Androgen receptor pathway activity assay for sepsis diagnosis and prediction of favorable prognosis.

Bouwman, W.; Verhaegh, W.; van de Stolpe, A.

Introduction Sepsis is a life-threatening complication of a bacterial infection. Accurate and timely diagnosis, as well as prognosis-prediction, is difficult. It is hard to predict which patients with a bacterial infection will develop sepsis. Aside from antibiotics-based treatment of the causative infection and circulation-supportive measures, treatment options remain very limited. Better understanding of the immuno-pathophysiology of sepsis may 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 in the various immune cell types. To develop an immune response-based assay for sepsis for diagnostic, prognostic and therapeutic purposes, signaling pathway activities were analyzed in whole blood samples from patients with sepsis. Methods A prevalidated and previously published set of signal transduction pathway (STP) assays was used to analyze public Affymetrix expression microarray data from multiple clinical studies with pediatric and adult patients with sepsis. STP activity measurement is based on computational interpretation of a preselected set of target gene mRNA expression levels. STP assays were used to calculate androgen receptor, estrogen receptor, JAK-STAT1/2, JAK-STAT3, Notch, Hedgehog, TGF{beta}, FOXO-PI3K, MAPK-AP1, and NF{kappa}B signal transduction pathway activity scores for individual patient samples. Results Activity of both AR and TGF{beta} pathways was increased in both children and adults with sepsis. Using the upper threshold of normal pathway activity range as threshold diagnostic assay parameters were determined. For pediatric sepsis diagnosis, the AR pathway assay showed high sensitivity (77%) and specificity (97%), with a PPV of 99% and NPV of 50%. For prediction of favorable prognosis (survival), PPV was 95%, NPV was 21%. The TGF{beta} pathway activity assay performed slightly less for diagnosing sepsis, with a sensitivity of 64% and specificity of 98% (PPV 99%, NPV 39%) Conclusion We have demonstrated potential clinical use of measuring AR and TGF{beta} pathway activity in sepsis patients. Both androgen receptor and TGF{beta} pathways have been described as immunosuppressive pathways, and increased activity in patients with sepsis suggests a causal relation with the immunopathology in sepsis. The AR pathway assay has been converted to a qPCR test for further testing 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. In view of their putative role in sepsis pathophysiology, both the AR and TGF{beta} pathways may present novel drug targets in sepsis.