Untargeted proteomics profiling in sepsis due to fungal and bacterial infections in patients with acute on chronic liver failure: a case-control study.

Acute on Chronic Liver Failure (ACLF) is acatastrophic event in patients with cirrhosis that carries high mortality.Immune paresis observed in ACLF predisposes to multiple infections and sepsisremains the most common reason for admission, multi-organ failures andmortality in such patients. Often, there is a significant overlap in systemicinflammatory response due to ACLF per se (sterile inflammation) and due toinfections (sepsis) that lead to misuse of broad-spectrum antimicrobials; evenin the absence of true sepsis. Moreover, there is a great dilemma indifferentiating fungal sepsis from bacterial sepsis. Also, the understanding asto why certain patients develop bacterial and others develop fungal infectionsremains uncertain. Current diagnostics for sepsis relies on cultures (yield:50% in bacterial and 20-30% in fungal infections) and biomarkers that lacksensitivity, negative predictive value and are often delayed in patients withACLF. Early diagnosis and adequate treatment of sepsis remain an unmet goal inthese patients

A novel technique of untargeted proteomics with a highthroughput strategy of liquid chromatography and mass spectrometry (LC/MS) canidentify whole proteome and the final effectors in any biological system. Itmay help identify unique protein signatures as well as pathways associated witha disease or condition. In this project, we aim to elucidate differences inplasma proteomics and clinical profile in ACLF patients with and without sepsis(bacterial/fungal) and find associations with the final outcomes. In addition,we will ascertain the pathophysiology of sepsis in ACLF using this approach.

The study will be conducted in two phases: discovery andverification. In the discovery phase, the consecutive non-repetitive patientswith ACLF admitted in the department will be serially evaluated for sepsis andfollowed up until transplant/death/discharge/90-days. They will be classifiedinto proven-infection, probable-infection, and no-infection groups. The plasmasamples of microbiologically proven infection and no-infection group will besubjected to proteomic analysis by LC/MS. Quantitative and qualitativedescription with pathways of activation will be ascertained between groups.Subgroup analysis will be done between bacterial and fungal infections,survivors and non-survivors, infection as-precipitant and as-complicationgroups, various grades of ACLF, non-infected ACLF and healthy controls. In theverification phase, the top three uniquely expressed protein makers identifiedin the discovery phase will be validated in the baseline samples of the groups.The outcomes will identify the unique biomarkers of sepsis in ACLF,fungal/bacterial infections and non-survivors in ACLF. It will also decipherthe pathophysiology of sepsis in ACLF and help design diagnostic, prognosticand personalized treatment strategies in these patients.