seems to be a general marker of inflammation
rather than specific for infection.
Biomarkers panels are another approach to
increase the diagnostic accuracy. Measurement of
a single biomarker may not be adequate to reflect
the complex pathophysiology of sepsis. Therefore,
some studies combined several biomarkers to
a panel, which resulted in a better separation of
sepsis and non-infectious systemic inflammation
than one biomarker alone. 10 However, it is
currently unclear which combination of
biomarkers is most appropriate.
Pathogen detection
Another option to diagnose sepsis is to directly
identify the underlying pathogen. The results of
microbiological samples currently do not play
a role in the treatment decisions of patients
with suspected sepsis because results of
microbiological samples may only be available up
to 72 hours after sampling. Furthermore, blood
culture is only positive in 30% of the patients with
sepsis. This shortcoming of culture-based
pathogen detection causes a diagnostic dilemma
because guidelines recommend that adequate
antimicrobial therapy should be initiated as soon
as possible.
Pathogen detection based on multiplex
polymerase chain reaction (PCR), which detects
specific sequences of bacterial and fungal
ribosomal RNA in the blood, might offer a
solution to this problem 11 because results of a PCR
may theoretically be available within one working
day. Several systems are commercially available
which have been investigated regarding their
accuracy to predict positive blood cultures.
In general, multiplex PCR produces twice as many
positive results than a single set of blood cultures,
which still leaves more than half of the septic
patients with a negative PCR. A meta analysis
of 34 studies calculated a pooled sensitivity for
combined bacteraemia and fungaemia of 0.75
and a combined specificity of 0.92. 12 Better results
have been reported for the detection of
fungaemia alone (sensitivity 0.95, specificity
0.92). 13 Indeed, antifungal therapy based on
PCR-based detection of fungi improved outcome
of patients after bone-marrow transplantation.
However, such studies in the critical care setting
are missing.
The method is limited by the fact that only
pathogens of the assay’s PCR target list can be
discovered and identification of antibiotic
resistance is very limited (that is, methicillin-
resistant staphylococci, vancomycin-resistant
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enterococci). Thus, PCR-based pathogen detection
cannot replace culture-based diagnosis and would
therefore significantly increase costs. Some
studies on cost effectiveness exist but results are
inconclusive. Data on the application of the PCR
into clinical practice revealed an average time to
result of 24 hours which significantly exceeds the
expected eight hours. 14 Faster availability of the
results would need 24 hours a day/seven days
a week coverage of technicians and equipment.
Instead of directly detecting pathogens in the
blood sample, other techniques focus on faster
pathogen detection in the blood culture. Several
methods have been introduced into clinical
practice and some of them have the potential to
reach the time to result of PCR. 15 These methods
do however need a positive blood culture as a
prerequisite. In this context, MALDI-TOF (matrix-
assisted laser desorption/ionisation time-of-flight
mass spectrometry) is a very promising method.
Introduction of MALDI-TOF together with an
antibiotic stewardship programme resulted in
a shorter time to appropriate antimicrobial
therapy. 16 More such studies are needed to
evaluate the impact of diagnostic methods
on the care of patients with sepsis.
Conclusions
There is currently no biomarker or biomolecular
technique available that alone allows a rapid and
reliable discrimination between sepsis and other
causes of systemic inflammation. Thus, diagnosis
and initiation of therapy remains a clinical
decision by assessing the patient’s history,
possible symptoms of infection, and development
of acute organ dysfunction. Still, biomarkers can
aid and shorten this clinical decision process
when the limitations of biomarkers are taken into
account. PCT is currently the most investigated
biomarker for this purpose and the only
biomarker that has been integrated into
treatment algorithms. CRP and IL-6 are inferior
to PCT for the diagnosis of sepsis in most of the
studies but also less well investigated. Likewise,
PCR-based pathogen detection might reduce the
time to prescription of an appropriate
antimicrobial therapy but cannot rule out the
presence of infection when negative. Currently,
the improvement in time to pathogen detection
by bimolecular techniques is a promising way to
aid the physician in the prompt prescription of
appropriate antimicrobial therapy. There is a lack
of clinical studies on the incorporation of new
diagnostic approaches into improved clinical
algorithms for the management of sepsis.
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