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Sepsis Biomarkers
Giuseppe Lippi
Section of Clinical Biochemistry, University of Verona
EFLM Secretary
Sepsis is defined as life-threatening organ
dysfunction caused by a dysregulated host
response to infection.
Septic shock is a subset of sepsis in which
underlying circulatory and cellular/metabolic
abnormalities are profound enough to
substantially increase mortality.
Sepsis:
• is the primary cause of death from
infection, especially if not recognized and
treated promptly.
• is a major public health concern,
accounting for more than $20 billion
(5.2%) of total US hospital costs.
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According to the conclusions of the task force
(Sepsis-3), the SOFA and qSOFA are not
intended as diagnostic criteria, but rather a
sort of red flag for triage.
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….
ESR
CRP
PCT
PSPCombined clinical and biomarker
assessment for a personalised emergency triage
Schuetz P, et al. Swiss Med Wkly. 2015;145:w14079
• Being present at symptoms onset (or even earlier), to allow
an early diagnosis
• Being highly sensitive and specific for infections, to allow an
accurate differential diagnosis between infectious and non-
infectious diseases
• Being capable of identifying the pathogen
• Being informative on clinical course
• Providing valuable information on the prognosis
• Guiding therapeutic decisions (e.g., antibiotic stewardship)
Ideal features of a sepsis biomarker • According to the Third International Consensus Definitions for Sepsis and Septic
Shock (Sepsis-3), sepsis is currently defined as a “life-threatening organ
dysfunction caused by dysregulated host response to infection”.
• This updated definition underscores the clinical importance of the “non-
homeostatic” host response to an infection rather than the infection per se, so
that the concepts of “bacteraemia”, “fungemia” and even of “bloodstream infection”
shall be no longer used as synonyms for sepsis.
• The first obvious consequence is that the measurement of biomarkers which
essentially reflect a disproportionate “non-homeostatic” host response would
appear more efficient for initial screening of patients with sepsis compared to
the direct isolation or identification of microorganisms from blood.
• In fact, a systemic biological response, up to systemic inflammatory response
syndrome (SIRS) and multi organ failure, can also occur in patients with severe
but localized infections, even before microorganisms have massively entered
the bloodstream.
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From prehistory…
… modern times ...
Sepsis biomarkers
… up to the future?
ESR (Erythrocyte Sedimentation rate)
• Extremely elevated ESR (>100 mm/hour)-high specificity for
infection, malignancy or arteritis.
• Rises within 24–48 hours of the onset of inflammation and falls
back slowly with resolution.
CRP (C Reactive Protein)
• Begins to rise after 12–24 hours and peaks within 2-3 days.
• Low levels of CRP elevation with values between 2 and 10 mg/L
measured by a “high sensitivity CRP” assay seen in noninfectious
“metabolic inflammatory” states such as cardiac ischemia, uremia
or smoking.
Tyroid (C cells)
Leucocytes Procalcitonin
Liver (histiocytes)
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Linscheid P, et al. Endocrinology 2003;144:5578-84.
Hyperprocalcitonemiain marked systemicinflammation or ininfection:- Occurs within 2–4 hrs- Reaches high values in
12–24 hrs- Then persists as long
as the inflammatoryprocess continues (i.e.,days to weeks).
- With recovery, levelsnormalize.
1°
Procalcitonin vs rest of the world…
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PCR
PCT PCT
PCR
Localized Infection Sepsis
Pooled sensitivity forPCT was 88% (95% CI,
80%-93%) vs. 75%(95% CI, 62%-84%) forCRP.
Pooled specificity forPCT was 81% (95% CI,67%-90%) vs. 67%
(95% CI, 56%-77%) forCRP
bacterial infections vs. viral infections
bacterial infections vs. noninfective
causes of inflammation
CRP
PCT
OR: - PCT 14.7- CRP 5.4
AUC, 0.78 vs. 0.71
vs
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• PCT correlated with bacterial load [vanNieuwkoop C, et al. Crit Care 2010;14:R206]
• PCT correlated with severity of infection andoutcome [Schuetz P, et al. Eur Respir J2011;37:384-92.// Haeuptle J, et al. Eur JClin Microbiol Infect Dis 2009;28:55-60.//Schuetz P, et al. Chest 2012;141:1063-73]
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Presepsin (soluble CD14-subtype; sCD14-ST)
• The normal in healthy adults is usually <320 pg/ml.
• In elderly patients or those with impaired renal
function values increase
• Presepsin levels in sepsis seem to be elevated even
earlier than PCT (1-3h after onset of the infection)
• The half life is around 4-8 hours.
• In sepsis survivors, presepsin declines after a few
hours whereas it remains elevated in those who die. Due to study bias, we conclude that presepsin cannot be
used to confirm or rule out sepsis when used alone, and its
results should be interpreted within the clinical context.
Presepsin showed a moderate diagnostic accuracy in differentiating
sepsis from non-sepsis which prevented it from being
recommended as a definitive test for diagnosing sepsis in isolation.
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Although presepsin displays moderate or above moderate
diagnostic value for sepsis, the limitations of the methodological
quality and sample size may weaken these findings.
Receiver operating characteristics analysis showed
the following areas under the curve:
Prediction of bacteraemia
• PCT: 0.876
• Presepsin: 0.788
• CRP: 0.602
Prediction of bacterial DNAaemia
• PCT: 0.880
• Presepsin: 0.777
• CRP: 0.632
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Not only diagnosis of sepsis…
Am J Respir Crit Care Med 2006;174:84-93.
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Total duration of AB treatment: -4.19 days
After multivariate adjustment,antibiotic therapy duration was significantly shorter
if the PCT algorithm was followed compared with when it was overruled
(5.9 vs 7.4 days; difference -1.51 days; p<0.001)
“To date, the efficacy and safety of PCT protocols to deescalate antibiotic overuse has been demonstrated in
more than 14 randomised, controlled trials in different clinical settings and including infections of
varying severity”
[Schuetz P, et al. Clinical outcomes associated with procalcitonin algorithms to guideantibiotic therapy in respiratory tract infections. JAMA 2013;309:717-8.// Schuetz P, et al.Procalcitonin algorithms for antibiotic therapy decisions: a systematic review ofrandomized controlled trials and recommendations for clinical algorithms. Arch Intern Med
2011;171:1322-31.// Schuetz P, et al. Procalcitonin to initiate or discontinue antibiotics inacute respiratory tract infections. Cochrane Database Syst Rev 2012;9:CD007498.].
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• In patients with community-acquired pneumonia, not fulfilling criteria for
sepsis or septic shock PCT could be used to support starting of antibiotic
• treatment.
• In patients with acute exacerbation of chronic obstructive pulmonary
disease (COPD), PCT could be useful in the diagnosis of bacterial
superinfection.
• In patients with community-acquired pneumonia, not fulfilling criteria for
sepsis or septic shock PCT could be used as a prognostic marker of worse
outcome.
• In non-critically ill patients, a PCT increase after 48 h of antibiotic therapy
must not justify treatment escalation.
• In this setting, PCT level should be monitored over time to guide treatment
discontinuation.
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PCR tests can be limited in their ability to detect pathogens for:
1. Preanalytical issues
2. Need for effective lysis across a broad range of microbes
3. Interference of human DNA or other inhibitory substances
4. Off-target interactions
5. Amplification bias
So that… yet none of them show promise to replace blood
culture due to their limited sensitivity for clinical specimens.
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• The diagnosis of viral sepsis is typically one of exclusion.
• There are currently no standard approaches to viral diagnostic
testing.
• Cell culture is the traditional gold-standard
• Commercial or laboratory-developed nucleic acid amplification
tests (e.g., polymerase chain reaction, PCR, or reverse
transcription-loop-mediated isothermal amplification) have
good sensitivity and specificity but requires sophisticated
equipment and trained laboratory staff
• In general, sepsis biomarkers are non-specific for distinguishing
viral infections