DOI 10.1378/chest.09-2927; Prepublished online June 24, 2010;Chest
René Lutter, Henk M. Jansen and Wim G. BoersmaJohannes M.A. Daniels, Marianne Schoorl, Dominic Snijders, Dirk L. Knol, therapy in acute exacerbations of COPDpredictive markers of response to antibiotic Procalcitonin versus C-reactive protein as
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Word count abstract: 244
Word count text: 2909
Procalcitonin versus C-reactive protein as predictive
markers of response to antibiotic therapy in acute
exacerbations of COPD
Authors:
Johannes M.A. Daniels, MD, PhD1
Marianne Schoorl2 ([email protected])
Dominic Snijders, MD1 ([email protected])
Dirk L. Knol, PhD3 ([email protected])
René Lutter, PhD4,5
Henk M. Jansen, MD, PhD5 ([email protected])
Wim G. Boersma, MD, PhD1
Institutions:
Departments of Pulmonary diseases1
and Clinical Chemistry, Haematology and Immunology,
2 Medical Centre Alkmaar,
Alkmaar, The Netherlands.
Department of Epidemiology and Biostatistics,3 VU University Medical Center, Amsterdam, The Netherlands.
Department of Experimental Immunology4 and Respiratory Medicine,
5 Amsterdam Medical Centre, University of
Amsterdam, Amsterdam, The Netherlands.
Corresponding author:
Johannes (Hans) M. A. Daniels, MD
Dept of Pulmonary Diseases
VU University Medical Center
PO box 7057
1007 MB Amsterdam
The Netherlands
Tel: +31204444782
Fax: +31204444328
E-mail: [email protected]
Funding source: This study was supported by an unrestricted grant from GlaxoSmithKline (Netherlands). The funding
source had no part in the study design, conduct or reporting of the study.
Conflict of interest: none of the authors report a conflict of interest.
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ABSTRACT
Background Rational prescription of antibiotics in acute exacerbations of COPD (AECOPD) requires
predictive markers. We aimed to analyze whether markers of systemic inflammation can predict response to
antibiotics in AECOPD.
Methods We used data from 243 exacerbations out of 205 patients from a placebo-controlled trial on
doxycycline in addition to systemic corticosteroids for AECOPD. Clinical and microbiological response, serum
C-reactive protein (CRP, cut-offs 5 and 50 mg/L) and serum procalcitonin (PCT, cut-offs 0.1 and 0.25 µg) were
assessed.
Results Potential bacterial pathogens were identified in the majority of exacerbations (58%). We found a
modest positive correlation between PCT and CRP (r= 0.46, p<0.001). The majority of patients (75%) had low
PCT levels, with mostly elevated CRP levels. While CRP levels were higher in the presence of bacteria
(median, 33.0 mg/L [IQR, 9.75-88.25] vs. 17 mg/L [IQR, 5.0-61.0] [p= 0.004]), PCT levels were similar. PCT and
CRP performed similarly as markers of clinical success and we found a clinical success rate of 90% in patients
with CRP ≤5 mg/L. A significant effect of doxycycline was observed in patients with a PCT <0.1 µg/L
(treatment effect, 18.4%; P=0.003). A gradually increasing treatment effect of antibiotics (6%, 10% and
18%), although not significant, was found for patients with CRP values of ≤5, 6-50 and >50 mg/L.
Conclusions Contrary to the current literature, this study suggests that patients with low PCT values do
benefit from antibiotics. CRP might be a more valuable marker in these patients. (ClinicalTrials.gov number,
NCT00170222).
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Abbreviations
AECOPD: acute exacerbation of COPD
COPD: chronic obstructive pulmonary diasease
CRP: C-reactive protein
GOLD: global initiative for chronic obstructive lung disease
IL-6: interleukin 6
IQR: interquartile range
PCT: procalcitonin
ROC: receiver operating characteristic
SAA: serum amyloid A
SD: standard deviation
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INTRODUCTION
Chronic obstructive pulmonary disease (COPD) constitutes a major health problem [1]. Acute exacerbations
of COPD (AECOPD) have considerable impact on morbidity, mortality and quality of life [2,3]. Common
triggers for AECOPD include viral and/or bacterial infection of the tracheobronchial tree and air pollution,
but the cause of approximately one-third of severe exacerbations cannot be identified [4]. Whereas patients
with signs of bacterial infection and more severe exacerbations seem to benefit from antibiotics [5,6],
prescribing antibiotics for viral infections or non-infectious causes of AECOPD is ineffective and increases the
risk of toxicity and development of bacterial resistance [7].
Biomarkers such as procalcitonin (PCT) and C-reactive protein (CRP) could assist in selecting patients that will
benefit most from antibiotic therapy. It appears that PCT is a more sensitive marker of bacterial infections in
general [8]. PCT was prospectively studied as a marker to guide antibiotic therapy in AECOPD [9]. The
authors found that PCT guided therapy in AECOPD led to a reduction of antibiotic use. While PCT is a
relatively new marker, CRP is already widely used as an aid in diagnosing infections and monitoring response
to antibiotics. It has been demonstrated that CRP levels rise during AECOPD, especially in patients with
sputum purulence and positive sputum cultures, but CRP has not been prospectively studied as a marker in
the management of AECOPD [10-13].
We have recently completed a randomized, double-blind, placebo-controlled trial of seven days of
doxycycline in addition to systemic corticosteroids for patients hospitalized with an acute exacerbation of
COPD [14]. The results indicate that add-on treatment with doxycycline is associated with a higher clinical
and bacterial success rate and a greater reduction in symptoms, all at 10 days after admission. We used data
from this trial to assess whether CRP and PCT can be used as markers in AECOPD. Our goals were to compare
CRP and PCT as markers of clinical outcome, bacterial presence and response to antibiotic therapy.
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METHODS
The methods, design and outcomes of the above mentioned trial have been described in detail previously
[14]. In short, 265 exacerbations from 223 patients were enrolled between August 2002 and February 2008
into a randomized placebo-controlled trial investigating the efficacy of doxycycline in addition to systemic
corticosteroids for AECOPD. The study population consisted of patients of ≥45 years of age, diagnosed with
COPD (GOLD stages I-IV [8]), presenting with an acute (≤14 days duration) exacerbation of the Anthonisen
type-1 (increased dyspnoea, sputum volume and sputum purulence) or type-2 (two of three symptoms)[6].
The most relevant exclusion criteria were fever (≥38.5 °C), prior antibiotic treatment for ≥24 hours, extensive
treatment with systemic corticosteroids (>30mg prednisolone equivalent dose for more than four days),
radiographic signs of pneumonia, history of severe AECOPD requiring mechanical ventilation and other
infectious diseases requiring antibiotic therapy.
Definition of clinical outcome
Treatment success was defined as cure: a complete resolution of signs and symptoms associated with the
exacerbation, or improvement: a resolution or reduction of the symptoms and signs without new symptoms
or signs associated with the infection. Treatment failure was defined as absence of resolution of symptoms
and signs, worsening of symptoms and signs, occurrence of new symptoms and signs associated with the
primary or a new infection or death [15].
Microbiology
At the laboratory for microbiology, Gram’s stain was performed and sputum quality was assessed. The
presence of >25 polymorphonuclear leukocytes and <10 squamous epithelial cells per low-power field in a
Gram-stained sputum was defined as a representative sputum. Representative sputum samples were
cultured quantitatively. Bacterial infection was defined as the presence of a potential pathogen in a
representative sputum sample. In the Netherlands the washing of sputum, in order to remove the
oropharygeal flora, is performed routinely. Microbiological analysis was carried out in accordance with the
guidelines of the American Society for Microbiology [16]. Paired serum samples were obtained within 30
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days for the detection of M. pneumonia, C. pneumoniae, L. pneumophila serogroup 1-7 (Serion ELISA classic,
Virion GmbH, Würzburg, Germany).
PCT and C-reactive protein
Serum CRP was measured by nephelometry (Beckman Coulter Inc., Fullerton, CA, USA) on the day of
admission. Since serum CRP levels peak at about 36 hours after infection, this test was repeated on the
second day of the admission. Cut-off values were set at 5mg/L (normal threshold) and 50mg/L (best single
cut-off value in previous analysis [14]). PCT levels were assessed with time-resolved amplified cryptate
emission technology on a Kryptor analyser (Brahms Diagnostica GmbH, Berlin, Germany) in 100 μL of serum
drawn at day 1 and stored at -30°C. The analytic sensitivity of the assay was 0.06 ng/mL and the detection
threshold was 0.02 ng/mL. Cut-off values were set at 0.1 µg and 0.25 µg as described before [9].
Statistical analysis
SPSS 16.0 for Windows (SPSS Inc, Chicago, Illinois) and Stata version 11.0 (StataCorp, College Station, Texas)
were used for data management and statistical analysis. Data are presented as mean ±SD unless stated
otherwise. Correlation between CRP and PCT values was examined with Spearman’s rank correlation test.
ROC curve analysis was used to evaluate CRP and PCT as markers of clinical success. Differences between the
treatment groups were analyzed with logistic regression analysis, correcting for within-patient clustering
with generalized estimating equations. Interaction between the treatment effect and subgroups according
to CRP and PCT values was examined with logistic regression analysis. The study protocol was approved by
the local ethics board and all patients provided written informed consent.
RESULTS
Baseline characteristics
In the original randomized trial, 265 exacerbations were enrolled. The per-protocol group of this trial,
consisting of 258 patients, was used for the current study. Fifteen patients were excluded because no serum
samples were stored which made assessment of PCT levels impossible (figure 1). We evaluated 243
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exacerbations from 205 patients. Ninety-five were assigned to doxycycline and 110 to placebo. Table 1
shows the baseline characteristics, which are similar to the original trial [14]. A potential bacterial pathogen
was identified in 71 (62%) exacerbations from the doxycycline group and 71 (55%) exacerbations from the
placebo group (table 2). The median PCT level was 0.06 µg/L (interquartile range [IQR], 0.04-0.11) in the
doxycycline group and 0.05 µg/L (IQR, 0.04-0.09) in the placebo group. The median CRP level was 30.0 mg/L
(IQR, 8.0-83.5) in the doxycycline group and 23.0 mg/L (IQR, 6.5-76.5) in the placebo group. In the overall
group, PCT values were <0.1 µg/L in 183 patients (75%), 0.1-0.25 µg/L in 38 patients (16%), and >0.25 µg/L in
22 patients (9%). CRP values were ≤5 mg/L in 42 patients (17%), 6-50 mg/L in 112 patients (46%) and >50
mg/L in 89 patients (37%). We found a modest positive correlation between PCT and CRP (r= 0.46, p<0.001)
(figure 2). At day 2 the CRP level had increased in 46 patients (19%) and in 12 patients (5%) the CRP increase
was beyond a cut-off value (five patients had increased from ≤5 mg/L to 6-50 mg/L and seven patients had
increased from 6-50 mg/L to >50 mg/L).
PCT and CRP as markers of bacterial presence
The median PCT level was 0.06 µg/L (IQR, 0.04-0.11) in the presence of bacteria and 0.06 µg/L (IQR, 0.04-
0.08) in the absence of bacteria (p= 0.288). The median CRP levels were 33.0 mg/L (IQR, 9.75-88.25) and 17.0
mg/L (IQR, 5.0-61.0) respectively, in the presence and absence of bacteria (p= 0.004) (figure 3). The areas
under the ROC curves for predicting bacterial presence were similar (0.540 for PCT and 0.609 for CRP,
p=0.19).
PCT and CRP as predictors of clinical outcome
The overall clinical success rate and clinical cure rate were 74% and 58% at day 10 and 56% and 45% at day
30. In patients with PCT levels of <0.1 µg/L, 0.1-0.25 µg/L and >0.25 µg/L, clinical success rates were 80%,
61% and 45% respectively (p<0.001) and clinical cure rates were 65%, 37% and 41% respectively
(p=0.001)(table 3). In patients with CRP levels of ≤5 mg/L, 6-50 mg/L and >50 mg/L, clinical success rates
were 90%, 76% and 64% respectively (p=0.005) and clinical cure rates were 71%, 59% and 52% respectively
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(p=0.058)(table 3). The areas under the ROC curves for predicting clinical outcome were similar on day 10
(0.712 and 0.670 for PCT and CRP respectively, p=0.43) and on day 30 (0.655 and 0.599 for PCT and CRP
respectively, p=0.27) (figure 4).
Relation of PCT and CRP with the treatment effect
At day 10 clinical success was observed in 91 patients from the doxycycline group (80%) and 89 patients
from the placebo group (69%) (Odds ratio, 1.8; 95% CI, 1.0 to 3.2; P=0.057), which is similar to the per-
protocol analysis of the original trial [14]. Figure 5 shows the treatment effect (clinical success at day 10 and
day 30) for different levels of PCT and CRP. A significant effect of doxycycline was observed in patients with a
PCT value of <0.1 µg/L (treatment effect, 18.4%; P=0.003)(figure 5) and not for patients with a PCT value
between 0.1 and 0.25 µg/L or >0.25 µg/L. We found a trend towards negative interaction between PCT and
the treatment effect (P=0.061). In the subgroups according to CRP level at day 1 we found that the
treatment effect increased as the CRP value increased, with an almost significant benefit from antibiotics for
patients with a CRP value of >50 mg/L (treatment effect, 18.8%; P=0.072)(figure 5). When taking the highest
CRP value of day 1 and day 2, we found a larger treatment effect for patients with a CRP value of >50 mg/L
(treatment effect, 21.4%; P=0.033). We did not find significant differences in treatment effects between the
subgroups according to CRP (P value for interaction). Because physicians were aware of CRP levels but
unaware of PCT levels, we compared the rates of open label antibiotic prescriptions for lack of efficacy,
which are shown in table 4.
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DISCUSSION
The current study is the first to assess the value of PCT and CRP as markers of bacterial presence, clinical
outcome and efficacy of antibiotics and it has revealed four important new findings. First, we only found a
moderate correlation between PCT and CRP in AECOPD. Importantly, most patients with a PCT level of <0.1
µg/L had an elevated CRP value, in many cases (27%) even exceeding 50 mg/L. Second, we found that CRP
was associated with bacterial presence while PCT was not. Third, we showed that the clinical success rate
was high (90%) in patients with a CRP value below the normal threshold (≤5mg/L). Finally, the current study
suggests a benefit from antibiotic therapy in patients with low PCT levels (<0.1 µg/L), although other
investigators discourage the use of antibiotics in these patients.
PCT and CRP are the most studied biomarkers in AECOPD and the current study shows only a moderate
correlation between the two. It is striking that the majority of patients (75%) had low PCT values, but
elevated CRP values. This suggests that elevation of CRP and PCT is triggered by different events. PCT is
produced primarily by parenchymal cells in response to microbial toxins and in response to certain host
inflammatory mediators (interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 [IL-6]). Although
PCT can be released in some non-infectious conditions, it is a relatively specific marker for invasive bacterial
infection such as sepsis and pneumonia [17,18], which is evidently not the case in most patients with
AECOPD. CRP on the contrary, can be elevated in most inflammatory, neoplastic and infective conditions
[19]. It is therefore likely to be more sensitive than PCT to the events taking place in the airways during
AECOPD. Our results are in line with the findings of a study that investigated the value of serum amyloid A
(SAA), CRP, IL-6 and PCT as biomarkers for AECOPD [20]. SAA and CRP were found to be sensitive markers,
and although no specific data on PCT were reported, the authors concluded that PCT was not an informative
biomarker. In that study however, procalcitonin was determined by immunolumunometric assay (PCT LIA,
detection limit, 0.3 ng/ml; BRAHMS, Henningsdorf, Germany), which is less sensitive than the Kryptor
analyser that was used in other studies and the current study. Another explanation for the low PCT levels
and elevated CRP levels in most patients could be a significant amount of viral respiratory infections. Rohde
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et al. [21] showed that CRP can increase during AECOPD triggered by viral infections, but the values that
were reported are much lower than those in the present study, which makes this an unlikely explanation. As
we did not perform PCR to detect viral infections, it is unknown to what extent our data were in fact
influenced by viral infections.
Airway inflammation and systemic inflammation increase during AECOPD and more so after acquisition of a
new bacterial strain [22]. Our data also show that CRP was related to bacterial presence in sputum, which is
in line with previous studies [11,13], while PCT was not. Therefore the presence of bacteria in sputum in
most cases of AECOPD does probably not represent an invasive bacterial infection such as a pneumonia, but
does trigger a local and systemic inflammatory response. A low PCT level therefore, may not necessarily
imply that patients will not benefit from antibiotic therapy. In fact, our findings indicate that doxycycline is
effective in patients with a PCT level <0.1 µg/L (treatment effect, 18.4%; P=0.003).
The benefit from antibiotics in patients with a low PCT value, as described above, seems to be in
contradiction with a study that investigated the efficacy and safety of PCT guidance compared to standard
therapy with antibiotic prescriptions in patients with AECOPD [9]. In the PCT arm antibiotics were prescribed
in 40% of the patients, while in the standard arm antibiotics were prescribed in 72% of the patients and no
differences were found in clinical outcome, recovery of lung function, rehospitalization and exacerbation
rates and time to the next exacerbation. Although this study proves that the use of antibiotics can be
reduced safely when guided by PCT levels, no conclusions can be drawn on whether PCT predicts the
response to antibiotic therapy because the study was not placebo-controlled. Furthermore, meta-analyses
have shown only a small benefit by antibiotic therapy in AECOPD [5,23,24]. Although it did not suggest
differences in clinical outcome, the trial by Stolz et al. [9] was powered on reducing antibiotic use and not on
detecting differences in clinical outcome. It would take a larger sample of patients to prove that reducing
such a moderately effective treatment does not affect patient outcome. It is important to mention that the
population of Stolz et al. [9] differed from ours in that PCT levels were generally higher. In their study 51% of
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patients had a PCT level of <0.1 µg/L as compared to 75% of the patients in our study. The large proportion
of patients with fever (defined as >38 °C, 41%) could explain this since patients with fever (defined as >38.5
°C) were excluded from our study to prevent enrolment of patients with pneumonia. On the other hand, the
percentage of positive sputum cultures was clearly higher in our study (58% versus 37%).
We showed that CRP levels at day 2 had increased in 46 patients (19%) and in 12 patients (5%) the CRP
increase was beyond a cut-off value. This percentage seems small, but when the highest value of day 1 and 2
was used, CRP seemed to predict the response to antibiotics better (figure 5). That CRP rises on the second
day of admission has also been observed in community acquired pneumonia [25]. This finding therefore
seems relevant for future studies.
The present study has several limitations. First, the study was primarily designed to assess the role of
antibiotics in addition to systemic corticosteroids in AECOPD and not to compare CRP and PCT as
biomarkers. It was also not powered to examine interaction between CRP and PCT and the treatment effect
of antibiotics. The results should therefore be interpreted with caution and this study should be regarded as
exploratory. Second, during the study, physicians had access to CRP values while PCT values were obtained
later from frozen serum samples. Knowledge of CRP values might have influenced physicians in their
therapeutic decisions and in the evaluation of clinical outcome. The low number of open label antibiotic
prescriptions in patients with low CRP levels (7%, table 4) might be so because physicians are comfortable to
withhold antibiotics at such CRP levels. A great advantage of the current study is the placebo-controlled
double blind design of this trial which provides unique insights in the role of these markers. Finally, 15
patients (6%) were excluded from present study because paired serum samples for PCT measurements were
not available. This could have created a selection bias, although the baseline characteristics and clinical
outcome at day 10 were similar to the original trial.
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In conclusion, CRP and PCT in AECOPD are only moderately correlated and CRP is associated with airway
bacterial presence while PCT is not. Furthermore, although antibiotic therapy in patients with low PCT levels
could be discouraged based on the literature, the current study suggests a benefit. This challenges the role
of PCT as a predictive marker in AECOPD. Patients with a CRP of ≤5 mg/L have favorable outcome regardless
of antibiotic therapy while patients with a CRP >50 mg/L show a trend to benefit from antibiotics. For these
reasons, it is important to further investigate the role of CRP in the management of AECOPD. Additionally, it
would be of interest to investigate in a randomized study whether patients with low PCT values really
benefit from antibiotic therapy.
Acknowledgements
We thank the patients who enrolled in this study, the physicians, nurses and secretaries of the department
of Pulmonary Diseases for their important contributions. We thank T. van der Ploeg for his work on the
sample size calculation and interim analysis and T. Tossijn-Groot and P. Singer of the department of
Microbiology for their hard work. JMAD, MS, DS, and WGB were responsible for data collection, analysis and
interpretation of the data, and manuscript preparation. DLK performed the statistical analysis. RL and HMJ
contributed to interpretation of the data and critical revision of the manuscript.
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Table 1. Baseline characteristics (n=205).
Characteristics Doxycycline
(n=95)
Placebo
(n=110)
Male sex - no. (%) 53 (56) 67 (61)
Age - yr 70.7 ± 9.6 72.8 ± 9.2
FEV1 - L* 1.1 ± 0.5 1.2 ± 0.5
Percent predicted FEV1* 42.7 ± 15.9 46.7 ± 18.6
GOLD stage – no. (%)#
I (FEV1 ≥ 80% of predicted) 1 (1) 6 (6)
II (FEV1 ≥ 50% of predicted and < 80% of predicted) 32 (34) 30 (27)
III (FEV1 ≥ 30% of predicted and < 50% of predicted) 33 (35) 56 (51)
IV (FEV1 < 30% of predicted) 29 (31) 18 (16)
Smoker - no. (%) 86 (91) 99 (90)
Recent smoker - no. (%) 27 (29%) 36 (33)
Pack years 39.1 ± 22.2 40.4 ± 25.7
Type of exacerbation according to Anthonisen et al. – no. (%)6
Type-1 58 (61) 76 (69)
Type-2 37 (39) 34 (31)
Duration of AECOPD, days 5.4 ± 3.8 6.1 (4.2)
PaO2, mmHg 70.1 ± 16.4 66.8 ± 10.2
PaCO2, mmHg 43.9 ± 11.5 41.7 ± 7.7
ICS treatment prior to admission - no. (%) 74 (80) 88 (87)
SCS treatment prior to admission - no. (%) †
31 (33) 30 (28)
Values are listed as mean ±SD unless stated otherwise. FEV1= forced expiratory volume in 1
second. GOLD= Global initiative for chronic obstructive lung Disease. AECOPD= acute exacerbation
of COPD. ICS= inhaled corticosteroids. SCS= systemic corticosteroids.
* Last recorded value in a stable state prior to admission # Based on the last recorded value in a stable state.
†Oral steroid treatment
during two weeks preceding admission.
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Table 2. Microbiological analysis and baseline PCT and CRP levels of 243
exacerbations.
Characteristics Doxycycline
(n=114)
Placebo
(n=129)
Bacterial presence on admission – no. (%) 71 (62) 71 (55)
H. influenzae 40 (35) 40 (31)
S. pneumonia 21 (18) 28 (21)
M. catarrhalis 20 (18) 24 (19)
Pseudomonas spp. 4 (4) 3 (2)
H. parainfluenzae 5 (4) 1 (1)
S. aureus 2 (2) 2 (2)
E. coli 1 (1) 1 (1)
Enterobacteria 0 (0) 1 (1)
X. matophilia 1 (1) 0 (0)
S. marcescens 0 (0) 1 (1)
M. pneumonia* 1 (1) 2 (2)
C. pneumonia* 0 (0) 2 (2)
PCT, µg/L - mean ±SD 0.16 ± 0.42 0.10 ± 0.19
PCT , µg/L - median (IQR) 0.06 (0.04-0.11) 0.05 (0.04-0.09)
CRP, mg/L - mean ±SD 53.3 ± 61.1 56.4 ± 74.6
CRP, mg/L - median (IQR) 30.0 (8.0-83.5) 23.0 (6.5-76.5)
*Serologic tests were used for the diagnosis of M. pneumoniae and C. peumoniae
infection. PCT= serum procalcitonin. CRP= serum C-reactive protein.
Table 3. Clinical success and cure for different levels of procalcitonin and C-reactive protein at day 10 and day 30.
Marker Clinical success at day 10,
no./total (%)
Clinical cure at day 10,
no./total (%)
Clinical success at day 30,
no./total (%)
Clinical cure at day 30,
no./total (%)
Procalcitonin
<0.1 µg/L 147/183 (80) 119/183 (65) 112/183 (61) 93/183 (51)
0.1 - 0.25 µg/L 23/38 (61) 14/38 (37) 16/38 (42) 10/38 (26)
>0.25 µg/L 10/22 (45) 9/22 (41) 7/22 (32) 6/22 (27)
p-value <0.001 0.001 0.006 0.005
C-reactive protein
≤5 mg/L 38/42 (90) 31/42 (76) 27/42 (64) 22/42 (52)
6 – 50 mg/L 84/112 (76) 66/112 (59) 67/112 (60) 53/112 (47)
>50 mg/L 61/89 (64) 45/89 (51) 41/89 (46) 34/89 (38)
p-value 0.005 0.041 0.068 0.243
Table 4. Open label antibiotic therapy for different levels of procalcitonin and C-
reactive protein. Marker
Procalcitonin Overall, no./total (%) Doxycycline, no./total (%) Placebo, no./total (%)
<0.1 µg/L 32/183 (17) 7/83 (8) 25/100 (25)
0.1 - 0.25 µg/L 10/38 (26) 5/17 (29) 5/21 (24)
>0.25 µg/L 11/22 (50) 6/14 (43) 5/8 (63)
C-reactive protein
≤5 mg/L 3/42 (7) 1/16 (6) 2/26 (8)
6 – 50 mg/L 23/112 (21) 7/53 (13) 16/59 (17)
>50 mg/L 27/89 (30) 10/45 (22) 17/44 (39)
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Figure 1. Trial profile.
Shows the screening, enrolment, random assignment and follow-up of patients.
367 Subjects were screened
265 Subjects underwent randomization
128 Subjects were assigned to receive doxycycline
137 Subjects were assigned to receive placebo
5 Had violations 5 Did not meet eligibility criteria
102 Were excluded 13 Refused to participate 89 Did not meet eligibility criteria
2 Had violations 1 Did not meet eligibility criteria 1 Withdrew consent after first dose
114 Included in analysis
129 Included in analysis
6 Did not provide paired serum samples
9 Did not provide paired serum samples
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Figure 2. Scatterplot of serum procalcitonin and serum C-reactive protein at day 1 (15 cases are outside the plot).
Additional grid lines indicate the cut-off values.
Figure 3. Boxplots of serum procalcitonin (A) and C-reactive protein (B) at day 1 in the presence and absence of
potential bacterial pathogens.
Figure 4. ROC curves for procalcitonin and C-reactive protein at day 1 as predictors of clinical success at day 10 (A and
B) and day 30 (C and D). AUC= area under the curve.
Figure 5. The treatment effect of doxycycline at day 10 (A) and day 30 (B) for different levels of procalcitonin, C-reactive
protein (CRP) at day 1 and the highest CRP value of day 1 and day 2#. *P values and P values for interaction were
corrected for within-patient clustering.
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References
1. Murray CJ, Lopez AD. Evidence-based health policy--lessons from the Global Burden of Disease Study. Science
1996;274(5288):740-743.
2. Seemungal TA, Donaldson GC, Bhowmik A, et al. Time course and recovery of exacerbations in patients with
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161(5):1608-13.
3. Fletcher CM, Peto R, Tinker CM, et al. Natural history of chronic bronchitis and emphysema. Oxford: Oxford
University Press;1976.
4. White AJ, Gompertz S, Stockley RA. Chronic obstructive pulmonary disease . 6: The aetiology of exacerbations
of chronic obstructive pulmonary disease. Thorax 2003;58(1):73-80.
5. Ram FS, Rodriguez-Roisin R, Granados-Navarrete A, et al. Antibiotics for exacerbations of chronic obstructive
pulmonary disease. Cochrane Database Syst Rev 2006; 19: CD004403.
6. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic obstructive
pulmonary disease. Ann Intern Med 1987;106(2):196-204.
7. World Health Organization (WHO). WHO report on infectious disease: overcoming antimicrobial resistance.
Geneva: WHO, 2000.
8. Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial
infection: a systematic review and meta-analysis. Clin Infect Dis 2004;39(2):206-17.
9. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized,
controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007;131(1):9-19.
10. Hurst JR, Donaldson GC, Perera WR, et al. Use of plasma biomarkers at exacerbation of chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2006;174(8):867-74.
Page 17 of 28
Copyright © 2010 American College of Chest Physicians at Vrije Universiteit, Medical Library on October 6, 2010chestjournal.chestpubs.orgDownloaded from
19
11. Weis N, Almdal T. C-reactive protein--can it be used as a marker of infection in patients with exacerbation of
chronic obstructive pulmonary disease? Eur J Intern Med 2006; 17(2): 88-91.
12. Gompertz S, O'Brien C, Bayley DL, et al. Changes in bronchial inflammation during acute exacerbations of
chronic bronchitis. Eur Respir J 2001;17(6):1112-9.
13. Dev D, Wallace E, Sankaran R, et al. Value of C-reactive protein measurements in exacerbations of chronic
obstructive pulmonary disease. Respir Med 1998; 92(4): 664-7.
14. Daniels JM, Snijders D, de Graaff CS, et al. Antibiotics in Addition to Systemic Corticosteroids for Acute
Exacerbations of COPD. Am J Respir Crit Care Med 2010;181:150-7.
15. Chow AW, Hall CB, Klein JO, et al. Evaluation of new anti-infective drugs for the treatment of respiratory tract
infections. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis
1992;15:S62-S88.
16. Isenberg, H. D. 1992. Clinical microbiology procedures handbook. American Society for Microbiology,
Washington, D.C.
17. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility
and limitations. Crit Care Med 2008;36(3):941-52.
18. Niederman MS. Biological markers to determine eligibility in trials for community-acquired pneumonia: a focus
on procalcitonin. Clin Infect Dis 2008;47(Suppl 3):S127-32.
19. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003;111(12):1805–12.
20. Bozinovski S, Hutchinson A, Thompson M, et al. Serum amyloid A is a biomarker of acute exacerbations of
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177(3):269-78.
21. Rohde G, Borg I, Wiethege A, Kauth M, Jerzinowski S, An Duong Dinh T, Bauer TT, Bufe A, Schultze-
Werninghaus G.Inflammatory response in acute viral exacerbations of COPD. Infection 2008;36(5):427-33.
22. Sethi S, Wrona C, Eschberger K, et al. Inflammatory profile of new bacterial strain exacerbations of chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177(5):491-7.
Page 18 of 28
Copyright © 2010 American College of Chest Physicians at Vrije Universiteit, Medical Library on October 6, 2010chestjournal.chestpubs.orgDownloaded from
20
23. McCrory DC, Brown C, Gelfand SE, et al. Management of acute exacerbations of COPD: a summary and
appraisal of published evidence. Chest 2001;119(4):1190-209.
24. Saint S, Bent S, Vittinghoff E, et al. Antibiotics in chronic obstructive pulmonary disease exacerbations. A meta-
analysis. JAMA 1995;273(12):957-60.
25. van der Eerden MM, de Graaff CS, Vlaspolder F, Bronsveld W, Jansen HM, Boersma WG. Evaluation of an
algorithm for switching from IV to PO therapy in clinical practice in patients with community-acquired
pneumonia. Clin Ther 2004;26(2):294-303.
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DOI 10.1378/chest.09-2927; Prepublished online June 24, 2010;Chest
Lutter, Henk M. Jansen and Wim G. BoersmaJohannes M.A. Daniels, Marianne Schoorl, Dominic Snijders, Dirk L. Knol, René
to antibiotic therapy in acute exacerbations of COPDProcalcitonin versus C-reactive protein as predictive markers of response
October 6, 2010This information is current as of
http://chestjournal.chestpubs.org/content/early/2010/06/23/chest.09-2927Updated Information and services can be found at:
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