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"Biomarkers in sepsis and septic shock" by Prof. Jérôme Pugin

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The research interest of the investigator has focused on the molecular and cellular pathogenesis of sepsis. In particular, he has worked on soluble proteins involved in the innate recognition of bacteria such as soluble CD14 and MD-2, as well as in the Toll-like receptors activated by Gram-negative and Gram-positive bacteria. Another area of study is the molecular pathogenesis and cell signaling of ventilator-induced lung injury, and lung inflammation in the context of acute respiratory distress syndrome. He has also identified and tested biomarkers in the field of clinical sepsis.

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"Biomarkers in sepsis and septic shock" by Prof. Jérôme Pugin

  1. 1. Use of of Biomarkers in the Care of Patients with sepsis Prof. Jérôme Pugin, MD Intensive Care University Hospitals Geneva, Switzerland October 21st, 2014 Seminar VHIR Vall d’Hebron
  2. 2. 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
  3. 3. 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
  4. 4. 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
  5. 5. • 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
  6. 6. Am J Respir Crit Care Med 2012
  7. 7. 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
  8. 8. Molecular signature of sepsis (host) Siqnature® (SIRS-Lab) http://www.sirs-lab.com/siqnature Bauer, Möller, Rußwurm,and Reinhart, ISF meeting 2008 Siqnature® score discriminates sepsis from SIRS better than PCT and CRP
  9. 9. 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 severe infections and sepsis in critically ill patients • Performed on whole blood (and other body fluids) • Take ~6 hrs • Sensitivity/Specificity in the clinical arena?
  10. 10. Vincent el al. In preparation Results of RADICAL study Standard cultures vs. molecular determination 609 suspicions of severe infectiosns in ICU patients Blood cultures, cultures of TA, BALs, ascites, etc.
  11. 11. Combining clinical data and biomarkers (ALI) Crit Care Med 2011
  12. 12. γINF 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
  13. 13. γINF 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
  14. 14. • 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
  15. 15. Müller et al., J Clin Endocrinol Metabol, 2000, 86: 396-404 Procalcitonin gene induction during experimental sepsis
  16. 16. • 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)
  17. 17. PCT algorithm for patients with respiratory tract infection Schuetz P BMC Med 20111
  18. 18. PCT algorithm for patients with sepsis Schuetz P BMC Med 20111
  19. 19. PCT is not a sepsis screening tool for patients admitted 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
  20. 20. Sepsis: definitions SIRS (≥ 2 criteria): Fever Leucocytosis Tachypnea Tachycardia Sepsis: SIRS + bacterial infection Severe sepsis: Sepsis + organ failure Septic shock: Severe sepsis + refractory shock ACCP/SCCM consensus conference 1992
  21. 21. .01 .1 1 10 100 1000 PCT(ng/mL) Septic shock Severe sepsis SepsisSIRS Harbarth et al. Am J Respir Crit Care Med 2001 Diagnostic yield of PCT in sepsis 1.1 ng/mL Sensitivity 97% Specificity 78%
  22. 22. 1 - specificity sensitivity 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 PCT adds to a clinical prediction model for the diagnosis of sepsis Harbarth et al. Am J Respir Crit Care Med 2001
  23. 23. .01 .1 1 10 100 1000 PCT(ng/mL) Septic shock Severe sepsis SepsisSIRS Procalcitonin 1 10 100 1000 10000 100000 IL-6(pg/mL) Septic shock Severe sepsis SepsisSIRS Interleukin-6 Harbarth et al. Am J Respir Crit Care Med 2001 Only PCT discriminates sepsis from SIRS
  24. 24. 0.1 1 10 100 Survived Sepsis- related death 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 Survived Sepsis- related death
  25. 25. Antibiotic guidance: who needs guidance?
  26. 26. Duration of antibiotic therapy in the ICU. Who cares? Bacterial resistance $$$ Toxicity - interactions
  27. 27. 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” …
  28. 28. Strategies to reduce antibiotics in ICU 1. Decrease empirical time! Lancet 2010 2. Use procalcitonin! Chastre et al. JAMA 2003 AJRCCM 2008
  29. 29. 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!
  30. 30. 0.1 1 10 100 1000 PCT(ng/mL) 0 2 4 6 8 10 12 14 16 Days 0.1 1 10 100 1000 PCT(ng/mL) 0 2 4 6 8 10 12 14 16 Days Survived Died Decrease of plasma procalcitonin levels with time in survivors vs. non-survivors Harbarth et al. Am J Respir Crit Care Med 2001 Would PCT help clinicians to stop antibiotics earlier ?
  31. 31. Christ-Crain et al. Am J Resp Crit Care Med 2006 Schuetz 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 : NO antibiotic therapy: > 0.1 < 0.25 : no > 0.25 < 0.5 : yes > 0.5 µg/L : YES PCT
  32. 32. 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%
  33. 33. 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?
  34. 34. PCT guidance in patients with severe sepsis and 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
  35. 35. Suspicion of severe sepsis or septic shock* Suspicion of severe sepsis or septic 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
  36. 36. %patientswithoutantibiotics n=68 HR: 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
  37. 37. 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 treatment duration does not affect outcome
  38. 38. 1315 patients assessed for eligibility 685 ineligible 158 had expected ICU stay <3 days 138 had SAPS II >65 104 had received AB for >24 hours 99 required prolonged therapy 63 not enrolled for logistic reasons 46 had do-not-resuscitate orders 31 were neutropenic 15 had no medical insurance 12 had been enrolled in other studies 10 refused consent 9 excluded for other reasons 630 randomized 311 assigned to Procalcitonin Group 319 assigned to Control Group 307 Included in analysis (1 lost to follow-up on day 15) 314 Included in analysis (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
  39. 39. 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 Durationoftreatment(days) 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
  40. 40. Use of procalcitonin to shorten antibiotic exposure in ICU patients : the ProRata trial Probabilityofsurvival,% 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.
  41. 41. Matthaiou et al. Intensive Care Med 2012 PCT guidance: duration of antibiotic therapy
  42. 42. Matthaiou et al. Intensive Care Med 2012 28-day mortality, PCT guidance vs. control
  43. 43. 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 the potential for harm remains a concern. Intensive Care Med Feb 2013 Crit Care Med Feb 2013
  44. 44. 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!
  45. 45. PASS study. Jensen et al. Crit Care Med 2011 Antibiotic escalation therapy based on PCT ! No effect on mortality Increased LOS Increased MOF
  46. 46. Days on antibiotics PCT-guided antibiotic therapy in critically ill patients. Days on antibiotics Bouadma et al. Lancet 2010 Nobre et al. AJRCCM 2008 Christ-Crain et al. AJRCCM 2006 (n=630) (n=302) (n=79)
  47. 47. 0 5 10 15 20 25 30 35 10 100 1000 10000 100000 D a y 0 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 GC GC

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