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Dengue Severity Predicted by Gene Expression Signature in Patient Blood

NEW YORK (GenomeWeb) – A team from the US and Colombia has identified a blood gene expression signature that shows promise for finding the dengue virus cases that are most prone to progress to severe infections, both in retrospective and prospective patient cohorts.

The researchers brought together whole blood or peripheral blood mononuclear cell (PBMC) gene expression findings from seven prior studies, spanning nearly 450 dengue virus-infected individuals from five countries. Using these data and an integrated analytical framework, they narrowed in on 20 genes with expression that varied in individuals with severe dengue infections.

As reported online today in Cell Reports, the team found that the 20-gene signature could also discern severe dengue cases in retrospective studies involving 84 infected individuals from three countries and in a prospective analysis of longitudinal samples from nearly three dozen dengue patients from Colombia.

In those cohorts, the investigators reported, the expression profiles of the 20 genes in question picked up severe dengue cases with 76 percent specificity and 100 percent sensitivity. If those results hold in future validation studies, they suggested that it may eventually be possible to pursue a prognostic assay that incorporates the blood-based expression signature.

"With a larger cohort, there's also an opportunity to refine the signature; we could potentially bring down the number of genes," co-senior author Shirit Einav, an infectious diseases and geographic medicine researcher at Stanford University, said in a statement. "There's no perfect test, but we're encouraged by these numbers, and this is already performing better than the current standard of care."

Late-stage clinical features are typically used to watch for progression from acute dengue virus infection to severe cases marked by bleeding, shock, organ failure, and other symptoms, the team explained. But this approach is often ineffective, prompting interest in blood-based markers for finding those at risk of the most dangerous forms of dengue.

"[S]ome patients end up admitted to the hospital unnecessarily, while others are discharged prematurely," Einay said.

Using an integrated multi-cohort analysis approach that "integrates biologically heterogeneous datasets to identify robust host gene signatures that are generalizable and prospectively validated," the researchers analyzed genome-wide expression data for 446 dengue virus patients from seven discovery datasets.

The team's initial analysis highlighted 59 genes with significant expression differences in the dengue hemorrhagic fever and/or dengue shock syndrome patients compared to individuals with uncomplicated dengue fever. With additional computational analyses, the set was whittled down to a set of 17 genes with lower-than-usual expression and three over-expressed genes in the severe dengue patients.

After validating the 20-gene signature in three retrospective cohorts, the researchers followed 34 Colombians with dengue fever, including eight individuals who developed severe dengue and 17 patients with Zika co-infections or other "warning signs." With high-throughput, microfluidic-based quantitative RT-PCR assays, they profiled expression of the 20-gene signature in blood samples from these patients, successfully identifying severe dengue fever cases with or without additional warning signs.

In a series of follow-up experiments, the team looked at the relationship between the severe dengue-associated expression signature and the proportion of different blood cell types. But while the suspicious signature was over-represented in certain blood cell types, the authors did not see shifts in the proportions of these cells, hinting that the expression changes identified are caused by shifts in expression within the blood cells.

"The roles of the 20 gene products in the pathogenesis of severe dengue will be studied in the future," the authors wrote, noting that many of them are implicated in various aspects of antiviral innate immune responses.