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Abstract
The diagnostic use of procalcitonin for bacterial infections remains a matter of debate. Most studies have used ambiguous outcome measures
such as sepsis instead of infection. We performed a systematic review and meta-analysis to investigate the diagnostic accuracy of
procalcitonin for bacteraemia, a proven bloodstream infection. We searched all major databases from inception to June 2014 for
original, English language, research articles that studied the diagnostic accuracy between procalcitonin and positive blood cultures in
adult patients. We calculated the area under the summary receiver-operating characteristic (SROC) curves and pooled sensitivities and
specicities. To minimize potential heterogeneity we performed subgroup analyses. In total, 58 of 1567 eligible studies were included in
the meta-analysis and provided a total of 16 514 patients, of whom 3420 suffered from bacteraemia. In the overall analysis the area
under the SROC curve was 0.79. The optimal and most widely used procalcitonin cut-off value was 0.5 ng/mL with a corresponding
sensitivity of 76% and specicity of 69%. In subgroup analyses the lowest area under the SROC curve was found in
immunocompromised/neutropenic patients (0.71), the highest area under the SROC curve was found in intensive-care patients (0.88),
sensitivities ranging from 66 to 89% and specicities from 55 78%. In spite of study heterogeneity, procalcitonin had a fair diagnostic
accuracy for bacteraemia in adult patients suspected of infection or sepsis. In particular low procalcitonin levels can be used to rule out
the presence of bacteraemia. Further research is needed on the safety and efcacy of procalcitonin as a single diagnostic tool to avoid
taking blood cultures.
Clinical Microbiology and Infection 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.
Keywords: Bacteraemia, diagnostic accuracy, infection, meta-analysis, procalcitonin, sensitivity and specicity
Original Submission: 24 August 2014; Revised Submission: 29 November 2014; Accepted: 20 December 2014
Editor: M. Paul
Article published online: 14 January 2015
Introduction
Infection and the subsequent sepsis syndrome are associated
with morbidity and mortality [1,2]. The fear of undertreatment
leads to the routine collection of specimens for microbiological
CMI
Methods
Search strategy and study selection
We used the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) statement for reporting this systematic review and meta-analysis [41]. A owchart of the
literature search can be found in the Supporting information
(Fig. S1). All prospective and retrospective, original, observational (casecontrol, cross-sectional, cohort and longitudinal)
studies published in English from inception until June 2014 were
considered eligible for inclusion. Studies were screened by title
and abstract and denite inclusion was decided upon after full
text review.
We included studies on adult hospitalized patients suspected
of infection or sepsis, in which bacteraemia with a known
pathogen was conrmed by blood culture and measurement of
procalcitonin levels was performed within 24 hours of inclusion. Studies had to give a detailed description of patient groups
and demographic variables. The comparison of procalcitonin
levels had to be between hospitalized patients with and without
bacteraemia, regardless of clinical symptoms. To be included for
analysis studies had to report the diagnostic accuracy estimates
of procalcitonin for bacteraemia; knowing area under the curve
(AUC), sensitivity, specicity and corresponding p-values. The
475
Clinical Microbiology and Infection 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved, CMI, 21, 474481
476
Reference
Country
Inclusion criteria
Finland
Switzerland
Australia
Hungary
Netherlands
USA
France
China
France
France
Israel
Germany
France
Denmark
Greece
Greece
France
South
Korea
Netherlands
Austria
Austria
South
Korea
Spain
Finland
Finland
South
Korea
South
Korea
Finland
Taiwan
South
Korea
Switzerland
Netherlands
Italy
Spain
Switzerland
Spain
Japan
Netherlands
Portugal
Sweden
Spain
Austria
With
bacteraemia
(n)
Male
(%)
Cut-off
Age
Type of
Assay values,
(years) Department patients Immunocompromised type ng/mL
QUADAS
92
295
123
39
300
108
161
55
60
165
187
44
29
154
115
158
347
147
13
16
12
23
53
14
117
25
9
22
16
15
10
34
28
52
58
84
48
66
71
51
50
58
65
57
58
30
53
50
70
56
8
15
52
48
61
56
60
76
65
53
58
58
83
47
56
61
56
52
33
61
ED
ED
ICU
ICU
Ward
ED
ICU
Mixed
Ward
Ward
ED
Ward
Ward
Ward
Ward
Ward
ED
ED
Medical
Medical
Mixed
Mixed
Medical
Medical
Mixed
Medical
Mixed
Medical
Medical
Medical
Medical
Medical
Medical
Medical
Medical
Medical
No
No
No
Yes
No
No
No
No
No
No
No
Yes
Yes
No
Yes
Yes
No
No
1
2
1
1
1
1
2
1
1
1
1
1
3
2
1
2
2
4
0.4
0.15
3.03
N.A.
N.A.
0.5
0.5
3.1
0.55
0.12
0.5
0.51
0.5
2.19
0.5
1
0.3
0.5
12
12
11
12
12
13
13
12
10
12
13
11
11
13
11
11
13
12
101
132
898
3343
12
55
666
331
68
48
58
59
64
69
67
65
ICU
ED
ED
Mixed
Mixed
Medical
Medical
Medical
No
No
No
No
2
4
3
1
2.44
N.A.
0.5
0.35
12
13
12
12
Febrile neutropenia
Cancer and suspicion for infection
Severe sepsis or septic shock
Febrile neutropenia
104
56
160
286
15
8
69
38
38
63
68
57
58
57
60
39
Ward
Ward
ICU
ED
Medical
Medical
Mixed
Medical
Yes
Yes
No
Yes
1
1
3
0.5
0.36
1.2
0.5
11
12
14
7
252
31
44
54
ED
Medical
No
0.5
Febrile neutropenia
SIRS and suspicion of infection
PCT measurements R
90
155
357
21
48
199
66
60
53
56
77
66
Ward
ED
Mixed
Medical
Medical
Medical
Yes
No
No
2
2
4
0.5
0.38
0.55
11
13
13
200
125
1009
685
925
103
116
581
108
94
61
298
50
27
133
48
73
23
65
131
15
21
19
75
52
60
55
59
59
31
65
38
63
41
51
58
60
65
69
64
73
59
59
66
61
54
47
58
Mixed
ED
Mixed
Ward
ED
Ward
ICU
Mixed
ICU
Ward
Ward
Ward
Mixed
Medical
Mixed
Medical
Medical
Mixed
Mixed
Mixed
Medical
Medical
Medical
Mixed
No
No
No
No
No
No
No
No
No
Yes
Yes
No
1
3
4
6
2
1
4
2
4
6
2
0.5
2.0
0.37
0.36
0.5
0.1
0.38
0.5
17
0.5
0.5
0.35
12
14
13
12
13
11
10
13
12
11
8
13
367
29
194
226
19
281
106
248
558
205
19
13
33
37
7
34
60
30
84
36
52
61
58
65
62
67
57
57
58
48
49
57
69
63
74
64
56
61
65
ED
Mixed
Ward
ED
Mixed
Ward
ICU
ward
ED
ED
Medical
Medical
Medical
Medical
Medical
Medical
Mixed
Medical
Medical
Mixed
No
No
Yes
No
No
No
No
No
No
No
2
1
2
3
5
2
4
2
1
6
0.15
<0.5
0.5
0.45
0.1
1.34
N.A.
0.5
0.5
N.A.
14
11
12
13
12
13
12
13
12
13
46
342
26
55
61
56
48
59
ICU
ED
Mixed
Mixed
No
No
1
2
0.7
0.5
13
13
Greece
Suspicion of catheter-related BSI*
Netherlands SIRS and suspicion of infection
CMI
Study
population
(n)
Clinical Microbiology and Infection 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved, CMI, 21, 474481
Mixed
54
65
120
3420
586
16 514
Febrile neutropenia
Febrile neutropenia
Finland
Germany
China
R*
The mean or median age is provided, if mean/median was not provided, the mean age was manually calculated of the subgroups. Studies in which patients were excluded because of antibiotic use before procalcitonin measurement are marked with
an *. All studies have a prospective study design, retrospective studies are marked with R. Assay type: 1 = Lumitest Brahms, 2 = Kryptor Brahms, 3 = Elecsys Brahms Cobas Analyzer, 4 = Vidas Biomereux, 5 = PCT sensitive Lia Brahms, 6 = Liason
Brahms PCT.
Abbreviations: BSI = bloodstream infection; ED, emergency department; ICU, intensive care unit; PCT, procalcitonin; QUADAS, quality assessment of diagnostic accuracy studies. SIRS, systemic inammatory response syndrome; VAP, ventilatorassociated pneumonia.
12
12 (714)
0.5
4
10
12
Mixed
No
0.5
0.13
0.62
3
1
Medical
Medical
66
57
Medical
52
61
48
19
18
100
53
336
55
52
Ward
Ward
No
ED
Yes
Yes
12
CMI
477
Results
Literature search
The literature search found a total of 1567 articles, of which
1443 studies were excluded because of: written language other
than English (n = 118), age < 18 years (n = 759), in vitro/animal
studies (n = 57) or lack of original data (reviews, meta-analyses,
case reports, editorials, commentaries and letters, meeting
abstracts, poster presentations, n = 509). We performed a full
text review of the 124 articles considered eligible for inclusion,
which resulted in the exclusion of another 66 studies that did
not provide AUC values/sensitivity/specicity (n = 29), did not
study bacteraemia (n = 26), did not compare with nonbacteraemia (n = 4), studied candidaemia (n = 3), used
healthy controls (n = 2), did not provide the procalcitonin level
for bacteraemia (n = 1), or used a longitudinal study design and
analysis (n = 1). The remaining 58 articles were used in the
meta-analysis. The complete reference list containing all
included and excluded studies is presented in the Supporting
information (Appendix S1). Table S1 (see Supporting
information) depicts the 66 studies excluded after full text
review.
Study characteristics and quality assessment
Table 1 provides some details of the included studies. In total,
16 514 patients were included, of whom 3420 had bacteraemia.
There was a slight tendency towards male preponderance. The
average age ranged from 33 to 77 years. Eight studies had a
retrospective and 50 a prospective study design. All 58 studies
provided AUC values, but only 49 studies provided sensitivity
Clinical Microbiology and Infection 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved, CMI, 21, 474481
478
CMI
Pooled
specicity
(95% CI)
I2
Overall (n = 3420)
0.79 76 (7280)
Control group
Non-bacteraemia
0.78 72 (6678)
(n = 1884)
SIRS (n = 931)
0.78 76 (6087)
Local infection and/or
0.84 84 (8087)
sepsis (n = 605)
Immunocompromised/neutropenic
Yes (n = 320)
0.71 66 (5476)
No (n = 3100)
0.79 79 (7583)
Department
ICU (n = 399)
0.88 89 (7994)
Mixed (n = 1009)
0.77 76 (6585)
Ward (n = 587)
0.76 71 (6378)
ED (n = 1425)
0.78 76 (6982)
Study type
Prospective (n = 2507)
0.79 76 (7180)
Retrospective (n = 913) 0.79 78 (6686)
69 (6472)
74 (6976)
66 (4482)
55 (4763)
78 (7183)
65 (6065)
68
66
71
68
(5777)
(5776)
(6477)
(6175)
77% 54 <0.001
31% 501 <0.001
90% 433 <0.001
77% 285 <0.001
69 (6473)
68 (5678)
Analysis
2/
Q
standard and vice versa, reporting of uninterpretable/intermediate test results and the explanation of withdrawals.
PCT+
PCT
Prevalence
Sensitivity
Specicity
PPV
NPV
BSI+
BSI
7
3
10
26
64
90
33
67
100
10%
71%
71%
21%
95%
Emergency department
BSI+
BSI
BSI+
BSI
6
2
8
29
63
92
11
1
12
28
60
88
35
65
100
8%
76%
68%
17%
97%
BSI, blood stream infection; NPV, negative predictive value; PCT, procalcitonin; PPV, positive predictive value, +, positive test, , negative test.
Clinical Microbiology and Infection 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved, CMI, 21, 474481
39
61
100
12%
89%
68%
28%
98%
CMI
Discussion
This study evaluates the diagnostic accuracy of procalcitonin for
bacteraemia in different subgroups of adult hospitalized patients
suspected of infection or sepsis. Overall, at a cut-off level of 0.5
ng/mL, procalcitonin had a fair diagnostic accuracy for bacteraemia with an area under the SROC curve of 0.79. The pooled
AUC values of procalcitonin for the diagnosis of bacteraemia in
subgroups ranged from 0.71 to 0.88, with sensitivities ranging
from 66% in immunocompromised/neutropenic patients to
89% in ICU patients and specicities ranging from 55% in bacteraemia versus local infections to 78% in immunocompromised/neutropenic patients. Based on these results low
procalcitonin levels in particular can be used to rule out the
presence of bacteraemia.
Two previous meta-analyses on the diagnostic accuracy of
procalcitonin for sepsis had contradicting conclusions while
having comparable results [12,18]. Tang et al. concluded that
there was no clear use for procalcitonin in diagnosing sepsis
(area under the SROC curve of 0.78, sensitivity of 71% and
specicity of 70%) [12]. However, their inclusion may be biased
by specically excluding sepsis originating from certain types of
common infection sites [12]. In contrast, Wacker et al.
concluded that procalcitonin was useful for the diagnosis of
sepsis (area under the SROC curve 0.85, sensitivity 77%,
specicity 79%) [18]. They included studies on adult and paediatric patients comparing sepsis to SIRS. Sepsis, however, was
dened as clinically suspected or microbiologically proven
infection [18]. Two other meta-analyses studying the diagnostic
use of procalcitonin for bacterial infection found an area under
the SROC curve ranging from 0.82 to 0.89, sensitivity 8388%,
specicity 8183% [28,34]. Both analyses had comparable results but again contradicting conclusions. Simon et al. compared
C-reactive protein and procalcitonin in a meta-analysis on the
diagnostic accuracy in either proven or suspected bacterial
infection, favouring procalcitonin to be used in clinical practice
[28]. In contrast, Lee et al. contended that procalcitonin should
479
not be used as single diagnostic tool for infection [34]. However, their conclusion was based on only four studies on the
diagnostic accuracy of procalcitonin for bacterial infection in
elderly patients [34]. As far as we know there is only one
previous meta-analysis on the diagnostic accuracy of procalcitonin for bacteraemia with an area under the SROC curve of
0.84, sensitivity 76% and specicity 70% [40]. This study
concluded that widespread use of procalcitonin is not recommended because of the moderate diagnostic accuracy of procalcitonin to predict bacteraemia [40]. This conclusion was
based on 17 included studies, of which not all contained bacteraemia as the primary endpoint. Even though previous metaanalyses showed similar results, their conclusions differ,
possibly because of differences in interpretation of clinically
useful AUC values. In contrast to our study, the abovementioned meta-analyses only used a small selection of the
available literature or used sepsis syndrome and not microbiologically documented infection as their endpoint. Our study
shows that procalcitonin can be used in the diagnostic process
of bacteraemia regardless of its clinical symptoms. As shown in
Table 3, low procalcitonin levels can be used to rule out the
presence of bacteraemia in different clinical settings.
This meta-analysis has several limitations. There is some
evidence for a concentrationresponse relation between procalcitonin levels and probability of infection and disease severity
[51]. The denition of our primary outcome measure, bacteraemia, does not acknowledge such a concentrationresponse
relation. Only a minority of the studies in this meta-analysis
formally excluded patients treated with antibiotics before inclusion [23,24,5256]. We cannot be certain that false-negative
results, due to possible antibiotic treatment before inclusion,
led to underestimation of the effect. Even though the effect size
is only fair (area under the SROC curve 0.79) its direction is
positive in almost all studies, in spite of heterogeneity. High
values of I2 are to be expected because of the variation in cutoffs used in the different included studies and sensitivity and
specicity both depend on cut-offs. To homogenize the results
we attempted to use the sensitivities and specicities corresponding with the cut-off value closest to 0.5 ng/mL if multiple
cut-off values were given. Other potential factors that could
have contributed to heterogeneity are variety in inclusion
criteria, underlying diseases, comorbidities, clinical course and
treatment before inclusion, variety in the control groups used
for comparison against bacteraemia, department of sample
collection, and differences in test performance of the various
procalcitonin assays. To reduce the inuence of these factors
on heterogeneity we performed analyses in the supposedly
more homogeneous patient subgroups. As expected, substantial heterogeneity remained in most subgroups. A Funnel plot
analysis based on the standard error of the natural logarithm of
Clinical Microbiology and Infection 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved, CMI, 21, 474481
480
Transparency declaration
None to declare.
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Clinical Microbiology and Infection 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved, CMI, 21, 474481