerbation had
increased numbers of BAL neutrophils and of BAL eosinophils. Remarkably,
patients with an exacerbation had significantly increased BAL levels of granulocyte/
macrophage colony-stimulating factor (GM-CSF) as well as increased serum levels
of GM-CSF, suggesting a role of this cytokine in the inflammatory processes of
chronic bronchitis. This cytokine stimulates differentiation of granulocytes and
macrophages and can activate them directly.
Aaron et al reported data on granulocyte inflammatory markers and airway
infection at baseline, during AECOPD and after convalescence in patients with
COPD by induced sputum. TNF-α and IL-8 were significantly elevated in the
sputum of patients during acute COPD exacerbation compared with the stable
disease state. Concentrations of these cytokines declined significantly 1 month
after the exacerbation. In only 3 of the 14 patients a bacterial or viral respiratory
tract infection could be confirmed, suggesting that the acute inflammatory
airway response occurs independently of a demonstrable viral or bacterial airway
infection. In addition, Papi et al. demonstrated that acute exacerbations are
associated with increased sputum neutrophilia, independent of association with
viral and/or bacterial infection, and also with increased sputum eosinophilia , in
case of virus-associated exacerbations.
Interesting data are reported on endothelin-1 (ET-1) levels in sputum during
exacerbation. ET-1 is a potent vasoconstrictive and bronchoconstrictive peptide.
ET-1 has been shown to stimulate mucus secretion, airway oedema, smooth
muscle mitogenesis, and also bronchial hyperresponsiviness and has important
pro-inflammatory effects in the airways [96, 97]. Sputum ET-1 levels significantly
rise during AECOPD and this increase in sputum ET-1 levels correlated with the
increase in plasma ET-1 levels and sputum IL-6 levels . Airway inflammation
was also assessed in relation to the frequency of exacerbations in patients with
COPD. Sputum concentrations of individuals with COPD who suffer from three or
more exacerbations per year have higher sputum concentrations of IL-6 and IL-8
in the stable state than those who have less frequent exacerbations. Patients
with more frequent exacerbations have also lower sputum values of secretory
leukoproteinase inhibitor (SLPI). SLPI not only acts as a protease inhibitor but
also has antiviral and antibacterial activity[100, 101].
Patterns of inflammatory response in a subset of COPD patients can also been
studied in this way. Hill et al studied the inflammatory nature of acute bacterial
exacerbations of COPD in subjects with alpha1-antitrypsine (AAT) deficiency .
It was found that at the start of an exacerbation, patients with AAT deficiency had
lower sputum AAT and SLPI with higher elastase activity compared with COPD
patients without deficiency. Both groups had a comparable acute phase response
as assessed by C-reactive protein but the AAT deficient patients had a minimal
rise in serum AAT. After treatment with antibiotics, in patients with AAT deficiency,
there were significant changes in many sputum proteins including a rise in SLPI
levels and a reduction in myeloperoxidase and elastase activity.
An increase in the concentration of the elastolytic enzyme matrix
metalloproteinase-9 (MMP-9) and a decrease of its major inhibitor, tissue inhibitor
of metalloproteinase-1, is also reported in sputum during exacerbations.
This is consistent with an increase in urinary desmosine, which is an indicator of
elastolysis. This may provide a causal link between exacerbations and accelerated
decline in lung function.
Further studies are needed to explore the cellular and molecular mechanisms
involved in exacerbations.
Systemic inflammation in AECoPD
Growing evidence is present in the literature that acute exacerbations are
associated not only with inflammatory changes in the airway, but also with a
systemic inflammatory response. Next to an increase in sputum endothelin,
increases in plasma endothelin levels are reported during AECOPD. In the
same study it was demonstrated that baseline endothelin levels under stable
conditions were inversely related with baseline forced expiratory volume in one
second and forced vital capacity. Increases in plasma fibrinogen levels were
also reported during AECOPD. There was a relation between the changes in
fibrinogen at exacerbation and IL-6 levels. It can be hypothesised that these
transient acute increases in plasma fibrinogen may contribute to an increase in
exacerbation-related cardiovascular morbidity and mortality in COPD patients.
Other authors reported increases in acute phase response as well as moderate
changes in both soluble TNF-receptors p55 and p75[105, 106]. In the latter study,
significant increases in the anti-inflammatory mediator, soluble interleukin 1
receptor II were reported.
Hurst et al. recently evaluated the relation between systemic and upper and lower
airway inflammation during acute exacerbations of COPD. Exacerbations
of COPD were associated with greater nasal, sputum and serum inflammation
than the stable state. The degree of systemic inflammation, as expressed by
serum IL-6 and C-reactive protein, was correlated with the degree of lower airway
inflammation as expressed by sputum IL-8. Furthermore systemic inflammation
was greater in the presence of a bacterial pathogen.
A recent report measured systemic cytokine levels during acute exacerbations in
relation to symptoms and lung function parameters. At admission for acute
exacerbation, there was increase in levels of plasma IL-6, IL-8 and LTB4, compared
to recovery, but no change in levels of TNF-α and SLPI. Furthermore, there was
a correlation between systemic inflammatory markers IL-6 and IL-8 and dyspnea
levels and between levels of IL-6 and TNF-α and changes in FEV1.
A recent study by Hurst et al. explored the diagnostic value of 36 different
biomarkers at exacerbation of COPD. To confirm the diagnosis of
exacerbation, the most selective biomarker was CRP. Besides CRP, only levels of
IL-6, myeloid progenitor inhibitory factor-1 (MPIF-1), pulmonary and activation-
regulated chemokine (PARC), adiponectin (ACRP-30) and soluble intercellular
adhesion molecule-1 (sICAM-1) were significantly different between baseline and
exacerbation. Systemic biomarkers were not helpful in predicting exacerbation
severity. A recent meta-analysis involving many clinical, cytological and
biochemical variables in COPD, could also not show any relationship of systemic
markers with exacerbation severity. Recently, copeptin, a precursor of
vasopressin, was suggested as prognostic biomarker for AECOPD.
In summary, markers of systemic inflammation that are upregulated in acute
exacerbations as compared to the stable state include CRP[106, 112], IL-8,
TNF-α  and its soluble receptors[105, 106], leptin [105, 113], endothelin-1,
eosinophil cationic protein , myeloperoxidase ,fibrinogen , IL-6 ,
α-1 antitrypsin , leukotriene E4  and leukotriene B4 , MPIF-1, PARC,
ACRP-30 and sICAM-1.
It is clear that systemic inflammation is upregulated in acute exacerbations
of COPD. This systemic inflammatory response may be related to the local
inflammatory response in the airways, possibly in the presence of bacterial or viral
infection, but the exact mechanisms are unknown. To date, none of the systemic
inflammatory markers is able to show a relationship with exacerbation severity and
the majority of tested biomarkers do not appear capable of enlightening clinical
judgment. This can partially be related to the selection of biomarkers and the
heterogeneity of acute exacerbations.
oxidative stress in AECoPD
Cigarette smoke is an important source of oxidants. Furthermore COPD patients
have an increased number of activated neutrophils and macrophages in their
airways that produce reactive oxygen species, leading to increased oxidative stress.
There are a number of studies that demonstrate this increased oxidative stress in
COPD patients especially during exacerbations. Circulating neutrophils of COPD
patients show an enhanced repiratory burst in reaction to pro-inflammatory
The concentration of exhaled H2O2, a reactive oxygen species, is also elevated in
patients with stable COPD and increases even further during an exacerbation.
Urinary levels of IsoprostaneF2αIII, a product of lipid peroxidation, and therefore a
marker for oxidative stress, are elevated in patients with an acute exacerbation and
decline after treatment. During acute exacerbations there is not only evidence
for an increase in oxidants, but also for a decrease in antioxidant capacity.
Total plasma antioxidant capacity (TEAC) is reduced in patients with acute
exacerbation of COPD, and returns to normal values during the course of
A recent report showed that 8-isoprostane levels are also increased in exhaled
breath condensate of COPD patients during exacerbations while levels of the
antioxidant enzyme glutathione(GSH) in bronchoalveolar lavage fluid are
decreased [120, 121]. Oxidative stress may be closely associated to increased
systemic inflammation during exacerbations[120, 122, 123].
Clinical consequences of AECoPD
Using disease specific instruments such as St. George Respiratory Questionnaire,
Chronic Respiratory Questionnaire, Baseline and Transitional Dyspnoea Index,
it has been shown that acute exacerbations of COPD have a significant impact
on the patient’s health related quality of life[5, 124-128]. The impact on health
status during and shortly after hospitalization for an acute exacerbation was
studied recently. This study showed that all COPD patients hospitalized for
an acute exacerbation suffer a serious deterioration in health status, regardless of
severity based on FEV1. Although health status improved during admission,
it deteriorated in the 3 months post-discharge. In an interview based study to
determine the importance and consequences of exacerbations on patient’s every
day lives , it was shown that exacerbations have a significant impact on the
patient’s physical and psychological well being, with common symptoms like
tiredness, malaise and low-mood.
Muscle function and activity pattern
Changes in skeletal and respiratory musle metabolism are also present in COPD
patients. In skeletal muscle of COPD patients, there is a change in fiber
composition towards a predominance of anaerobic type 2 muscle fibers while in
the diaphragm an increase in type 1 fibers occurs[130, 131]. However, few data are
available on how and if muscle metabolism changes during acute exacerbations.
One study reported that peripheral muscle weakness is significantly increased
during an acute exacerbation of COPD, when compared to patients with stable
disease. Quadriceps muscle force was further reduced during the hospital stay
and was only partially recovered 3 months after discharge from the hospital. In this
study, peripheral muscle force was related to systemic levels of interleukin-8 (IL-8)
and insulin-like growth factor-1 (IGF-1), suggesting these cytokines may be involved
in peripheral muscle weakness in hospitalized patients with COPD.
In COPD patients, time spent outdoors declines over time and deteriorates acutely
during an exacerbation. In addition, patients with frequent exacerbations
recover their physical activity level to a lesser extent than patients without frequent
exacerbations. These results were confirmed by Pitta et al. Furthermore it was
shown that patients with hospitalization for an AECOPD in the previous year had
a lower activity level than patients without a recent hospitalization. Furthermore,
patients with a lower activity level one month after discharge were more likely to
be readmitted. In another study by Garcia-Eymerich et al, it was demonstrated that
COPD patients who perform some level of physical activity have a lower risk of
COPD admission and mortality.
COPD is characterized by complex metabolic disturbances. Weight loss and in
particular depletion of fat-free mass is a common finding in COPD patients.
Weight loss is mainly a result of a disturbed balance between energy expenditure
and energy intake. In COPD patients total daily energy expenditure is high as a
result of decreased mechanical efficiency.. There is also evidence in a subset
of patients, that increased resting energy expenditure may be related to systemic
During acute exacerbation, there is an impaired energy balance, caused by a
decreased dietary intake, especially in the first few days of the exacerbation and an
increased resting energy expenditure. Limited information is available about
the underlying mechanisms of this impaired energy balance.
Recent research indicates that the hormone leptin is involved in body weight and
energy balance homeostasis. During acute exacerbations of COPD, increased
leptin concentration were found, decreasing again after treatment. These
elevated leptin concentrations may be induced by the systemic inflammatory
response as well as by glucocorticoid treatment and contribute to the impaired
energy balance during acute exacerbations.
Prevention strategies for AECoPD
At present, the value of influenza vaccination in patients with COPD is well
documented and all patients with COPD are recommended to receive influenza
vaccination over a yearly basis. Nichol et al [13, 139] demonstrated the efficacy
and cost effectiveness of influenza vaccination: vaccination was associated with
a 30% to 40% reduction in the rate of hospitalization for all acute and chronic
respiratory conditions. The estimates of vaccine efficacy for preventing respiratory
illness, hospitalization and death were 56%, 50% and 68% respectively. The
value of pneumococcal vaccination for COPD patients is more controversial. Two
randomized controlled trials evaluating the efficacy of pneumococcal vaccination
among patients with COPD do not show statistically significant protective
benefits [140, 141]. One recent Spanish randomized controlled trial showed
that pneumococcal vaccination is effective in preventing community acquired
pneumonia in patients with COPD aged less than 65 years and in those with
severe airflow obstruction. No differences were found among the other groups
of patients with COPD . A recent meta-analysis concluded that evidence
from randomized controlled trials shows no significant effect of pneumococcal
vaccination on morbidity and mortality in patients with COPD.
Maintenance therapy with bronchodilating agents
Both inhaled beta-2- agonists and anticholinergic medications are considered
as initial bronchodilator therapy for patients with COPD. In a 16-week study, it
was found that salmeterol (42 or 84 microgr) inhaled twice daily significantly
reduced the number of exacerbations besides improvement in daytime and
nighttime symptom scores, dyspnea ratings following the 6-min walk test, use
of bronchodilators, patient/physician assessment and days unable to perform
work compared to placebo . It has been suggested that additional effects of
long acting bronchodilating agents, salmeterol and formoterol, on neutrophils,
pulmonary epithelium, airway smooth muscle, and respiratory muscles may
contribute to the overall clinical efficacy in COPD and may therefore reduce the
number of exacerbations and particularly decrease the severity .
In a 3-month, randomized, double-blind, placebo-controlled, multicentre study,
Casaburi et al compared the bronchodilator efficacy and safety of tiotropium
bromide, a long-acting anticholinergic agent, and placebo. They reported a trend
for fewer COPD exacerbations in the tiotropium group (16% vs 21.5% ) but this
difference was not significant. Tiotropium was demonstrated to provide superior
efficacy relative to placebo for both in-clinic spirometry and daily measurements of
peak flow and these observations were accompanied by better symptom control
and subjective global assessments.
Several long term studies investigating the effects of tiotropium have determined
the incidence of acute exacerbations as a secondary end-point[147-149]. Patients
receiving tiotropium consistently experienced 20 to 30% fewer exacerbations
and hospitalizations than patients in the placebo or ipratropium study arms[147-
149]. The differences between tiotropium and salmeterol were not statistically
significant. Recently two randomized controlled trials have specifically
investigated the prevention of acute exacerbations of COPD with tiotropium[150,
151]. In a large prospective study in 1829 patients with moderate to severe COPD,
tiotropium significantly reduced the percentage of patients experiencing one
or more exacerbations, compared to placebo. The number of hospitalizations
due to AECOPD was also reduced with tiotropium, although this difference
was not statistically significant ( p = 0.056). As secondary endpoints, the time
to first exacerbation, health care resource for acute exacerbations (including
frequency of hospitalizations and unscheduled clinic visits) and treatment days
were also reduced with tiotropium. In a French randomized controlled trial,
tiotropium significantly reduced time to first exacerbation, the proportion of
patients experiencing at least one exacerbation and the number of exacerbations
and exacerbations days. Addition of salmeterol or fluticasone-salmeterol to
tiotropium therapy did not statistically influence rates of COPD exacerbation but
did improve hospitalization rates in patients with moderate to severe COPD, in a
recent randomized double blind controlled trial. 
Maintenance therapy with inhaled steroids
The efficacy of inhaled steroids in the treatment of COPD remains controversial.
Although inhaled steroids do not modify disease progression in COPD , there
is increasing evidence that they reduce the number of exacerbations, especially
inpatients with more severe disease. Paggiaro et al compared the effect of inhaled
fluticasone propionate (500 microgram twice daily) with placebo in the treatment
of patients with COPD . They reported that the total number of exacerbations
was lower after treatment with fluticasone propionate and the distribution of
number of exacerbations per patient was lower in the fluticasone group. although
not significantly. Significantly more exacerbations in the placebo group were
defined as moderate or severe than in the fluticasone group. Exacerbations in
that study were defined as worsening of COPD symptoms, requiring changes to
normal treatment, including antimicrobial therapy, short courses of oral steroids,
and other bronchodilator therapy. Moderate exacerbations were those requiring
treatment by a family physician or as a hospital outpatient; severe exacerbations
resulted in admission to hospital.
The Isolde trial studied the effect of long term inhaled corticosteroids on lung
function, exacerbations, and health status in patients with moderate to severe
COPD . In that study, there was no significant difference in the annual
rate of decline in FEV1; however, median exacerbation rate was reduced by 25%
from 1.32 a year on placebo to 0.99 a year on with fluticasone proprionate. The
effects of fluticasone propionate on exacerbations were seen predominantly in
patients with FEV1 < 50% predicted. During the Isolde run-in the withdrawal
of inhaled corticosteroids was associated with an increased likelihood of an
exacerbation,suggesting that these drugs do modify the risk of symptomatic
deterioration in COPD . A recent Cochrane meta-analysis of 47 trials including
over 13000 patients showed that inhalation steroids were beneficial in reducing the
frequency of acute exacerbations.
Furthermore, statistical modelling showed that the beneficial effect of fluticasone
on deterioration in health status to be largely due to its effect on exacerbation
Discontinuation of inhaled steroids was associated with a more rapid onset and
higher recurrence rate of aute exacerbations in one study.
Maintenance therapy with combination therapy
Several studies have investigated the effect of combination therapy of long-
acting β-2 agonists with inhaled steroids on acute exacerbations. The Tristan
study was designed to evaluate combination therapy of long-acting β-2 agonist
salmeterol and inhalation corticosteroid fluticasone versus each component alone
or placebo. Each of the active treatments reduced exacerbation frequency
to a similar degree in this study. In a study comparing the combination
of formoterol and budesonide versus each component alone or placebo, the
combination therapy reduced the mean number of severe exacerbations per
patient per year by 24 % versus placebo and by 23 % versus formoterol alone.
In the recently published TORCH study, a large randomized double blind trial
designed to measure the effect of combination therapy fluticasone and salmeterol
on survival in COPD, the combination therapy also significantly reduced the
annual rate of exacerbations, while the effect on survival was not statistically
significant. However, in this study, the probability of having pneumonia
reported as an adverse event was higher among patients receiving medications
containing fluticasone propionate (19.6% in the combination-therapy group and
18.3% in the fluticasone group) than in the placebo group (12.3%, P<0.001 for
comparisons between these treatments and placebo).
Withdrawal of fluticasone in patients using the combination fluticasone/salmeterol
has been shown to result in acute and persistent deterioration in lung function and
dyspnoea and an increase in mild exacerbations.
The most recent Cochrane review showed a signicant reduction in morbidity and
mortality from combination therapy with inhaled steroids and LABA compared
with inhaled steroids alone.
It is not well understood why patients with COPD benefit from inhalation
corticosteroids, but a number of studies have shown a reduction in local
Mucolytic drugs and anti-oxidants
A recent systematic review of the available literature showed that oral mucolytic
drugs have significant effect on exacerbation rates in people with chronic
bronchitis and COPD: mucolytic treatment was associated with a reduction of
20 % in number of exacerbations per patient per year. Mucolytic therapy
significantly reduced the number of days of illness per subject per month and
the number of days that subjects took antibiotics. None of the studies reported
the effect of treatment with mucolytics on hospital admission for AECOPD.
Acetylcysteine was used in most of these studies suggesting that the beneficial
results in this review were largely related to this drug. Acetylcysteine has mucolytic
and antioxidant effects, although the mucolytic activity of acetylcysteine is not
well documented in chronic bronchitis . Another mechanism might be the
antioxidative effect as one of its metabolites is a free thiol. Isobutyrylcysteine, a
derivative of acetylcysteine with higher levels of free thiols did not, however, have
any effects on the number of exacerbations.
Disappointingly, a large recent randomized controlled trial, designed to investigate
the effect of N-acetylcysteine on outcomes in COPD , was not able to detect a
difference in the number of exacerbations per year between N-acetylcysteine and
Subgroups of patients with more severe COPD or patients who have frequent or
prolonged exacerbations may probably benefit more of this regular treatment .
Collet et al reported data of a double-blind placebo controlled randomized clinical
trial to study the effect of an immunostimulating agent OM-85 BV to prevent acute
respiratory exacerbation in patients with COPD . OM-85 BV is an immuno-
stimulating agent made from eight different species of bacteria that are frequently
present in the lower respiratory tract. The mechanism of action of OM-85 BV
seems to be related to direct activation of lung macrophages and enhancement
of antigen presentation to T- lymphocytes. These authors demonstrated that the
total number of days of hospitalization for a respiratory problem was 55% less
in the group treated with OM-85 BV than in the placebo group; the risk of being
hospitalised for a respiratory problem was 30 % lower in the treated group than in
the placebo group. In a recent double blind study in patients with chronic bronchitis
or mild COPD, the beneficial effect of OM-85 in reducing the frequency of acute
exacerbations was confirmed. However, a meta-analysis in which 13 trials were
included, found a non-statistically significant trend in favour of OM-85 BV . A
trial with another immunomodulating agent, AM-3 found an improvement in quality
of life, but no difference in exacerbation frequency. Further trials are required to
properly define the potential role of these immunomodulatory agents prevention of
In stable COPD patients, a 6 week pulmonary rehabilitation programme has been
shown to reduce the number of days in hospital over one year by 11 days compared
with a control group, who received standard medical care. One study by Guell
et. al found a significant reduction in the number of acute exacerbations, but not
hospitalizations in stable COPD patients undergoing an outpatient rehabilitation
A recent meta-analysis showed that pulmonary rehabilitation after acute
exacerbations of COPD significantly reduces the risk of unplanned hospital
admissions with a pooled relative risk of 0.26. The recently published evidence
based clinical guidelines on pulmonary rehabilitation from the American College
of Chest Physicians state that pulmonary rehabilitation improves dyspnoea and
quality of life and reduces the number of hospital days and other measures of
health care utilization in COPD patients.
Management of AECoPD
Hospital management of acute exacerbations of COPD has been summarized in
the GOLD document .
Oxygen therapy is the cornerstone of hospital treatment for AECOPD.
Supplemental oxygen should be titrated to improve the patient’s hypoxemia.
Adequate levels of oxygenation ( PaO2 > 8.0 kPa, 60 mmHg, or SaO2 > 90 %)
are easy to achieve in uncomplicated exacerbations, but CO2 retention can occur
insidiously with little change in symptoms. Once oxygen is started, arterial blood
gases should be checked 30-30 minutes later to ensure satisfactory oxygenation
without CO2 retention or acidosis.
Short acting inhaled β2 agonists and anticholinergic agents are the main treatment
modality for AECOPD as they relieve symptoms and improve airflow obstruction.
Short acting β-2 agonists such as salbutamol and terbutalin act by increasing the
concentration of cyclic adenosine monophosphate (c-AMP), while anticholinergics
such as ipratropium and oxitropium bromide are non-selective muscarinic
antagonists. Although there are no trials of short acting bronchodilator agents,
their use in acute exacerbations is unquestioned. There are no clinical studies
that have evaluated the use of inhaled long-acting bronchodilators (either β2
agonists or anticholinergics) with or without inhaled glucocorticosteroids during
Oral or intravenous corticosteroids are recommended in treating patients with
AECOPD in addition to other treatments[182, 183].
Two large randomized controlledtrials examining the role of systemic steroids
in COPD exacerbations have been reported. Niewoehner et al  conducted
a double blind, randomised trial of systemic glucocorticosteroids or placebo in
addition to other therapies for exacerbation of COPD. The primary end point was
treatment failure, defined as death from any cause or the need for intubation and
mechanical ventilation, readmission to the hospital for COPD, or intensification of
drug therapy. Patients were assigned to three treatment groups: group 1 received
eight weeks of glucorticoid therapy; group 2 received two weeks of glucocorticoids
Management of severe but not life-threatening exacerbations of COPD in the
emergency department or the hospital∗
Assess severity of symptoms, blood gases, chest X-ray
Administer controlled oxygen therapy and repeat arterial blood gas measurement
after 30-60 minutes
•? Combine?β-2 agonists and anticholinergics
Add oral or intravenous glucocorticosteroids
Consider antibiotics (oral or occasionally intravenous) when signs of bacterial
Consider non-invasive mechanical ventilation
At all times:
∗local resources need to be considered
and the third group received placebo. Rates of treatment failure were significantly
higher in the placebo group than in the two glucocorticoid groups combined at
30 days and at 90 days. Systemic glucocorticoids were associated with a shorter
initial hospital stay and with a small improvement in FEV1 on the first day .
Significant treatment benefits were no longer evident at six months and the 8-week
regimen was not superior to the 2-week regimen. Davies et al  investigated
the role of oral corticosteroids in treating patients with AECOPD requiring
hospital admission. Patients were randomly assigned to oral prednisolone 30
mg once daily, or identical placebo for 14 days in addition to standard therapy.
FEV1 after bronchodilation increased more rapidly and to a greater extent in the
corticosteroid treated group. Up to day 5 of hospital stay, daily increases in FEV1
after bronchodilation were statistically significant. Hospital stays were also shorter
in the corticosteroid-treated group.
The exact dose of corticosteroids that should be recommended is not known, but
high doses are associated with a significant risk of side effects. 30 to 40 mg of oral
prednisolone daily for 7-10 days is effective and safe.  Prolonged treatment
does not result in greater efficacy and increases the risk of side effects.
The role of methylxanthins (theophylline and aminophylline) in the treatment
of exacerbations is controversial. The available data do not support the use
of methylxanthines for the treatment of exacerbations of chronic obstructive
pulmonary disease. Potential benefits of methylxanthines for lung function and
symptoms could not be confirmed in meta-analysis of available trials, whereas the
potentially important adverse events of nausea and vomiting were significantly
increased in patients receiving methylxanthines. Another recent randomized
controlled trial also found no evidence for any clinically important additional effect
of aminophylline treatment when used with high dose nebulised bronchodilators
and oral corticosteroids.
They are currently considered as second-line intravenous therapy, in patients with
inadequate or insufficient response to short-acting bronchodilators .
The use of antibiotics in AECOPD remains unsettled despite their extensive use.
The role of bacterial infections in AECOPD has been described above.
The best randomized controlled trial of antibiotic use for AECOPD was performed by
Anthonisen et al.. In that study, antibiotics led to an earlier resolution of all three
symptoms defining an acute exacerbation (increased dyspnoea, increased sputum
volume, and increased sputum purulence). Stockley et al. showed a relationship
between sputum purulence and the presence of bacteria, suggesting that patients
with purulent sputum should be treated with antibiotics, if they also have at least one
of the other symptoms (dyspnoea or increased sputum volume).
In a retrospective cohort analysis of visits for AECOPD, Adams et al demonstrated
that patients, treated with antibiotics had significantly lower relapse rates than
those who did not receive antibiotics; relapse from AECOPD was not related to the
severity of underlying disease or to the severity of the AECOPD. It was found that
the specific choice of antibiotic is important because those treated with amoxicillin
had the highest relapse rates of all groups, suggesting that the choice of antibiotic
should probably based on the resistance profiles to antibiotics.
There have been a number of systematic reviews of the use of antibiotic treatment
in patients with AECOPD[188-190]. The most recent included 13 randomized
controlled trials of antibiotic use in AECOPD. The conclusion was that
antibiotics effectively reduce the risk of treatment failure and mortality in severe
exacerbations of COPD, but for patients with mild to moderate exacerbations,
further research is needed in order to guide antibiotic prescription.
The current GOLD guidelines recommend the use of antibiotics in patients with
all three major symptoms (increased dyspnoea, increased sputum volume and
increased sputum purulence), to patients with two major symptoms if one of
them is increased sputum purulence, and to patients with a severe exacerbation
requiring mechanical ventilation.
The primary objectives of mechanical ventilatory support in AECOPD are to
decrease mortality and morbidity and to relieve symptoms.
Ventilatory support can be delivered non-invasively or invasively (conventionally)
using different modes that are, in essence, positive pressure devices for
noninvasive ventilation using either a nasal or a facial mask, or via an endotracheal
tube or a trachostomy for invasive ventilation.
Non-invasive ventilation has been studied in several randomized controlled
trials in patients with acute respiratory failure,consistently providing positive
results with success rates of 80-85 %[191-193]. NIV decreases mortality, the need
for endotracheal intubation and treatment failure. Moreover, NIV increases pH,
reduces hypercapnia and respiratory rate and shortens length of hospital stay by
more than 3 days and decreases complication rate[192, 193]. It is cost-effective
compared with usual therapeutic care alone.
Indications and contraindications for the use of NIV were published in the GOLD
Indications for invasive mechanical ventilation in AECOPD have already been
mentioned. NIV has been used to shorten the period of invasive ventilation in
cases of weaning failure and in those with a long stay in the intensive care unit[195,
196]. However, it was not effective in avoiding reintubation and did not reduce
In a recent study among patients with chronic hypercapnic COPD that had been
discharged from the hospital with NIV, mortality was 16 % after 1 year, 35 % after
2 years and 75 % after 5 years. Independent predictors of mortality were
nutritional status, hyperinflation and base excess. In patients at risk, a reduction of
these risk factors after initiation of NIV was associated with improved survival.
outcome and prognosis of AECoPD
Outcome and prognosis of AECOPD are still poorly documented. However,
especially patients with more frequent exacerbations have a worse health status
compared to COPD patients with fewer exacerbations (0 to 2 exacerbations/
year) . The same authors reported that although lung function changes during
AECOPD may be small, they can be persistent and in some cases lung function
and symptoms did not recover to baseline values even at 3 months. Therefore,
closer monitoring of patients may be useful and all patients should be followed
after an exacerbation until recovery has occurred .
Several studies have investigated predictive factors related to an increased COPD
related mortality risk. Patient characteristics that have been reported to influence
survival in stable COPD patients include FEV1 [200-202],age [200, 202], arterial
carbon dioxide tension (PaCO2) , cardiac factors , diffusion capacity
and BMI[203, 204].
Other studies have investigated more specifical factors related to mortality after
acute exacerbations of COPD. Factors that have been reported as risk factors
Indications and relative contraindications for NIV
paradoxical abdominal motion
•? Moderate?to?severe?acidosis?(?pH?≤ 7.35) and/or hypercapnia
(pCo2 ≥ 6.0 kPa, 45 mm Hg)
Exclusion criteria (any may be present)
for mortality after exacerbation are PaCO2, oxygen saturation and resting oxygen
consumption , low BMI [6, 203], older age [6, 206, 207], cardiac factors
[6, 206, 207] and other co-morbidity , severity of illness, serum albumin,
functional status and arterial oxygen tension (PaO2) .
A prospective cohort study of 1016 adult patients admitted to hospital for
AECOPD described the outcomes of patients hospitalised with AECOPD and
the determinants related to survival in that cohort . The in-hospital mortality
in that study was 11%; at 6 months, 34.7% of patients died. Survival time was
independently related to severity of illness, body mass index, age, prior functional
status, PaO2/FIO2, congestive heart failure, serum albumin, and the presence
of cor pulmonale. The authors concluded that patients as well as caregivers
should be aware of the likelihood of poor outcomes following hospitalization for
exacerbation of COPD, particularly associated with hypercapnia.
More recent studies have documented similar outcomes. A Turkish study
in 205 patients, hospitalised for acute exacerbation of COPD showed an in-
hospital mortality of 8.3 %, with 1-,2- and 3- year mortality rates of 33, 43 and
49 % respectively. In this study, long term mortality was associated with
longer disease duration, lower serum albumin, lower PaO2, and lower BMI.
A Spanish study among 304 patients reported a mortality of 55.2 % after 5
years of follow-up, but this study also included patients who were treated as
outpatients. It was shown that besides older age and PaCO2, severe (requiring
hospital management) acute exacerbations are an independent predictor
of mortality. Patients with more than 3 exacerbations and patients requiring
admission had higher mortality rates.
Similar results were reported about hospital and 1-year survival of patients
admitted to ICU with AECOPD . Hospital mortality was 24%; mortality rates
were 41% at 90 days after discharge, 47% at 180 days and 59% at 1 year. Median
survival for all patients was 224 days. These figures should be considered when
making decisions or evaluating therapies. Generally, it is believed that patients
admitted to ICU with acute respiratory failure due to acute exacerbations of COPD
have a worse outcome. Recent retrospective reports have also shown that outcome
for these patients is similar to patients treated for an acute exacerbation without
the need for intubation [211, 212].
Further prospective studies of outcome of AECOPD, based on adequate staging
of the disease process, are urgently needed in order to support adequate decision
making in the management of AECOPD.
The definition of acute exacerbation of COPD is generally based on medical
symptoms like dyspnoea, cough and sputum production. The majority of acute
exacerbations is related to bacterial infection, viral infection and/or air pollution,
although exact causal relationships have not been established. Acute exacerbations
are not only associated with local inflammation in the airways, but there is growing
evidence that systemic inflammation is upregulated as well during AECOPD.
Acute exacerbations have an important detrimental impact on patient’s
quality of life and activity pattern. Prevention of these episodes is therefore an
important goal in COPD management. Influenza vaccination, maintenance
therapy with bronchodilating agents, inhalation steroids and anti-oxidants and
pulmonary rehabilitation are to some extent beneficial in reducing the number of
Treatment of acute exacerbations consists of bronchodilating agents, oral or
intravenous glucocorticosteroids, and antibiotics in case of severe exacerbations.
In patients with respiratory failure due to acute exacerbations, non invasive or
invasive ventilatory support may be indicated.
Acute exacerbations of COPD still have a high mortality rate. Future research
should focus on phenotyping of patients and reducing modifiable risk-factors.
Aims and outline of the thesis
As discussed in chapter 1 of this thesis, the general introduction, acute
exacerbations of COPD are very heterogeneous and not well characterized.
In general, this thesis aims at assessing the clinical implications and the
involvement of systemic processes in the pathophysiology of of acute
exacerbations of COPD, in order to better characterize these episodes.
To gain more insight in clinical outcomes of acute exacerbation, two studies are
performed in patients hospitalized for an acute exacerbation.
These studies are described in chapters 2 and 8 of this thesis.
Further studies are aimed at investigating systemic inflammation and its relation
to acute exacerbations. These studies are performed in hospitalized patients
(described in chapter 3) and outpatient populations. (chapter 4, 5 and 6)
In chapter 2, the contribution of respiratory bacterial infections to acute exacerbations
of COPD is studied. The specific aims of this study are to investigate the frequency
of respiratory bacterial infections in hospitalized patients, admitted for an acute
exacerbation of COPD, to identify the responsible pathogens by sputum culture and
to assess patient characteristics in relation to sputum culture results.
The study described in chapter 3 of this thesis is aimed to further characterize
the systemic inflammation during acute exacerbation and in the stable state. The
course of different systemic inflammatory and anti-inflammatory parameters
during hospitalization and in the follow-up period , when patients were clinically
stable, is assessed.
The next studies are performed in COPD patients in the clinically stable state to
investigate systemic levels of different inflammatory cytokines as well as markers of
haemostasis and the innate immune system, and to identify a possible relation of
these markers with the occurrence of acute exacerbations.
In chapter 4, different systemic inflammatory parameters in a large cohort of
COPD patients, who were clinically stable, are studied, to determine if an elevated
systemic inflammatory status at baseline is related to the number of moderate and
severe exacerbations during a one year follow-up period. In this study, risk factors
for an acute exacerbation are identified, particularly in relation to parameters of
systemic inflammation and haemostasis.
The study described in chapter 5 of this thesis was set up to investigate systemic
levels of different markers of inflammation and haemostasis in clinically stable
COPD patients. In these patients, systemic levels of hs-CRP, total plasma
homocysteine (tHcy) and fibrinogen are determined and a possible relation of
these markers to clinical characteristics is studied.
In chapter 6, the contributing role of MBL, a key component of the innate immune
system, to the development of acute exacerbations is evaluated.
The aim of this study is to determine if serum MBL levels, measured at baseline,
are related to the occurrence of moderate and severe exacerbations of COPD.
In chapter 7, the current knowledge regarding systemic inflammation and its
effects during acute exacerbations is extensively reviewed, in order to outline the
context of our results.
The aim of the study described in chapter 8 of this thesis is to investigate mortality
and risk factors for mortality in patients admitted for an acute exacerbation of
COPD during a one-year follow-up period.
Finally, chapter 9 comprises the general discussion and summary.
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