Interleukin-6
Interleukin (IL)-6 is directly induced by the
primary cytokines of sepsis; tumour necrosis
factor (TNF) and IL-1. IL-6 is the most rapid
biomarker as it reaches peak levels within two
hours after the infectious stimulus. Because this
biomarker persists much longer in the
bloodstream than TNF and IL-1, and it is closely
linked to the systemic inflammatory response
during sepsis, IL-6 seems to be predestined for the
diagnosis of sepsis. Serum IL-6 levels are closely
related to the severity and outcome of sepsis in
patients and levels decrease in patients where the
infection is controlled. However, large prospective
studies to investigate the performance of this
biomarker are missing. Available studies show
conflicting results about the ability to accurately
identify patients with sepsis. As true for other
biomarkers of sepsis, major surgery and major
trauma can induce the release of IL-6 without
presence of infection. The role of IL-6 as sepsis
in healthy humans, sepsis causes a massive
release of PCT into the bloodstream within
4–12 hours of onset of infection. PCT levels are
associated with outcome; patients with septic
shock present the highest PCT serum
concentrations (4–45ng/ml) while patients with
uncomplicated lower respiratory tract infections
have PCT levels between 0.1 and 0.5ng/ml. A
meta-analysis including 3244 surgical and medical
patients from 30 studies calculated a sensitivity
of 0.77 and a specificity of 0.79 to discriminate
sepsis from non-infectious causes of sepsis. 5 Thus,
PCT is a very useful marker in the early diagnosis
of sepsis. Because of its high sensitivity for most
prevalent types of infections, PCT is widely
acknowledged as a highly sensitive biomarker
to aid in the diagnosis and ruling out of bacterial
sepsis, with a high negative predictive value
above 95%. 6 However, there are many relevant
conditions where PCT can be elevated when
infection is not present, such as cardiac arrest,
trauma, severe surgery, and some autoimmune
diseases. It is noteworthy that patients with
medullary thyroid carcinoma present high PCT
serum concentrations of ≥100ng/ml independent
of aninfectious disease. PCT is currently the most
investigated biomarker for early sepsis diagnosis
and can aid the clinician well in this respect.
PCT serum concentrations decrease with
a half-life of about 24 hours when the infection
is sufficiently treated. It has been shown that in
contrast to constantly increased levels, adequately
decreasing PCT levels are associated with an
improved outcome. Several studies have therefore
addressed the question whether PCT can be used
to identify the appropriate time to finish
antimicrobial therapy. Indeed, PCT-guided
treatment algorithms resulted in a significant
reduction in duration of antimicrobial therapy
without harming the patients. 7 These studies were
mainly performed in community acquired lower
respiratory tract infections. Some smaller studies
addressed this question in the critical care setting
on patients with severe sepsis and septic shock.
Although these studies delivered promising
results it is currently unclear whether a PCT
algorithm can be safely and efficiently applied
in this patient population.
Lactate
Lactate levels in circulation can be used as
a marker for systemic tissue hypoperfusion in
patients with circulatory shock. Lactate is usually
cleared by the liver and the kidneys, and the
normal blood lactate concentration in unstressed
patients is 1–1.5mmol/l. In patients suffering a
shock or hypoperfusion, lactate levels are often >
2mmol/l, and levels >4mmol/l indicate the need
for urgent admission to the ICU and resuscitation.
Elevated lactate levels are associated with
increased mortality in sepsis. Monitoring the
patient’s lactate levels enables monitoring of
disease progression and gives vital information
on the severity of the disease and the treatment
efficacy.
Lactate levels should be measured within three
hours of admission and repeated within six hours
if elevated, as recommended by the Surviving
Sepsis Campaign guidelines. 1 Lactate and PCT are
complementary biomarkers for the detection of
sepsis and septic shock.
biomarker remains to be established. Recently,
a study on a larger cohort of neonates and infants
showed a good diagnostic accuracy for diagnosing
sepsis in a paediatric population. 8
New
biomolecular
methods and
biomarkers
should be future
tools to aid the
prompt diagnosis
of sepsis
25
HHE 2018 | hospitalhealthcare.com
Other biomarkers
The soluble triggering receptor expressed on
myeloid cells-1 (sTREM-1) is a member of the
immunoglobulin superfamily, which is
upregulated on phagocytes after exposure to
bacteria and fungi and then released into body
fluids. High sTREM-1 levels are associated with
a poor outcome. Clinical data for this biomarker
are still limited but available studies report a
diagnostic accuracy for differentiating sepsis from
non-infectious causes of inflammation which is
similar to PCT (sensitivity 0.79, specificity 0.8). 9
However, other inflammatory diseases as well as
pancreatitis without infection may affect
sTREM-1-levels. Therefore, sTREM-1 seems to be
an interesting biomarker for the diagnosis of
sepsis but larger studies are warranted.
Soluble urokinase plasminogen activator
receptor (suPAR) appears in the blood and
other body fluid after it is cleaved from the
membrane of immune cells. High suPAR levels
of greater than 12ng/ml are associated with
a poor outcome. However, current data do not
support the application of suPAR as a biomarker
for the diagnosis of sepsis as this protein