Sepsis : Update Biomarkers Prof. Jérôme Pugin Soins Intensifs Hôpitaux Universitaires de Genève

Intravenous E.coli endotoxin injection vs. saline to healthy human volunteers Transcriptomic analysis in blood leukocytes at times 0, 2, 4 6, 9, 24 hours after injection

Endotoxin NaCl

Blue : Downregulated Red : Upregulated

Calvano et al. Nature 2005

Red : pathways upregulated Blue : pathways downregulated • Mitochondrial respiratory chain complex I and III • Mitochondrial permeability • ATP synthase complex • Pyruvate dehydrogenase complex • Ribosomal proteins • Proteasome Based on 292 representative genes of the inflammatory pathway

gINF

IL-18

IL-1ra sTNFR2

sTNFR1 IL-10

IL-4

IL-12

Endothelin Nitrites

NO

iNOS

Lymphotoxin

IL-8 IL-6 IL-1ß

PCT

C3a

sVCAM-1

sE-selectin

sICAM-1 LBP

cortisol

Neopterin

CRP

HMGB-1

MIF

C5a

D-dimers

APC

TNF

ATIII

PGE2

PGI2

TxA2

LPS

LTB4

sCD14

ESM-1

albumin

HLA-DR

Sepsis

Why do I want a biomarker and what for? • To make a diagnosis?

• To make a decision? - antibiotic therapy? - ICU admission, stratification? - diagnostic procedure? - to start specific therapy (steroids, …)?

• To monitor?

• To predict outcome?

• To enroll patients into studies?

• To perform epidemiological studies?

• To understand the disease?

PCT, PSP?

PCT ? ? cortisol

PCT, CRP, lactate

IL-6, PCT, PSP

LPS, IL-6, PCT?

Genetics

Many

Adapted from Samraj et al. Shock 2013

• Excellent diagnostic yield

sensitive discriminative with other sepsis-like situations • Cross-validated • Easy & rapid to measure • Cheap • Impact on the care of the sepsis patient

The ideal biomarker

1. Sepsis is a continuum between colonization, infection and systemic infection with various levels of severity

2. Sepsis is a heterogeneous syndrome

3. Consequences (organ dysfunction) of sepsis vary

4. Clinical definition of sepsis is vague

5. Bacterial pathogens triggering sepsis are numerous

It is unlikely that a single biomarker will yield perfect diagnosis in the context of sepsis

• Single biomarker: simple, rapid, cheap, sensitive, usually not very specific • Single biomarker associated with clinical signs: probably better, introduces the

clinical context • Multiple biomarkers: technology? Less rapid, more expensive, increased

specificity, lack of sensitivity? • Combine bacterial and host markers?

Single vs. multiple biomarkers

gINF

IL-18

IL-1ra sTNFR2

sTNFR1 IL-10

IL-4

IL-12

Endothelin Nitrites

NO

iNOS

Lymphotoxin

IL-8 IL-6 IL-1ß

PCT

C3a

sVCAM-1

sE-selectin

sICAM-1 LBP

cortisol

Neopterin

CRP

HMGB-1

MIF

C5a

D-dimers

APC

TNF

ATIII

PGE2

PGI2

TxA2

LPS

LTB4

sCD14

ESM-1

albumin

HLA-DR

Sepsis

• Recognized by Assicot et al. as a marker of severe bacterial infection in children

(Lancet 1993)

• Serum PCT levels increase 4-8 hrs after experimental sepsis or LPS injection to

humans, and peak after 12-24 hrs

• Serum PCT levels are slightly elevated in severe parasite et fungal infections

• Serum PCT levels are low in any viral diseases

• “False positives”: 2 first days of life, heat stroke, multiple trauma, some surgical

patients, medullar thyroid cancer

Procalcitonin: FAQs

Müller et al., J Clin Endocrinol Metabol, 2000, 86: 396-404

Procalcitonin gene induction during experimental sepsis

.01

.1

1

10

100

1000

PC

T (

ng

/mL

)

Septic

shock

Severe

sepsis

Sepsis SIRS

Harbarth et al. Am J Respir Crit Care Med 2001

Diagnostic yield of plasma PCT in sepsis

1.1 ng/mL

Sensitivity 97%

Specificity 78%

PCT adds to a clinical prediction model for the diagnosis of sepsis

1 - specificity

sen

sit

ivit

y

1.00

0.75

0.50

0.25

0 .00

0.00 0.25 0.50 0.75 1.00

Clinical model with PCT

Clinical model without PCT

Harbarth et al. Am J Respir Crit Care Med 2001

Sepsis

Antibiotic therapy: who needs guidance?

When to stop the antibiotic therapy?

“We said 8 days” “Patient is stable” “Patient is transferred to the ward” “Patient develops a rash” “Renal function is deteriorating” “The attending is changing” “Cultures came back negative” …

% p

atients

without

antibio

tics

n=68 HR: 1.9 (1.2-3.1) p=0.009

Probability to have antibiotics stopped based on PCT algorythm

Time to antibiotic discontinuation (days)

PCT

controls

0 5 10 15 20

0.00

0.25

0.50

0.75

1.00

Nobre et al. Am J Respir Crit Care Med 2008

Control

(n=37)

PCT

(n=31) p value

28-day mortality 16.2% 16.1% 0.74

Clinical cure 83.8% 90.3% 0.33

Nosocomial infection 29.7% 22.6% 0.20

Infection replase, % 2.7% 3.2% 0.70

Shortening of antibiotic treatment duration does not affect outcome

All

patients

VAP abdominal

infection

UTI (+) Blood

cultures

N

CAP

20 14

9.9

6.1

10.6

5.6

9.4

7.3

10.8

8.1

14.5

7.4

12.8

9.8

0

2

4

6

8

10

12

14

16

Du

rati

on

of

treatm

en

t (d

ays)

314 307 101 79 66 75 18 24 53 55

PCT-guided

Control

Use of procalcitonin to shorten antibiotic exposure in ICU patients. the ProRata trial

Bouadma et al. Lancet 2010

Prob

ab

ilit

y o

f su

rviv

al,

%

Days after inclusion

Procalcitonin (n=311)

Control group (n=319)

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60

Bouadma et al. Lancet 2010

p = n.s.

Use of procalcitonin to shorten antibiotic exposure in ICU patients. the ProRata trial

PCT algorithm for patients with sepsis

Schuetz P BMC Med 2011

Antibiotic stewardship We recommend daily assessment for de-escalation of antimicrobial therapy in patients with sepsis and septic shock.

(Expert recommendation)

We suggest that measurement of procalcitonin levels can be used to support shortening the duration of antimicrobial therapy in sepsis patients.

(Weak recommendation; low quality of evidence)

Early sensitive, speciic and prognostic marker of sepsis

Point of care testing, few microliters of blood

Results in 5 min

Pancreatic stone protein

Abioscope®

Benninga et al.

Results of Abionic study in February 2020 296 patients included; Multicentric, CH (Geneva, Lausanne and Bern), France. Italy, UK ICU patients at risk to develop sepsis, sampled every 12 hours: will PSP anticipate diagnosis of inectiion ans sepsis ?

Diagnostic and prognostic yield of sepsis biomarkers

Eggimann et al. Biomark.Med. (2019) 13(02), 135–145

« Molecular biomarkers are taking front stage at present, but machine learning and other computational measures using bigdata sets are promising.» S. Opal and X. Wittebole Crit Care Clin 2020; 36:11-22

R.J.Piso KSO

2.3 MioCHF

5 ICUs from university hospitals + ETH Zürich

Hundreds of physiological, clinical, microbiological, laboratory variables per patient continuously feeding a shared data warehouse

Tagging patients with sepsis (ICU)

Machine learning Defining algorithms for sepsis prediction and prognosis

Personalized Swiss Sepsis Study

• Define the question before using (choosing) a sepsis biomarker : Diagnosis? Detection? Risk stratification? Antibiotic guidance? Prognosis?

• Procalcitonin remains the #1 biomarker for diagnosis and antibiotic guidance • Many have prognostic values… • Biomarkers frequently comfort the clinician impact on patient care? • Pancreatic stone protein seems to add prediction + prognosis + early • Digital prediction and prognosis based on algorithms (machine learning, big data)?

Conclusions

Thank you for your attention!