Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: a randomized, placebo-controlled trial.

(See the Editorial Commentary by Barrett on pages 1225–6.) Dengue is the most common vector-borne viral infection of humans, with around 50 million infections estimated to occur annually and some 2.5 billion people living in areas of risk [1]. A broad spectrum of disease manifestations is seen, ranging from asymptomatic infection to a systemic plasma leakage syndrome typically accompanied by thrombocytopenia and coagulation derangements. Severe plasma leakage may progress to life-threatening dengue shock syndrome (DSS). Globally the burden of severe disease falls primarily on children, and dengue ranks among the leading causes of hospitalization and death for pediatric populations in Asia [1]. Currently neither vaccines nor effective antiviral agents are available and treatment remains supportive with particular emphasis on careful fluid management during the period of plasma leakage [2]. Relatively little is known about the specific mechanisms responsible for the microvascular dysfunction that results in plasma leakage. Although occasionally reported during primary infections, complications such as DSS are strongly associated with sequential or secondary infections [3–5]. Antibody-dependent enhancement resulting in increased viral replication is one factor thought to underlie this phenomenon [6–8], although a variety of other mechanisms likely also contribute to the final disease phenotype [9–13]. Severe complications rarely develop until 4–5 days after fever onset, at a time when intrinsic viral clearance mechanisms have reduced measurable plasma viremia to low levels [14], suggesting that immunopathogenic responses triggered by the virus are crucial [8, 15]. Although no specific pathway has been identified linking such immunopathogenic events with definitive effects on the microvasculature, preliminary evidence points to transient disruption of the surface glycocalyx, a matrix of proteoglycans and glycosaminoglycans lining the vascular endothelium that regulates microvascular filtration [16–18]. Corticosteroids are highly effective anti-inflammatory agents, frequently employed as adjunctive therapy in disease states where the host immune response is thought to contribute significantly to disease pathogenesis. In the 1980s parenteral steroids were used to treat patients with DSS in several small studies, but without evidence of benefit [19–21]. However, for established shock, recent research indicates that steroid use is only helpful in patients with inadequate cortisol responses [22, 23]. Among patients with less severe sepsis there is some evidence that early administration of corticosteroids improves outcome and/or reduces the need for hospitalization [24, 25]. There is also a growing body of work indicating that steroids modulate the function of the endothelial glycocalyx and may prevent damage to this layer [26, 27]. Extensive experience has been gained using short-course oral steroid therapy to suppress the inflammatory response associated with acute asthma, and children now commonly receive 1–2 mg/kg oral prednisolone for 3 days at the onset of an exacerbation [28–30]. Side effects are rarely reported, although there have been concerns regarding behavioral disturbance with 2 mg/kg doses, and the trend is now toward using lower doses [31–33]. Because DSS occurs around the fifth day of illness, intervention with steroids early in infection may prevent or ameliorate the severity of this serious complication. Preliminary evidence indicates that corticosteroids do not increase dengue viral replication in cell culture (M. Hibberd, PhD, Genome Institute of Singapore), and no important adverse effects were reported in the original studies of steroid therapy for DSS. However, before considering a large-scale efficacy trial we wished to assess whether immunomodulation during the viremic phase interferes with viral clearance mechanisms. Thus the primary objective of this study was to assess the safety of short-course oral corticosteroid therapy used early in the evolution of acute dengue infection. In addition we investigated potential dose-response effects of corticosteroids in relation to the clinical and virological safety parameters examined.