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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