SIRS and Bacterial Sepsis Discrimination by Biomarkers in ICU
Condition: SIRS; Sepsis; Severe Sepsis; Septic Shock
MeSH terms: Sepsis; Toxemia; Shock, Septic
Study type: Observational

Summary: 
      Aim of the study : The primary aim of the investigators study is to highlight the presence of
      biomarkers (biological indicators of the presence of inflammation or infection) of infectious
      processes during the systemic inflammatory response (SIRS) allowing, first to discriminate
      non-infectious inflammation from infectious processes and secondary to determine the
      microbial pathogen responsive of the infection. For this purpose the investigators will
      conduct a combinatorial approach of several blood markers including usual markers of
      inflammation and other blood and cells markers. Expression of small pieces of RNA (miRNA)
      known to inhibit determined gene expression, will also be analysed in monocytes (a specific
      group of white blood cells involved in the fist line of defences against microbes.

      Study design : For this purpose the investigators will include 300 patients admitted to the
      intensive care unit with suspicion of infection. Serial blood sample will be take for
      biological parameters analysis. Efficiency of each single parameters and of different
      combinations of different markers to determine the presence or absence of infection
      responsive of clinical inflammation will be studied.
    

Detailed description: 
      Aim of the study : The project's main objective is the establishment of the diagnostic
      performance of the association of diagnostic markers of infectious processes linked to the
      pathogen or host during the systemic inflammatory response syndromes (SIRS) in critical care
      patients allowing, first to discriminate non infectious SIRS from sepsis and, secondary to
      determine the microbial pathogen responsive of the inflammation. For this purpose, we will
      conduct a combinatorial approach of several plasma markers including usual markers (CRP, PCT,
      other soluble mediators (soluble TREM-1, IL-6, IL-1Ra, IL-10, CXCL2, CXCL8, CCL2 and CCL5),
      cell markers (CD14 / HLA-DR expression on monocytes and TLR2, 4, 9 expression on NK cells)
      together with modified expression of microRNA (miRNA) in circulating monocytes.

      Study design : This study will include patients admitted to the ICU with SIRS and suspected
      sepsis, according to usual criteria. Infection definition will be based on a combination
      clinical, bacteriological and cyto-or histo-pathological according to the disease involved.

      A serial measurement of biological parameters previously described will be realized from D0
      to D3.

      Evaluation criteria : The primary endpoint is to determine the ability of each individual
      parameter and of the different combination to discriminate between sepsis and noninfectious
      inflammation. The diagnostic performance of biomarkers studied will be done by calculating
      the sensitivity, specificity, positive and negative predictive value of each test alone or in
      combination with respect to the existence of an infection (sepsis) or not (SIRS). According
      to data from the literature and our own experience, the expected proportion of patients with
      sepsis among the holders of SIRS was 50%. The discriminatory ability of each test will be
      performed by using ROC curves and calibration using the Hosmer-Lemeshow several layers of
      increasing severity. The level of service provided is a p-value <5%. There are no plans to
      statistical criteria for stopping the search in case of biological data missing.

      The value of the area under the ROC curve (AUC) of the PCT is 78% (95% CI 69-77). Assuming
      that one of the tests or combinatorial approach will increase the AUC to 85%, the number of
      patients needed for this study is estimated to be 300.

      Conduct of research : Study will be conducted in 5 different sites. Patients admitted with or
      who develop a SIRS during hospitalization will be included. There will be nothing peculiar in
      the therapeutic management and patients will be covert by the international guidelines.

        -  Inclusion criteria:

             -  Patient admitted with or who develop SIRS during ICU hospitalisation

             -  Two or more parameter of the SIRS definition

             -  Patient does not preclude its participation in the study

        -  Non inclusion criteria

             -  Decision of withdrawal or withholding therapeutic interventions

             -  No affiliation to a social security scheme

      The measurement of biological endpoints will be conducted once daily, from D0 (admission) to
      D2 using a blood sample. The study of monocyte expression of miRNA will be performed on a
      portion of the cohort, corresponding to patients selected on the St. Joseph site (intensive
      care unit and surgical intensive care unit) because of complexity to implement, and cost
      level (requiring specific funding).

      Total projected duration of the search: The recruitment period will run for 23 months with
      the aim to include all 300 patients. Patients included in the research will be followed until
      day 28 or day of hospital leaving, if earlier.

      Stopping rules of the study to a patient: patient can discontinue their participation at any
      time during the research.

      Security evaluation : Being a non-interventional study (biological collection) in the usual
      care of patients, no serious adverse event is expected to be related to research.

      Any new data security, potentially leading to a reassessment of the benefits and risks of
      research, or which may be sufficient to consider changes in the conduct of research must be
      reported.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        ICU patients whatever was their admission indication presenting a SIRS with or without
        sepsis.
      
Biospecimen description: 
      blood, urin, CSF, BAL
    
Keywords: SIRS; Sepsis; Severe Sepsis; Septic Shock; Inflammatory processes; Cytokines; HLA-DR; HLA type II; Chemokines; TLR expression; mRNA expression in whole blood; Bacterial DNA detection; Prognosis factors; Infection; Diagnosis