CLINICAL CONTROVERSIES

Procalcitonin as a Sepsis Biomarker

Opposing authors provide succinct, authoritative discussions of controversial issues in emergency medicine.
Authors are provided the opportunity to review and comment on opposing presentations. Each topic is
accompanied by an Editors Note that summarizes important concepts. Participation as at authoritative
discussant is by invitation only, but suggestions for topics and potential authors can be submitted to the section
editors.

Editors Note: Procalcitonin has been promoted as an

effective biomarker for patients with suspected sepsis, but
it is unclear whether assessing procalcitonin levels leads to
improved patient outcomes. In this Clinical Controversies
series, our discussants present the pros and cons of using
procalcitonin to identify and manage patients with
suspected sepsis.

PROCALCITONIN: AN EFFECTIVE SCREENING

TOOL AND SAFE THERAPEUTIC
DECISIONMAKING AID FOR EMERGENCY
DEPARTMENT PATIENTS WITH
SUSPECTED SEPSIS
Philipp Schuetz, MD, MPH; Beat Mueller, MD
Medical University Department, Internal Medicine and
Emergency Medicine, Kantonsspital Aarau, Aarau,
Switzerland
Todays standard sepsis denition is based on the
long-established recognition that the host response is an
important aspect of the sepsis syndrome. Unfortunately,
the systemic inammatory response syndrome criteria have
been less useful to diagnose sepsis than anticipated, lacking
sensitivity, specicity, and ease of clinical application.1 Had
the host-response biomarker procalcitonin been available
by then, it would certainly have been preferred over the
WBC count as the laboratory-based systemic inammatory
response syndrome criterion, considering procalcitonins
advantages, outlined below. Although not a perfect
sepsis biomarker, procalcitonin is currently the best
such biomarker in regard to diagnosis, therapeutic
guidance, and risk stratication. Unlike any other sepsis
markers, numerous clinical studies have documented that
procalcitonin-guided sepsis care results in cost-effective
and targeted management of patients. Several arguments
support its use in daily clinical practice.
First, because of its regulation, procalcitonin is
more specic toward bacterial infections than other
inammatory biomarkers. Procalcitonin is up-regulated by
microbial toxins and certain proinammatory mediators
318 Annals of Emergency Medicine

(eg, interleukin-1b, tumor necrosis factor-a, interleukin-6)

and down-regulated as these substances subside during
recovery. Conversely, procalcitonin expression is attenuated
by cytokines typically released during viral infection (eg,
interferon-g).2 By agging the presence and tracking the
status of systemic bacterial infection, procalcitonin
measurements aid in determining bacterial sepsis risk
and course, as well as bacterial sepsis treatment efcacy.3,4
Second, procalcitonin is helpful in identifying sepsis and
bacteremia risk. A 2007 meta-analysis including 17
observational sepsis studies totaling greater than 2,000 patients
found a high discriminatory value of procalcitonin (area under
the curve 0.84) for bacteremia, with blood culture as the
reference standard.5 In accordance with a large pneumonia
cohort, low initial procalcitonin levels were estimated to make
bacteremic disease highly unlikely.6 Applying this nding to
decisionmaking about blood culture could substantially cut
the number of negative culture results.6 For patients with
coagulase-negative staphylococcus growth in blood cultures,
low procalcitonin level effectively rules out true bacteremia
and points to culture contamination.7
Third, for patients presenting with systemic inammatory
response syndrome, procalcitonin level differentiates true
infection from other causes with high diagnostic accuracy. A
recent meta-analysis including 30 high-quality observational
studies totaling greater than 3,200 patients found
procalcitonin to have an overall area under the curve of 0.85
to differentiate sepsis versus systemic inammatory response
syndrome in different settings.8 Results were similar for
medical, surgical, or pediatric patients, with sensitivities and
specicities of approximately 75% to 80%. Despite
heterogeneity in underlying sepsis studies, these results
illustrate that procalcitonin is the most promising
biochemical marker for sepsis diagnosis.
Fourth, procalcitonin is the only widely available
biomarker that improves choices about initiation and
duration of antibiotic treatment in patients with respiratory
infections. Interventional evidence demonstrates that in
mostly septic patients with pneumonia or other respiratory
infection, procalcitonin protocols9 led to signicant
Volume 66, no. 3 : September 2015

Clinical Controversies

diminution in antibiotic (over)exposure. Protocols using

serially measured procalcitonin to guide early antibiotic
treatment discontinuation resulted in sharp reductions
(30% to 70%) in antibiotic courses. A recent individual
patient data meta-analysis including greater than 4,200
patients found that antibiotic exposure decreased from
(median) 8 days to 4 days in procalcitonin arms versus
control arms. Mortality in procalcitonin arms was similar,
and treatment failure risks were signicantly lower
compared with when procalcitonin was not applied to
antibiotic-related decisionmaking.3,10 These studies led to
procalcitonins inclusion in the current sepsis guidelines,
which suggest that a low procalcitonin measurement will
assist clinicians in discontinuing empiric antibiotics when
no evidence of infection is found.11
Fifth, procalcitonin has prognostic implications
associated with clinical outcome. Procalcitonin level
performed better than WBC count or C-reactive protein
(CRP) level in detecting serious bacterial infection
among children with fever of no apparent source. A US
study found an approximately 90% negative predictive
value for sepsis mortality when procalcitonin level
decreased by greater than or equal to 80% within 72
hours of ICU admission.12 When procalcitonin level did
not decrease or even increased, positive predictive values
for mortality were approximately 36% to 48%. The high
prognostic value of procalcitonin level in identifying
patients at high risk for adverse outcomes was also found
in a large Danish study.13 Although antibiotic therapy
escalation in patients with persistently increased
procalcitonin level did not decrease mortality in this
study, this likely illustrates the limitations of current
sepsis treatment rather than a limitation in the
prognostic ability of the test.
Sixth, an individual patient data meta-analysis found
procalcitonin-guided care to be cost-effective.14 Although
initial costs of procalcitonin testing are higher compared with
that of older biomarkers such as CRP, procalcitonin-guided
care still results in important cost savings because of improved
patient care and shorter antibiotic courses. Similar cost data are
not available for CRP, lactate, and other infection markers.
Sepsis is not a well-dened disease, but rather a complex
syndrome developing from heterogeneous underlying
infections. Consequently, current sepsis markers have lower
diagnostic performance compared with that of other
diagnostic markers such as troponin and D-dimer used
in other clinical conditions. Instead of evaluating novel
sepsis markers according to their ability to diagnose the
syndrome with the arbitrary sepsis denition established
more than 25 years ago,4 we should focus on the results of

Volume 66, no. 3 : September 2015

comparative efcacy research trials. These trials will

measure whether a potential sepsis biomarker ultimately
improves identication of at-risk patients by assessing
effects on antibiotic exposure and clinical outcomes. As a
diagnostic and prognostic tool, procalcitonin has been put
to the test and the results are encouraging. The converging
crises of increasing resistance and collapse of antibiotic
research need urgent action. More widespread
procalcitonin use in sepsis patients is an evidence-based rst
step to limit prolonged courses of unnecessary
antimicrobials, blunt the further development of
antimicrobial resistance, and cut costs while maintaining
signicant gains achieved in reducing sepsis mortality.
http://dx.doi.org/10.1016/j.annemergmed.2015.03.029

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