Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances.

Cornelia A M Van De Weg,Rosalba M Brouns,Joost C M Meijers,Eric C M Van Gorp,Cláudio S Pannuti,Henk-Jan Van Den Ham,Riemsdijk W A Van Den Berg,Albert D M E Osterhaus,Byron E E Martina,Esper G Kallas,Mihai G Netea,Ralph M H G Huits

doi:10.1371/journal.pntd.0003214

Abstract

BackgroundDuring a dengue outbreak on the Caribbean island Aruba, highly elevated levels of ferritin were detected in dengue virus infected patients. Ferritin is an acute-phase reactant and hyperferritinaemia is a hallmark of diseases caused by extensive immune activation, such as haemophagocytic lymphohistiocytosis. The aim of this study was to investigate whether hyperferritinaemia in dengue patients was associated with clinical markers of extensive immune activation and coagulation disturbances.Methodology/Principal FindingsLevels of ferritin, standard laboratory markers, sIL-2R, IL-18 and coagulation and fibrinolytic markers were determined in samples from patients with uncomplicated dengue in Aruba. Levels of ferritin were significantly increased in dengue patients compared to patients with other febrile illnesses. Moreover, levels of ferritin associated significantly with the occurrence of viraemia. Hyperferritinaemia was also significantly associated with thrombocytopenia, elevated liver enzymes and coagulation disturbances. The results were validated in a cohort of dengue virus infected patients in Brazil. In this cohort levels of ferritin and cytokine profiles were determined. Increased levels of ferritin in dengue virus infected patients in Brazil were associated with disease severity and a pro-inflammatory cytokine profile.Conclusions/SignificanceAltogether, we provide evidence that ferritin can be used as a clinical marker to discriminate between dengue and other febrile illnesses. The occurrence of hyperferritinaemia in dengue virus infected patients is indicative for highly active disease resulting in immune activation and coagulation disturbances. Therefore, we recommend that patients with hyperferritinaemia are monitored carefully.

Highlights

Outbreaks of dengue virus (DENV) infection have become more frequent in the American and Caribbean region, even threatening to spread in the United States [1]
Ferritin levels are increased in inflammatory conditions, but in this study we found that ferritin levels were much higher in dengue virus infected patients than in patients with other febrile illnesses
This indicates that ferritin could be used as a marker to discriminate between dengue and other febrile diseases

Summary

Introduction

Outbreaks of dengue virus (DENV) infection have become more frequent in the American and Caribbean region, even threatening to spread in the United States [1]. Brazil is the country with most reported dengue cases in the Americas. DENV-2 outbreak in 2010 caused more than 34.000 cases and 64 deaths in the State of Sao Paulo, Brazil [2]. During a dengue outbreak on the Caribbean island Aruba, highly elevated levels of ferritin were detected in dengue virus infected patients. Ferritin is an acute-phase reactant and hyperferritinaemia is a hallmark of diseases caused by extensive immune activation, such as haemophagocytic lymphohistiocytosis. The aim of this study was to investigate whether hyperferritinaemia in dengue patients was associated with clinical markers of extensive immune activation and coagulation disturbances

Objectives

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Discussion

Conclusion