Biomarcadores estratificação do risco e orientação terapêutica Pedro Póvoa Faculdade de Ciências Médicas Universidade Nova de Lisboa Unidade de Cuidados Intensivos Médicos Hospital de São Francisco Xavier Centro Hospitalar de Lisboa Ocidental 14º Simpósio de Infecção e Sepsis 1 a 3 de Abril de 2009 Porto
Biomarkers risk stratification and treatment guidance Pedro Póvoa Professor of Medicine Medical Sciences Faculty New University of Lisbon Medical Intensive Care Unit São Francisco Xavier Hospital 14º Simpósio de Infecção e Sepsis 1 a 3 de Abril de 2009 Porto
Biomarkers Sepsis Risk stratification Treatment guidance
Risk stratification & Cancer TNM staging (Denoix, 40s) is a descriptor of how much the cancer has spread T size or direct extent of the primary tumor N degree of spread to regional lymph nodes M presence of metastasis Correct staging is critical: Prognosis Treatment (related to disease stage) Hermanek Cancer 1999;86:2189
ACCP/SCCM Consensus Conference SIRS; 2 criteria temperature >38 C or <36 C tachycardia >90 beats/min tachypnea >20 breaths/min or PaCO2 < 32 mmhg leucocytosis >12.000/mL, leucopenia <4.000/mL or >10% band cells Sepsis SIRS that has a proven or suspected microbial etiology Severe Sepsis Sepsis with signs of organ dysfunction, hypoperfusion or hypotension; hypoperfusion includes lactic acidosis, oliguria and altered mental state Septic Shock sepsis induced hypotension despite adequate fluid resuscitation CCM 1992;20:864
3768 pts 3 ICU, 3 wards 50 40 46 Sepsis 649 (26%) SIRS 2527 (68%) Severe Sepsis 467 (18%) Septic Shock 110 (4%) Mort tality (%) 30 20 10 7 10 17 16 20 285 (44%) Previously classified as SIRS 271 (58%) Previously classified as SIRS or sepsis 78 (71%) Previously classified as SIRS, sepsis or Severe sepsis 0 3 No SIRS SIRS2 SIRS3 SIRS4 Sepsis Severe Sepsis Septic Shock Continuum from SIRS to sepsis to severe sepsis to septic shock Rangel-Frausto JAMA 1995;273:117
Markers provide information in one or more of three domains: diagnosis, prognosis, and response to therapy (>80 putative markers of sepsis). All correlate with the risk of mortality (prognosis), yet none has shown utility in stratifying patients with respect to therapy (diagnosis) or in titrating that therapy (response). Their limitations arise from the challenges of establishing causality in a complex disease process such as sepsis and of stratifying patients into more homogeneous populations. The latter suggests the need for a staging system analogous to those used in other complex disease processes such as cancer. A candidate framework for such a system, based on the infection, the host response, and the extent of organ dysfunction (the IRO system) Marshall J Crit Care Med 2003; 31:1560
IRO system - staging Stage I presence of the insult (infection) with only a modest (or absent) response and no organ dysfunction: I1R1O0. Such a population might be appropriate for trials of a new antibiotic. Stage II presence of the insult with modest response and organ dysfunction of the primary site of infection or the presence of inflammation of unknown origin with moderate response and absent organ dysfunction: I1 (acute lung injury) R1 (inflammatory-induced injury) O1 (organ dysfunction limited to the respiratory system) could be used to designed a study to prevent ventilator-induced lung injury and its sequelae Stage III presence of an insult with severe response and a moderate organ dysfunction: Ix (inflammation, cause not specified) R2 (evidence of microvascular thrombosis; for example, elevated D-dimers) and O1 (organ dysfunction compatible with microvascular ischemia involving two or more organ systems) could be used to study an anticoagulant. Stage IV presence of an insult with severe response and organ dysfunction: Ix (inflammation, cause not specified) R3 (biochemical evidence of marked systemic inflammation) and O2 (established organ dysfunction necessitating extracorporeal support) could be designed to study a salvage therapy such as plasmapheresis. Marshall J et al. Crit Care Med 2003; 31:1560
1. Current concepts of sepsis, severe sepsis and septic shock remain useful 2. These definitions do not allow precise staging or prognostication of the host response to infection 3. SIRS remains an useful concept (although overly sensitive and non-specific) 4. An expanded list of signs and symptoms of sepsis may better reflect the clinical response to infection 5. PIRO, a hypothetical model for staging sepsis is presented, which, in the future, may better characterize the syndrome on the basis of 1. Predisposing factors and premorbid conditions, 2. the nature of the underlying Insult (Infection) 3. the characteristics of the host Response 4. the extent of the resultant Organ dysfunction
PIRO system/stratification optimum individualized treatment Predisposition Genetic susceptibility Coexisting health complications Insult (Infection) Pathogen, toxicity and sensitivity Location and compartmentalization Biomarkers in Sepsis Can we use them in risk stratification? Response Increased biomarkers or biomediators Manifested physiologic symptoms Organ Dysfunction Number of failing organs Carrigan Clin Chem 2004;50:1301
Predisposition Preinfection risk of CAP N=3075 (70-79 yrs) 161 CAP Follow-up 6.5 yrs TNF, IL6, CRP (inclusion) TNF >3.7 pg/ml AOR 1.6 (95%CI, 1.02-2.7) IL6 >2.4 pg/ml AOR 1.7 (95%CI, 1.1-2.8) No comorbidities biomarkers, no risk Comorbibities biomarkers, risk Yende AJRCCM 2005;172:1440
Insult Biomarkers and Diagnosis of Infection Sensitivity (%) Specificity (%) AUC PCT 70-91 68-92 0.64-0.95 CRP 10-98 44-99 0.68-0.82 Simon CID 2004;39:206. Erratum: CID 2005;40:1386 van der Meer BMJ 2005;331:26 Uzzan CCM 2006;34:1996 Tang Lancet Infect Dis 2007;7:210 PROBLEMS 1. ACCP/SCCM Consensus Conference criteria to define the presence or absence of sepsis (assessing degrees of clinical severity) 2. Gold standard, that is presence of documented infection versus no infection and no antibiotic therapy (Cohen CCM 2001;29:880) Póvoa Curr Opin Infect Dis 2008;21:157
PANEL OF BIOMARKERS Prospective N=1800 Multiplex technology: xmap AUC for bacterial cause of SIRS: supar 0.50 strem-1 0.61 MIF 0.63 PCT 0.72 neutrophil count 0.74 CRP 0.81 0.84 (95% CI 0.71 to 0.91) for the composite three-marker test 0.88 (95% CI 0.81 to 0.92) for the composite six-marker test Increases costs More time consuming Interpretation? Kofoed Clin Chem 2006;52:1284 Kofoed Critical Care 2007;11:R38
Fast PCR pathogen detection DNA fingerprinting
Fast PCR pathogen detection
Biomarkers of infection Single determination value in the diagnosis of infection Serial determinations as predictor of infection monitoring clinical course and response to antibiotic therapy Póvoa ICM 2002;28:235 Póvoa Curr Opin Infect Dis 2008;21:157
CRP controls and infected day -5 to day 0 N=63 pts (28 controls; 35 infected documentation) p<0.001 1,00,75,50 days sensibilidade sensitivity,25 0,00 0,00 Max daily CPR AUC (day -5 to day 0) 0.86 (95% CI: 0.75 0.93),25 1-specificity 1 - especificidade,50,75 1,00 maximum daily CRP > 4.1 mg/dl infection sensitivity 0.92, specificity 0.71, LR+ 3.22, LR- 0.11 Póvoa Critical Care 2006;10:R63
PCT with and without VAP D-5 to D1 N=73 pts (32 with and 41 without VAP) BAL diagnosis 1 with Sensiti ivity 0.75 0.5 without 0.25 0 0 PCT Increase PCT 0.25 0.5 0.75 1 1 Specificity PCT kinetics low diagnostic accuracy for VAP Luyt C et al. ICM 2008;34:1434
Response simplified hypothetical host response to infection sample SIRS steroids monoclonal Ab rhapc CARS immunonutrition INF - γ CSF plasmafiltration... Immune Monitoring: Can we assess the immune status to design an intervention? Hotchkiss NEJM 2003;348:138
22 RCT Macias Critical Care 2005; 9:R607
Anti-inflammatory therapies in sepsis Macias Critical Care 2005; 9:R607
Panels of Biomarkers 60 septic pts (mortality 48.3%) 17 cytokines (IL1β, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12, IL13, IL17, INFγ, G-CSF, GM-CSF, MCP-1, MIP-1, TNFα) Multiplex cytokine kit 1020 measurements 310 (30.4%) undetectable Organ dysfunction (SOFA) IL8, MCP-1 Mortality (small differences) IL1β, IL4, IL6, IL8, MCP-1, G-CSF Severe sepsis (N=14) Septic shock (N=46) IL1β 0.17 1.22 0.01 IL6 1027 5632 0.007 IL7 0.00 8.475 <0.001 IL8 52.63 145.3 0.01 IL10 2.27 27.45 <0.001 IL13 0.27 7.21 0.008 INFγ 0.00 33.1 0.03 MCP-1 6.295 753.9 <0.001 TNFα 0.00 14.46 <0.001 pg/ml p Bozza Critical Care 2007;11:R49
Genomics and sepsis Tang CCM 2009;37:882
Organ dysfunction TNM system/sepsis analogy (Presence of metastasis organ dysfunction) Cancer Metastatic disease influences treatment and prognosis Sepsis Organ dysfunction influences prognosis; treatment?
Organ dysfunction Severity of sepsis & Biomarkers PCT Data from 12 published papers CRP N=158 septic pts (76 documented) r s = 0.18; r 2 s = 0.03; p=0.035 Carrigan Clin Chem 2004;50:1301 Silvestre J et al. ICM 2009 (in press)
Organ Dysfunction Biomarkers N=150 ICU pts N=158 septic pts (76 documented) Castelli Minerva Anestesiol 2006;72:69 Silvestre J et al. ICM 2009 (in press)
PIRO stratification VAP PIRO, N=441 (Lisboa T Chest 2008;134:1208) P Comorbidities, I bacteremia, R systolic BP < 90 mm Hg, O ARDS (score range: 0-4) simple, clinical tool for VAP stratification and predicting ICU mortality (AUC VAP PIRO 0.81 >> APACHE II 0.53) CAP PIRO, N=529 (Rello J CCM 2009 ahead of print) P Comorbidities, age >70 years, I bacteremia, multilobar opacities in x-ray, R shock, severe hypoxemia, O ARDS, acute renal failure (score range: 0-8) simple, clinical tool for CAP stratification and predicting ICU mortality (AUC CAP PIRO 0.88 > IDSA/ATS criteria 0.8, APACHE II 0.75) SAPS 3 PIRO, N=2628 (Moreno R ICM 2008;34:496) P age, location from which the patient was admitted to the ICU, comorbidities, length of stay before ICU admission, reasons for ICU admission, I acquisition of infection, extension of infection, site of infection, and infective agent, R organ dysfunction/failure (score range: 0-114) complex (additional calculations), clinical tool of septic patients stratification and predicting ICU mortality (AUC SAPS 3 PIRO 0.772 > SAPS 3 0.735)
PIRO staging system NO USE OF BIOMARKERS!
Biomarkers Sepsis Risk stratification Treatment guidance procalcitonin
Procalcitonin ProRESP study 243 pts with suspected LRTI Standard, N = 119 PCT guided, N = 124 PCT guided group 0.1µg/l no infection no AB 0.1 0.25µg/l infection unlikely no AB 0.25 0.5µg/l possible infection AB > 0.5µg/l infection AB Re-evaluation 6-24h after admission Christ-Crain Lancet 2004;363:600
Procalcitonin Christ-Crain Lancet 2004;363:600
Procalcitonin ProCAP study 302 pts suspected of CAP AB based on PCT: < 0.1µg/l strongly discouraged 0.1 0.25µg/l discouraged 0.25 0.5µg/l encouraged > 0.5µg/l strongly encouraged Re-evaluation 6-24h after admission Primary end point - AB use Outcome: PCT vs standard Cured 85% vs 85% (p=.65) Mortality 12% vs 13% (p=.73) Christ-Crain AJRCCM 2006;174:84
Procalcitonin ProCOLD study 208 AECB Primary outcome AB exposure Subsequent AB 6 months PCT group (N=102); Standard (N=106) AB based on PCT ( criteria!): 0.1µg/l no infection 0.1 0.25µg/l possible infection > 0.25 µg/l bacterial infection Re-evaluation 6-24h after admission PCT vs standard (6 months) Hospitalization 17.7 vs 20.8 (p=.5) Mortality 4.9 vs 8.5 (p=.4) Stolz Chest 2007;131:9
Procalcitonin antibiotic stewardship ICU setting N=79 (69% respiratory) (39 PCT-guided; 40 control) 203 (72%) pts excluded! PCT-guided stop AB if D1 PCT 1 µg/l reevaluated D5 1) PCT >90% 2) PCT < 0.25 µg/l D1 PCT < 1 µg/l (at least 3d AB) 1) PCT < 0.1 µg/l positive blood cultures at least 5 days AB Mortality (PCT-guided 20.5%;control 20%) Intention to treat analysis - NS PCT-guided AB <4-day in the duration of antibiotic therapy (p=0.003) (N=25!) smaller antibiotic exposure (p=0.0002) <2-day ICU stay (p=0.03) Nobre AJRCCM 2008;177:498
Can Biomarkers be useful in risk stratification and treatment guidance? YES! YES!