Use of of Biomarkers in the Care of Patients with sepsis

Prof. Jérôme Pugin, MD

Intensive CareUniversity HospitalsGeneva, Switzerland

October 21st, 2014Seminar VHIRVall d’Hebron

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

PCT??cortisol

PCT, CRP, lactate

IL-6, PCT

IL-6, PCT?

Genetics

Many

Adapted from Samraj et al. Shock 2013

Diagnosis of sepsis

The ideal marker:

• 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

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?

Single vs. multiple biomarkers

Am J Respir Crit Care Med 2012

The challenges:

1. Find specificity in host response to severe bacterial infection as compared with systemic response due to other SIRS conditions (immense overlap!)

2. Combining infection and host response markers

3. Timing issue (sepsis is an ongoing process)

Host response to severe bacterial infection

Molecular signature of sepsis (host)

Siqnature® (SIRS-Lab)

http://www.sirs-lab.com/siqnatureBauer, Möller, Rußwurm,and Reinhart, ISF meeting 2008

Siqnature® score discriminates sepsis from SIRS better than PCT and CRP

Molecular signature of the pathogen

• SeptiFastTM (Roche), VYOOTM (SIRS-lab), Plex ID (Abbott)

• PCR-based methods or oligoarray

• Detect a wide variety of pathogens causing severeinfections and sepsis in critically ill patients

• Performed on whole blood (and other body fluids)

• Take ~6 hrs

• Sensitivity/Specificity in the clinical arena?

Vincent el al. In preparation

Results of RADICAL studyStandard cultures vs. molecular determination

609 suspicions of severe infectiosns in ICU patientsBlood cultures, cultures of TA, BALs, ascites, etc.

Combining clinical data and biomarkers (ALI)

Crit Care Med 2011

γINF

IL-18

IL-1ra sTNFR2

sTNFR1IL-10

IL-4

IL-12

Endothelin Nitrites

NOiNOS

Lymphotoxin

IL-8 IL-6IL-1ß

PCT

C3a

sVCAM-1

sE-selectin

sICAM-1LBP

cortisol

Neopterin

CRP

HMGB-1

MIF

C5a

D-dimers

APC

TNF

ATIII

PGE2

PGI2

TxA2

LPS

LTB4

sCD14

ESM-1

albumin

HLA-DR

Sepsis

γINF

IL-18

IL-1ra sTNFR2

sTNFR1IL-10

IL-4

IL-12

Endothelin Nitrites

NOiNOS

Lymphotoxin

IL-8 IL-6IL-1ß

PCT

C3a

sVCAM-1

sE-selectin

sICAM-1LBP

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

• Pulmonary sepsis vs. ARDS?

• Abdominal sepsis vs. uninfected severe pancreatitis?

• Bacterial vs. viral meningitis?

• Bacterial vs. inflammatory arthritis?

• Organ Tx rejection vs. bacterial sepsis?

• Bacterial vs. nonbacterial origin in FUO?

• Bacterial vs. nonbacterial origin in respiratory tract infection?

Suprin E. ICM 2000, van Langevelde P. CID 2000, Viallon A. CID 1999, Schwarz S. CCM 2000, Hedlund J. Infection 2000, Boeken U. ICM 2000, Hammer. Ann Transpl 1999, Kuse ER. CCM 2000, Aouifi A. CCM 2000, Wanner GA. CCM 2000, Mimoz O. ICM 1998, Rau B. Gut 1997, Muller CA. Gut 2000, Brunkhorst FM. CCM 2000, Christ-Crain. Lancet 2004.

Usefulness of PCT as a diagnostic test (> 600 studies)

PCT algorithm for patients with respiratory tract infection

Schuetz P BMC Med 20111

PCT algorithm for patients with sepsis

Schuetz P BMC Med 20111

PCT is not a sepsis screening tool for patientsadmitted to the ICU

Plasma PCT levels in 100 patients admitted to the ICU(sepsis prevalence: <15%)

Ugarte et al. Crit Care Med 1999

The highest the prevalence (pre-test probability), the greatest the performance for a diagnostic test

Sepsis: definitions

SIRS (≥ 2 criteria): FeverLeucocytosisTachypneaTachycardia

Sepsis: SIRS + bacterial infection

Severe sepsis: Sepsis + organ failure

Septic shock: Severe sepsis + refractoryshock

ACCP/SCCM consensus conference 1992

.01

.1

1

10

100

1000

PC

T (

ng

/mL

)

Septic shock

Severesepsis

SepsisSIRS

Harbarth et al. Am J Respir Crit Care Med 2001

Diagnostic yield of PCT in sepsis

1.1 ng/mLSensitivity 97%

Specificity 78%

1 - specificity

sen

siti

vity

1.00

0.75

0.50

0.25

0.00

0.00 0.25 0.50 0.75 1.00

Clinical model with PCTClinical model without PCT

PCT adds to a clinical prediction modelfor the diagnosis of sepsis

Harbarth et al. Am J Respir Crit Care Med 2001

.01

.1

1

10

100

1000

PC

T (

ng

/mL

)

Septic shock

Severesepsis

SepsisSIRS

Procalcitonin

1

10

100

1000

10000

100000

IL-6

(p

g/m

L)

Septic shock

Severesepsis

SepsisSIRS

Interleukin-6

Harbarth et al. Am J Respir Crit Care Med 2001

Only PCT discriminates sepsis from SIRS

0.1

1

10

100

SurvivedSepsis-relateddeath

PCT (ng/ml) IL-6 (pg/ml)

At the time of admission to the ICU, IL-6 is a better prognostic marker than PCT

Harbarth et al. Am J Respir Crit Care Med 2001

1

10

100

1000

10000

100000

SurvivedSepsis-relateddeath

Antibiotic guidance: who needs guidance?

Duration of antibiotic therapy in the ICU.Who cares?

Bacterialresistance $$$

Toxicity -interactions

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 fellow (attending) is changing”“Cultures came back negative”…

Strategies to reduce antibiotics in ICU

1. Decrease empirical time!

Lancet 2010

2. Use procalcitonin!

Chastre et al. JAMA 2003

AJRCCM 2008

1. Decrease empirical time!

VAP: 8 vs. 15 days antibiotic therapy

Chastre et al. JAMA 2003

Cave: increased relapse of nonfermentative GNB!Cave: increased relapse of nonfermentative GNB!

0.1

1

10

100

1000

PC

T (

ng

/mL

)

0 2 4 6 8 10 12 14 16

Days

0.1

1

10

100

1000

PC

T (

ng

/mL

)

0 2 4 6 8 10 12 14 16

Days

Survived Died

Decrease of plasma procalcitonin levels with timein survivors vs. non-survivors

Harbarth et al. Am J Respir Crit Care Med 2001

Would PCT help clinicians to stop antibiotics earlier ?

Christ-Crain et al. Am J Resp Crit Care Med 2006Schuetz et al. BMC Health Services Research 2007

Concept :To guide antibiotic therapy initiation and

duration on PCT values in CAP patients

Initiate or continue < 0.1 µg/L : NOantibiotic therapy: > 0.1 < 0.25 : no

> 0.25 < 0.5 : yes> 0.5 µg/L : YES

PCT

Christ-Crain et al. Am J Resp Crit Care Med 2006

PCT guidance in CAP: 6 days less antibiotic therapy,identical outcome!

PCT Control

Cure 85% 85%

Mortality 12% 13%

Duration of antibiotic therapy in the ICU:

• Mostly empiric

• Rarely tailored for a given patient

• Rarely customized for a given bacterium or infection

Does one size fit all?

PCT guidance in patients with severe sepsisand septic shock?

Inclusion criteria

• Patient suspected of severe sepsis or septic shock

• Initiation of antibiotic therapy < 48hr

Exclusion criteria

• High-risk bacteria (P.aeruginosa, A.baumanii)

• Infection known to require prolonged antibiotic therapy

(e.g. endocarditis, deep abcesses, osteomyelitis)

• Severe immune suppression/neutropenia

Nobre et al. Am J Respir Crit Care Med 2008

Suspicion of severe sepsis orseptic shock*

Suspicion of severe sepsis orseptic shock*

Antibiotic therapyAntibiotic therapy

PCT D1PCT D1

PCT D5PCT D5

• in non-complicated infections** and patient stable

antibiotics

PCT DxPCT DxPCT decrease > 90% on Dx**

antibiotics

Cultures

Stopping rules

Daily PCT measurement

PCT decrease > 90% on D5** PCT decrease < 90% on D5

% p

atie

nts

without

antibio

tics

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

Probability to have antibiotics stopped

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

PCT-guided shortening of antibiotic treatmentduration does not affect outcome

1315 patients assessed for eligibility

685 ineligible158 had expected ICU stay <3 days138 had SAPS II >65104 had received AB for >24 hours99 required prolonged therapy63 not enrolled for logistic reasons46 had do-not-resuscitate orders31 were neutropenic15 had no medical insurance12 had been enrolled in other studies10 refused consent9 excluded for other reasons

630 randomized

311 assigned toProcalcitonin Group

319 assigned toControl Group

307 Included inanalysis

(1 lost to follow-up on day 15)

314 Included inanalysis

(1 lost to follow-up on day 22)

4 withdrew consent 1 randomized twice

The ProRata Trial

4 withdrew consent

Bouadma et al. Lancet 2010

Allpatients

VAP abdominalinfection

UTI (+) Bloodcultures

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

trea

tmen

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

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

Pro

bab

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.

Matthaiou et al. Intensive Care Med 2012

PCT guidance: duration of antibiotic therapy

Matthaiou et al. Intensive Care Med 2012

28-day mortality, PCT guidance vs. control

Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection (grade 2C).

… no evidence demonstrates that this practice reduces the prevalence of antimicrobial resistance.

… clinical experience with this strategy is limited and thepotential for harm remains a concern.

Intensive Care Med Feb 2013Crit Care Med Feb 2013

Conclusions

1. It is unlikely that a single biomarker will be sufficient to diagnose & manage sepsis

2. The ideal marker(s) will associate marker(s) of infection and host response

3. Procalcitonin remain the best sepsis marker, so far

4. Shortening the duration of antibiotic therapy should be a priority in our ICUs

5. Empirical rules should be replaced by rules tailored for a given patient

6. PCT guidance allows:

- to decrease the overall duration of antibiotic therapy

- a customization of antibiotic therapy

…without apparent harm!

- It remains to be shown if PCT guidance is cost-efficient!

PASS study. Jensen et al. Crit Care Med 2011

Antibiotic escalation therapy based on PCT !

No effect on mortalityIncreased LOSIncreased MOF

Days on antibiotics

PCT-guided antibiotic therapy in critically ill patients. Days on antibiotics

Bouadma et al. Lancet 2010Nobre et al. AJRCCM 2008Christ-Crain et al. AJRCCM 2006

(n=630)

(n=302)

(n=79)

0 5 10 15 20 25 30 3510

100

1000

10000

100000

D a y0 5 10 15 20 25 30 35

0.01

0.1

1

10

100

1,000

D a y

75 yr old, diabetic, COPD, hospitalized for a severe community acquired pneumonia.Treated by ceftriaxone for 9 days, difficult weaning from the ventilator. Tracheostomized on day 14. Treatment with glucocorticoids starting Day 14. Bowel obstruction (feces +++), with colonic perforation on Day 20 with fecal peritonitis and septic shock. E.coli and E.feacium in blood cultures. Died on Day 31 in persistent multiple organ failure.

SCAP Peritonitis SCAP Peritonitis

Procalcitonin IL-6

GCGC