Diagnosis of sepsis and systemic inflammatory response syndrome

Abstract

The present invention relates a method for the diagnosis, prediction or risk stratification for mortality and/or disease outcome of a subject that has or is suspected to have sepsis, comprising determining the presence and/or level of antitrypsin (ATT) or fragments thereof in a sample taken from said subject and/or determining the presence and/or level of transthyretin (TTR) or fragments thereof, wherein the presence and/or level of ATT and/or TTR or fragments thereof is correlated with an increased risk of mortality and, wherein said increased risk of mortality and/or poor disease outcome is given if the level of ATT is below a certain cut-off value and/or the level of fragments thereof is above a certain cut-off value and/or said increased risk of mortality and/or poor disease outcome is given if the level of TTR is below a certain cut-off value and/or the level of fragments thereof is below a certain cut-off value. The invention relates in general to the use of ATT and/or TTR or its fragments for the diagnosis of sepsis, and to nucleotides of SEQ ID NO. 2 to 14.

1 . A method for the diagnosis, prediction or risk stratification for mortality or disease outcome of a subject that has or is suspected to have sepsis, comprising the steps of (a)-(c):
 (a) determining the level of antitrypsin (ATT) or fragments thereof in a sample taken from said subject,   (b) wherein the level of ATT or fragments thereof is correlated with an increased risk of mortality or poor disease outcome and, wherein   (c) said increased risk of mortality or poor disease outcome is given if the level of ATT is below a certain cut-off value and/or the level of fragments thereof is above a certain cut-off value;
 and/or comprising the steps of (d)-(f): 
   (d) determining the level of transthyretin (TTR) or fragments thereof in a sample taken from said subject,   (e) wherein the level of TTR or fragments thereof is correlated with an increased risk of mortality or poor disease outcome and, wherein   (f) said increased risk of mortality or poor disease outcome is given if the level of TTR or fragments thereof is below a certain cut-off value.   
     
     
         2 . A method according to  claim 1 , wherein the level of ATT or fragments thereof and/or the level of TTR or fragments thereof may preferably be correlated with the prediction or risk stratification for mortality or disease outcome by a method which is selected from the following alternatives:
 (a) correlation with respect to the median of the level in an ensemble of pre-determined samples,   (b) correlation with respect to quantiles in an ensemble of pre-determined samples, and   (c) correlation with a mathematical model, such as for example Cox Regression.   
     
     
         3 . A method according to any of the preceding claims,
 (a) wherein the cut-off value of the level of ATT is about 2 g/l, and may deviate depending on the patient analysed by about 20%;   (b) wherein the cut-off value of the level of TTR is about 10 mg/dl, and may deviate depending on the patient analysed by about 20%   
     
     
         4 . A method according to any of the preceding claims, wherein the level of ATT or fragments thereof and/or the level of TTR or fragments thereof is correlated with an increased risk for mortality
 (a) for ATT below the median level of the normal population   (b) for ATT fragments above the median level of the normal population; and   (c) for TTR and fragments thereof below the median level of the normal population.   
     
     
         5 . A method according to any of the preceding claims comprising the steps of (a)-(c):
 (a) taking a sample from a subject;   (b) determining the level of ATT or fragments thereof; and   (c) correlating the level of ATT or fragments thereof with a perquantile risk of mortality or survival;   
       and/or comprising the steps of (d)-(f):
 (d) taking a sample from a subject; 
 (e) determining the level of TTR or fragments thereof; and 
 (f) correlating the level of TTR or fragments thereof with a perquantile risk of mortality or survival. 
 
     
     
         6 . A method according to any of the preceding claims, wherein a sample is taken at one or more of the following time points: when the subject is first admitted to a medical institution or in the ambulance, when the subject is in the emergency room, when the subject is in the intensive care unit, before treatment, after initiation of treatment, 24 hours after initiation of treatment, 48 hours after initiation of treatment and/or 72 hours after initiation of treatment. 
     
     
         7 . A method according any of the preceding claims, wherein the subject is under a condition selected from the group comprising: a preliminary form of infection like sepsis, escalated forms of infection like sepsis, severe sepsis and septic shock. 
     
     
         8 . A method according to any of the preceding claims, wherein in addition to prediction or risk stratification for mortality or disease outcome of said subject the determination of the level of ATT or fragments thereof and/or of the level of TTR or fragments thereof in a sample taken from said subject, is used to differentially diagnose whether said subject is likely to have systemic inflammation (SIRS), initial sepsis, severe sepsis or septic shock. 
     
     
         9 . A method according to any of the preceding claims, wherein said sample is selected from a group comprising a plasma sample, a serum sample, a whole blood sample, a blood sample or fractions thereof, a lymphatic fluid sample, a urine sample and an extract of any of the aforementioned samples. 
     
     
         10 . A method of medical decision making for individual patient therapy related to the severity of the disease by monitoring therapy response to a certain drug in a subject with sepsis or a sepsis like disease, comprising the steps of (a)-(d):
 (a) taking at least two samples from said subject at various time points selected from the group of,
 i. before initiation of therapy, 
 ii. after initiation of therapy, and/or 
 iii. at one or more further time point; 
   (b) determining the level of ATT or fragments thereof in said sample,   (c) associating the level of ATT or fragments thereof in said samples with a positive or a negative response to said certain drug;   (d) said positive response is given if the level of ATT increases during drug treatment and/or if the level of ATT fragments decreases during drug treatment;   
       and/or comprising the steps of (e)-(h):
 (e) taking at least two samples from said subject at various time points selected from the group of,
 i. before initiation of therapy, 
 ii. after initiation of therapy, and/or 
 iii. at one or more further time point; 
 
 (f) determining the level of TTR or fragments thereof in said sample, 
 (g) associating the level of TTR or fragments thereof in said samples with a positive or a negative response to said certain drug; 
 (h) said positive response is given if the level of TTR or fragments thereof increases during drug treatment. 
 
     
     
         11 . A method for differentially diagnosing a disease in a subject, wherein the disease is selected from the group comprising (i) systemic inflammation (SIRS), (ii) initial sepsis, (iii) severe sepsis or (iv) septic shock, the method comprising the steps of (a)-(d):
 (a) determining the level of ATT or fragments thereof in a sample taken from said subject, and   (b) correlating the level of ATT or fragments thereof to (i) initial sepsis, (ii) severe sepsis or (iii) septic shock, and   (c) wherein said correlation of the level of ATT or fragments thereof to (i) initial sepsis, (ii) severe sepsis or (iii) septic shock is given if the level of ATT is below a certain cut-off value and/or the level of ATT proteolytic fragments is above a certain cut-off value;   
       and/or comprising the steps of (d)-(f):
 (d) determining the level of TTR or fragments thereof in a sample taken from said subject, and 
 (e) correlating the level of TTR or fragments thereof to (i) initial sepsis, (ii) severe sepsis or (iii) septic shock, 
 (f) wherein said correlation of the level of TTR or fragments thereof to (i) initial sepsis, (ii) severe sepsis or (iii) septic shock is given if the level of TTR of fragments thereof is below a certain level. 
 
     
     
         12 . A kit for diagnosis of sepsis or predicting the prognosis in a patient with sepsis, comprising:
 (a) an antibody specific for ATT or fragments thereof and/or TTR or fragments thereof, and   (b) standard data showing the correlation between the level of ATT or fragments thereof contained in samples and prognosis and/or standard data showing the correlation between the level of TTR or fragments thereof and prognosis, and optionally   (c) a manual.   
     
     
         13 . A polypeptide having the sequence of any one of SEQ ID NOS. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. 
     
     
         14 . A polynucleotide encoding a polypeptide according to  claim 13 . 
     
     
         15 . An antibody specifically binding to a polypeptide according to  claim 13 . 
     
     
         16 . Use of a polypeptide according to  claim 13  and/or SEQ ID NO. 1 in a method for diagnosing sepsis.