Increased systemic inflammation is a risk factor for COPD exacerbations

Article (PDF Available)inChest 133(2):350-7 · March 2008with546 Reads
DOI: 10.1378/chest.07-1342 · Source: PubMed
Abstract
COPD is characterized by episodic increases in respiratory symptoms, so-called exacerbations. COPD exacerbations are associated with an increase in local and systemic inflammation. Data of a previously published study in a well-characterized COPD cohort were analyzed to define predictive factors of acute exacerbations, particularly focusing on systemic inflammation. To determine if an elevated systemic inflammatory status measured at baseline is related to the occurrence of acute exacerbations in patients with COPD. The occurrence of moderate (requiring oral prednisolone) and severe exacerbations (requiring hospitalization) was prospectively recorded over 1 year. At the beginning of the study, lung function values (FEV1, FVC, functional residual capacity, and diffusion capacity of the lung for carbon monoxide [Dlco]) and serum levels of C-reactive protein, fibrinogen, lipopolysaccharide binding protein, tumor necrosis factor (TNF)-alpha, and its soluble receptors (soluble TNF receptors 55 and 75) as markers of systemic inflammation were determined. Two hundred seventy-seven person-years of follow-up were analyzed in the total group of 314 patients: 186 patients were responsible for 411 exacerbations (374 moderate and 37 severe). Multivariate analyses showed that a higher initial fibrinogen level and a lower FEV1 predicted a higher rate of both moderate and severe exacerbations. Additional independent predictors of a severe exacerbation were a higher number of prestudy severe exacerbations and lower Dlco. A higher number of prestudy moderate exacerbations was the only additional independent risk factor for the rate of moderate exacerbations. This study demonstrates that besides lung function impairment systemic inflammation manifested by elevated fibrinogen levels is an independent risk factor for exacerbations of COPD. Attenuation of systemic inflammation may offer new perspectives in the management of COPD patients to reduce the burden of exacerbations.

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Clinical implications of
acute exacerbations in COPD
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The studies described in this thesis were supported by research grants from
AstraZeneca BV and GlaxoSmithKline BV.
Publication of this thesis was nancially 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
PROEFSCHRIFT
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
door
Karin Groenewegen-Sipkema
Promotor:
Prof. dr. E.F.M. Wouters
Beoordelingscommissie:
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
CONTENTS
Chapter 1 General Introduction
Chapter 2 Bacterial infections in acute exacerbations
of COPD; a one-year prospective study
Chapter 3 Longitudinal follow-up of systemic
inflammation after acute exacerbations
of COPD
Chapter 4 Increased systemic inflammation is a risk
factor for COPD exacerbations
Chapter 5 Elevated plasma homocysteine levels in
stable COPD patients
Chapter 6 Low serum MBL levels offer no increased
risk for acute exacerbations of COPD
Chapter 7 Systemic inflammation in COPD: the role
of acute exacerbations
Chapter 8 Mortality and mortality-related factors
after acute exacerbations of COPD
Chapter 9 General Discussion and summary
Samenvatting
Abbreviations
Curriculum Vitae
Dankwoord
9
53
69
85
101
117
135
159
177
191
203
205
206
CHAPTER 1
General introduction
10
General introduction
Introduction
Chronic obstructive pulmonary disease (COPD) is dened according to the
recently updated GOLD guidelines as “a preventable and treatable disease with
some signicant extrapulmonary effects that may contribute to the severity
in individual patients. Its pulmonary component is characterized by airow
limitation that is not fully reversible. The airow limitation is usually progressive
and associated with an abnormal inammatory response of the lung to noxious
particles or gases. The chronic airow 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”[1]. 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 denition 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 denition of an exacerbation
currently exists. In 1999 a working denition 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[2]. In the 2006 GOLD
guidelines, acute exacerbations were dened 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[1]. 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 dened 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[2]. However, such
operational denitions 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
1
11
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[3]. 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[4]. 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[5] and when associated with ventilatory failure to premature
death[6]. 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[7].
However, largely as a consequence of the demographic developments in the
western world, signicant increases in the number of hospitalizations can be
expected as long as no marked changes in the system of health care delivery are
realised [8].
The presently used denition of acute exacerbations of COPD, largely based on
experienced symptomatology by the patient without measurable parameters in
order to dene 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 [5]. Another
study reported that the risk of hospitalization was higher in the patients with more
severe airow limitation[9]. However, others did not nd an association between
hospitalization risk and the degree of airow 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
COPD[12].
The role of smoking has only been limitedly addressed: smoking habits had no
12
General introduction
signicant impact on the risk of hospitalization[10]. Among other external factors,
inuenza vaccination has been shown to reduce the risk of admission [13]. High
levels of air pollution are also related to a higher risk for admission[14].
In a small number of chronic hypercapnic patients, Vitacca et al. reported that
basal body weight, the decline in FEV
1
and the rate of deterioration of arterial blood
gases were related to the necessity of ICU admission for acute exacerbations[15].
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 ow limitation as assessed by the forced expiratory
manoeuvre provides additional information[16].
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[10]. In this study,
the risk of being hospitalized was signicantly 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 signicantly increased by gas
exchange impairment and pulmonary haemodynamic worsening: by multivariate
analysis only arterial carbon dioxide tension (PaCO
2
) 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 modiable and non-
modiable potential risk factors of exacerbation and the admission for a COPD
exacerbation was estimated in a case-controlled approach[17]. Among a wide
variety of potential risk factors, it was demonstrated that previous admissions,
lower FEV
1
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[18].
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[19]. 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[20]. These
ndings were conrmed 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[21]. A retrospective study conducted in Hong Kong
identied 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[22]. A prospective study from
1
13
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[23]. 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[24]. A Swedish group reported that walking distance is
an independent predictor of readmission for acute exacerbations[25].
Patients that are readmitted also seem to have lower health status and a higher
level of anxiety[26].
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 identied modiable 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 nding
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 [27]. The
mass, strength, length, coordination and endurance capacity of the respiratory
muscles, the impedance of the ventilatory pump, and gas exchange efciency are
interdependent factors controlling ventilation and contribute to the sensation of
dyspnea and effort[28]. 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[28]. 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 hyperination (DH) is generally considered as an important factor
of exercise related breathlessness in COPD[31]. Most studies about dynamic
hyperination have been performed in patients undergoing mechanical ventilation
for acute respiratory failure as a consequence of AECOPD. As a result of dynamic
hyperination, tidal breathing becomes shifted upwards on the pressure-volume
curve, closer to TLC[32]. In this situation, increased pressure must be generated
14
General introduction
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[32] .
Acute dynamic hyperination furthermore shortens the inspiratory muscles,
particularly the diaphragm and causes functional muscle weakness.[32] The
accessory muscles of breathing are maximally recruited and inspiratory threshold
loads increase signicantly . This has been suggested to account for nearly 60 % of
the increased static inspiratory work of breathing during an exacerbation[32].
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 ow limitation
changed relatively little throughout the study period. Both studies demonstrated
that changes in lung volume rather than airow 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 (PvO
2
) is a contributing factor [29]. Lower PvO
2
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 ow due to release of hypoxic vasoconstriction is
demonstrated after 100% oxygen breathing during AECOPD but is not signicantly
different between CO
2
retainers and non-CO
2
-retainers [35]. 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,
CO
2
retainers manifested a signicant 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[35]. 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 inammatory process. One study
reported an association between serum levels of IL-8 and LTB4 and the magnitude
of dyspnoea, respiratory rate and inspiratory capacity[39].
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.
1
15
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[40]. Exacerbations may also be accompanied by fever,
wheezing, chest tightness and number of non-specic 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
AECOPD.
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 difculties have to
be assessed very carefully. Specic 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
Pneumonia
Pulmonary embolism
Pneumothorax
Pleural effusion
Rib fractures/Chest trauma
Right and/or left heart failure or arrythmias
Inappropriate use of sedatives
Gastro-oesopheagal reflux and/or aspiration
Bronchus carcinoma
16
General introduction
rate> 25 breaths/min and a heart rate > 110 beats> min are arbitrary cut-off points
indicating severe exacerbation [43].
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 rst time that patients are referred to evaluate their
respiratory condition. During AECOPD even simple lung function tests can be
difcult to perform properly, and their routine use is not recommended according
to the latest GOLD guidelines[1].
In the hospital, measurement of arterial blood gases is essential to assess the
severity of an exacerbation. Arterial oxygen tension (PaO
2
) < 8.0 kPa and/ or
an arterial oxygen saturation (SaO
2
) < 90% when breathing room air indicate
respiratory failure. In addition, a PaO
2
< 5.3 kPa, PaCO
2
> 8.0 kPa and pH < 7.25 are
generally accepted criteria for ICU admission of AECOPD[1].
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 specic 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 inammation as manifested
by increased levels of acute phase proteins like C- reactive protein.
In general, it can be assumed that criteria reecting 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
Medical history Signs of severity
Duration or worsening of new
symptoms
Use of accessory respiratory muscles
Number of previous episodes
(exacerbations/hospitalizations)
Paradoxical chest wall movements
Present treatment regimen Worsening or new onset central cyanosis
Development of peripheral oedema
Hemodynamic instability
Signs of right heart failure
Reduced alertness
1
17
patients. The GOLD document [1] identied 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
exacerbations.
Indications for ICU admission of patients with AECOPD are dened more strictly,
as recently summarised in the GOLD document [1]:
Indications for hospital assessment or admission for AECOPD
Marked increase in intensity of symptoms such as sudden development of resting
dyspnea
Severe underlying COPD
Onset of new physical signs (eg. cyanosis, peripheral oedema)
Failure of exacerbation to respond to initial medical treatment
Significant comorbidities
Frequent exacerbations
Newly occurring arrythmias
Diagnostic uncertainty
Older age
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
ventilation
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
18
General introduction
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 specic cause can be identied[44].
Bacterial infections
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 dene 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 reect conditions
in the lower airways. Fourth, the three bacteria most strongly implicated in causing
exacerbations (non-typeable Haemophilus inuenzae, Moraxella catarrhalis, and
Streptococcus pneumoniae) are exclusively human pathogens, limiting the use of
animal models [45].
Patients with COPD have a number of predisposing factors for bacterial infection,
such as impaired mucociliary clearing and impaired neutrophil function leading to
abnormal inammatory 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
dene the microbial ora 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 signicant
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 sufcient to cause invasive
infection [49].
Fagon et al found evidence of bacterial infection in 50% of patients who required
mechanical ventilation [48]. In contrast to these data, Soler et al found 72% of
positive cultures in ventilated patients for AECOPD [51]. 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 FEV
1
a higher incidence of Pseudomonas and
1
19
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 inammation in pathogen-
positive than in pathogen-negative exacerbations. Soler et al reported that the
presence of potentially pathogenic micro-organisms in their study was signicantly
associated with higher percentages of neutrophils and TNF-alpha concentration
in broncho-alveolar lavage uid[51]. 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.
inuenzae exacerbations were associated with signicantly higher sputum IL-8,
TNF-alpha, and NE. M. catarrhalis exacerbations demonstrated signicantly higher
sputum TNF-alpha and NE when compared to pathogen-negative exacerbations.
H. parainuenzae-associated exacerbations had an inammatory prole similar to
pathogen-negative exacerbations. This increased airway inammation associated
with isolation of H. inuenzae and M. catarrhalis supports an etiological role of
those pathogens in AECOPD [54]. Furthermore, bacterial strains of H. inuenzae
isolated from patients with acute exacerbation cause more airway inammation in
a mouse model than bacterial strains from patients isolated when no symptoms
are present [55]. Recently, a number of studies have investigated the role of non-
typeable Haemophilus Inuenzae (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
exacerbations[56].
Earlier studies of immune response to Haemophilus inuenzae after acute
exacerbations of COPD have contradictory results, mostly due to limitation in
study design and a failure to detect strain-specic immune responses[57]. More
recent studies have shown that immune response to bacterial pathogens after
acute exacerbations of COPD is characterized by considerable strain specicity,
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 signicantly increased risk
of exacerbation[57]. Furthermore, it was demonstrated that patients develop a
strain-specic 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. inuenzae[58].
Although most studies of immune response to respiratory pathogens have focused
on antibody production, lymphocyte proliferative response is also important. Abe
20
General introduction
et al. examined the lymphocyte response to OMP (outer membrane protein) P6 of
H. inuenzae in COPD patients who had experienced a H. inuenzae exacerbation
in the past 12 months, patients without such an exacerbation and healthy controls.
They demonstrated that susceptibility to H. inuenzae exacerbation was associated
with a specic decrease in T-lymphocyte proliferation to P6[59].
Hill et al conrmed that bacterial load and species contribute to airway
inammation in patients with stable chronic bronchitis [60]. 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
inammation 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 inuenced airway inammation. Sputum myeloperoxidase activity was
greater in patients colonized with Pseudomonas aeruginosa than in patients
colonized with non-typeable H. inuenzae, 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
inammatory cytokines MPO, TNF-α and IL-8 during exacerbations in patients
with documented bacterial or viral infection compared with patients without
infection [61].
White et al. conducted a longitudinal study of bacterial cultures and sputum
markers of inammation[62]. 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
inammation after acute exacerbation is related to bacterial eradication.
Combined assessment of bacterial load and inammatory proles 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
inammation 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
of COPD.
Viral infections
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%. Inuenza, para-
inuenza, and coronavirus were the most frequent pathogens to be signicantly
associated with exacerbations [63, 64]. Interestingly, Smith et al. reported that
Haemophilus inuenzae and Streptococcus pneumoniae were isolated more than
1
21
twice as often as expected following inuenza virus infection [64].
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,[65] 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[65].
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[67]. The most commonly detected viruses in that
study were picornaviruses (including rhinovirus, 36 %), inuenza 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[69]. 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[68]. In this study the majority of viruses detected was rhinovirus;
other detected viruses were coronaviruses, inuenza 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 inammation and more accelerated decline in FEV1[70].
Interestingly, frequent exacerbators (i.e. those with an exacerbation frequency
greater than the median) experience signicantly more common colds than
infrequent exacerbators, whereas the likelihood of an exacerbation during a cold is
unaffected by exacerbation frequency[66].
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. inuenzae were present, had higher bacterial
load and higher serum levels of IL-6[71]. In a study by Papi et al, patients with
exacerbations with co-infections had more marked lung function impairment and
longer hospitalisations[44]. In that study, sputum eosinophilia was associated with
viral exacerbations.
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 inammatory 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
22
General introduction
transcription families may be potential therapeuric targets for virus induced
exacerbations[72, 73].
Atypical infections
Considerable confusion exists in the literature regarding the signicance of atypical
pathogens in acute exacerbations of COPD.[74] 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 inammation 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 inammation and C. Pneumoniae infection during COPD exacerbations
is yet lacking.
Air pollution
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 signicantly associated with admissions for COPD independent of
environmental characteristics[82]. In this study, the most consistent effects were
for ozone, but signicant 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[83]. PM10 has free radical
activity and can enhance inammatory 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[84].
PM10 may also increase proinammatory activity in airway epithelial cells via
alteration in the balance between histone acetylation and deacetylation[85].
Several studies and meta-analyses have shown that exacerbations in severe COPD
are particularly related to ozone (O3)[86, 87].
Pulmonary embolism
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[88]. Malignant disease, history of thrombo-embolism, and a decrease in
PaCO2 from baseline were risk factors for PE in this study.
1
23
Local inflammation in AECOPD
In recent years, there is a growing interest in the local as well as systemic
inammatory consequences of AECOPD. Airway inammation is presumed to
play an important role in the pathogenesis of worsening of airow obstruction
seen during acute exacerbations of COPD. Several studies have demonstrated an
increase in local airway inammation 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)[91].
There is an upregulation of leucocyte adhesion molecules like E- selectin, which
are involved in the recruitment of cells to inammatory sites, in the bronchial
mucosa of stable COPD patients, suggesting a role for these molecules in the
pathogenesis of COPD.[92] Also during exacerbations, upregulation of E-selectin
has been found[93]. 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[94]. Balbi et al [95] analysed airway inammation 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 signicantly 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 inammatory processes of
chronic bronchitis. This cytokine stimulates differentiation of granulocytes and
macrophages and can activate them directly.
Aaron et al reported data on granulocyte inammatory markers and airway
infection at baseline, during AECOPD and after convalescence in patients with
COPD by induced sputum[61]. TNF-α and IL-8 were signicantly elevated in the
sputum of patients during acute COPD exacerbation compared with the stable
disease state. Concentrations of these cytokines declined signicantly 1 month
after the exacerbation. In only 3 of the 14 patients a bacterial or viral respiratory
tract infection could be conrmed, suggesting that the acute inammatory
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
24
General introduction
case of virus-associated exacerbations[44].
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-inammatory effects in the airways [96, 97]. Sputum ET-1 levels signicantly
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 [76]. Airway inammation
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[98]. Patients
with more frequent exacerbations have also lower sputum values of secretory
leukoproteinase inhibitor (SLPI)[99]. SLPI not only acts as a protease inhibitor but
also has antiviral and antibacterial activity[100, 101].
Patterns of inammatory response in a subset of COPD patients can also been
studied in this way. Hill et al studied the inammatory nature of acute bacterial
exacerbations of COPD in subjects with alpha1-antitrypsine (AAT) deciency [102].
It was found that at the start of an exacerbation, patients with AAT deciency had
lower sputum AAT and SLPI with higher elastase activity compared with COPD
patients without deciency. Both groups had a comparable acute phase response
as assessed by C-reactive protein but the AAT decient patients had a minimal
rise in serum AAT. After treatment with antibiotics, in patients with AAT deciency,
there were signicant changes in many sputum proteins including a rise in SLPI
levels and a reduction in myeloperoxidase and elastase activity[102].
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[103].
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 inammatory changes in the airway, but also with a
systemic inammatory response. Next to an increase in sputum endothelin,
increases in plasma endothelin levels are reported during AECOPD.[76] In the
same study it was demonstrated that baseline endothelin levels under stable
1
25
conditions were inversely related with baseline forced expiratory volume in one
second and forced vital capacity[76]. Increases in plasma brinogen levels were
also reported during AECOPD. There was a relation between the changes in
brinogen at exacerbation and IL-6 levels[104]. It can be hypothesised that these
transient acute increases in plasma brinogen 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,
signicant increases in the anti-inammatory mediator, soluble interleukin 1
receptor II were reported[106].
Hurst et al. recently evaluated the relation between systemic and upper and lower
airway inammation during acute exacerbations of COPD[107]. Exacerbations
of COPD were associated with greater nasal, sputum and serum inammation
than the stable state. The degree of systemic inammation, as expressed by
serum IL-6 and C-reactive protein, was correlated with the degree of lower airway
inammation as expressed by sputum IL-8. Furthermore systemic inammation
was greater in the presence of a bacterial pathogen[108].
A recent report measured systemic cytokine levels during acute exacerbations in
relation to symptoms and lung function parameters[39]. 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 inammatory markers IL-6 and IL-8 and dyspnea
levels and between levels of IL-6 and TNF-α and changes in FEV
1
[39].
A recent study by Hurst et al. explored the diagnostic value of 36 different
biomarkers at exacerbation of COPD[109]. To conrm 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 signicantly different between baseline and
exacerbation. Systemic biomarkers were not helpful in predicting exacerbation
severity[109]. 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[110]. Recently, copeptin, a precursor of
vasopressin, was suggested as prognostic biomarker for AECOPD[111].
In summary, markers of systemic inammation that are upregulated in acute
exacerbations as compared to the stable state include CRP[106, 112], IL-8[39],
TNF-α [113] and its soluble receptors[105, 106], leptin [105, 113], endothelin-1[76],
eosinophil cationic protein [114], myeloperoxidase [114],brinogen [104], IL-6 [104],
α-1 antitrypsin [102], leukotriene E4 [115] and leukotriene B4 [39], MPIF-1, PARC,
ACRP-30 and sICAM-1[109].
It is clear that systemic inammation is upregulated in acute exacerbations
of COPD. This systemic inammatory response may be related to the local
26
General introduction
inammatory 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
inammatory 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-inammatory
stimuli[116].
The concentration of exhaled H2O2, a reactive oxygen species, is also elevated in
patients with stable COPD and increases even further during an exacerbation[117].
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[118]. 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
treatment[119].
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 uid are
decreased [120, 121]. Oxidative stress may be closely associated to increased
systemic inammation during exacerbations[120, 122, 123].
Clinical consequences of AECOPD
Health status
Using disease specic 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 signicant 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[125]. This study showed that all COPD patients hospitalized for
1
27
an acute exacerbation suffer a serious deterioration in health status, regardless of
severity based on FEV
1
[125]. 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 signicant impact on the
patient’s physical and psychological well being, with common symptoms like
tiredness, malaise and low-mood[126].
Muscle function and activity pat tern
Changes in skeletal and respiratory musle metabolism are also present in COPD
patients[129]. In skeletal muscle of COPD patients, there is a change in ber
composition towards a predominance of anaerobic type 2 muscle bers while in
the diaphragm an increase in type 1 bers 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 signicantly increased
during an acute exacerbation of COPD, when compared to patients with stable
disease[132]. 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[133]. In addition, patients with frequent exacerbations
recover their physical activity level to a lesser extent than patients without frequent
exacerbations. These results were conrmed by Pitta et al[134]. 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[18].
Metabolic changes
COPD is characterized by complex metabolic disturbances. Weight loss and in
particular depletion of fat-free mass is a common nding in COPD patients[135].
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 efciency.[136]. There is also evidence in a subset
of patients, that increased resting energy expenditure may be related to systemic
inammation[137].
During acute exacerbation, there is an impaired energy balance, caused by a
decreased dietary intake, especially in the rst few days of the exacerbation and an
28
General introduction
increased resting energy expenditure[138]. 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[105]. These
elevated leptin concentrations may be induced by the systemic inammatory
response as well as by glucocorticoid treatment and contribute to the impaired
energy balance during acute exacerbations.
Prevention strategies for AECOPD
Vaccination
At present, the value of inuenza vaccination in patients with COPD is well
documented and all patients with COPD are recommended to receive inuenza
vaccination over a yearly basis. Nichol et al [13, 139] demonstrated the efcacy
and cost effectiveness of inuenza 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 efcacy 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 efcacy of pneumococcal vaccination
among patients with COPD do not show statistically signicant protective
benets [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 airow obstruction. No differences were found among the other groups
of patients with COPD [142]. A recent meta-analysis concluded that evidence
from randomized controlled trials shows no signicant effect of pneumococcal
vaccination on morbidity and mortality in patients with COPD[143].
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 signicantly
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 [144]. 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 efcacy in COPD and may therefore reduce the
1
29
number of exacerbations and particularly decrease the severity [145].
In a 3-month, randomized, double-blind, placebo-controlled, multicentre study,
Casaburi et al compared the bronchodilator efcacy 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 signicant. Tiotropium was demonstrated to provide superior
efcacy relative to placebo for both in-clinic spirometry and daily measurements of
peak ow and these observations were accompanied by better symptom control
and subjective global assessments[146].
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
signicant[147]. Recently two randomized controlled trials have specically
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 signicantly 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 signicant ( p = 0.056). As secondary endpoints, the time
to rst exacerbation, health care resource for acute exacerbations (including
frequency of hospitalizations and unscheduled clinic visits) and treatment days
were also reduced with tiotropium[151]. In a French randomized controlled trial,
tiotropium signicantly reduced time to rst exacerbation, the proportion of
patients experiencing at least one exacerbation and the number of exacerbations
and exacerbations days[150]. Addition of salmeterol or uticasone-salmeterol to
tiotropium therapy did not statistically inuence rates of COPD exacerbation but
did improve hospitalization rates in patients with moderate to severe COPD, in a
recent randomized double blind controlled trial. [152]
Maintenance therapy with inhaled steroids
The efcacy of inhaled steroids in the treatment of COPD remains controversial.
Although inhaled steroids do not modify disease progression in COPD [42], 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
uticasone propionate (500 microgram twice daily) with placebo in the treatment
of patients with COPD [153]. They reported that the total number of exacerbations
was lower after treatment with uticasone propionate and the distribution of
number of exacerbations per patient was lower in the uticasone group. although
not signicantly. Signicantly more exacerbations in the placebo group were
dened as moderate or severe than in the uticasone group. Exacerbations in
30
General introduction
that study were dened 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 [154]. In that study, there was no signicant difference in the annual
rate of decline in FEV
1
; however, median exacerbation rate was reduced by 25%
from 1.32 a year on placebo to 0.99 a year on with uticasone proprionate. The
effects of uticasone propionate on exacerbations were seen predominantly in
patients with FEV1 < 50% predicted.[155] 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 [156]. A recent Cochrane meta-analysis of 47 trials including
over 13000 patients showed that inhalation steroids were benecial in reducing the
frequency of acute exacerbations[157].
Furthermore, statistical modelling showed that the benecial effect of uticasone
on deterioration in health status to be largely due to its effect on exacerbation
frequency[158].
Discontinuation of inhaled steroids was associated with a more rapid onset and
higher recurrence rate of aute exacerbations in one study.[159]
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 uticasone versus each component alone
or placebo.[160] Each of the active treatments reduced exacerbation frequency
to a similar degree in this study[160]. 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[161].
In the recently published TORCH study, a large randomized double blind trial
designed to measure the effect of combination therapy uticasone and salmeterol
on survival in COPD, the combination therapy also signicantly reduced the
annual rate of exacerbations, while the effect on survival was not statistically
signicant[162]. However, in this study, the probability of having pneumonia
reported as an adverse event was higher among patients receiving medications
containing uticasone propionate (19.6% in the combination-therapy group and
18.3% in the uticasone group) than in the placebo group (12.3%, P<0.001 for
comparisons between these treatments and placebo).
1
31
Withdrawal of uticasone in patients using the combination uticasone/salmeterol
has been shown to result in acute and persistent deterioration in lung function and
dyspnoea and an increase in mild exacerbations.[163]
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[164].
It is not well understood why patients with COPD benet from inhalation
corticosteroids, but a number of studies have shown a reduction in local
inammation[165-169].
Mucolytic drugs and anti-oxidants
A recent systematic review of the available literature showed that oral mucolytic
drugs have signicant 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[170]. Mucolytic therapy
signicantly 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.[170]
Acetylcysteine was used in most of these studies suggesting that the benecial
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 [171]. 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[172].
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
placebo[173].
Subgroups of patients with more severe COPD or patients who have frequent or
prolonged exacerbations may probably benet more of this regular treatment[170] .
Additional strategies
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 [9]. 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
32
General introduction
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 benecial effect of OM-85 in reducing the frequency of acute
exacerbations was conrmed[174]. However, a meta-analysis in which 13 trials were
included, found a non-statistically signicant trend in favour of OM-85 BV [175]. A
trial with another immunomodulating agent, AM-3 found an improvement in quality
of life, but no difference in exacerbation frequency[176]. Further trials are required to
properly dene the potential role of these immunomodulatory agents prevention of
AECOPD.
Pulmonary rehabilitation
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.[177] One study by Guell
et. al found a signicant reduction in the number of acute exacerbations, but not
hospitalizations in stable COPD patients undergoing an outpatient rehabilitation
program[178].
A recent meta-analysis showed that pulmonary rehabilitation after acute
exacerbations of COPD signicantly reduces the risk of unplanned hospital
admissions with a pooled relative risk of 0.26[179]. 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[180].
Management of AECOPD
Hospital management of acute exacerbations of COPD has been summarized in
the GOLD document [1].
Oxygen
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[1].
Bronchodilator therapy
Short acting inhaled β2 agonists and anticholinergic agents are the main treatment
1
33
modality for AECOPD as they relieve symptoms and improve airow 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[181]. 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
AECOPD[1].
Glucocorticosteroids
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 [183] 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, dened as death from any cause or the need for intubation and
mechanical ventilation, readmission to the hospital for COPD, or intensication 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
Bronchodilators
• Increasedoseand/orfrequency
• Combineβ-2 agonists and anticholinergics
• Usespacersand/orair-drivennebulizers
• Consideraddingintravenousmethylxanthinesifneeded
Add oral or intravenous glucocorticosteroids
Consider antibiotics (oral or occasionally intravenous) when signs of bacterial
infection
Consider non-invasive mechanical ventilation
At all times:
• Monitoruidbalanceandnutrition
• Considersubcutaneousheparin
• Identifyandtreatassociatedconditions(eg.heartfailure,arrythmias)
• Closelymonitorconditionofthepatient
local resources need to be considered
34
General introduction
and the third group received placebo. Rates of treatment failure were signicantly
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 rst day .
Signicant treatment benets were no longer evident at six months and the 8-week
regimen was not superior to the 2-week regimen. Davies et al [182] 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.
FEV
1
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 FEV
1
after bronchodilation were statistically signicant. 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 signicant risk of side effects. 30 to 40 mg of oral
prednisolone daily for 7-10 days is effective and safe. [184] Prolonged treatment
does not result in greater efcacy and increases the risk of side effects[184].
Methylxanthins
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 benets of methylxanthines for lung function and
symptoms could not be conrmed in meta-analysis of available trials, whereas the
potentially important adverse events of nausea and vomiting were signicantly
increased in patients receiving methylxanthines[185]. 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[186].
They are currently considered as second-line intravenous therapy, in patients with
inadequate or insufcient response to short-acting bronchodilators [181].
Antibiotics
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.[40]. In that study, antibiotics led to an earlier resolution of all three
symptoms dening 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)[41].
1
35
In a retrospective cohort analysis of visits for AECOPD, Adams et al demonstrated
that patients, treated with antibiotics had signicantly 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 specic 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 proles to antibiotics[187].
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[188]. 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[188].
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[1].
Ventilatory support
The primary objectives of mechanical ventilatory support in AECOPD are to
decrease mortality and morbidity and to relieve symptoms[1].
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[194].
Indications and contraindications for the use of NIV were published in the GOLD
guidelines[1].
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
mortality[197].
In a recent study among patients with chronic hypercapnic COPD that had been
36
General introduction
discharged from the hospital with NIV, mortality was 16 % after 1 year, 35 % after
2 years and 75 % after 5 years[198]. Independent predictors of mortality were
nutritional status, hyperination and base excess. In patients at risk, a reduction of
these risk factors after initiation of NIV was associated with improved survival[198].
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) [5]. 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 [199].
Several studies have investigated predictive factors related to an increased COPD
related mortality risk. Patient characteristics that have been reported to inuence
survival in stable COPD patients include FEV
1
[200-202],age [200, 202], arterial
carbon dioxide tension (PaCO
2
) [201], cardiac factors [201], diffusion capacity[201]
and BMI[203, 204].
Other studies have investigated more specical factors related to mortality after
acute exacerbations of COPD. Factors that have been reported as risk factors
Indications and relative contraindications for NIV
Selection criteria
• Moderatetoseveredyspneawithuseofaccessorymusclesand
paradoxical abdominal motion
• Moderatetosevereacidosis(pH 7.35) and/or hypercapnia
(pCO2 6.0 kPa, 45 mm Hg)
• Respiratoryfrequency>25breathsperminute
Exclusion criteria (any may be present)
• Respiratoryarrest
• Cardiovascularinstability(hypotension,arrythmiaias,myocardialinfarction)
• Changeinmentalstatus;uncooperativepatient
• Highaspirationrisk
• Viscousorcopioussecretions
• Recentfacialorgastroesophagealsurgery
• Craniofacialtrauma
• Fixednasopharyngealabnormalities
• Burns
• Extremeobesity
1
37
for mortality after exacerbation are PaCO
2
, oxygen saturation and resting oxygen
consumption [205], low BMI [6, 203], older age [6, 206, 207], cardiac factors
[6, 206, 207] and other co-morbidity [207], severity of illness, serum albumin,
functional status and arterial oxygen tension (PaO
2
) [6].
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 [3]. 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, PaO
2
/FIO
2
, 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[208]. In this study, long term mortality was associated with
longer disease duration, lower serum albumin, lower PaO
2
, and lower BMI[208].
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[209]. It was shown that besides older age and PaCO
2,
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[209].
Similar results were reported about hospital and 1-year survival of patients
admitted to ICU with AECOPD [210]. 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 gures 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.
Conclusive remarks
The denition of acute exacerbation of COPD is generally based on medical
symptoms like dyspnoea, cough and sputum production. The majority of acute
38
General introduction
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 inammation in the airways, but there is growing
evidence that systemic inammation 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. Inuenza vaccination, maintenance
therapy with bronchodilating agents, inhalation steroids and anti-oxidants and
pulmonary rehabilitation are to some extent benecial in reducing the number of
exacerbations.
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 modiable 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 inammation 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 specic 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 inammation during acute exacerbation and in the stable state. The
course of different systemic inammatory and anti-inammatory parameters
1
39
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 inammatory 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 inammatory parameters in a large cohort of
COPD patients, who were clinically stable, are studied, to determine if an elevated
systemic inammatory 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 identied, particularly in relation to parameters of
systemic inammation and haemostasis.
The study described in chapter 5 of this thesis was set up to investigate systemic
levels of different markers of inammation and haemostasis in clinically stable
COPD patients. In these patients, systemic levels of hs-CRP, total plasma
homocysteine (tHcy) and brinogen 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 inammation 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.
40
General introduction
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51
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CHAPTER 2
Bacterial infections in acute
exacerbations of COPD; a
one-year prospective study
Respiratory Medicine 2003 Jul;97 (7): 770-777
KH Groenewegen
AM Schols
EFM Wouters
54
Bacterial infections in acute exacerbations of COPD
Abstract
Study objective
to investigate the frequency of respiratory bacterial infections in hospitalized
patients, admitted with an acute exacerbation of COPD, to identify the responsible
pathogens by sputum culture and to assess patient characteristics in relation to
sputum culture results.
Methods
We prospectively evaluated clinical data and sputum culture results of 171 patients,
admitted to the pulmonology department of the University Hospital Maastricht
with an acute exacerbation of COPD from January 1st 1999 until December 31st
1999.
Results
85 patients (50 %) had positive sputum cultures, indicating the presence of
bacterial infection. Pathogens most frequently isolated were: H.inuenzae (45 %),
S. pneumoniae (27 %), and P. aeruginosa (15 %).
Patients with more severely compromised lung function had a higher incidence
of bacterial infections (p = 0.026). There were no signicant differences in age,
lung function parameters, blood gas results and length of hospital stay between
patients with and without bacterial infection. There were no correlations between
the type of bacteria isolated and clinical characteristics.
Conclusion
Incidence of bacterial infection during acute exacerbations of COPD is about
50 %. Patients with and without bacterial infection are not different in clinical
characteristics or in outcome parameters. Patients with lower FEV
1
have a higher
incidence of bacterial infections, but there is no difference in the type of bacterial
infection.
In the future the pathogenic role of bacterial infection in exacerbations of COPD
should be further investigated, especially the role of bacterial infection in relation
to local and systemic inammation.
2
55
Introduction
Chronic obstructive pulmonary disease (COPD) comprises a heterogeneous
group of conditions, characterized by varying degrees of expiratory ow limitation.
Exacerbations punctuate the clinical course of COPD in many patients. These
episodes of acute exacerbation can vary considerably in severity: part of the
exacerbations will remain unreported while some episodes require hospital
admission. Hospital admission for acute exacerbations forms the major
component of the economical burden of COPD in western countries [1]. These
exacerbations are characterized by varying combinations of symptoms as increase
in cough, sputum production, worsening of dyspnea or changes in sputum
purulence.
Recent studies have indicated that health status of patients with COPD has been
inuenced by the presence and frequency of these acute exacerbations [2,3]. The
exact role of periods of acute exacerbations in the pathogenesis of COPD remains
unclear, especially the relationship between bronchial inammation and lung
defense during these possible noxious events [4]. Some studies have indicated that
recurrent exacerbations may be associated with increased airway inammation
although many factors may inuence the state of inammation in the airways [5].
Recent data also suggest presence of decreased antiproteinase activity in sputum
of patients with recurrent exacerbations [4].
Exacerbations are not only heterogeneous in severity and symptom characteristics
but are also in nature. Although several events may lead to acute exacerbations,
respiratory tract infections are often considered as the initiating event contributing
to the deterioration in the clinical condition. Especially the role of bacterial
infections and the value of antibiotic therapy have been a matter of debate for
many decades [6-8].
An important problem in dening the role of bacteria in these episodes of acute
exacerbation is the bacterial colonization of the lower airways even in the absence
of symptoms of an exacerbation [7]. Careful investigations have reported presence
of bacterial pathogens in only about 50 % of exacerbations [9-15]. However , these
studies have been performed in different populations of COPD patients, and most
frequently in outpatients.
Recently two studies have investigated the type of bacterial pathogens isolated in
sputum of COPD patients, hospitalized for an acute exacerbation [12,13]. In these
studies a correlation was found between lung function and the type of bacteria
isolated: patients with more compromised lung function had a higher incidence
of infections with Pseudomonas aeruginosa and other Gram-negative bacteria
isolated from their sputum. These ndings suggested that patients with more
advanced lung disease may need a different pharmacological therapy than patients
with milder disease.
The generalisation of these ndings as well as the interpretation of them as
56
Bacterial infections in acute exacerbations of COPD
disease-specic ndings are hampered by limited availability of data on distribution
of bacterial ora in COPD patients from different geographical areas as qualitative
differences in bacterial ora can be related to many other factors. Therefore it
seems interesting to investigate prospectively the prevalence of acute bacterial
infections during these episodes of hospital admission as well as if specic patient
proles are related to a different pattern of micro-organisms in patients admitted
for an acute exacerbation of the disease.
Furthermore, we questioned if presence of bacterial infection inuences the clinical
outcome of hospital admissions for acute exacerbations.
Material and Methods
Study population and study design
All patients, admitted with an acute exacerbation of COPD to the pulmonology
ward of the University Hospital Maastricht, between January 1st 1999 and
December 31st 1999, were prospectively evaluated. All patients were diagnosed as
having COPD, according to the criteria of the American Thoracic Society [16]. Acute
exacerbation was dened by the presence of an increase in at least two of the three
following symptoms: dyspnoea, cough and sputum purulence.
Admission to the hospital was deemed necessary based on the clinical situation
of the patient or the presence of complicating factors as respiratory failure. In all
cases the need for admission was decided by a senior chest physician, experienced
in the management of COPD patients. Chest X-rays were performed in each
patient on admission and patients with lobar inltrates or radiologic signs of
pneumonia on chest X-ray were excluded from the study.
Patients were included only once in the study even if hospitalized more frequently.
For all included patients the following data were assessed: medical history,
lung function measurements, blood gases, duration of hospital stay, previous
treatment, chronic corticosteroid use and results of sputum cultures. Medical
history, previous treatment and use of corticosteroids were recorded from the
patients charts on standardized forms. Chronic use of oral corticosteroids was
dened as the use of daily oral corticosteroids for at least one year in a dosage of
at least 5 mg Prednisolone or equivalent. On admission, arterial bloodgases at rest
were assessed by puncture of the radial artery during room air breathing. Patients
were discharged from the pulmonary ward by decision of a senior chest physician,
unaware of the goals of the present study. Total duration of hospital stay was
recorded, counting from the rst day of admission before 0.00 hrs. until the day of
discharge.
Patients were treated with a standard protocol consisting of intravenous
administration of corticosteroids and theophylline and nebulisation of salbutamol
and ipratropiumbromide as bronchodilating agents. O
2
was
titrated by follow-
2
57
up of blood gas values as well as continuous monitoring of oxygen saturation.
Antibiotics were not prescribed until the results of the sputum cultures were
available, unless the clinical condition of the patient necessitated early intervention
based on documented resistance pattern of isolated microorganisms.
Lung function data
Spirometries were performed daily during admission for the exacerbation.
Spirometries were performed using the portable pneumotachograph from Jaeger
pulmonary function equipment (Würzburg, Germany). The value after recovery,
prior to discharge from the hospital was used in the analyses. Based on the ATS
criteria [16], lung function was rated in 3 stages of severity: stage I: FEV1 of 50 %
predicted , stage II: FEV1 between 35 and 50 % predicted, stage III: FEV1 35 %
predicted.
Sputum cultures
At least one sample of spontaneously expectorated sputum for microbiologic
evaluation was obtained in all patients during admission. This is part of
common medical practice in the our hospital for patients admitted for an acute
exacerbation, and also it is recommend in the recently published GOLD guidelines
for the management of COPD [17]. Samples were collected in sterile sputum cups
and sent to the laboratory within 1 hour after expectoration.
A Gram stain of the sputum in the area of maximal purulence was examined for
polymorphonuclear leukocytes and epithelial cells. The number of leukocytes
was semiquantitatively described as: none, sporadic, few, moderate or many. A
sputum sample was considered representative if many leukocytes were present
in the absence of epithelial cells. Another portion of a the documented purulent
material was used for microbiological analysis. Sputa were processed according
to standard microbiological methods [18]. A sputum culture was considered as
positive (proving bacterial infection) if signicant bacterial growth was present as
dened by the number of bacteria (higher than 10
5
colony forming units = cfu) in
a representative sample. Identied bacteria were classied into 3 groups : group
1 included H.inuenzae and M. catarrhalis, group 2 included S.pneumoniae and
other Gram positive cocci and group 3 included Pseudomonas and other Gram
negative micro-organisms. Other identied bacteria are considered non-pathogenic
micro-organisms (NPM's), belonging to the oropharyngeal or gastrointestinal
ora.
A microbial resistance pattern was available for all pathogens. For all pathogens
resistance patterns were determined for Amoxicillin, Amoxicillin/Clavulanic
acid, Doxycyclin and Co-trimoxazole. In case of isolation of Pseudomonas and
other Gram negative species resistance patterns to Gentamycin, Piperacillin,
Ciprooxacine, Ooxacine and Cefuroxim were determined additionally.
58
Bacterial infections in acute exacerbations of COPD
Statistical analysis
The statistical analyses were performed using the Statistical Products and Service
Solutions (SPSS;Chicago,IL,USA) for Windows Package. Groups were compared
by analysis of variance.(ANOVA). The X
2
test was used to compare categorical
variables. Results are presented as mean ± SD unless stated otherwise.
Results
Patient characteristics
Between January 1st 1999 and December 31st 1999 171 patients were included
with acute exacerbation of COPD. Characteristics of the study population are
summarized in table 1. Most patients were elderly with severely impaired lung
function (mean FEV
1
was 0.84 L or 34.6 % predicted).
Hypoxia as well as hypercapnia were very common ndings on admission; 141 (=
85 %) of the patients had arterial oxygen tension < 8.7 kPa, arterial carbon dioxide
tension higher than 5.9 kPa was measured in 93 patients (= 55 %).
63 Patients (= 37 %) had been treated with antibiotics prior to admission to the
hospital. Prescribed antibiotics by general practitioners were: Doxycycline (37 %),
Amoxicillin (21 %), Amoxicillin/Clavulanic acid (29 %) and Azithromycine (10 %).
Information concerning the remaining 3 % could not be retrieved. 43 % of the
patients had also received a boost of oral corticosteroids prior to admission.
Mean hospital stay was 11.7 days and median hospital stay was 10 days. 13 Patients
died during their hospital stay, resulting in an in-hospital mortality of 8 %.
17 Patients were admitted to ICU because of progressive respiratory failure: In 15
patients failure of conservative treatment in the rst 48 hours necessitated referral
to the ICU; In 2 patients clinical condition deteriorated after initial improvement.
Intubation and mechanical ventilation was necessary in 10 patients, 4 patients
received non-invasive ventilation (BiPAP) and in 3 patients conservative treatment
could be continued under close supervision. Patients transferred to ICU had a
longer duration of hospital stay (p = 0.005; mean 17.3 days, median 15 days). One
patient died during ICU admission (6 %).
Microbiological analysis
Sputum cultures could be obtained in 142 patients.( = 83 %). Other patients were
unable to expectorate sputum spontaneously during hospitalization. Samples were
considered not representative based on microbiological criteria in 54 cases.
In 85 of the 88 representative samples (97 %) a signicant bacterial growth
was reported; in 61 samples (72 %) there was growth of one single species in
signicant concentrations, in 22 samples (26 % ) there was growth of 2 different
species in signicant concentrations and in 4 samples (5 %) growth of 3 different
species in signicant concentrations was present.
2
59
The most frequently isolated species were Haemophilus inuenzae (23 cases as
single pathogen, 15 cases in combination with other pathogens, overall 38/85 cases
or 45 %) and Streptococcus pneumoniae ( 9 cases as single pathogen, 15 cases in
combination with other pathogens, overall 24/85 cases or 28 %).
Pseudomonas aeruginosa was isolated in 13/85 cases (15 %). Other bacteria
isolated were: Moraxella catarrhalis (3 cases as single pathogen, 2 cases in
combination, overall 5/85 cases or 6 %), and Klebsiella pneumoniae (1 case as
single pathogen, 3 cases in combination, overall 4/85 cases or 5 %). In 14/85 cases
(16 %) non-pathogenic microorganisms (NPM’s) were found. These data are
schematically presented in gure 1.
No resistant strains of S. pneumoniae to Amoxicillin were isolated. For H.
inuenzae as well as for M. catarrhalis 2 β-lactamase producing strains were
identied. No resistant Pseudomonas strains were isolated in the studied
population. No signicant differences were found in mean FEV
1
, PaO
2
and PaCO
2
between the patients with and without positive sputum culture (table 1).
Table 1. Clinical characteristics of the COPD population and the patients with and
without bacterial infection.
whole
group
(n = 171)
negative
sputum culture
(n = 86)
positive
sputum culture
(n = 85)
p-
value
Age (years) 70.6 ± 8.6 71.7 ± 7.8 69.5 ± 8.9 0.023
FEV
1
(l, % pred) 34.6 ± 12.6 34.1 ± 13.3 35.2 ± 1.9 NS
PaO
2
(kPa) 7.49 ± 2.2 7.16 ± 2.0 7.82 ± 2.5 NS
PaCO
2
(kPa) 6.74 ± 2.1 6.12 ± 2.1 6.66 ± 2.2 NS
hospital stay (days) 11.7 ± 8.8 10.5 ± 5.6 12.9 ± 10.8 NS
Sex (M/F) 104/67 50/36 54/31 NS
Pretreatment with
antibiotics (y/n)
63/108 30/56 33/52 NS
Pretreatment with
corticosteroids (y/n)
73/98 29/57 31/54 NS
Chronic corticosteroids
(y/n)
17/154 8/78 9/76 NS
ICU admission (y/n) 17/154 10/76 7/78 NS
Died during admission
(y/n)
13/158 6/80 7/77 NS
60
Bacterial infections in acute exacerbations of COPD
Figure 1. Types of isolated micro-organisms found during acute exacerbations of COPD
NPM’s
'
others
H
. infl. and P. aeru
H. infl. and S. pneu
Klebsiella
M. catarrhalis
P.aeruginosa
S.pneumoniae
.
H
.
influenzae
Percent
40
30
20
10
0
Figure 1. Types of isolated micro-organisms found during acute exacerbations of COPD.
Figure 2. Distribution of groups ofbacteria isolated according to FEV1 impairment.
group 1 = H. influenza and M. catharralis
group 2 = S. pneumoniae and other Gram positive cocci
group 3 = Pseudomonas aeruginosa and other Gram negative micro-organisms
group of mi cro-organism
grgr oup 3oup 2group 1
cent
50
40
30
20
FEV1
>35 %
<= 35 %
Per
10
Figure 2. Distribution of groups ofbacteria isolated according to FEV
1
impairment.
group 1 = H. influenzae and
M. catarrhalis
group 2 = S. pneumoniae
and other Gram positive
cocci
group 3 = Pseudomonas
aeruginosa and other Gram
negative micro-organisms
2
61
A course of antibiotics or a boost of corticosteroids, prescribed prior to admission,
did not inuence the outcome of sputum cultures. 52.4 % of patients who
had received antibiotics and 51.7 % of patients who had received a boost of
corticosteroids prior to admission had bacterial infection.
No difference in duration of hospitalization could be demonstrated between
patients with and without bacterial infection on admission.
In the group of patients with positive sputum culture (n = 85), 10 patients were
transferred to ICU of whom 5 patients were intubated for mechanical ventilation
while in the negative sputum culture group (n = 86) 7 patients were transferred to
ICU of whom 4 required mechanical ventilation.
Admission to ICU was not related to the presence and type of bacterial infection
during exacerbation.
In comparison of patients with Pseudomonas infection to those with H. inuenzae
or S. pneumoniae infections, it was demonstrated that the former group was
signicantly older; other parameters were not different between these groups.
Lung function parameters
Based on lung function data obtained prior to discharge from the hospital, marked
airow obstruction was present in the majority of the patients: 81 patients (47 %)
had severe COPD 55 patients (32 %) had moderate COPD and 22 patients (13
%) had mild COPD, according to ATS staging.
In 12 patients, no spirometric data
could be obtained during hospital stay. 10 of these patients had an established
diagnosis of severe COPD based on clinical records. In 2 patients, the diagnosis of
COPD was established on clinical grounds and the information regarding medical
Figure 3. Positive sputum cultures after stratification for FEV
1
.
FEV
1
< 35 %FEV
1
35-50 %FEV
1
50-70 %
% of patients with bacterial infection
70
60
50
40
30
20
10
0
p = 0.08 between sev e re and moderate COPD
p = 0.015 between sev e re and mild COPD
Figure 3. Positive sputum cultures after stratification for FEV
1
62
Bacterial infections in acute exacerbations of COPD
history as obtained by their general practitioner.
The incidence of bacterial infection was signicantly related to the degree of airow
limitation (gure 3): patients with severe COPD had signicantly more bacterial
infections than patients classied as moderate (p = 0.015) or mild COPD. (p=0.08)
However, the type of bacteria isolated was not related to the degree of airow
limitation (gure 3).
Discussion
The present study conrms previous data reporting a higher incidence of bacterial
infections in patients with a severe impairment in lung function during hospital
admissions for acute exacerbations. However, no relationship between the
type of bacteria isolated and the degree of lung function impairment could be
demonstrated. Presence of bacterial pathogens was found in 50 % of all admitted
patients. No differences in clinical characteristics could be demonstrated between
patients with and without isolation of bacterial pathogens neither with the type of
bacterial pathogens. Micro-organisms most frequently isolated were Haemophilus
inuenzae (45 %) and Streptococcus pneumoniae (27 %). Other pathogens
isolated were Pseudomonas aeruginosa (15 %), Moraxella catarrhalis (6 %) and
Klebsiella pneumoniae (5 %). Presence of bacterial pathogens did not inuence
the clinical outcome dened by the length of hospital stay and the need for ICU
admission.
One of the most important ndings in the present study is the relation between
the occurrence bacterial infections and the degree of airow limitation: patients
with a lower FEV
1
had a higher incidence of bacterial infection. This is in line with
previous studies on the prevalence of bacteria in stable COPD patients [8].
However, opposite to previously reported data we found no shift in the type
of micro-organism isolated in patients with more severely compromised lung
function [12,13]. Indeed, both Eller and Miravitlles reported in patients with lower
FEV
1
a higher incidence of Pseudomonas and Enterobacteriacae 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.
Our data were even obtained in patients with more severely compromised lung
function.
The incidence of Pseudomonas infections in our study was comparable with the
data reported by Miravitlles, but markedly lower than in the study of Eller. Further
data with more specic characterization of the patients suffering from acute
exacerbations will be required in order to relate these ndings to the disease
condition itself. Presence of bronchiectasis [19], nutritional status [20], as well as
previous use of antibiotics [21] can inuence the type and frequency of colonization
of the airways in COPD.
2
63
Remarkably, the incidence of positive sputum cultures in half of our patient
population was quite similar to previous data [2, 10,14,15].
In exacerbated
outpatients, prevalence of positive bacterial cultures, obtained by protected
specimen brush, was 51.6 % [10]. In a bronchoscopic study of 54 mechanically
ventilated patients with acute exacerbation of COPD, bacterial infection was found
in 50 % of patients [14]. In another study among mechanically ventilated patients
using protected specimen brush, Fagon et al. reported distal bronchial infection in
50 % of patients during acute exacerbation [22]. In a large study of 1016 in-patients
with acute exacerbation respiratory infection was found in 47 % of sputum cultures
[15]. Therefore, it seems a consistent nding that bacterial infection is present in 50
% of exacerbations, in hospital as well as in outpatient populations.
However, it remains difcult to distinguish bacterial colonization of the lower
airways from an actual bacterial infection. In a bronchoscopic study among 18
stable COPD patients, using protected specimen brush samples, Cabello et al.
found that the distal airways were colonized (dened as >= 10
2
cfu/ml) in 83 %
of COPD patients [11]. Quantitative cultures of BAL samples in the same patient
group remained negative in 88 %, suggesting colonization rather than infection.
In another study using protected specimen brush samples, Monso et. al found
positive cultures in 25 % of stable COPD patients and 52 % of exacerbated COPD
patients [10]. In the stable COPD patients, concentrations of bacteria were much
lower, again indicating colonization instead of bacterial infection.
Besides differences in quantity of isolated micro-organisms, recent studies suggest
differences in the level of inammation in stable COPD patients as well as during
exacerbations between both conditions of presence of bacteria in the airways.
Bresser et al. demonstrated that persisting strains of H. inuenzae induce a weaker
inammatory response than non-persisting strains [23], while the local airway
inammation in COPD patients clinically infected with H. inuenzae is much more
pronounced [24]. Sethi et al demonstrated that exacerbated chronic bronchitis
patients with H.inuenzae and M. catharralis isolated from sputum had increased
airway inammation when compared to pathogen-negative exacerbations [25].
Other studies indicate that bacterial infection contributes signicantly to the
inammatory process in the airways. In acute exacerbations of COPD associated
with H. inuenzae infection, an increase in sputum IL-8, TNF-α and neutrophil
elastase was found in contrast to exacerbations without bacterial infection,
indicating increased airway inammation in the presence of H. inuenzae [26].
This inammatory process in the airway continues despite antibiotic and steroid
therapy for exacerbations, as was demonstrated by unchanging sputum cell counts
during the course of an exacerbation [27].
However, the possible role of bacterial infections in the pathogenesis of acute
exacerbations is still incompletely understood.
In the present study, the outcomes in terms of hospital stay or subsequent
need for ICU admission were not related to the presence or the type of bacterial
64
Bacterial infections in acute exacerbations of COPD
infections. Our ndings are in line with the disputed role of antibiotics in the
treatment of acute exacerbations. Studies concerning the effect of antibiotic
treatment have shown either no benet or minimal clinical benet from antibiotic
treatment [7]. Meta-analysis of randomized controlled clinical trials demonstrated a
clinically unimportant improvement in patients receiving antibiotics [28]. A recently
performed meta-analysis on antibiotic treatment in acute exacerbations concluded
that patients with more severe exacerbations are more likely to benet from
antibiotic treatment [29].
A recent study in exacerbated outpatients by Adams et al. demonstrated lower
relapse rates in outpatients treated with antibiotics, compared to patients
untreated with antibiotics, but even higher relapse rates in patients treated with
Amoxicillin [9]. These results indicate that type of antibiotics used to treat acute
exacerbations have an impact on the failure rate.
In this respect it is interesting to compare exacerbations of COPD to ventilator-
associated pneumonia (VAP), a combination of clinical parameters in mechanically
ventilated patients, that is presumed to be caused by bacteria and treated with
antibiotics. In a recent bronchoscopic study among VAP patients, using protected
specimen brush and BAL samples, bacterial infection was not proven in 43 % of
patients and withholding antibiotics in these patients had no effect on outcomes
[30]. In another bronchoscopic study of VAP patients, the bacterial burden was not
correlated with inammatory mediators or with patient outcome [31].
Some limitations of the present study need further discussion. Spontaneously
expectorated sputum was used for microbiological sampling, in contrast to for
example induced sputum or bronchoscopic sampling. The suitability of sputum
samples to analyze bacterial infection is a matter of debate. Recently a good
concordance between the results of two sampling methods, valid sputum samples
and quantitative protected specimen brush, was shown [32]. At present, especially
in patients with severe COPD, spontaneously expectorated sputum seems a
clinically reliable method to assess presence and type of bacterial infections when
other methods have to be avoided.
The present study has not included data on viral infections or infections with
atypical organisms like Chlamydia and Mycoplasma. The presence of viral infection
and Mycoplasma and Chlamydia during COPD exacerbations has been evaluated
in different studies. In an outpatient population of mild to moderate COPD
exacerbations, incidence of Chlamydia pneumoniae was found to be 4 % [33]. In
a study of mechanically ventilated patients with acute exacerbations of COPD,
an incidence of C. pneumoniae of 18 % was found [14]. The same study found
no evidence for Mycoplasma pneumoniae infection and an incidence of 16 %
for respiratory viruses. In a Turkish study of outpatients with acute exacerbation,
incidence of C. pneumoniae was 22 % and M. pneumoniae incidence was 6 % [34].
So far, most studies concerning respiratory pathogens have been performed in
either outpatient populations with mild exacerbation, or mechanically ventilated
2
65
patients with severe exacerbations in an ICU setting. Neither of these populations
can be considered representative for the majority of admissions for COPD
exacerbations in a clinical setting, as in the present study. Therefore , the role of
these non-bacterial pathogens in the pathogenesis of COPD exacerbations needs
further exploration.
The present study indicates that the role of bacterial infections in the complex
pathogenesis of COPD exacerbations as well as its clinical signicance needs
further evaluation in the near future and can not be restricted to the limited
discussion of the role of antibiotic treatment in the management of these acute
events in the clinical course of patients with acute exacerbations. Especially, the
role of bacterial infections in relation to the local and systemic inammatory
response has to be unraveled. The impact of acute exacerbations on the socio-
economic burden of this disease as well as on the health status of the individual
patient urgently needs to prioritize acute exacerbations in order to better
understand the natural course of COPD.
66
Bacterial infections in acute exacerbations of COPD
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1999;160:349-353
CHAPTER 3
Longitudinal follow-up of
systemic inflammation a fter
acute exacerbations of COPD
Respiratory Medicine 2007: 101 (17):2409-2415
KH Groenewegen
MA Dentener
EFM Wouters
70
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
Abstract
Background
Acute exacerbations are important in the clinical course of COPD, yet the
underlying mechanisms are poorly understood. Systemic inammation is now
considered as an important component in the disease process. In this study we
evaluated longitudinally the systemic inammation during hospital treatment for
acute exacerbation and after clinical recovery.
Methods
Blood was collected on day 0, 1, 4 and 8 in 21 patients admitted for an acute
exacerbation of COPD and at 1 month, 3 months and 6 months after discharge.
Systemic inammation was determined by measurement of the pro-inammatory
markers interleukin (IL)-6, soluble tumor necrosis factor (TNF) receptors
sTNFR55 and sTNFR75, the anti-inammatory mediator sIL-1RII, and Bactericidal
Permeability Increasing protein (BPI) as a marker of neutrophil activation. In
addition, plasma level of Trolox antioxidant capacity (TEAC) was determined.
Healthy age-matched controls were measured for the same markers at one time-
point.
Results
All inammatory markers analyzed were elevated on rst day of admission for
exacerbation of COPD, as compared to healthy controls. During treatment, levels
of IL-6, and sTNFR75 rapidly decreased, whereas sTNFR55 and BPI remained
elevated. Moreover, sIL-1RII and TEAC increased during rst 8 days of treatment.
In the stable condition all inammatory markers returned to values comparable to
healthy controls, with the exception of BPI which remained persistently elevated
compared to healthy controls.
Conclusion
This study clearly demonstrates upregulation of systemic inammation in
acute exacerbations of COPD. Attenuation of systemic inammation offers new
perspectives in the management of COPD patients and to reduce the burden of
exacerbations.
3
71
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
Introduction
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and
mortality throughout the world. Hospital admission for acute exacerbations forms
the major component of the economical burden of COPD in western countries[1].
Generally, acute exacerbations are characterized by varying combinations of
symptoms as increase in cough, sputum production, worsening of dyspnoea
or changes in sputum purulence. Despite the important role of these acute
exacerbations in the clinical course of COPD, underlying pathogenic mechanisms
are poorly understood.
Inammation is a prominent feature of COPD as shown by the presence in the
airways of activated neutrophils and macrophages and increased numbers of
inammatory mediators[2, 3]. Exacerbations of COPD are generally considered
to reect a are-up of these underlying inammatory processes, although
information about the inammatory response in the lungs, particularly during severe
exacerbations, is still limited. Recent studies showed increased airway inammation
during exacerbations, as measured by increased sputum neutrophil, eosinophil
and lymphocyte counts, increased sputum myeloperoxidase (MPO) and IL-8, and
activation of NF-kappa B in sputum macrophages, compared to the stable phase[4-7].
Besides the abnormal local inammatory response, systemic inammation is
now considered an important component in the disease process. This systemic
inammation is related to the systemic consequences of COPD, including
involuntary weight loss, muscle dysfunction and wasting, and increased
cardiovascular morbidity[8]. Increased systemic inammation during acute
exacerbations of COPD is indicated by increased levels of the acute phase proteins
C-Reactive Protein (CRP) and brinogen, elevated levels of cytokines as IL-6, and the
neutrophil marker MPO[9-11]. In addition, the anti-inammatory mediator sIL-1RII
was shown to increase progressively during treatment of exacerbation
[12]. Recently
Hurst et al. published an extensive evaluation of a panel of potential biomarkers at
exacerbation, from which CRP was the most selective biomarker[13]. Moreover, a
decreased plasma anti-oxidant capacity was observed during exacerbations[14].
Most of the presently available data are obtained in cross-sectional studies not
taking into account the time to recovery to the baseline stable state. The aim of our
study was to evaluate longitudinally the course of a panel of systemic inammatory
mediators, and the anti-oxidant capacity, during hospital treatment for acute
exacerbation and after clinical recovery, in patients with severe COPD, as a control
group healthy age-matched control subjects were analysed. Our hypothesis was
demonstration of a differential time response pattern of a panel of inammatory
mediators as well as of anti-oxidative capacity during and in the recovery phase of
acute exacerbations and assessment of COPD related disease marker in the stable
disease condition.
72
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
Material and Methods
Study population
Patients with acute exacerbation
The study population consisted of 21 patients consecutively admitted to the
University Hospital Maastricht for an acute exacerbation of COPD. COPD was
dened as forced expiratory volume in one second (FEV1) < 80 % predicted for age
and height, β2 agonist reversibility of < 11 % of predicted and airow obstruction
evidenced by a ratio of FEV1 to forced vital capacity (FVC) of < 0.70 of predicted
according to ATS criteria[15]. Patients with important co-morbid conditions as
malignancies, diabetes mellitus, thyroid and cardiovascular diseases were excluded
from the study in order to avoid non-COPD related interfering factors. Patients
already treated with antibiotics and/or corticosteroid therapy on admission were
also excluded from the study. Furthermore, if patients had a recurrent exacerbation
within the follow-up period of 6 months, they were excluded from the study.
The presence of an acute exacerbation was dened as the presence of one or more
the following symptoms: (1) increased cough and sputum volume, (2) increased
sputum purulence, and (3) increased dyspnea. All 21 patients were classied
as a type 1 exacerbation, based on the Anthonisen criteria[16]. The patients
were treated according to a standard protocol with nebulized salbutamol and
ipratropiumbromide, intravenous prednisolone in a dosage of 0.5 mg/kg. Duration
of intravenous therapy was 4 days, on day 4 patients were switched to an oral
tapering schedule of prednisolone. Specic antibiotic treatment was administered
to patients in case of positive sputum cultures. A sputum culture was considered
as positive (proving bacterial infection) if signicant bacterial growth was present
as dened by the number of bacteria (higher than 105 colony forming units =
cfu) in a representative sample. Antibiotic treatment was based on resistance
assessment of identied bacteria. Patients were evaluated for inammatory
markers on day 0 (admission) before start of treatment, day 1, day 4 and day 8 of
hospitalisation for acute exacerbation. Patients were discharged based on clinical
judgment of an experienced, independent chest physician.
After discharge, patients were evaluated after 1 month, 3 months and 6 months.
Patients with symptoms of acute exacerbation, based on the Anthonisen criteria,
were excluded from the study. The study was approved by the medical ethical
committee of the University hospital Maastricht and all participants have given
their written informed consent.
Healthy controls
The healthy control group consisted of 20 subjects who were age and gender
matched and without any evidence of COPD based on questionnaires and lung
function tests. Control subjects without manifested morbid conditions were
chosen to nd out COPD related changes in systemic mediators during the
3
73
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
recovery period and after the supervised 6 month period when the disease was
considered stable.
Lung function measurements
On admission for an acute exacerbation, arterial blood gases at rest were assessed
by puncture of the radial artery during room air breathing. On days 1, 4 and 8
of admission and 1, 3 and 6 months after discharge, forced expiratory volume
in 1 second (FEV
1
) and inspiratory vital capacity (IVC) were calculated from the
ow-volume curve, using a portable pneumotachograph (Jaeger instruments,
Würzburg, Germany). Flow-volume curves were performed at a standardized
time point, one hour after medication. Lung function values were expressed as a
percentage of the reference values.
Measurement of inflammatory parameters and TEAC in
plasma
Blood was collected in EDTA containing tubes. (Sherwood Medical, St. Louis, MO,
US) The blood samples were put on ice immediately and kept on ice during the
entire preparation. Plasma was separated by centrifugation at 167 g for 10 minutes
at 4º C and two aliquots were centrifuged at 3000 rpm. Supernatants were
collected and stored at - 70º C until analysis for cytokines and anti-oxidants.
Inammatory mediators were measured in plasma by sandwich enzyme-linked
immunosorbent assay (ELISA), as described previously[12]. Briey, for detection of
sTNFR55 and sTNFR75, monoclonal antibodies MR1-1 and MR2-2 were used for
coating and specic biotin labelled polyclonal rabbit anti-human (h)-sTNF-R IgG as
detector reagents. For sIL-1RII measurements, plates were coated with monoclonal
antibody 8.5 against shIL-1RII and detection was carried out with a biotinylated
polyclonal rabbit anti-shIL-1RII IgG. For IL-6 and BPI measurements, plates were
coated with murine monoclonal antibody 5E1 and human BPI specic monoclonal
antibody 4E3, respectively. Biotinylated polyclonal rabbit anti-human IL-6 antiserum
and biotinylated polyclonal rabbit anti-human BPI IgG were used as detection
antibodies. All plasma samples were measured in the same run.
For analysis of TEAC, plasma was deproteinized. An aliquot of 150 microliters of
plasma was deproteinized by mixing with an equal volume of 10% (w/v) TCA,
and after centrifugation for 5 min at 14,000 rpm the supernatant was used for
spectrophotometrical analysis. TEAC was determined enzymatically (Sigma) as
described by Van den Berg et al[17].
Statistics
Differences in parameters within an individual patient between two time points
were compared using Wilcoxon matched pairs signed rank test. Because we
have performed planned comparisons in a relatively small small sample size, no
multiple comparisons tests were performed[18]. Differences between patients
74
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
and controls were measured using the Mann-Whitney U test. Signicance was
determined at the 5 % level. Data were analyzed using the SPSS for Windows
statistical package (version 12.0, SPSS Inc, Chicago, IL, US). Data were expressed
as mean (± SD).
Results
Clinical parameters
The characteristics of the COPD patients on admission for an acute exacerbation
and healthy controls are summarized in table 1. On average, the duration of
admission was 9.4 days (range 5-14). There was a small improvement in FEV
1
during the clinical course of acute exacerbation, which was not statistically
signicant.(from 0.90 L ± 0.03 L on admission to 0.97 L ± 0.04 L on day 8; p =
0.19) There was a signicant improvement in PaO
2
during admission (from 53.9
mm Hg ± 10.2 mm Hg on admission to 64.7 mm Hg ± 8.7 mm Hg on day 8; p =
0.001). PaCO
2
values did not change signicantly (data not shown).
12 of 21 patients had a positive sputum culture, 9 patients with 1 micoorganism
and 3 patients with 2 micro-organisms. Micro-organisms cultured were S.
pneumonia (6 patients), H. inuenzae (8 patients), Moraxella catarrhalis
(1 patient). 3 patients had both H. inuenzae and S. pneumoniae cultured from
their sputum. No differences existed in any of the measured parameters between
patients with and without positive bacteriological sputum cultures.
Inflammatory markers
Figure 1 shows the time course of the inammatory mediators on day 0, 1, 4
and 8 during admission for an acute exacerbation of COPD and at 1 month, 3
months and 6 months after discharge. As comparison, levels were also measured
in healthy controls. The cytokine IL-6 was not detectable in the healthy control
subjects with the assay used, therefore, detection limit of the assay (20 pg/ml)
was indicated in the gure. On day of admission, IL-6 was signicantly enhanced
in patients as compared to healthy controls (p = 0.033). After one day of treatment
levels dropped strongly (day 0 to day 1: p= 0.043) and were no longer different
from control subjects. Surprisingly, enhanced levels of IL-6 were seen 1 month
after discharge, however this enhancement was not signicant. Likewise, the
sTNFR75 was enhanced at admission of exacerbation, and declined thereafter
(day 0 to day 1: p=0.01; day 1 to day 4: p=0.019). After 1 months of discharge
increased levels of sTNFR75 were observed (day 8 to month 1: p=0.028), and
declined thereafter (month 1 to month 6: p=0.013). Soluble TNFR55 was elevated
during all time points of acute exacerbation of COPD, with exception of the day
4 time point (day 1 to day 4: p=0.004). After 1, 3 and 6 months levels were no
longer different as compared to healthy controls. The anti-inammatory marker
3
75
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
Table 1. Characteristics of COPD patients with acute exacerbation and healthy
controls.
Values of patients are values on admission. Data are presented as mean ± SD.
Patients
(n = 21)
Controls
(n = 20 )
p-value
Age yrs 66.7 ± 9.0 60.6 ± 3.4 NS
Sex F/M 6/15 6/14 NS
BMI (kg/m2) 23.5 ± 4.7 25.9 ± 2.7 NS
FEV1 % pred 35.0 ± 14.4 108.2± 14.2 0.0001
IVC % pred 62.9 ± 22.9 114.8 ± 12.4 0.0001
Smokers current/ex/none 7/13/1 1/11/8 NS
Packyears 40 ± 20 20 ± 15 0.0001
Inhaled steroids Y/N 19/2 0/20 0.0001
Bacterial infection Y/N 12/9 NA
PaO2 mm Hg 53.2 ± 10.5 NA
PaCO2 mm Hg 47.2 ± 16.5 NA
Figure 1. Course of cytokines during and after acute exacerbation of COPD
A
Level of IL-6 (ng/ml)
*
#
#
#
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
d
a
y
0
d
a
y
1
d
a
y
4
d
a
y
8
1
m
o
n
th
6
m
o
n
th
s
3
m
o
n
th
s
B
Level of sTNFR 75 (ng/ml
*
#
#
0
0.5
1
1.5
2
2.5
3
day
0
day
1
day
4
day
8
3
months
6
months
1
month
Figure 1. Course of cytokines during and after acute exacerbation of COPD.
76
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
Figure 1. Continued.
C
Level of sTNF R 55 (ng/ml)
*
*
*
0
0.5
1
1.5
2
2.5
d
a
y
0
d
a
y
1
d
a
y
4
d
a
y
8
1
m
o
n
th
3
m
o
n
th
s
6
m
o
n
th
s
D
Level of s IL1 RII (ng/ml)
*
*
*
*
0
1
2
3
4
5
6
7
8
9
10
day 0day 1day 4 day 8 1 month 3 months 6 months
E
Level of BPI (ng/ml)
*
* #
* #
*
*
*
*
0
0.5
1
1.5
2
2.5
3
3.5
4
d
a
y
0
d
a
y
1
d
a
y
4
d
a
y
8
1
m
o
n
th
3
m
o
n
th
s
6
m
o
n
th
s
3
77
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
sIL-1RII was signicantly increased on the day of admission and increased further
during treatment of exacerbation (day 0 to day 1: p = 0.031; day 1 to day 4: p =
0.038). In the recovery period sIL-1RII decreased to levels comparable to healthy
controls (day 8 to 1 month; p=0.004). Also the neutrophil marker BPI was elevated
on admission (p = 0.0001), and remained elevated during and after recovery of
exacerbation, as compared to control subjects. Highest BPI levels were seen on
day 8 and lowest at 3 months after exacerbation (day 8 to month 3: p= 0.01).
Anti-oxidant capacity
The change in levels of systemic anti-oxidant TEAC during treatment of acute
exacerbation and after recovery is shown in gure 2. There was a signicant
increase in TEAC levels during treatment of acute exacerbation, compared to
admission values (day 0 to day 8: p=0.003). After discharge levels decreased
signicantly (month 3 to month 6: p= 0.017).
Discussion
This study showed elevated levels of systemic inammatory markers IL-6,
sTNFR55, sTNFR75, and sIL-1RII as well as neutrophil protein BPI, on admission
for acute exacerbation of COPD. During treatment, there was a rapid decrease
in IL-6, and sTNFR75, whereas in contrast sTNFR55 and BPI remained elevated.
Moreover, sIL-1RII and TEAC increased during rst 8 days of treatment. In the
stable condition, inammatory markers returned to values comparable to healthy
Figure2. Course of TEAC during and afteracute exacerbations of COPD
Level of TEAC (mmol/l)
#
520
540
560
580
600
620
640
660
680
700
day
0
day
1
day
4
day
8
1month
3months
6months
Figure 2. Course of TEAC during and after acute exacerbations of COPD.
78
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
controls, with the exception of BPI which remained persistently elevated compared
to healthy controls.
Growing evidence exists about the upregulation of systemic inammation,
as manifested by an elevated acute phase response, as part of the underlying
pathogenetic processes ongoing during acute exacerbations[19]. In this study
elevated levels of IL-6 were found on admission for an acute exacerbation,
compared to healthy controls. During recovery and follow-up, IL-6 is in the same
range as in healthy controls, suggesting a short are-up of systemic inammation
at the beginning of the exacerbation. IL-6 is the most important cytokine in
the hepatic synthesis of acute phase proteins. Moreover, IL-6 is important in
regulating levels of brinogen, the precursor to brin in the coagulation cascade.
Elevated brinogen levels and IL-6 are associated with increased cardiovascular
mortality and morbidity[20, 21]. It has already been demonstrated that during acute
exacerbation levels of brinogen and IL-6 rise further[22]. In this way, increased
systemic inammation can predispose to cardiovascular events.
TNFα is a pro-inammatory cytokine, which has been found in increased levels
in airways and circulation of COPD patients[23-25]. TNFα mediates intracellular
signaling via two receptors: a 55 kDa receptor (TNFR55) and a 75 kDa receptor
(TNFR75). A variety of inammatory stimuli, including endogenous TNFα
formation is known to induce proteolytic shedding of the extracellular cytokine-
binding domains of the TNF receptors[26]. Therefore soluble TNF receptors are
considered as pro-inammatory markers. Earlier studies of our group have shown
an increase in soluble TNF receptors during treatment of acute exacerbation[27].
In this study we found that on admission for acute exacerbation, before start of
treatment, levels of both sTNF-receptors were elevated. During treatment sTNFR75
levels rapidly decreased whereas sTNFR55 remained elevated. One, 3 and 6
months after acute exacerbation, levels of both TNF receptors were not different
from healthy controls.
Beside monitoring of the changes in inammatory mediators to predict diagnosis,
outcome and prognosis of acute exacerbations, further studies are needed to
integrate these ndings in order to better understand ongoing processes during
exacerbations of COPD. Acute phase responses are involved in activation of
the classical component pathway. Biochemical markers as CRP, IL-6 and TNF-
α are generally considered as biochemical markers of endothelial dysfunction;
particularly CRP represents one of the strongest independent predictors of
vascular morbidity and mortality[28, 29]. The role of systemic inammation to
shift the hemostatic balance to favour the activation of coagulation during acute
exacerbation remains largely unexplored during acute exacerbations of COPD[30].
IL-1 is a pro-inammatory cytokine, and has two receptors: type I receptor which
mediates cellular activation and type II receptor which acts as a decoy receptor[12].
Both IL-1 receptors are present in soluble forms and the soluble receptors
inactivate sIL-1. In patients with stable COPD normal levels of sIL-1RII have been
3
79
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
found, which increase during treatment of acute exacerbations, indicating that an
upregulation of anti-inammatory cytokines is present during treatment of COPD
exacerbations[12]. In this study we have conrmed and expanded those ndings.
We found elevated levels of sIL-1 RII on admission for acute exacerbation, before
start of treatment. These levels increased further during treatment. This supports
the hypothesis that recovery of acute exacerbations is associated with an increase
in anti-inammatory capacity. After a follow-up period of 1, 3 and 6 months, sIL-
1RII levels are comparable to healthy controls. Future studies should include the
course of other anti-inammatory mediators such as IL-10 in the course of acute
exacerbation. Modulation of anti-inammatory effects can contribute to fasten the
recovery after acute exacerbations.
BPI is stored within the azurophilic granules of neutrophils and can be released
upon direct stimulation of the neutrophil by bacterial endotoxins, but also by
inammatory stimuli like TNF-α [31]. Therefore it can be used as a marker for
neutrophilic activation. So far no data exist on BPI levels in COPD patients. We
demonstrated increased systemic levels of BPI in COPD patients with an acute
exacerbation in comparison to healthy control subjects. These data suggest
ongoing neutrophilic activation in COPD patients, in clinically stable patients
and during acute exacerbations. This is in line with other reports indicating
that recruitment and activation of neutrophils is an important event in the
pathogenesis of COPD[3, 32]. Elevated levels of serum MPO and serum ECP
have been found during exacerbations indicating neutrophilic and eosinophilic
activation[9]. Noguera et al. reported that circulating neutrophils from COPD
patients produced more reactive oxygen species and the level of expression of
several surface adhesion molecules in circulating neutrophils is higher in stable
COPD patients than in healthy controls. Interestingly, this difference disappeared
during acute exacerbations, suggesting neutrophil sequestration in the pulmonary
circulation [33]. A recent study found activated neutrophils in the circulation of
stable COPD patients, which correlated with disease severity[34]
.
The question is whether and to what extent the course of inammatory parameters
was inuenced by the anti-inammatory treatment our patients received.
Corticosteroids are potent immunosuppressive agents that are known to affect
T-cell mediated inammation by the inhibition of proliferation and cytokine
production, as well as the immuno-stimulatory function of monocytes and
macrophages[35]. Moreover, in vitro experiments have shown
that exposure of
cells to the steroid analogue dexamethasone resulted
in enhanced membrane
expression of IL-1RII followed by augmented
release of the receptor over a
period of 18-24 hours[36]. Treatment with systemic steroids thus may be partially
responsible for the course of systemic inammatory mediators that we have
observed after admission. In line herewith, studies in cardiac surgery patients
have shown a decrease in circulating levels of TNF and IL-6 after treatment with
corticosteroids[37, 38]. Since our patients did not receive corticosteroids before
80
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
admission, the enhanced levels of inammatory parameters observed on day
0 cannot be attributed to treatment effects. Steroid treatment of patients was,
according to a standard schedule, tapered after 4 days during a period of 15 days.
Interpretation of the course of systemic inammatory parameters in the recovery
period is therefore also most likely not inuenced by steroid therapy.
A number of studies have demonstrated an increased oxidative stress in COPD
patients, especially during exacerbations[14, 39, 40]. Our study demonstrates an
increase in total anti-oxidant capacity during treatment of acute exacerbation,
suggesting that improvement in antioxidant capacity may be a contributing factor
in recovery from acute exacerbations.
These results were found in a group of patients with severe COPD, admitted for
an acute exacerbation, who remained stable during 6 months of follow-up. We
realize this is probably a selected population, since patients with exacerbations in
the follow-up period and patients with cardiovascular co-morbidity were excluded.
Therefore these results are probably not generally applicable in all populations of
COPD patients. Otherwise, our results after the 6 month follow-up period clearly
illustrate the importance of careful assessment and monitoring of the clinical
condition in the evaluation of inammatory systemic mediators. This will be
particularly important when systemic inammation will be evaluated as part of the
phenotyping of COPD.
In conclusion, this study clearly demonstrated upregulation of systemic
inammation in acute exacerbations of COPD. During recovery pro-inammatory
markers declined whereas levels of sIL-1RII and TEAC increased. In stable state
inammatory markers were no longer enhanced with the exception of neutrophil
marker BPI. Attenuation of systemic inammation offers new perspectives in the
management of COPD patients and to reduce the burden of exacerbations.
3
81
Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD
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CHAPTER 4
Increased systemic
inflammation is a risk factor
for COPD exacerbations
Chest 2008 Feb;133:350-357
KH Groenewegen
DS Postma
WCJ Hop
PLML Wielders
N Schlösser
EFM Wouters
for the COSMIC study group
86
Increased systemic inflammation is a risk factor for COPD exacerbations
Abstract
Background
Chronic obstructive pulmonary disease (COPD) is characterized by episodic
increases in respiratory symptoms, so called exacerbations. COPD exacerbations
are associated with an increase in local and systemic inammation.
Data of a previously published study in a well-characterized COPD cohort were
analysed to dene predictive factors of acute exacerbations, particularly focussing
on systemic inammation.
Objective
To determine if an elevated systemic inammatory status measured at baseline is
related to the occurrence of acute exacerbations in COPD.
Methods
The occurrence of moderate (requiring oral prednisolone) and severe
exacerbations (requiring hospitalisation) was prospectively recorded during one
year. At the beginning of the study lung function values (FEV
1
, FVC, FRC and
DLCO) and serum levels of CRP, brinogen, LBP, TNF-α and its soluble receptors
sTNFR55 and sTNFR75 as markers of systemic inammation were determined.
Results
277 person-years of follow-up were analyzed in the total group of 314 patients: 186
patients were responsible for 411 exacerbations (374 moderate and 37 severe).
Multivariate analyses showed that a higher initial brinogen level and a lower FEV
1
predicted a higher rate of both moderate and severe exacerbations. Additional
independent predictors of a severe exacerbation were a higher number of prestudy
severe exacerbations and lower DLCO. A higher number of prestudy moderate
exacerbations was the only additional independent risk factor for the rate of
moderate exacerbations.
Conclusion
This study demonstrates that besides lung function impairment systemic
inammation manifested by elevated brinogen levels is an independent risk
factor for exacerbations of COPD. Attenuation of systemic inammation may offer
new perspectives in the management of COPD patients to reduce the burden of
exacerbations.
4
87
Increased systemic inflammation is a risk factor for COPD exacerbations
Introduction
Chronic obstructive pulmonary disease (COPD) is characterized by episodic
increases in respiratory symptoms, so called exacerbations. These episodes
contribute considerably to the increased morbidity, mortality and health care costs
associated with this disease condition[1-4].
The denition of acute exacerbation of COPD is largely based on reported
symptomatology by the patient, mostly an increase in dyspnea, cough and sputum
production.
Different studies have reported that airway inammation increases in acute
exacerbations[5-8].
Besides an increase in airway inammation, COPD exacerbations are associated
with an increase in systemic inammation. It has been established that stable
COPD is associated with low grade systemic inammation as demonstrated by an
increase in blood leukocytes [6], acute phase proteins C-reactive protein (CRP)[6]
and brinogen [7], and inammatory cytokines[2, 8].
During acute exacerbations of COPD, higher levels of IL-6 as well as acute phase
proteins CRP, brinogen and lipopolysaccharide binding protein (LBP) have been
demonstrated, declining again during recovery[7, 9].
It is now recognized that exacerbations are an important outcome in COPD, as
patients prone to frequent exacerbations have impaired health status [3], reduced
physical activity levels [10], increased lower airway bacterial colonization [11] and
accelerated lung function decline[12, 13].
Thus, identication of patients at risk for development of acute exacerbations is
important since it could lead to more appropriate therapeutic interventions or
more specic treatment of identiable risk factors. A number of risk factors for
acute exacerbations have been described, i.e. hypercapnia [14, 15], previous hospital
admissions [3, 14], current smoking [14], impaired health status [3, 16], pulmonary
hypertension [15] and hypoxia [14], low BMI [17] and low FEV
1
[14]. Most of these
factors have been identied in COPD patients who were hospitalized for an acute
exacerbation.
However, limited prospective data are available on patients who have moderate
exacerbations with treatment out of hospital.
We hypothesized that besides lung function characteristics an elevated systemic
inammatory status is related to the occurrence of acute exacerbations in COPD.
We analysed data of a one-year prospective study in a well-characterized COPD
cohort to dene predictive factors of acute exacerbations, including both moderate
and severe exacerbations, particularly focussing on systemic inammation.
88
Increased systemic inflammation is a risk factor for COPD exacerbations
Material and Methods
Study design
This study is a secondary study of the COSMIC (COPD and Seretide: a Multi-
Center Intervention and Characterization) study, a multicenter trial to investigate
the effects of steroid withdrawal in comparison with combination therapy (long
acting beta-2 agonist salmeterol and inhaled steroid uticasone) during a one year
follow-up period[18].
The COSMIC study had a multi-center, randomized, double blind, parallel-group
design. All patients received combined salmeterol 50µg and uticasone 500 µg
(Seretide® 50/500) twice daily (in the morning and evening) via the Diskus®
inhaler during a three-month run-in period. Thereafter patients were randomized
to a 12-month treatment with either salmeterol/uticasone (SFC) or salmeterol (S)
alone. Inhaled salbutamol was used as relief medication and anticholinergics and
methylxanthines in constant dose were allowed throughout the study. After the 3
month run-in period at the randomisation visit, systemic inammatory parameters
were measured next to previously described clinical parameters[18].
Patients
Inclusion and exclusion criteria have been previously described[18]. In short, entry
criteria were: age 40-75 years, established history of COPD, current or ex-smokers
with at least 10 pack years, pre-bronchodilator FEV
1
30-70% of predicted, FEV
1
/
FVC <88% for men and <89% for women, and reversibility 400µg with salbutamol
<10% of FEV
1
predicted. Importantly, all patients had a history of at least two
documented COPD exacerbations in the year preceding the study inclusion.
Patients requiring systemic corticosteroids or antibiotics or hospitalization for
lower respiratory tract infection and/or COPD exacerbation in the 3-month run-in
period were also excluded. 314 of the randomized patients were included in this
substudy. Approval from ethics committees at each participating site and written
informed consent from all patients was obtained.
Measurements
Static and dynamic lung volumes
FEV
1
, forced vital capacity (FVC), peak expiratory ow (PEF) were calculated
from the ow volume curve using a spirometer (Masterlab®, Jaeger, Würzburg,
Germany). The Tiffeneau-index was calculated as FEV
1
/FVC. Lung function
parameters were expressed as percentage of reference values [19]. After stopping of
short-acting bronchodilating medication for 6 hours and long acting beta-agonists