Plasma cell-free DNA: a potential biomarker for early prediction of severe dengue

Nguyen Thi Ngoc Phuong,Vu Thi Que Huong,Tran Van An,Shyam Prakash Dumre,Le Hong Phuc,Thuan Minh Tieu,Mostafa Ebraheem Morra,Shusaku Mizukami,Mohamed Gomaa Kamel,Nguyen Tien Huy,Lan Nguyen Weiss,Nguyen Van Thuong,Tran Thi Ngoc Ha,Kenji Hirayama,Dao Huy Manh

doi:10.1186/s12941-019-0309-x

Abstract

BackgroundConsiderable progress has been made in dengue management, however the lack of appropriate predictors of severity has led to huge number of unwanted admissions mostly decided on the grounds of warning signs. Apoptosis related mediators, among others, are known to correlate with severe dengue (SD) although no predictive validity is established. The objective of this study was to investigate the association of plasma cell-free DNA (cfDNA) with SD, and evaluate its prognostic value in SD prediction at acute phase.MethodsThis was a hospital-based prospective cohort study conducted in Vietnam. All the recruited patients were required to be admitted to the hospital and were strictly monitored for various laboratory and clinical parameters (including progression to SD) until discharged. Plasma samples collected during acute phase (6–48 h before defervescence) were used to estimate the level of cfDNA.ResultsOf the 61 dengue patients, SD patients (n = 8) developed shock syndrome in 4.8 days (95% CI 3.7–5.4) after the fever onset. Plasma cfDNA levels before the defervescence of SD patients were significantly higher than the non-SD group (p = 0.0493). From the receiver operating characteristic (ROC) curve analysis, a cut-off of > 36.9 ng/mL was able to predict SD with a good sensitivity (87.5%), specificity (54.7%), and area under the curve (AUC) (0.72, 95% CI 0.55–0.88; p = 0.0493).ConclusionsTaken together, these findings suggest that cfDNA could serve as a potential prognostic biomarker of SD. Studies with cfDNA kinetics and its combination with other biomarkers and clinical parameters would further improve the diagnostic ability for SD.

Highlights

Considerable progress has been made in dengue management, the lack of appropriate predictors of severity has led to huge number of unwanted admissions mostly decided on the grounds of warning signs
We aimed to investigate the association of plasma cell-free DNA (cfDNA) with severe dengue (SD), and evaluate whether cfDNA could be a predictive biomarker for SD at early acute phase of illness
No significant difference was observed between SD and nonSD patients for most demographic and clinical features, and laboratory findings (DENV serotypes, platelet counts)

Summary

Introduction

Considerable progress has been made in dengue management, the lack of appropriate predictors of severity has led to huge number of unwanted admissions mostly decided on the grounds of warning signs. The use of ‘warning signs’ has contributed significantly in clinical management, it is difficult to accurately recognize SD patients in early phase of disease using these warnings signs [6, 7]. The use of warning signs as proxy indicators for admission has added extra burden to the hospitals, and more importantly, some dengue patients without warning signs may progress to SD—a serious drawback of this system [2, 3]. From the patient management point of view, early prediction of dengue severity could be a game changer in reducing hospital burden and mortality while enhancing the quality of care to the severe patients [8]. There have been growing efforts made on the discovery of predictors based on severity biomarkers alone or in combination with dengue clinical signs [8,9,10,11], these are either not validated clinically or the evidence is not adequate for clinical application [12,13,14]

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