SEPSIS BIOMARKERS
UPDATES
DR.MAGDY KHAMES ALY
CRITICAL CARE MEDICINE
ZMH AL BATAYEH
NOV 2017
OBJECTIVES
• Simplifying the understanding of sepsis
biomarkers role.
• Identify the best biomarker for sepsis
diagnosis
• Define the role of each biomarker in sepsis
• Define the best model to diagnose sepsis
early
INTRODUCTION
• Sepsis is one of the most common causes of death
in severely injured patients worldwide. The early
detection of sepsis still has to be solved in clinical
practice.
• The delayed diagnosis often contributes to
inappropriate antimicrobial treatment and
subsequent high mortality.
• Sepsis biomarkers are produced during the host
response to infection.
• Traditional biomarkers are polypeptides and/or
proteins derived from this response.
• Omics-based biomarkers are screening out from
all kinds of molecules of host response while
high-throughout omics technologies are
emerging.
OMICS
Technologies that measure some characteristic of a
large family of cellular molecules, such as genes,
proteins, or small metabolites, have been named by
appending the suffix “-omics,” as in “genomics.”
Omics refers to the collective technologies used to
explore the roles, relationships, and actions of the
various types of molecules that make up the cells of
an organism.
ROLES OF BIOMARKERS
• Diagnosis
–Identifying or ruling out sepsis.
–Identifying patients who may benefit from
specific therapies.
• Follow up the response to therapy.
• Prognosis.
THE PERFECT SEPSIS BIOMARKER
• Should be highly sensitive and specific for sepsis to allow the
differentiation between infectious and non-infectious causes of
inflammation, organ dysfunction and shock.
• Linked to the main underlying processes
–Inflammation
–Coagulation
–Tissue damage
–Tissue repair
• Should be present at the onset or even before the appearance of the
clinical signs of sepsis to have prognostic value.
• Should be easy and safe to measure with low cost for the patients and
for the hospital.
• Should be biologically plausible.
The list of proposed sepsis biomarkers is indeed long.
Nevertheless, only a couple have gained widespread
use.
QUESTIONS TO BE
ANSWERED
• Does the biomarker aid diagnosis?
• Does it provide additional prognostic info?
–For outcome
–For progression/decline
• Better than scoring systems?
THE ROC CURVE
• The ROC curve is a widely used tool for comparing
diagnostic tests.
The curve is constructed by plotting the diagnostic
sensitivity and specificity values for every individual cut-off
on a graph with 1-specificity on the x-axis and sensitivity on
the y-axis.
• The shape of an ROC curve and the area under the curve
(AUC) helps estimate the discriminative power of a
marker. The closer the curve is located to the upper lefthand corner and the larger the AUC, the better the marker
is at discriminating between septic and non-septic patients.
• A perfect biomarker has an AUC of 1, whereas a nondiscriminating marker has an area of 0.5.
Kofoed K, Andersen O, Kronborg G, et al. Use of plasma C-reactive protein, procalcitonin,
neutrophils, macrophage migration inhibitory factor, soluble urokinase-type plasminogen
activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination
to diagnose infections: a prospective study. Crit Care 2007; 11: R38.
Displayed are ROC curves comparing:
•
Soluble urokinase-type plasminogen activator receptor (suPAR),
• Soluble triggering receptor expressed on myeloid cells (sTREM)-1,
• Macrophage migration inhibitory factor (MIF),
• Neutrophil count,
•
Procalcitonin (PCT),
• C-reactive protein (CRP),
• Combined three-marker and Six-marker tests for detection of
bacterial versus non-bacterial causes of systemic inflammation.
• The six-marker combination is the best-performing marker
model (ROC-AUC 0.88)
C-REACTIVE PROTEIN (CRP)
• Acute phase protein
• Synthesized in liver
• IL-6 (and IL-1 and TNFα) stimulate synthesis
• Binds bacterial polysaccharide/ chromatin
– Activates the classical complement pathway
– Increase the immune inflammatory response in
bacteria infection
CLINICAL SIGNIFICANCE (CRP)
Diagnostic use:
• CRP is used mainly as a marker of inflammation.
• Normal concentration in healthy human serum is between 5 and 10
mg/L, increasing with aging
• Higher levels are found in late pregnant women, mild inflammation
and viral infections (10–40 mg/L),
active inflammation, bacterial infection (40–200 mg/L),
severe bacterial infections and burns (>200 mg/L).
Follow/up treatment:
• Measuring and charting CRP values can prove useful in determining
disease progress or the effectiveness of treatments.
Limitations
CRP is a non‐specific marker of inflammation so doe
s not indicate the
organ or organs affected.
CRP measurements can only be used to assess cardi
ovasular risk status if they are made in the absence o
f acute inflammation.
CLINICAL SIGNIFICANCE
PROCALCITONIN
Diagnostic:
• To aid in the diagnosis and risk stratification of bacterial sepsis.
• To aid in the diagnosis of renal involvement in children with urinary
tract infection.
• To aid in distinguishing bacterial from viral infections, including
meningitis.
• To monitor therapeutic response to antibacterial therapy and reduce
antibiotic exposure.
• To aid in the diagnosis of systemic secondary infection after surgery
and in severe trauma, burns, and multiorgan failure.
• To aid diagnosis of infected necrosis and associated systemic
complications in acute pancreatitis.
Prognostic:
Proposed applications of serum procalcitonin measurement
include the following:
• To aid the choice and timing of the initiation of antibiotic
treatment (Procalcitonin Algorithm)
• To assist with elucidating prognosis of severe localized
infections (eg, pneumonia)
• To aid with elucidating prognosis of critically ill patients
with systemic infection
• Predicting the need of antibiotic treatment in sepsis and to
shorten the duration of antibiotics required
• Use as independent predictor of graft failure late after
renal transplantation
PROCALCITONIN (PCT)
• REFERENCE VALUES (EXCEPT NEWBORN)
SIGNIFICANTLY LOWER IN LEUKOPENIC
PATIENTS
•
< 0.05ng/ml
•
0.5-2ng/ml
• Healthy individuals
Probability of sepsis is low,
local infection possible
• Grey zone, recheck 6-12hrs
later
•
>2ng/ml
• Probability of sepsis is high
LIMITATIONS
• Procalcitonin, although useful in bacterial sepsis, has no
value in the assessment of fungal or viral infections and
shows no response to intracellular microorganisms (ie,
Mycoplasma) or in local infections with no systemic
response.
• Similar to CRP, clinical conditions associated with high
baseline procalcitonin levels include burns, major
surgery, and systemic inflammatory processes.
• To date, the use of procalcitonin, both as an indicator of
severe infection and predictor of antibiotic
choices/duration, has been center-specific, with
insufficient data from multicenter/multinational studies
to support its use as a routine laboratory marker in
clinical practice.
PROCALCITONIN VERSUS
C-REACTIVE PROTEIN
• Studies investigating the use of PCT and CRP have found
the diagnostic performance of CRP and PCT to be rather
similar. With regard to diagnosing bacteremia in particular,
PCT have shown excellent diagnostic ability; this is in
accordance with the suggested notion that PCT is superior to
CRP in diagnosing systemic infection.
• What makes PCT particularly interesting is that several
well-designed studies have proven that algorithms based on
PCT concentrations as the main guide can shorten the length
of antibiotic treatment and decrease the use of antibiotics.
SOLUBLE CD14 SUBTYPE
PRESEPSIN
• In 2004, a new biomarker sCD14-subtypes (presepsin) was found and its
value was shown in the diagnosis and evaluation of sepsis
PRESEPSIN
• In 2004, a new biomarker sCD14-subtypes (presepsin)
was found and its value was shown in the diagnosis and
evaluation of sepsis.
• CD14 acts as a co-receptor (along with the Toll-like
receptor TLR 4 and MD-2) for the detection of bacterial
lipopolysaccharide (LPS).
• By activating a proinflammatory signaling cascade on
contact with infectious agents, CD14 has a role as a
recognition molecule in the innate immune response
against microorganisms.
• During inflammation, plasma protease activity
generates soluble CD14 (sCD14) fragments. One of
them, called sCD14 subtype (sCD14-ST), or presepsin.
PRESEPSIN VS PCT
In comparison with PCT
Diagnostic accuracy:
• The best diagnostic cutoff for presepsin was 600
pg/ml. At that level, sensitivity and specificity were
78.95% (95% CI, 69.4 to 86.6)
• The best diagnostic cutoff in terms of sensitivity and
specificity for PCT was 0.18 ng/ml, corresponding to
89.47% sensitivity (range, they actually were 95% CI
81.5% to 94.8%) and 75.90% specificity (range,
65.3% to 84.6%)
PRESEPSIN VS PCT
• The receiver operating characteristic (ROC) curves
were designed including those patients with a
definitive diagnosis of sepsis or severe sepsis/septic
shock.
• The results were significant for both biomarkers. The
areas under the curve (AUCs) calculated from the
ROC curve were 0.701 (95% confidence interval (CI),
0.63 to 0.77; P < 0.001,) for presepsin and 0.875
(95% CI, 0.82 to 0.92; P < 0.001) for PCT,
respectively. The difference between the two AUCs
was significant (P < 0.001)
PRESEPSIN VS PCT
THE ROC CURVES WERE SIGNIFICANT FOR BOTH
BIOMARKERS, BUT THE AUC CALCULATED FOR PCT WAS
WIDER, DEMONSTRATING A BETTER DIAGNOSTIC
ACCURACY THAN PRESEPSIN.
PRESEPSIN VS PCT
Prognostic role
• Analysis of 60-day mortality showed the superiority of
presepsin compared to PCT. Presepsin concentrations at
the first evaluation in the ED were higher in nonsurvivor
septic patients than in survivors. No significant correlation
was found between PCT values and 60-day mortality. These
results pointed out the possible prognostic role of presepsin
in predicting in-hospital mortality and promptly identifying
high-risk patients.
• The close correlation between presepsin initial values and
in-hospital mortality suggests its potential usefulness for
the early recognition of high-risk septic patients, who could
benefit from a more aggressive approach starting in the ED.
FUTURE SEPSIS
BIOMARKERS
Triggering receptor expressed on myeloid cells-1(TREM-1)
• TREM-1 is expressed mainly on macrophages and neutrophils, and has
been identified as an amplifier of the immune response that strongly
enhances leukocyte activation in the presence of microbial products
• A soluble TREM-1 variant (sTREM-1) has been detected in several
body fluids
• Initially, sTREM-1 was only found in fluids from patients with
microbial infections, but recent studies have found elevated sTREM-1
plasma levels in patients with non-infectious conditions, such as
inflammatory bowel disease and chronic obstructive pulmonary
disease, and in patients undergoing cardiac surgery
• The latter results suggest that sTREM-1 can be released by a broad
spectrum of inflammatory stimuli.
TRIGGERING RECEPTOR EXPRESSED
ON MYELOID CELLS-1(TREM-1)
• The first promising result of the use of sTREM-1 in plasma to
diagnose sepsis in ICU patients [31] indicated that sTREM-1
might be that perfect diagnostic sepsis biomarker that
everybody had been looking for.
• A recently published meta-analysis of the diagnostic value of
sTREM-1 concluded that sTREM-1 represents a reliable
biological marker of bacterial infection
• But because of deficient studies and the heterogeneity in study
design and setting, and the limited size of the studies published
make it impossible to draw firm conclusions on the diagnostic
accuracy of sTREM-1.
CYTOKINES
• Based on our present knowledge,
measurements of single cytokines will not
have great impact on the future diagnosis of
sepsis. However, it is plausible that real-time
monitoring of a panel of cytokines and
receptors will be important to determine the
level of dysregulation of the innate immune
system and to guide future sepsis
treatments.
PENTRAXIN-3
• Pentraxin-3 (PTX-3) is an acute-phase protein involved in
inflammatory and infectious processes.
• Specifically for the presence of at least sepsis. In addition,
PTX-3 correlated with disease severity and degree of
organ dysfunctions as assessed by clinical scores such as
the SOFA score, as has also been described in earlier
studies
• Circulating PTX3 concentrations are elevated in sepsis
and even higher in septic shock
• Consistent with the current observations, multiple
previous studies presented significant and valuable AUCs
for discriminating sepsis or septic shock from healthy
controls
PENTRAXIN-3
• The diagnostic superiority of PTX-3 over PCT or CRP is still
under debate, as different studies so far have been
inconsistent regarding their diagnostic capacity in patients
with sepsis and septic shock, applying different criteria and
definitions of the sepsis syndrome. No study is currently
available applying the newest Sepsis-3 definitions for novel
biomarker analyses.
• In summary, PTX-3 valuably discriminates the different
stages of sepsis severity during the first week of intensive
care treatment according to latest Sepsis-3 definitions.
BIOMARKER COMBINATIONS
• No single marker may be able to have the high accuracy
needed for fast and accurate guidance of treatment of sepsis
patients.
• Therefore, the search for a single “magic bullet” marker
might ultimately be fruitless, but a combination of
markers could improve diagnosis, prognosis and
treatment efficacy, and thereby survival. Instead of
a single marker, a combination of markers may be
the right approach to crack the “sepsis code”.
• A combination of the three best-performing markers (CRP,
PCT and neutrophil count) and all six markers were found
to be more accurate in detecting inflammatory response
caused by bacterial infection than individual markers alone
with an ROC-AUC of 0.88
BIOMARKER COMBINATIONS
• Shapiro et al published results from a multicenter study of
ED patients with suspected sepsis . Nine biomarkers were
assayed and multivariable logistic regression was used to
identify an optimum combination of biomarkers to create a
panel. Among the nine biomarkers tested, the optimum
three-marker panel was neutrophil gelatinase-associated
lipocalin, protein C and interleukin-1 receptor antagonist.
• The ROC-AUC for the accuracy of the sepsis score derived
from these three biomarkers was 0.80 for severe sepsis, 0.77
for septic shock and 0.79 for death. In the future,
multimarker panels will probably add to the diagnostic
accuracy and risk assessment in sepsis.
BIOMARKER COMBINATIONS
CONCLUSIONS
• Accurate and timely diagnosis of infection and monitoring of
treatment effects are very important for patient outcomes.
• Current evidence suggests that CRP will remain an important marker
of inflammation and infection, and that PCT will enhance the
clinicians’ ability to diagnose infection in critically ill patients and
probably guide therapy. Thus I foresee that PCT will be measured in
more patients in the future.
• A sepsis biomarker that has attracted a lot of attention during the last
years is sTREM-1. On the one hand there are studies showing that
sTREM-1 is the ideal sepsis biomarker, and on the other hand there
are studies showing that sTREM-1 is as accurate as a toss of a coin.
• Given the complexity and variability of sepsis it is understandable that
no single biomarker possesses all of the “perfect biomarker” qualities.
Combining information from several sepsis markers is simple and may
facilitate diagnosis and risk assessment in septic patients.
THANK YOU