1. 54 | December 2014 Healthcare EXECUTIVE
W
orldwide sepsis
is a major cause
of morbidity and
mortality. The ACCP/SCCM
defined sepsis as systemic
inflammatory response caused
by infection. In simple words,
“sepsis arises when the body’s
response to an infection damages
its own tissues and organs.” It can
lead to complications like shock,
multi-organ failure, and death,
particularly if not identified early.
Mortality occurs in one-third to
one-half of all sepsis patients.
In developing countries, sepsis
accounts for 60-80 percent of
all deaths. Every few seconds,
someone in the world dies of
sepsis.
Sepsis is a consequence of
infection that is difficult to
predict, diagnose, and treat.
Patients who develop sepsis
have an increased risk of
complications and death and
face higher healthcare costs with
longer treatment.
Challenges in
Diagnosis of Sepsis
However, the major challenge
remains as how to prove that
there is infection? Culture best
identifies it but in only about
30 percent of patients with
sepsis. Moreover, false positivity
of cultures further complicates
the situation. Clinical signs of
sepsis, such as fever, tachycardia,
and leucocytosis, are
DIAGNOSTIC
DOSSIER
Procalcitonin in Sepsis:
Utility or Futility?
Procalcitonin (PCT) is an extensively well studied and sensitive sepsis biomarker,
efficient in guiding clinicians with antibiotic decision, writes
Dr. Sutirtha Chakraborty
Figure 1 Available evidence concerning PCT in different infections
derived from observational and randomized-controlled intervention
studies (Ref: Scheutz et al. BMC Medicine 2011)
non-specific and overlap with
signs of systemic inflammatory
response syndromes (SIRS)
of non-infectious origin
making detection of sepsis a
clinical challenge. Thus, delay
in diagnosis and treatment
of sepsis is responsible for
increased mortality.
Clinical utility of
Procalcitonin
To prove the presence
of bacterial infection,
serum biomarkers like
Procalcitonin (PCT)
are considered useful.
It is the prohormone
of calcitonin, released
into the circulation of
patients in response
to bacterial infection.
PCT is an extensively
well studied sepsis
biomarker for clinical
use. A major advantage
of PCT compared to
other biomarkers, is
its early and rapid
increase in response to
bacterial infections and
sepsis. Among all sepsis
markers, only PCT has
achieved universal use
throughout developed Europe
in the last decade. High PCT
concentrations are commonly
found in bacterial infection, in
contrast to much lower levels in
viral infection. PCT levels also
show a trend with the clinical
severity of sepsis, severe sepsis
and septic shock.
Although PCT is virtually
undetectable (less than 0.1 ng/ml)
in healthy individuals, elevated
serum PCT concentrations are
not always specific for bacterial
sepsis. Many studies have linked
elevated PCT to SIRS, localized
bacterial infection, autoimmune
disease, burns, severe trauma,
surgery, pancreatitis, as well
as viral, parasitic, and fungal
infections.
In spite of these challenges,
PCT has some other obvious
clinical advantages like:
1) Improved accuracy of early
clinical sepsis diagnosis
2) Can be used to assess the
effectiveness of sepsis
treatment

2. Healthcare EXECUTIVE December 2014| 55
3) Role in antibiotic
stewardship.
For respiratory tract
infection in ICU patients with
baterial sepsis and post-operative
infections, randomized-controlled
studies have shown the efficacy
of using PCT algorithms to
guide antibiotic decisions.
PCT guided antibiotic therapy
leads to significant reduction
of the length of antibiotic
therapy. However in order to
judiciously use it for assessment
of therapeutic effectiveness
and antibiotic stewardship,
serial measurements of PCT
are needed. Surviving sepsis
campaign: international
guidelines (2012) suggest that
PCT measurements can be used
for the sepsis diagnosis and to
discontinue antibiotic therapy
Figure 2 The two phases of sepsis: Phase 1, a hyper-inflammatory phase is characterized by
SIRS. This may resolve or the patient may progress to what is called severe sepsis. In Phase 2
there is evidence of compensatory anti-inflammatory response syndrome (CARS) with immune
suppression and multiple organ dysfunction (Reference: Faix JD, Crit Rev Clin Lab Sci. 2013)
in patients who initially looked
septic, but have no subsequent
evidence of infection.
Global trends in PCT
use
PCT was approved for use
in Europe much earlier than
in the U.S., which may explain
the increased acceptance there.
Additionally, the BRAHMS PCT
(now Thermo Fisher) assay
is available through multiple
vendors internationally (through
a licensing agreement with
BRAHMS). In the U.S., there
are only a limited number of
manufacturers that offer PCT;
there are often times a barrier
to adoption as budget-conscious
hospitals may not want to bring
in an additional system for a
single test.
However, in developing nations
the major hindrance to PCT
adoption is cost although its use
is gradually becoming popular.
PCT in Antibiotic
Stewardship
Around 50 percent of
antibiotic use in in-patient setting
is often inappropriate or not
required. Usually viruses are
the cause of acute bronchitis,
but despite this as much as
80 percent of patients are
prescribed antibiotics. Also
the length of antimicrobial
treatment for most infections
has been poorly studied and
it is likely that treatment
durations are inappropriately
long. The appropriate use of
antibiotics is essential because
they might compromise patient
safety through drug side effects,
increased antibiotic resistance,
and collateral risks such as
Clostridium diffiicile-associated
diarrhea. PCT has been
extensively evaluated as a
biomarker to assist the clinician
in the diagnosis and treatment of
bacterial infection. PCT has been
studied most rigorously for lower
respiratory tract infections and
sepsis and its use is associated
with decreased antimicrobial
usage without worsening of
clinical outcomes. (References:
John JF et al Clin Infect Dis.
1997, PRORATA Trial, Lancet.
2010;375:463-74)
Cost effectiveness of
PCT testing
One of the biggest criticisms
for PCT testing has been cost.
But studies have shown that PCT
is a cost-effective biomarker in
the overall sepsis management.
Heyland and colleagues (2011)
evaluated the economic and
clinical impact of PCT guided
antibiotic therapy. The authors
reviewed 5 intensive care unit
based randomized controlled
trials that compared PCT guided
antibiotic treatment versus
the usual care of a septic ICU
patient (n = 947). The combined
results confirmed the reduction
in antibiotic exposure in the
PCT arm with no influence on
mortality as compared to the
control group.
Nobre et al. have hypothesized
that a shorter antibiotic course,
shorter length of stay in ICU, and
shorter hospitalization in general,
achieved by the PCT- guided
treatment, would clearly off-set
the cost of PCT testing.
Challenges in PCT
testing & future
directions
The negative predictive value
of PCT as a marker of bacterial
infection is very high and hence
it is very useful to rule out sepsis
particularly in ED and critical
care settings. Nevertheless,
falsely low PCT levels can be
seen during the early course or

3. 56 | December 2014 Healthcare EXECUTIVE
localized state of an infection.
PCT can identify bacterial sepsis
and risk stratifies the clinical
course but it cannot identify
the causative organism or its
antibiotic sensitivity/resistance
pattern. The future needs highly
sensitive PCT assays, so that
subtle changes of PCT at very
low concentrations can
be monitored, increasing
the sensitivity of the test and
thus the safety of patients.
Major clinical decisions
regarding antibiotic stewardship
are taken in the PCT range of
0.25 – 0.50 ng/mL. Thus accuracy
and reproducibility at such low
range of the analyte is of great
clinical importance. PCT has the
ability to be the “Troponin of
Bacterial Sepsis” provided such
“high sensitive” assays can be
developed by the IVD industry.
Key Principles of PCT
Interpretation
Interpret in the clinical
context of the patient
Patients with septic shock
should not have antibiotics
withheld based on normal PCT.
Patients with mild elevations
in PCT who exhibit no signs or
symptoms of infection may be
closely monitored with serial
measurements.
Serial measurements are
preferred and provide
more useful information
Patients very early in the onset
of infection may have a normal
PCT value. Patients who have
persistently normal PCT levels
are unlikely to have bacterial
infection. Patients with other
inflammatory events such as
major surgery who have steadily
decreasing PCT levels often do
not need antibiotics.
Consider the dynamics of
the disease
PCT needs to be clinically
used taking into consideration
the dynamics of the infective
process. Patients with rising
PCT suggest that there is a lack
of control of the infection. Also
patients with severe infections
(bacteremic pneumonia) will
generally take longer time for
PCT levels to normalize.
Be aware of conditions
which may affect PCT
levels
PCT rise is triggered by
non-infective conditions like
severe stress, trauma, heat stroke
etc. Thus PCT should not be
requested in the first 48 hours of
a major surgery. Similarly PCT
should not be used in neonates in
the first 72 hours of birth.
Conclusions
Like any biomarker, PCT
is not perfect and has some
significant limitations. Moreover,
it is an expensive biomarker with
costs significantly higher than
CRP, blood counts etc. Hence, it
cannot be recommended as the
single definitive test for sepsis
diagnosis, but rather it must be
interpreted in context of medical
history, physical examination,
microbiological assessment
and other relevant laboratory
parameters. Nevertheless,
PCT use has the evidence base
of several high quality large
clinical trials making it one of
the strongest contenders of the
sepsis biomarker arena.
Dr. Sutirtha Chakraborty,
Chief Consultant,
Department of Clinical
Biochemistry,
Peerless Hospital & B. K. Roy
Research Center,
Kolkata.
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