Prognostic Biomarkers in Invasive Candidiasis

About This Grant

Abstract There remains an urgent need for expanded understanding of the pathophysiology of invasive fungal infections (IFI), and improved tools for diagnosis and management of these devastating diseases. Invasive candidiasis alone causes significant morbidity and mortality, especially in solid organ transplant patients where up to 40% of these infections result in death. Given the unacceptably high mortality rates, it is a priority to identify patients who may need more aggressive antifungal treatment or surgical debridement. Conversely, earlier cessation of antifungal therapy in patients deemed at lower risk of infective sequelae also reduces risk of medication interaction (particularly between immunosuppressants and antifungal therapy), side-effects, and antifungal resistance. Despite this, there are limited tools to accurately diagnose and predict the severity and outcomes of these infections. Microbial pathogen-based measures are slow, poorly sensitive, reliant on a high volume of circulating pathogen, and poorly suited to define treatment response. We and others have developed compelling evidence that examination of transcriptional responses in circulating immune cells can provide solutions to these dilemmas. Utilization of host gene expression patterns as biomarkers is a promising approach with proven efficacy as a diagnostic and prognostic tool in a myriad of infectious and noninfectious syndromes. We have previously developed a gene expression signature that accurately diagnoses Candidemia with a high degree of accuracy (auROC 0.94). In this project we proposed to utilize this diagnostic signature, made up of canonical elements of the immune response to Candida spp, to define the longitudinal evolution of the host response to invasive candidiasis, in order to develop prognostic markers and correlates of treatment response. Serial blood samples of patients with a confirmed diagnosis of invasive candidiasis from three pre-existing biobanks will be utilized. We will perform bulk RNA- sequencing on whole blood samples, and expression patterns (or signatures) will be described and correlated with clinical outcomes, specifically time to resolution, disease progression and mortality. Results of these endeavors will support development of PCR-based noninvasive diagnostics that offer earlier, more directed (and thus more effective) therapy, and reduce the need for potentially harmful empiric antimicrobial agents, thus offering a true paradigm shift in the way invasive candida infections are managed in these high-risk populations.