Il-6 detection based early diagnosis and prediction of systematic inflammatory response syndrome and sepsis in asymptomatic patients

Abstract

Methods, systems and kits for the early diagnosis or prediction of systemic inflammatory response syndrome (SIRS) including sepsis in asymptomatic patients, such as patients undergoing a surgical intervention, are provided. Some embodiments include a method and system for the detection or diagnosis of SIRS, or detection or diagnosis of a risk to suffer from or develop SIRS, in an asymptomatic patient comprising the steps of determining the level of IL-6 (or a variant thereof) in a sample from the patient; comparing the level of IL-6 (or a variant thereof) to a reference level; detecting or diagnosing SIRS or diagnosing a risk to suffer from or develop SIRS, wherein the sample is isolated at least 2 times at short intervals and the determining and comparing steps are both repeated for each sample. Also provided are methods, systems and kits for therapy monitoring and mortality prediction.

1 . A method of providing a diagnosis of at risk for systemic inflammatory response syndrome (SIRS) or sepsis in an asymptomatic patient, the method comprising the steps of:
 determining a level of IL-6 or a variant thereof in a first sample of the asymptomatic patient, the IL-6 of variant thereof having a sequence identity to the human IL-6 molecule of at least 80% over the entire length of the human IL-6;   determining a level of the IL-6 or the variant thereof in a second sample of the asymptomatic patient, the second sample being isolated from the patient at a time interval of between 15 minutes +/−20% and 12 hours +/−20% after the first sample;   comparing the level of IL-6 or the variant thereof determined in each of said steps of determining to a reference level; and   providing a diagnosis of at risk for systemic inflammatory response syndrome (SIRS) or sepsis if the IL-6 level increases over time.   
     
     
         2 . The method of  claim 1 , wherein the asymptomatic patient is a patient who displays less than 2 symptoms of the symptoms selected from group consisting of: white blood cell count of more than 12,000/μ/L +/−20% or less than about 4000/μ/L +/−20%; a body temperature of more than 38° C. +/−20% or less than 36° C. +/−20%; a heart rate of more than 90 beats/minute +/−20% or a partial pressure of CO 2  of less than 32 mm Hg +/−20%; a respiratory rate of more than 20 breaths/minute +/−20%; and more than 10% immature white blood cells among the counted white blood cells. 
     
     
         3 . The method of  claim 1 , wherein the time interval is of between 1 hour +/−20% and 3 hours +/−20%. 
     
     
         4 . The method of  claim 1 , wherein said step of providing comprises providing a diagnosis of at risk for systemic inflammatory response syndrome (SIRS) or sepsis if the level of IL-6 or the variant thereof determined in said steps of determining is above to the reference level and a diagnosis of not at risk for systemic inflammatory response syndrome (SIRS) or sepsis if the level of IL-6 or the variant thereof determined in said steps of determining is below the reference level. 
     
     
         5 . The method of  claim 1 , wherein the reference level is obtained by multiplying a baseline level of IL-6 or said variant thereof by a factor selected from the group consisting of: at least 50+/−20%; at least 100+/−20%; at least 500+/−20%; and at least 1000+/−20%. 
     
     
         6 . The method of  claim 1 , wherein said steps of determining consist of contacting, in vitro, the first and second samples, respectively, with one of a murine anti-IL-6 monoclonal antibody M-BE8 and a M-23C7. 
     
     
         7 . The method of  claim 1 , wherein said steps of determining consist of contacting, in vitro, the first and second samples, respectively, with one of: an antibody which binds to IL-6 or a fragment or variant thereof; an antibody which binds to IL-6 and can be bound by one of murine anti-IL-6 monoclonal antibody M-BE8, M-23C7, a fragment thereof, and a variant thereof; and a murine anti-IL-6 monoclonal antibody M-BE8 or M-23C7 or a fragment or variant thereof. 
     
     
         8 . The method of  claim 1 , wherein the asymptomatic patient is a patient selected from the group of a trauma patient, a patient with burns, a patient undergoing a treatment, a patient undergoing an invasive treatment, and a patient undergoing a surgical intervention. 
     
     
         9 . The method of  claim 8 , wherein the patient is undergoing an invasive treatment, the first sample being isolated from the patient at least once before the treatment and the second sample being isolated from the patient at least once after the treatment. 
     
     
         10 . The method of  claim 1 , wherein the method further comprises at least one of collecting the first sample from the patient by a minimal invasive step, excludes a surgical step of collecting the second sample, and is an in vitro method. 
     
     
         11 . The method of  claim 1 , wherein said step of providing comprises providing a diagnosis of at risk for systemic inflammatory response syndrome (SIRS) or sepsis if the IL-6 level of the second sample increases by greater than 10 fold over the IL-6 level of the first sample. 
     
     
         12 . A kit adapted for carrying out the method of  claim 1 , comprising:
 i) a means for determining the level of IL-6 or said variant thereof;   ii) a means for comparing the determined level of IL-6 or said variant thereof, with reference levels; and   iii) an instruction for carrying out the method.   
     
     
         13 . A method of monitoring an asymptomatic patient for onset of SIRS, comprising the steps of:
 determining a level of IL-6 or a variant thereof in a sample of the asymptomatic patient, the IL-6 of variant thereof having a sequence identity to the human IL-6 molecule of at least 80% over the entire length of the human IL-6;   comparing the level of IL-6 or said variant thereof determined in said step of determining to a reference level; and   based on said step of comparing, identifying said onset of SIRS if the level of IL-6 determined in said step of determining is greater than the reference level.   
     
     
         14 . The method of  claim 13 , wherein the reference level is obtained by multiplying a baseline level of IL-6 or said variant thereof by a factor selected from the group consisting of: at least 100+/−20%; at least 500+/−20%; and at least 1000+/−20%. 
     
     
         15 . The method of  claim 13 , wherein said steps of determining consist of contacting, in vitro, the first and second samples, respectively, with one of a murine anti-IL-6 monoclonal antibody M-BE8 and a M-23C7.