Abstract
Introduction: Sepsis is a life-threatening complication of a bacterial infection. It is hard to predict which patients with a bacterial infection will develop sepsis, and accurate and timely diagnosis as well as assessment of prognosis is difficult. Aside from antibiotics-based treatment of the causative infection and supportive measures, treatment options have remained limited. Better understanding of the immuno-pathophysiology of sepsis is expected to lead to improved diagnostic and therapeutic solutions.Functional activity of the innate (inflammatory) and adaptive immune response is controlled by a dedicated set of cellular signal transduction pathways, that are active in the various immune cell types. To develop an immune response-based diagnostic assay for sepsis and provide novel therapeutic targets, signal transduction pathway activities have been analyzed in whole blood samples from patients with sepsis.Methods: A validated and previously published set of signal transduction pathway (STP) assays, enabling determination of immune cell function, was used to analyze public Affymetrix expression microarray data from clinical studies containing data from pediatric and adult patients with sepsis. STP assays enable quantitative measurement of STP activity on individual patient sample data, and were used to calculate activity of androgen receptor (AR), estrogen receptor (ER), JAK-STAT1/2, JAK-STAT3, Notch, Hedgehog, TGFβ, FOXO-PI3K, MAPK-AP1, and NFκB signal transduction pathways.Results: Activity of AR and TGFβ pathways was increased in children and adults with sepsis. Using the mean plus two standard deviations of normal pathway activity (in healthy individuals) as threshold for abnormal STP activity, diagnostic assay parameters were determined. For diagnosis of pediatric sepsis, the AR pathway assay showed high sensitivity (77%) and specificity (97%), with a positive prediction value (PPV) of 99% and negative prediction value (NPV) of 50%. For prediction of favorable prognosis (survival), PPV was 95%, NPV was 21%. The TGFβ pathway activity assay performed slightly less for diagnosing sepsis, with a sensitivity of 64% and specificity of 98% (PPV 99%, NPV 39%).Conclusion: The AR and TGFβ pathways have an immunosuppressive role, suggesting a causal relation between increased pathway activity and sepsis immunopathology. STP assays have been converted to qPCR assays for further evaluation of clinical utility for sepsis diagnosis and prediction of prognosis, as well as for prediction of risk at developing sepsis in patients with a bacterial infection. STPs may present novel therapeutic targets in sepsis.
Highlights
Sepsis is a life-threatening complication of a bacterial infection
No consistent differences in androgen receptor (AR) and TGFβ pathway activity scores were observed between men and women (Figures 1F, 2F, and Supplementary Figure 6), between patients categorized as “sepsis” vs. “septic shock” (Figures 1D, 2D, and Supplementary Figure 4), nor between patients categorized as “SAPSII-low” and “SAPSII-high” (Figures 3A, 4A, and Supplementary Figure 7)
No difference was found between patients with gram-negative and grampositive bacterial infections
Summary
Sepsis is a life-threatening complication of a bacterial infection. It is hard to predict which patients with a bacterial infection will develop sepsis, and accurate and timely diagnosis as well as assessment of prognosis is difficult. To develop an immune responsebased diagnostic assay for sepsis and provide novel therapeutic targets, signal transduction pathway activities have been analyzed in whole blood samples from patients with sepsis. Sepsis is a life-threatening infection in which the immune response is dysregulated resulting in multi-organ dysfunction or failure [1]. Sepsis is generally a complication of severe bacterial infection and characterized by a systemic inflammatory response leading to septic shock. Detailed assessment of the functional immune response in a patient with sepsis may enable a personalized treatment approach and improve treatment efficacy. Diagnostic assessment of immune function is currently limited to routine blood measurements, such as numbers of immune cells and inflammation markers (e.g., C-reactive protein), but is not informative on the functional activity state of the various types of immune cells, responsible for the abnormal immune response in a sepsis patient
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