Rapid Detection of Sepsis

The ability to diagnosis sepsis rapidly and accurately in its early stages remains one of the biggest challenges faced by hospitals. Early detection is critical to improved outcomes for patients and more efficient use of health care resources.

R&D Antibodies has discovered and proven that a specific protein is found exclusively in blood of people suffering from the onset of sepsis. This protein, an enzyme called inducible nitric oxide synthase (iNOS), is a new plasma biomarker of the sepsis pathology. R&D Ab® has completed three proof-of-concept clinical trials which included more then 340 study subject and the analysis of more than 1200 blood samples. These clinical studies have convincingly proven our biochemical diagnostic test can detect sepsis early, even before other physiological symptoms appear. In 2010, a $2.6M grant was awarded by the NIH to find the pivotal clinical study to obtain FDA marketing clearance for this new IVD test.

Sepsis has very low Standard Of Care in hospitals

There is currently no rapid accurate diagnostic test for sepsis and severe sepsis. R&D Ab® is striving to change this deplorable situation. We have developed the first accurate IVD test to diagnose the sepsis pathology early. More people die each year of severe sepsis and septic shock that many other major diseases. As a patient's clinical condition deteriorates from sepsis to severe sepsis with organ dysfunction to septic shock with multiple organ failure and an inability to maintain normal blood pressure, their risk of dying from the sepsis pathology increases dramatically. The sooner the sepsis pathology is detected and appropriate therapies applied the better the outcome for that patient.

The detection of iNOS in plasma can be used to initiate current “standard of care” therapies, such as broad spectrum antibiotics and antifungals. Everyone in the sepsis field agrees that the earlier effective treatment can be applied the better the outcome for the patient. Our IVD test detects the onset of the pathology 24 – 48 hours earlier than the attending physicians can see the physiological symptoms of the sepsis pathology.

The superiority of plasma iNOS as compared to other possible biomarkers of sepsis was assessed using the data collected in our third clinical study. The plasma levels for four potential biomarkers of the SIRS/sepsis pathology in the trauma patients who were enrolled in our third clinical study were analyzed by traditional methods for IVD tests even though our study was not designed to answer this type of regulatory question. The 36 normal healthy individuals are depicted as Group A in this chart. The ICU patients who remained SIRS/septic negative throughout the entire study period are Group B in this analysis. The plasma levels of the four potential biomarkers for the ICU patients who became septic during the study period are shown 24 hours before the symptoms of sepsis were recognized by the attending doctors and are Group C in this chart. The plasma concentrations are shown for the confirmed septic patients who were enrolled in our study and who had not received antibiotics prior to enrollment as Group D. Only plasma iNOS is specific for the onset of the SIRS/sepsis pathology since it is the only biomarker that differentiates Group B from Group C and from Group D. A separate analysis has shown that plasma iNOS has a 96% positive predictive value for organ dysfunction that results from an episode of sepsis.

Data from our 3rd clinical trial was analyzed to determine if iNOS could predict organ damage in trauma patients associated with the sepsis pathology (Table below). These analyses showed our IVD test for iNOS predicted hemodynamic, pulmonary and renal dysfunction associated with sepsis for trauma patients, and had a positive predictive value of 96% and negative predictive value of 80%. The sensitivity of the IVD test was calculated to be 88% and the specificity was calculated to be 92%. The PPV, NPV, sensitivity and specificity assay characteristics are remarkable since our trial was not designed to generate data to answer this type of regulatory agency question. Our trials were designed to generate data to answer very basic scientific questions, such as is iNOS present in the plasma of septic patients. Unfortunately, not all the patients in our clinical studies had blood cultures done and the MDs didn’t always note on the patient’s chart if they suspected sepsis. Thus, for some of the patients in our clinical studies it was impossible to correlate plasma iNOS with the sepsis pathology. Therefore, we analyzed our clinical data for trauma patients based upon the functioning of the three organs MDs follow the closest for the onset of sepsis, namely the heart, lungs and kidneys.

Plasma iNOS Predicts Hemodynamic, Pulmonary and Renal
Dysfunction in Trauma Patients

N = 187

 

Heart, Lung or Kidney Dysfunction

 

 

Present

Absent

iNOS

Positive

107

5

 

Negative

15

60

Sensitivity = 88%

PPV = 96%

Specificity = 92%

NPV = 80%

PPV = positive predictive value and NPV = negative predictive value. These analyses were based upon the follow criteria: [1] hemodynamic dysfunction was defined as mean arterial pressure (MAP) < 70 mm Hg or the patient was receiving one or more pressor drugs; or [2] renal dysfunction was defined as blood urea nitrogen (BUN) > 20 mg/dl; or [3] pulmonary dysfunction was defined as a diagnosis of respiratory failure or mechanical ventilation for > 24 hours or SIMV with changes in blood gasses and pH.

 
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