Research Article: Corticosteroids for Dengue – Why Don’t They Work?

Date Published: December 12, 2013

Publisher: Public Library of Science

Author(s): Thi Hanh Tien Nguyen, Than Ha Quyen Nguyen, Tuan Trung Vu, Jeremy Farrar, Truong Long Hoang, Thi Hoai Tam Dong, Van Ngoc Tran, Khanh Lam Phung, Marcel Wolbers, Stephen S. Whitehead, Martin L. Hibberd, Bridget Wills, Cameron P. Simmons, Scott B. Halstead.

Abstract: BackgroundDysregulated immune responses may contribute to the clinical complications that occur in some patients with dengue.FindingsIn Vietnamese pediatric dengue cases randomized to early prednisolone therapy, 81 gene-transcripts (0.2% of the 47,231 evaluated) were differentially abundant in whole-blood between high-dose (2 mg/kg) prednisolone and placebo-treated patients two days after commencing therapy. Prominent among the 81 transcripts were those associated with T and NK cell cytolytic functions. Additionally, prednisolone therapy was not associated with changes in plasma cytokine levels.ConclusionThe inability of prednisolone treatment to markedly attenuate the host immune response is instructive for planning future therapeutic strategies for dengue.

Partial Text: Dengue is an acute, mosquito-borne illness caused by any of the four types of dengue virus (DENV1-4). There are an estimated 390 million symptomatic and asymptomatic infections per year [1]. The clinical evolution is variable, ranging from non-specific febrile illness to severe and sometimes fatal disease. One of the commonest complications observed is a transient vasculopathy, manifesting as increased vascular permeability with altered haemostasis, typically 3–6 days after fever onset. Dysregulated host immune responses, particularly those associated with secondary infections, are widely held to contribute mechanistically to the vasculopathy that characterizes severe dengue [2]. No specific therapies or licensed vaccines are currently available and management relies on assiduous supportive care.

The current study was linked to a randomized controlled trial of early prednisolone therapy for dengue that demonstrated the safety of prednisolone but did not provide evidence of improved clinical or laboratory outcomes for patients [3]. Here we provide insights into these trial findings by identifying a surprisingly small prednisolone-associated footprint (just 81 transcripts differentially abundant from 47,231 evaluated) on the whole-blood gene expression profile that manifests during DENV infection. Furthermore, acute-phase plasma cytokine concentrations were not measurably attenuated by prednisolone treatment. The limited immunomodulation achieved by prednisolone is consistent with it having negligible measurable benefits in the clinical trial in which this current study was nested.