Procalcitonin vs C-Reactive Protein as Predictive Markers of Response to Antibiotic Therapy in Acute...

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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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1

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

([email protected])

Marianne Schoorl2 ([email protected])

Dominic Snijders, MD1 ([email protected])

Dirk L. Knol, PhD3 ([email protected])

René Lutter, PhD4,5

([email protected])

Henk M. Jansen, MD, PhD5 ([email protected])

Wim G. Boersma, MD, PhD1

([email protected])

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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mailto:[email protected]


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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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105x76mm (600 x 600 DPI)

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96x81mm (600 x 600 DPI)

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96x77mm (600 x 600 DPI)

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87x85mm (600 x 600 DPI)

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89x87mm (600 x 600 DPI)

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89x87mm (600 x 600 DPI)

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89x87mm (600 x 600 DPI)

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201x105mm (600 x 600 DPI)

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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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