Review

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Diagnostic and prognostic

markers in sepsis
Expert Rev. Anti Infect. Ther. 11(3), 265–275 (2013)

Jean-Louis Vincent* Sepsis is a common and serious complication in intensive care unit patients. An important factor
and Marjorie Beumier in optimizing survival rates in septic patients is the ability to start treatment early in the course
of disease; there is, therefore, a need for accurate diagnostic tests. In recent years, there has
Department of Intensive Care, Erasme
Hospital, Université libre de Bruxelles, been a move away from the rather vague and nonspecific signs that were previously used to
Route de Lennik 808, 1070 Brussels, diagnose sepsis towards the possible adjunctive role of biomarkers. Many biomarkers have been
Belgium proposed and assessed clinically, but none alone is specific enough to definitively determine
*Author for correspondence:
Tel.: +32 2 555 3380
diagnosis. The future direction of research is most likely a greater focus on the use of panels or
Fax: +32 2 555 4555 combinations of markers with clinical signs. Some biomarkers may also be useful for prognosis
jlvincen@ulb.ac.be and guiding therapy. Here, the authors will review our changing approaches to sepsis diagnosis
and discuss some of the markers that seem most relevant at the present time.

Keywords: biomarkers • C-reactive protein • procalcitonin • sepsis

Sepsis is a frequent and serious complication in
intensive care unit (ICU) patients. Despite many
years of active research to find an ­effective and
specific therapy, the only real treatment still relies
on organ system support and effective antimicro-
bial eradication with antibiotics and/or surgical
intervention. An important factor in optimizing
survival rates in these patients is the speed of diag-
nosis, allowing rapid, effective intervention [1–3] .
However, diagnosing sepsis is not always straight-
forward, particularly in c­ ritically ill patients who
often have complex ongoing disease processes.
Many of these patients will also recently have
received antimicrobial therapy that can render
microbial cultures negative; several observational
studies have reported negative culture results in
as many as 30–40% of ICU patients with severe
sepsis [4–6] . Even when cultures are positive,
results can take several days to become available,
thus slowing the diagnostic process.
The traditional approach to sepsis diagnosis
was based on clinical signs and symptoms (or
markers) of sepsis, such as fever, tachycardia and
tachypnea, supported by relevant microbiological
data. More recently, biological laboratory mark-
ers (biomarkers) have been used, ranging from
the relatively simple white blood cell count and
C-reactive protein (CRP) to more complex bio-
markers, such as procalcitonin (PCT) or cytokine
levels and (to some extent) ­coagulation markers.
Importantly, all of these markers are more help-
ful at ruling out than at ruling in an infection.
Virtually, all patients in the ICU have some
inflammatory response associated with fever at
one time or another, but these responses do not
all require antibiotic administration. Hence, sep-
sis biomarkers could be helpful to decrease the
use of antibiotics or unnecessary diagnostic tests,
such as CT scans, to identify a source of sepsis.
In addition to aiding diagnosis, biomarkers of
sepsis can potentially be used for prognostication
to predict the development of organ dysfunction,
to guide antibiotic therapy and to evaluate the
response to therapy [7] . Many biomarkers have
been proposed over the years [7] , but there is lit-
tle consensus on which is best and the exact role
of individual markers remains uncertain. Many
of the biomarkers that have been proposed are
mediators of the inflammatory response to sep-
sis, that is, they are essential players in the devel-
opment and promulgation of the syndrome of
sepsis; others are merely present as a consequence
of the sepsis process [8] . Because of the complex-
ity of the sepsis response, different markers may
have different roles in terms of diagnostics,
prognostics and therapeutic guidance; some may
even express different elements at different times
during the sepsis response in the same patient.
Biomarker development represents an impor-
tant and ongoing area of research within the
global sepsis field. Here, the authors will p ­ rovide
an overview of how the biomarker field has devel-
oped over the years, moving from clinical signs of
sepsis to individual biomarkers and into multiple

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 Review Vincent & Beumier
biomarker panels. The authors will discuss some of the established
and newer markers of sepsis and conclude with a section on how
this field will likely evolve in the near future.
The past: signs of sepsis
Clinical signs of sepsis have been recognized for many hundreds of
years, with Galen and Celsus describing the four signs of peripheral
vasodilatation (rubor), fever (calor), pain (dolor) and redness or
increased capillary permeability (tumor). Much more recently, Bone
et al. described the sepsis syndrome as consisting of clinical evi-
dence of infection plus presence of hypothermia (temperature <96°F
[35.5°C]) or hyperthermia (greater than 101°F [38.3°C]), tachycar-
dia (>90 beats/min), tachypnea (>20 breath/min) and the presence
of at least one end-organ demonstrating inadequate perfusion or
dysfunction, expressed as poor or altered cerebral function, hypox-
emia (PaO2 <75 mmHg on room air), elevated plasma lactate above
1.5–2 mEq/l or oliguria (urine output <30 ml/h or 0.5 ml/kg body
weight/h) [9] . Later, these typical clinical signs (fever, tachycardia,
tachypnea) together with raised white blood cell count became
known as the systemic inflammatory response syndrome (SIRS)
criteria [10] , which have been widely used to support a diagnosis of
sepsis when combined with the presence of known or suspected
infection. The SIRS criteria have prognostic value, as ICU and
hospital mortality rates increase with increasing numbers of SIRS
criteria, being higher in patients who are also infected [11] . However,
this is true for any abnormality in medicine. Moreover, none of the
four criteria is specific for sepsis, and this concept is, therefore, of
little diagnostic use. For example, fever affects many ICU patients
at some point during their ICU stay, but only about 35–50% of
them will have sepsis [12–15] ; other common causes of fever in this
population of patients include cerebral hemorrhage, postoperative
fever, trauma, acute myocardial infarction, pancreatitis or adverse
drug reaction [13,14] . Similarly, tachypnea and tachycardia are com-
mon findings in nonseptic ICU patients, and can be present even in
normal, healthy individuals, for example when exercising. A raised
white blood cell count has been used for many years to indicate the
presence of infection, but again is nonspecific and may be raised in
other conditions, such as pancreatitis, acute myocardial infarction,
pulmonary edema and following surgery or trauma. In 2001, an
International Sepsis Definitions Conference revisited sepsis defini-
tions and concluded that the SIRS criteria were too nonspecific and
suggested a longer list of signs of sepsis, including typical hemo-
dynamic alterations, signs of organ dysfunction and presence of
inflammatory markers [16] . Nevertheless, although the presence of
several of these signs of sepsis provides a strong indication that sepsis
is possible and is associated with increased mortality, more specific
markers are needed to confirm diagnosis.
The present: biomarkers of sepsis
In the early 1980s, cardiologists were faced with an interesting
problem. New thrombolytic agents had been developed to treat
patients with acute myocardial infarction, but they had a narrow
time window and were only effective if administered rapidly after
disease onset. So rapid diagnosis was key, but the tests available
at the time took several hours to give a result. New more rapidly
266
available biomarkers were needed, and this search led to the devel-
opment of assays for cardiac troponin [17] , which has become a
diagnostic and prognostic marker of acute myocardial infarction.
The need for such biomarkers in sepsis was also recognized, and
the literature began to see increasing numbers of papers related
to potential biomarkers. Indeed, as the pathophysiology of sepsis
began to be unraveled, multiple potential candidate (bio)markers
were proposed and tested. More than 170 different compounds
have been suggested as potential biomarkers of sepsis [7] ; some
have been fairly extensively studied, such as CRP and PCT, others
have been more recently suggested and less well studied. To list
all the biomarkers that have been suggested would be virtually
impossible, so we will discuss some of the most relevant at the
present time (a more extensive list is provided in Box 1).
C-reactive protein
CRP was first described in the early 1930s [18] , and CRP levels
are widely used as a relatively nonspecific marker of inflamma-
tion. Many studies have now been published that demonstrated
increased CRP levels in patients with sepsis [19–21] . As an acute
phase protein, however, CRP levels are increased to some extent
in most conditions associated with inflammation, including rheu-
matoid arthritis, Crohn’s disease, acute myocardial infarction
and pancreatitis, to list but a few [22] . As such, CRP is a very
nonspecific marker of sepsis. Nevertheless, it is a cheap and widely
available test and when levels are raised in a patient with signs
suggestive of sepsis, it provides useful supporting evidence. In
112 ICU patients, Póvoa et al. reported that a serum CRP concen-
tration of >8.7 mg/dl had a sensitivity of 93.4% and a s­ pecificity
of 86.1% for infection [19] ; the combination of CRP >8.7 mg/dl
and temperature >38.2°C increased the specificity for infection
­diagnosis to 100%.
Because baseline CRP levels are often raised as a result of comor-
bid chronic inflammatory conditions, changes in concentrations
over time are more useful than single values [23–25] . Póvoa et al. [23]
showed that CRP concentrations increased over time in infected
patients, but remained unchanged in non-infected patients. A
maximum daily CRP variation of greater than 4.1 mg/dl predicted
nosocomial infection with a sensitivity of 92.1% and a specificity
of 71.4%; moreover, when combined with a CRP concentration
greater than 8.7 mg/dl, the sensitivity and specificity increased to
92.1 and 82.1%, respectively. Similarly, as a prognostic marker, a
decrease in CRP level after 48 h was associated with a mortality
rate of 15.4%, while an increased CRP level was associated with
a mortality rate of 60.9% in patients with CRP concentrations
>10 mg/dl on ICU admission (p < 0.05) [24] .
Because CRP levels decrease as sepsis resolves, it has been sug-
gested that levels could be used to guide antimicrobial therapy.
In 50 adult ICU patients with sepsis, Schmit & Vincent [26]
reported that an increase in CRP of at least 2.2 mg/dl in the
first 48 h was associated with ineffective initial antibiotic therapy
with a sensitivity of 77% and a specificity of 67%. Similarly, in
patients with ventilator-acquired pneumonia, serum CRP levels
were significantly lower in patients with appropriate antibiotic
treatment than in those with inappropriate empirical treatment at
Expert Rev. Anti Infect. Ther. 11(3), (2013)
 Diagnostic & prognostic markers in sepsis Review

96 h (10.3 ± 10 mg/dl vs 19.2 ± 14 mg/dl;

Box 1. Some of the many suggested biomarkers that have been
p < 0.05) [27] , and in patients with com-
tested clinically, grouped where possible according to
munity-acquired pneumonia, a less than
pathophysiological role.
60% decrease in CRP levels by 3 days
after admission (odds ratio [OR]: 6.98; • Cytokines: TNF-α, IL-1, -2, -4, -8, -10, -12, -18 and HMGB1
95% CI: 1.56–31.33) was associated with • Receptors: RAGE, TLR4, sTREM and suPAR
an increased risk of having received inap- • Coagulation system: vWF, activated partial thromboplastin time waveform analysis,
propriate empiric antibiotic treatment antithrombin, protein C and thrombomodulin
[28] . However, use of CRP levels to guide • Acute phase proteins: CRP, pentraxin 3 and PCT
therapy has not been tested ­prospectively • Cell surface markers: CD14, CD40, CD64 and mHLA-DR
in adult patients with sepsis. • Apoptosis marker: Gas6
• Endothelial: E-selectin, L-selectin, VCAM-1, VEGF and endocan
Procalcitonin • Miscellaneous: Copeptin, ANP, HSP, lactoferrin, resistin and gelsolin
PCT was described more recently than ANP: Atrial natriuretic peptide; CRP: C-reactive protein; HMGB1: High mobility group box 1; HSP: Heat
CRP and is not routinely measured in all shock protein; PCT: Procalcitonin; RAGE: Receptor for advanced glycation end products; sTREM: Soluble
triggering receptor expressed on myeloid cells-1; suPAR: Soluble urokinase-type plasminogen receptor;
hospital laboratories. PCT levels have been TLR: Toll-like receptor; vWF: von Willebrand factor.
shown to be raised in patients with sepsis
[29,30] and may be particularly useful in distinguishing bacterial this approach on antibiotic utilization in many of these studies
from other forms of infection [31] . In patients with community- [43–47] , with no adverse effects on patient outcomes, not all stud-
acquired pneumonia, PCT values >0.25 µg/l had a sensitivity ies support these findings [48] . Several meta-analyses of studies
of 96% and specificity of 40% for predicting bacteremia [32] . using this approach have also been conducted. Schuetz et al. [49]
Similarly, in patients with febrile urinary tract infection present- recently reported, in a meta-analysis of 14 trials in patients with
ing to the emergency department, PCT values >0.25 µg/l had a acute respiratory infection, that use of PCT to guide initiation
sensitivity of 95% and specificity of 50% for a diagnosis of bacte- and duration of antibiotic treatment was effective in reducing
remia [33] . In patients admitted to the emergency department with antibiotic exposure in these patients without increasing rates of
symptoms of systemic infection, a PCT threshold of 0.15 ng/ml treatment failure or mortality. Another meta-analysis suggested
had a sensitivity of 75%, specificity of 79% and negative predic- that although PCT-guided antibiotic therapy was associated with
tive value of 98% for a diagnosis of bloodstream infection [34] . a reduction in antibiotic usage and reduced costs, an associated
Several studies have suggested that PCT is a more reliable marker 7% increase in hospital mortality could not be excluded [50] .
of sepsis than CRP [35–38] .
Higher PCT levels have been associated with increased mortality Cytokine levels
rates [39,40] . In ICU patients with sepsis, Giamarellos-Bourboulis Various cytokines, key mediators of the sepsis response, have been
et al. [39] reported mortality rates of 25.6% in those with PCT less assessed for their role as biomarkers of sepsis. Serum levels of IL-6,
than or equal to 0.85 ng/ml, but 45.3% in those with PCT greater TNF and IL-8, to mention just a few, have been shown to be
than 0.85 ng/ml (OR for death: 2.404; 95% CI: 1.385–4.171; increased in patients with sepsis [29,51,52] . Raised serum levels have
p = 0.002). As with CRP, PCT levels are raised in other inflamma- also been shown to be associated with development of organ func-
tory conditions, including pancreatitis, acute myocardial infarc- tion and mortality [51,53] . These cytokines are all involved in the
tion and postcardiac surgery. Trends in c­ oncentrations over time inflammatory response to infection, but levels are also increased in
are again of more value than single measurements. Karlsson et al. patients with other inflammatory processes, such as arthritis and
[41] reported that although PCT concentrations did not differ myocardial infarction. Several recent studies have used multiplex
between hospital survivors and nonsurvivors, mortality rates were technology to measure multiple cytokine levels simultaneously.
lower in patients whose PCT concentration decreased by more In a multicenter cohort study of 60 patients with severe sepsis,
than 50% in 72 h than in those in whom levels decreased by less Bozza et al. [54] evaluated the prognostic value of 17 cytokines
than 50% (12.2 vs 29.8%; p = 0.007). Nevertheless, the precise (IL-1β, -2, -4, -5, -6, -7, -8, -10, -12, -13, -17, IFN-γ, granulocyte
role of PCT remains unclear with meta-analyses reporting con- colony-stimulating factor [G-CSF], granulocyte–macrophage
flicting findings. Indeed, one review concluded that ‘Procalcitonin colony-stimulating factor, MCP-1, MIP-1 and TNF-α). Levels
should be included in diagnostic guidelines for sepsis and in clini- of cytokines were correlated with disease severity and develop-
cal practice in intensive care units’ [36] , whereas another published ment of organ dysfunction. IL-1β, -4, -6, -8, MCP-1 and G-CSF
a year later noted that ‘The findings … do not lend support to had good accuracy for predicting early mortality, whereas IL-8
the widespread use of the procalcitonin test in critical care set- and MCP-1 had the best predictive value for 28-day mortality.
tings’ [42] , although differences in the search criteria and ­studies In multivariate analysis, only MCP-1 was independently associ-
included in these meta-analyses may explain these different ated with prognosis (OR for hospital mortality: 1.41; 95% CI:
conclusions. The use of PCT levels to guide antibiotic therapy 1.02–1.93; p = 0.036). In 30 patients with sepsis, Mera et al. [55]
has been tested in several clinical trials in different groups of also measured 17 cytokines and reported that the initial levels of
infected patients. However, despite reported beneficial effects of IL-8 were the most predictive for fatal outcome. Levels of IL-1β,

www.expert-reviews.com 267
 Review Vincent & Beumier
-6, -8, -12, IFN-γ, G-CSF and TNF-α remained high in non-
survivors. In a study of 126 emergency department patients with
SIRS or sepsis, in which levels of 22 cytokines were analyzed, only
soluble IL-2 receptor (sIL-2R) levels were independently associ-
ated with a diagnosis of severe sepsis. IL-1β, sIL-2R and IL-8
levels were independently associated with a diagnosis of septic
shock [56] . However, using principal component analyses and hier-
archical clustering analyses, the authors demonstrated that there
were no typical cytokine profiles associated with a diagnosis of
severe sepsis or septic shock.
Soluble triggering receptor expressed on myeloid cells-1
Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1)
is a member of the immunoglobulin superfamily, the expression
of which is upregulated in the presence of bacteria or fungi [57,58] .
Serum levels of sTREM-1 are increased in patients with sepsis
[59–62] , and several studies have suggested that they are more sensi-
tive and specific for infection than other markers, including CRP
and PCT [59,60] . However, in emergency department patients, the
specificity and sensitivity for diagnosis of sepsis were only 59 and
60%, respectively [63] . In addition, a decrease in sTREM-1 levels
over time was associated with a favorable outcome [58] , suggest-
ing a potential place in following response to therapy. Levels of
sTREM-1 have also been studied in other body fluids. Raised
sTREM-1 levels have been reported in the broncho­a lveolar lavage
fluid of patients with pneumonia [64,65] , and urinary levels have
been associated with early diagnosis of sepsis, disease severity and
prognosis [66] . In logistic regression analysis, urinary sTREM-1
levels were a risk factor for development of acute kidney injury in
patients with sepsis (OR: 1.02; Wald coefficient: 5.246; p = 0.022)
[66] . In a recent study in emergency department patients with sep-
sis who underwent early goal-directed resuscitation, sTREM-1
concentrations were significantly higher at admission and pre-
early goal-directed resuscitation in nonsurvivors than in survi-
vors (514.1 pg/ml [interquartile range: 412.7–1749.5 pg/ml] vs
182.4 pg/ml [interquartile range: 54.3–327.0 pg/ml]; p = 0.001);
PCT and CRP levels were the same in the two groups [67] . In mul-
tivariate regression analysis, sTREM-1 values at admission were
independently associated with poor prognosis (OR for 28-day
mortality: 2.78; 95% CI: 1.116–6.945; p = 0.028).
CD64
CD64 is a membrane glycoprotein, which binds the Fcγ part of
IgG. The expression of CD64 on the neutrophil membrane is
negligible in health, but upregulated in response to proinflamma-
tory cytokines as, for example, in sepsis and other inflammatory
conditions, such as arthritis. Neutrophil CD64 expression has
been reported to have variable sensitivity and specificity for sepsis
diagnosis and prognosis [63,68–71] . In a study of 132 emergency
department patients with fever, 87% of whom had bacterial infec-
tion, the CD4 index was higher in patients with infection than
in those without (3.7 ± 3.2 vs 2.5 ± 2.3; p = 0.03); the area under
the receiver operating characteristic curve (AUROC) for detec-
tion of bacterial infection was 0.66 (95% CI: 0.52–0.8) and for
prediction of survival it was 0.71 (95% CI: 0.57–0.85) [69] . In 163
268
infants with suspected sepsis, the sensitivity and specificity of the
CD4 index using a cutoff of 2.30 were 70 and 62%, respectively;
when combined with an absolute neutrophil count of <7500 or
>14,500 cells/mm3, the sensitivity increased to 95% with a nega-
tive predictive value of 93% [70] . In 293 ICU patients with at
least two SIRS criteria, using a cutoff of 2.2, the CD64 index
predicted bacterial infection with a sensitivity and specificity of
63 and 89%, respectively, and positive and negative predictive
values of 85 and 70%, respectively [71] . In 631 emergency depart-
ment patients with suspected sepsis, the sensitivity of CD4 for
diagnosing sepsis was 66% and the specificity 65% with ­positive
and negative predictive values of 79 and 49%, respectively.
Clot waveform analysis
In patients with sepsis, the optical transmission waveform obtained
during measurement of the activated partial thromboplastin time
is altered, giving a biphasic pattern. The presence of this abnormal
waveform has been used to support a diagnosis of sepsis [72] . In
331 ICU patients, 59.3% of patients with a biphasic waveform on
admission and 45.3% with a biphasic waveform during the total
ICU stay developed sepsis. The sensitivity of the waveform analy-
sis for detection of sepsis was poor, varying between 22 and 55%
at admission and between 48 and 74% during the entire ICU stay,
depending on the threshold value of the slope used. The specificity
for sepsis, however, was good, varying between 92 and 98% at
admission and between 81 and 94% during the total ICU stay [73] .
In 187 patients with SIRS, presence of a biphasic waveform (90%
sensitivity, 92% negative predictive value) was better than PCT
(71% sensitivity, 67% negative predictive value) or CRP (88%
sensitivity, 89% negative predictive value) for diagnosis of severe
sepsis and septic shock [74] . The biphasic waveform on day 3 also
had better specificity (91%) and negative predictive value (98%)
for prediction of 28-day sepsis-related mortality (CRP specific-
ity 57%, negative predictive value 95%; PCT specificity 83%,
negative predictive value 95%) [74] . Combination of an abnormal
waveform plus a PCT level >1 ng/ml on admission to the ICU
was associated with a sensitivity of 79% and specificity of 96%,
with a negative predictive value of 96% [75] .
Growth arrest-specific protein 6
Gas6 is an intracellular vitamin-K dependent protein released
by leukocytes and endothelial cells in response to injury. Gas6
has roles in cell survival (antiapoptotic), proliferation, migration
and adhesion [76,77] . In a matched case–control study, plasma
Gas6 levels were higher in patients with severe sepsis (median:
110 [interquartile range: 75–139] ng/ml) than in those with
organ failure unrelated to infection (median: 85 [56–101] ng/ml;
p = 0.026) and in healthy control subjects (median: 54 [49–68]
ng/ml; p = 0.0001) [77] . In the patients with severe sepsis, Gas6
levels correlated disease severity as assessed using the APACHE
II score (Spearman correlation coefficient: 0.45; p = 0.012) and
the Organ Dysfunction and Infection (ODIN) score (nonpara-
metric test for trend, p = 0.030) [77] . In 232 patients with fever
and suspected infection, Gas6 levels were significantly higher
in patients with sepsis than in controls (healthy blood donors;
Expert Rev. Anti Infect. Ther. 11(3), (2013)
 Diagnostic & prognostic markers in sepsis
p < 0.001); levels were also significantly higher in patients with
severe sepsis than in those with sepsis (p < 0.001) [78] . In 45
ICU patients with septic shock, Gas6 levels correlated with the
Sequential Organ Failure Assessment (SOFA) score (Spearman
rank-order coefficient: 0.37; p = 0.01) and with hepatic function
as assessed by aspartate transaminase concentrations (Spearman
rank-order coefficient: 0.42; p = 0.006) and prothrombin time
(Spearman rank-order coefficient: 0.45; p = 0.02). Gas6 concen-
trations were also higher in patients who required renal support
than in those who did not (median: 76.5 [52–164] pg/ml vs 10.5
[1.5–80.5] pg/ml; p = 0.04). Gas6 levels were also strongly cor-
related with plasma PCT concentrations (Spearman rank-order
coefficient: 0.44; p = 0.005). There were no differences in Gas6
levels among survivors and nonsurvivors [76] .
Angiopoietin
Angiopoietin (Ang)-1 and -2 are endothelial-derived vascular
growth factors that have contrasting roles in endothelial activa-
tion during sepsis: Ang-1 stabilizes the endothelium, whereas
Ang-2 promotes loss of barrier integrity and vascular leak [79] .
Increased levels of Ang-2 have been reported in patients with
severe sepsis compared with those with no evidence of inflamma-
tory response (p < 0.05) [80] . In patients with sepsis, Ang-2 levels
correlated with disease severity as measured by the APACHE
II (r = 0.395; p = 0.007) or SOFA (r = 0.402; p = 0.006) scores
and were higher in nonsurvivors than in survivors (24.9 ng/ml
[21.5–38.0] ng/ml vs 13.5 [8.1–21.6] ng/ml; p = 0.02) [81] . In
a study of 70 patients with severe sepsis, survivors had higher
peak Ang-1 levels (median: 13 vs 10 ng/ml; p = 0.019) and lower
nadir Ang-2 levels (median: 2.8 vs 6.2 ng/ml; p = 0.013) than did
nonsurvivors [79] . Lower Ang-1 levels (<5.5 ng/ml) on admission
were independently associated with an increased risk of death at
28-days compared with higher Ang-1 levels (OR: 0.282; 95%
CI: 0.086–0.93; p = 0.03) [79] . Raised levels of Ang-2 have also
been reported in patients with trauma and after cardiopulmonary
bypass surgery.
Soluble urokinase-type plasminogen receptor
Urokinase-type plasminogen receptor (uPAR) is expressed on var-
ious cell types, including neutrophils, lymphocytes, monocytes,
macrophages and vascular endothelial cells. uPAR is involved in
multiple immunological functions, including migration, adhe-
sion, angiogenesis, fibrinolysis and cell proliferation [82,83] . During
inflammatory disease processes, such as sepsis, uPAR is cleaved
from the cell surface by proteases, releasing a soluble form of
the receptor, soluble uPAR (suPAR). Elevated levels of suPAR
have been reported in patients with sepsis compared with patients
without (on admission, median: 11.05 [1.87–20] ng/ml vs 7.62
[0–20] ng/ml; p < 0.001) [82] . However, in this prospective study
of 273 critically ill patients, 197 of whom had sepsis, the AUROC
for prediction of sepsis was only 0.62, compared with 0.86 for
CRP and 0.78 for PCT. In 151 patients with SIRS and suspected
community-acquired sepsis, 96 of whom had bacterial infections,
the AUROC for diagnosis of bacterial sepsis was 0.50 for suPAR,
0.72 for PCT and 0.81 for CRP, again suggesting that suPAR
www.expert-reviews.com
Review
had lower diagnostic capability than did these other biomarkers
[84] . In an ongoing study in critically ill patients, a cutoff suPAR
value of 5.5 ng/ml had a sensitivity of 75% and a specificity of
72% for diagnosing sepsis (AUROC: 0.75; 95% CI: 0.66–0.83)
[85] . Several studies have suggested that suPAR may be of more
value as a prognostic marker than for diagnosis [82,83,86,87] . In 543
acutely ill medical patients, baseline suPAR levels were signifi-
cantly lower in 30-day (4.97 ng/ml vs 7.31 ng/ml; p = 0.0002) and
90-day (4.87 ng/ml vs 7.29 ng/ml; p < 0.0001) survivors than in
nonsurvivors [87] . Increased suPAR levels remained significantly
associated with 30-day mortality (hazard ratio [HR]: 1.10; 95%
CI: 1.01–1.20) and 90-day (HR: 1.11; 95% CI: 1.04–1.19) after
adjusting for age, sex, CRP levels and the Charlson Score. In a
recent meta-analysis of six studies that had assessed the prognos-
tic role of suPAR, suPAR had better prognostic ability and was
superior in predicting mortality than other commonly used mark-
ers, including CRP, PCT and sTREM-1, although it performed
less well than the SAPS II score [86] . In another recent study,
Giamarellos-Bourboulis et al. developed and validated a mortality
risk prediction rule with four levels of risk, using combinations of
APACHE II values (<17 or >17) and serum suPAR concentrations
(<12 ng/ml or >12 ng/ml). The score had a negative predictive
value of 94.5% in patients with sepsis [88] .
HLA
The above mentioned biomarkers have largely been indicative of
the proinflammatory phase of sepsis, but sepsis is also associated
with an anti-inflammatory state, which, if prolonged, can lead
to immunodepression or so-called immune ‘paralysis’. Monocyte
HLA-DR is part of the major histocompatibility class II antigen
complex. The main role of HLA-DR in infection is in antigen
presentation to T-helper cells resulting in release of proinflamma-
tory cytokines, but in patients with sepsis, this pathway can be
impaired leading to immunodepression [89] . Several studies have
suggested that HLA-DR expression may be indicative of progno-
sis. In an early study in surgical patients with sepsis, Volk et al.
reported a survival rate of 81% in patients with normal monocyte
HLA-DR expression, but only 19% in patients with a persistently
(at least 5 days) reduced HLA-DR expression of <30% [90] . More
recently, in patients with septic shock, Monneret et al. also dem-
onstrated significant differences in HLA-DR expression in sur-
vivors and nonsurvivors; the percentage of monocytes expressing
HLA-DR was reduced in all patients during the first 48 h of septic
shock, but on days 3–4 the percentage increased in survivors but
not in nonsurvivors (43 vs 18%; p < 0.001) [91] . In multivariate
logistic regression analysis, low monocyte HLA-DR expression
(<30%) at days 3–4 was significantly associated with mortal-
ity after adjustment for other confounders with an adjusted OR
of 6.48 (95% CI: 1.62–25.93). In a recent retrospective study,
Trimmel et al. were, however, unable to identify a specific cutoff
value for HLA-DR expression that was correlated with mortal-
ity, raising questions about the value of absolute values for risk
prediction [92] . Supporting this, in patients with severe sepsis, Wu
et al. reported that there were no differences between survivors
and nonsurvivors using a 30% cutoff for HLA-DR expression;
269
 Review Vincent & Beumier
however, a change in monocyte HLA-DR expression of 4.8%
over the first 3 days of ICU admission did allow discrimination
between survivors and ­nonsurvivors with a sensitivity of 89.0%
and a specificity of 93.7% [93] .
The future
Combined panels or scores
Given the complexities of the sepsis response, the different times
at which individual biomarkers are elevated, and the fact that
most, if not all, markers currently available or under research
are also raised in other inflammatory conditions, it is unlikely
that any single marker will ever be of use to diagnose sepsis.
Combinations or panels of biomarkers, potentially combined with
clinical signs and other markers of sepsis, are more likely to be
able to guide diagnosis or treatment, or assist in prognostication
[94] . This approach is already widely used in daily practice as
physicians regularly combine the results of several individual tests
to help diagnose and prognose. However, which combinations
are most predictive and how the different tests can be best com-
bined are challenges for the future. Results from studies assessing
multiplex panels of cytokines have been discussed above [54–56] ;
here we will mention some of the other systems that have already
been proposed.
Peres Bota et al. [95] devised an Infection Probability Score using
logistic regression techniques. The score incorporates four rou-
tinely used signs of sepsis (temperature, heart rate, respiratory
rate, white blood cell count), CRP concentrations and the SOFA
score. Using a cutoff value of 14 points, the Infection Probability
Score had a positive predictive value for infection of 53.6% and
a negative predictive value of 89.5%. Patients with a score of less
than 14 had only a 10% chance of having an infection. Other
groups have similarly developed composite scoring systems for
infection. In a pilot study, neural networks using the levels of
expression of IL-1β, -6, -8, -10, TNF-α, FasL and CCL2 mRNA
correctly predicted development of sepsis in an average of 83%
of patient cases between 4 and 1 days before clinical diagnosis
with high sensitivity and specificity (91 and 80%, respectively)
[96] . Andaluz-Ojeda et al. [97] used a score combining serum levels
of IL-6, -8 and -10, to predict outcome in patients with severe
sepsis or septic shock; the HRs for mortality with the combined
score were two- to three-fold higher than those obtained with the
individual interleukin values. Kofoed et al. [84] reported an area
under the curve for prediction of a bacterial cause of inflammation
was 0.88 (95% CI: 0.81–0.92) for a composite score combining
measures of suPAR, sTREM-1, macrophage migration inhibitory
factor, CRP, PCT and neutrophil count, significantly larger than
the area under the curves of any of the individual markers. Gibot
et al. [98] produced a ‘bioscore’ consisting of plasma concentrations
of sTREM-1 and PCT and the neutrophil expression of CD64.
The bioscore had better predictive value for infection than any
of the biomarkers alone.
Proteomics, genomics & PCR
New proteomic, genomic, multiplex and microarray techniques
are being used to identify potential biomarker candidates that
270
could be used to diagnose, guide therapy or evaluate prognosis in
patients with sepsis, as they are already used in some types of can-
cer [99] . Importantly, these new technologies enable the expression
of multiple proteins or genes to be evaluated simultaneously, mov-
ing us away from the individual biomarker concept into a model
in which patterns or profiles of gene and/or protein expression
are used to identify and follow sepsis. Data are already available
supporting the potential of these techniques. Using microarray
technology with 54,675 transcripts and gene-expression profil-
ing on peripheral blood mononuclear cells, Tang et al. identi-
fied a molecular signature of 138 genes that could differentiate
between patients with sepsis and SIRS, with 91% accuracy in the
development cohort and 80% accuracy in a validation cohort of
critically ill patients [100] . Using similar techniques in an equine
model of sepsis, Sutherland et al. developed a panel of 42 genes
linked to innate and early adaptive immune function/activation
pathways. This panel was shown to discriminate between non-
infected postsurgical patients and patients with sepsis with an
AUROC of 0.92 ± 0.0586 [101] .
Molecular methods based on PCR technology have also been
developed to help in the diagnosis of infection [102] . Blood cultures
take several days to process and in many critically ill patients with
sepsis, cultures will be negative. By being able to amplify specific
regions of bacterial DNA, these PCR probes allow minute traces
of DNA to be detected, providing positive results when tradi-
tional cultures are negative and giving a much more rapid result.
Several such tests are now commercially available in Europe. For
example, SeptiFast (Roche Diagnostics, Mannheim, Germany)
and VYOO (SIRS-LAB, Jena, Germany) enable identification
of 25–41 of the most common bacterial and fungal pathogens;
SepsiTest™ (Molzym, Bremen, Germany) uses an all-pathogen
approach to detect fungemia or bacteremia. In 391 patients with
suspected sepsis, the SeptiFast assay was shown to have better
specificity for pathogen identification (100 vs 94%; p = 0.005)
and a higher positive predictive value (100 vs 75%; p = 0.005)
than blood cultures [103] . In 187 patients with SIRS, sepsis or
neutropenic fever, the SepsiTest had a diagnostic sensitivity and
specificity of 87.0 and 85.8%, respectively, compared with blood
cultures [104] . However, some studies have reported false-negative
or -positive results with these tests [105,106] , and identification of
resistance patterns, an important consideration for appropriate
antimicrobial prescription, is also limited with present assays.
Although these tests may be of use in diagnosing the presence of
infection, further studies are needed to identify whether they can
effectively guide initial antimicrobial therapy with an impact on
patient outcomes.
Expert commentary & five-year view
Sepsis markers are currently more useful to rule out a diagno-
sis of sepsis than to actually identify sepsis, but potential new
markers are being identified all the time. Importantly, as new
biomarkers are developed, there is a need for improved stand-
ardization of assays, so that the usefulness of different markers
can be compared more effectively [107] . The heterogeneous groups
of patients included in different studies also make comparisons
Expert Rev. Anti Infect. Ther. 11(3), (2013)
 Diagnostic & prognostic markers in sepsis Review

difficult. Clearer identification of cutoff

Table 1. Examples of variables that could be used in the PIRO method
points or thresholds for biomarker levels
of staging sepsis.
is also needed. Combination panels of bio-
markers or sepsis scores are likely to replace Feature Clinical Laboratory
individual biomarker levels, but the chal- Predisposing factors Age, immunosuppression, Genetic factors, cellular markers
lenge over the next 5 years will be to deter- comorbidities, alcoholism, (HLA-DR)
mine which variables should be included in drugs
such scores, particularly as recent studies Infection Signs of pneumonia, Chest x-ray, CT scan,
using simultaneous measurement of multi- meningitis, peritonitis, microbiological results, bacterial
ple cytokine levels have not suggested any purpura DNA, endotoxin
predictive benefit over individual levels Response Fever, tachycardia, WBC, CRP, PCT, sepsis markers
[56] . New technologies such as proteomics, tachypnea
genomics, multiplex and PCR will con- Organ dysfunction Circulatory shock, PaO2/FiO2, BUN, creatinine,
tinue to develop, and increasingly complex respiratory failure, oliguria platelet count
mathematical, statistical and analytical BUN: Blood urea nitrogen; CRP: C-reactive protein; PCT: Procalcitonin; WBC: White blood cell.
methods will be needed to extract relevant
information from the vast amounts of data obtained using these is used to stage patients with cancer, with important implications
technologies [99,108] . Studies will be conducted to determine the for directing therapies and predicting outcomes, although again,
impact of these methods on patient-based outcomes and evaluate further study is needed to determine which elements should be
their cost–effectiveness. With continued advances in this field, we included in such a system.
believe that in the not too distant future, physicians will be able
to determine and follow changes in specific ‘inflammatory’ pat- Financial & competing interests disclosure
terns at point-of-care that will indicate the likelihood of a patient The authors have no relevant affiliations or financial involvement with any
developing sepsis, which immunomodulatory therapies should organization or entity with a financial interest in or financial conflict with
be started and how the patient is responding, and the patient’s the subject matter or materials discussed in the manuscript. This includes
likely prognosis. These patterns will be included into a staging employment, consultancies, honoraria, stock ownership or options, expert
system such as the PIRO system (Table 1) [16,109] , to provide a global testimony, grants or patents received or pending, or royalties.
‘sepsis status’ for individual patients, much as the TMN system No writing assistance was utilized in the production of this manuscript.

Key issues
• Accurate and early diagnosis of sepsis may help reduce unnecessary antibiotic therapy and investigative tests and by enabling rapid
treatment can improve outcomes.
• The systemic inflammatory response syndrome criteria for sepsis diagnosis are too nonspecific to be of practical use.
• An ideal biomarker should be easy, rapid and inexpensive to measure, specific to sepsis, present early in the course of disease and
correlated with disease severity.
• Currently available biomarkers are more useful to rule out than to rule in a diagnosis of infection.
• Panels of biomarkers may be of more use than any individual marker for diagnosis of sepsis, but this approach needs further study to
identify which components should be included.

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