Refl ection and Reaction
http://infection.thelancet.com Vol 7 August 2007
Meta-analysis of procalcitonin for sepsis detection
In a meta-analysis on the accuracy of an insensitive
procalcitonin assay, Benjamin Tang and colleagues
found that the assay failed to diff erentiate sepsis from
other non-infectious causes of systemic infl ammatory
response syndrome (SIRS) in critically ill patients.1
Based on our experience,2–8 we believe this meta-
analysis deserves several comments, clarifi cations, and
First, circulating procalcitonin is a peptide of only
114 aminoacids, lacking the N-terminal dipeptide
alanine-proline.3 Other functions of procalcitonin
that are more important than participation in calcium
homeostasis are pivotal roles in the metabolic and
infl ammatory host response to microbial infections.
Administration of procalcitonin to septic hamsters
with peritonitis doubled their death rate.9,10 Conversely,
treatment with antiserum reactive against calcitonin
precursors increased survival in monomicrobial and
polymicrobial sepsis even when the animals were
moribund. At the same time, circulating calcium levels
remained within the normal range.3
Second, by including only 18 of 672 published studies
(less than 3%), Tang and colleagues made a selection
bias probable, which argues against a comprehensive
review of the literature. Accordingly, several other meta-
analyses in critically ill patients have drawn opposite
Third, any observational study and meta-analysis
investigating the diagnostic accuracy of a given marker
is biased by the choice of the gold standard. The
aetiology of a presumed bacterial cause of fever cannot
be detected in 50–80% of patients with suspected
bloodstream infections.2 Thus, a gold standard to
diff erentiate infectious from non-infectious causes
in patients with SIRS does not exist, and therefore all
observational studies are prone to a potential bias.
This cannot be resolved by meta-analysing a limited
selection of inherently fl awed observational studies.
Fourth, the authors state: “Investigators were
contacted for further study details if needed”.
Unfortunately, we were never contacted. Parameters of
diagnostic accuracy depend on the cut-off levels applied.
The likelihood of a bacterial infection increases gradually
with increasing procalcitonin levels; obviously, the
sensitivity and specifi city of this blood marker depend
on the cut off applied. The reported levels of the cut-off
to calculate diagnostic accuracies were very variable in
the observational publications considered for this meta-
analysis. Sepsis is merely a syndrome and optimum cut-
off ranges for procalcitonin are likely to depend on the
origin of infection. Cut-off ranges have to be calculated
by multilevel likelihood ratios and adapted to diff erent
settings and types of infection.
Fifth, we do agree that a biomarker must be part
of, rather than in preference to, a clinical assessment.
Tang and colleagues suggest that the additive value
of procalcitonin to supplement a clinician’s bedside
assessment should be evaluated. This analysis has been
done repeatedly and procalcitonin improves the clinical
diagnosis of sepsis in critically ill patients13 and patients
with community-acquired pneumonia.8
Finally, the potential to change clinical decision
making is, indeed, the most important performance
measure for a biomarker. Therefore, randomised
intervention studies have to be done in which the
antimicrobial therapy is guided by a biomarker and
in which clinical outcome is the primary measure of
effi cacy. If the patient recovers without antibiotics,
there is no serious bacterial illness. For procalcitonin,
and only for this marker, this observation has been
shown in four intervention trials enrolling more
than 1250 patients with respiratory tract infections,
including comorbid, critically ill, and septic patients.
Procalcitonin guidance reduced antibiotic use in
243 patients with lower respiratory tract infections by
almost 50%.4 Procalcitonin-guided antibiotic duration
was shortened by 55% (from 12·9 days to 5·8 days)
in more than 300 patients who mostly had severe
community-acquired pneumonia.6 Long-term safety
was shown with a similar readmission rate between the
procalcitonin-guided and control groups over 6 months
in more than 200 acute exacerbations of chronic
obstructive lung disease.7 In primary care, procalcitonin
guidance safely reduced antibiotic exposure by 75%5
(Müller et al, unpublished data). Similar fi ndings were
also reported in meningitis, another critical illness.14
Therefore, all intervention studies successfully
validated the superiority of procalcitonin guidance over
a standard management without any excess of adverse
outcome and fewer antibiotic-related side-eff ects. In
Refl ection and Reaction Download full-text
http://infection.thelancet.com Vol 7 August 2007 499
this context, the fi ndings and conclusion of the meta-
analysis by Tang and colleagues seem dubious. Used
appropriately, procalcitonin clearly improves clinical
decision making in and outside the intensive care unit.
The time has arrived to move beyond the observational
reporting and meta-analysing of diagnostic accuracies
for procalcitonin. Specifi c cut-off ranges should be
proposed and more intervention studies done to
really tackle the existing vicious cycle of diagnostic
uncertainty, antibiotic overuse, and emerging multi-
*Beat Müller, Mirjam Christ-Crain, Philipp Schuetz
Department of Internal Medicine, University Hospital Basel,
Petersgraben 4, CH-4031 Basel, Switzerland
BM has served as a consultant and received payments from Brahms to attend
meetings; he received research support and fulfi lled speaking engagements. All
other authors declare that they have no confl icts of interest.
1 Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for
sepsis diagnosis in critically ill patients: systematic review and meta-
analysis. Lancet Infect Dis 2007; 7: 210–17.
MÜller B, Prat C. Markers of acute infl ammation in assessing and
managing lower respiratory tract infections: focus on procalcitonin. Clin
Microbiol Infect 2006; 12 (suppl 9): 8–16.
Becker KL, Nylen ES, White JC, Muller B, Snider RH Jr. Procalcitonin and the
calcitonin gene family of peptides in infl ammation, infection, and sepsis: a
journey from calcitonin back to its precursors. J Clin Endocrinol Metab 2004;
Meta-analysis of procalcitonin for sepsis detection
We read with great interest Benjamin Tang and
colleagues’ meta-analysis regarding the accuracy of
biomarker procalcitonin for sepsis diagnosis.1 Tang and
colleagues argued that they did not include investigations
that estimated the accuracy of procalcitonin towards the
clinical condition septic shock “since these conditions
were usually recognised by simple clinical criteria”. This
statement is correct, but ironically it also applies to the
condition Tang and colleagues mainly investigate in the
meta-analysis—namely sepsis. Although not always of
great clinical use regarding treatment of the causative
agent, sepsis criteria (in the most used form as systemic
infl ammatory response syndrome [SIRS] plus evidence
of localised infection) are very easy to apply, and it does
not appear relevant to focus on identifying additional
expensive biomarkers for sepsis diagnosis alone.
Conversely, if the biomarker could off er some more
specifi c information on aetiology and/or proposed
treatment and monitoring of treatment eff ect, it
would be attractive. Procalcitonin may off er some of
this information regarding infections caused by a wide
spectrum of bacteria, and to a lesser degree on Candida spp
infections and malaria, but only if measurements are made
according to the best documented method, that is daily
Since clinical investigations have mainly focused
on accuracy of a single measurement of procalcitonin
to assess sepsis, less focus has been placed on its
usefulness to identify and monitor the course of bacterial
infections.2,4 Procalcitonin plasma levels do not increase in
viral infection,2 and only to a lesser degree in severe fungal
infection.5 Conversely, procalcitonin levels increase rapidly
while systemic bacterial infection is progressing, either
because of lack of source control, lack of antimicrobial
spectrum, or both. Other conditions that might cause
transient increases in procalcitonin levels include clinical
4 Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Eff ect of procalcitonin-
guided treatment on antibiotic use and outcome in lower respiratory tract
infections: cluster-randomised, single-blinded intervention trial. Lancet
2004; 363: 600–07.
Briel M, Christ-Crain M, Young J, et al. Procalcitonin-guided antibiotic use
versus a standard approach for acute respiratory tract infections in primary
care: study protocol for a randomised controlled trial and baseline
characteristics of participating general practitioners [ISRCTN73182671].
BMC Fam Pract 2005; 6: 34.
Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of
antibiotic therapy in community-acquired pneumonia: a randomized trial.
Am J Respir Crit Care Med 2006; 174: 84–93.
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: 9–19.
MÜller B, Harbarth S, Stolz D, et al. Diagnostic and prognostic accuracy of
clinical and laboratory parameters in community-acquired pneumonia.
BMC Infect Dis 2007; 7: 10.
Nylen ES, Whang KT, Snider RH Jr, Steinwald PM, White JC, Becker KL.
Mortality is increased by procalcitonin and decreased by an antiserum
reactive to procalcitonin in experimental sepsis. Crit Care Med 1998; 26:
10 Wagner KE, Martinez JM, Vath SD, et al. Early immunoneutralization of
calcitonin precursors attenuates the adverse physiologic response to sepsis
in pigs. Crit Care Med 2002; 30: 2313–21.
11 Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Procalcitonin as a
diagnostic test for sepsis in critically ill adults and after surgery or trauma: a
systematic review and meta-analysis. Crit Care Med 2006; 34: 1996–2003.
12 Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin
and C-reactive protein levels as markers of bacterial infection: a systematic
review and meta-analysis. Clin Infect Dis 2004; 39: 206–17.
13 Harbarth S, Holeckova K, Froidevaux C, et al. Diagnostic value of
procalcitonin, interleukin-6, and interleukin-8 in critically ill patients
admitted with suspected sepsis. Am J Respir Crit Care Med 2001; 164:
14 Marc E, Menager C, Moulin F, et al. Procalcitonin and viral meningitis:
reduction of unnecessary antibiotics by measurement during an outbreak.
Arch Pediatr 2002; 9: 358–64 (in French).