Abstract
BackgroundCandidemia is one of the most common nosocomial bloodstream infections in the United States, causing significant morbidity and mortality in hospitalized patients, but the breadth of the host response to Candida infections in human patients remains poorly defined.MethodsIn order to better define the host response to Candida infection at the transcriptional level, we performed RNA sequencing on serial peripheral blood samples from 48 hospitalized patients with blood cultures positive for Candida species and compared them to patients with other acute viral, bacterial, and non-infectious illnesses. Regularized multinomial regression was utilized to develop pathogen class-specific gene expression classifiers.ResultsCandidemia triggers a unique, robust, and conserved transcriptomic response in human hosts with 1641 genes differentially upregulated compared to healthy controls. Many of these genes corresponded to components of the immune response to fungal infection, heavily weighted toward neutrophil activation, heme biosynthesis, and T cell signaling. We developed pathogen class-specific classifiers from these unique signals capable of identifying and differentiating candidemia, viral, or bacterial infection across a variety of hosts with a high degree of accuracy (auROC 0.98 for candidemia, 0.99 for viral and bacterial infection). This classifier was validated on two separate human cohorts (auROC 0.88 for viral infection and 0.87 for bacterial infection in one cohort; auROC 0.97 in another cohort) and an in vitro model (auROC 0.94 for fungal infection, 0.96 for bacterial, and 0.90 for viral infection).ConclusionsTranscriptional analysis of circulating leukocytes in patients with acute Candida infections defines novel aspects of the breadth of the human immune response during candidemia and suggests promising diagnostic approaches for simultaneously differentiating multiple types of clinical illnesses in at-risk, acutely ill patients.
Highlights
Candidemia is one of the most common nosocomial bloodstream infections in the United States, causing significant morbidity and mortality in hospitalized patients, but the breadth of the host response to Candida infections in human patients remains poorly defined
To define the utility of host-based biomarkers for diagnosis of candidemia in human subjects and the ability of such a classifier to discriminate between fungal infection and other pathogen classes, we examined transcriptomic responses in a cohort of patients with culture-confirmed Candida blood infection compared with other acute infectious and non-infectious illnesses
Forty-eight hospitalized patients with candidemia were enrolled through the Infectious Diseases Data and Specimen Repository program at Duke University (Durham, NC) at the time of first blood culture positivity for Candida spp. between the years 2011 and 2014
Summary
Candidemia is one of the most common nosocomial bloodstream infections in the United States, causing significant morbidity and mortality in hospitalized patients, but the breadth of the host response to Candida infections in human patients remains poorly defined. The gold standard diagnostic test for candidemia is the blood culture. Blood cultures suffer from variable sensitivity and a delay to positivity [11,12,13]. This has led to the development of additional laboratory markers of fungal infection, including serum 1, 3-beta-D-glucan (BDG)—a cell wall component of many yeasts and molds. Due to the inadequacies in currently available methods, improved diagnostic approaches are clearly needed
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