Abstract
BackgroundDengue virus infection causes a wide spectrum of illness, ranging from sub-clinical to severe disease. Severe dengue is associated with sequential viral infections. A strict definition of primary versus secondary dengue infections requires a combination of several tests performed at different stages of the disease, which is not practical.Methods and FindingsWe developed a simple method to classify dengue infections as primary or secondary based on the levels of dengue-specific IgG. A group of 109 dengue infection patients were classified as having primary or secondary dengue infection on the basis of a strict combination of results from assays of antigen-specific IgM and IgG, isolation of virus and detection of the viral genome by PCR tests performed on multiple samples, collected from each patient over a period of 30 days. The dengue-specific IgG levels of all samples from 59 of the patients were analyzed by linear discriminant analysis (LDA), and one- and two-dimensional classifiers were designed. The one-dimensional classifier was estimated by bolstered resubstitution error estimation to have 75.1% sensitivity and 92.5% specificity. The two-dimensional classifier was designed by taking also into consideration the number of days after the onset of symptoms, with an estimated sensitivity and specificity of 91.64% and 92.46%. The performance of the two-dimensional classifier was validated using an independent test set of standard samples from the remaining 50 patients. The classifications of the independent set of samples determined by the two-dimensional classifiers were further validated by comparing with two other dengue classification methods: hemagglutination inhibition (HI) assay and an in-house anti-dengue IgG-capture ELISA method. The decisions made with the two-dimensional classifier were in 100% accordance with the HI assay and 96% with the in-house ELISA.ConclusionsOnce acute dengue infection has been determined, a 2-D classifier based on common dengue virus IgG kits can reliably distinguish primary and secondary dengue infections. Software for calculation and validation of the 2-D classifier is made available for download.
Highlights
Dengue virus (DENV) is a member of the family Flaviviridae, genus Flavivirus, with four antigenically distinct serotypes (DENV-1 to DENV-4)
Once acute dengue infection has been determined, a 2-D classifier based on common dengue virus IgG kits can reliably distinguish primary and secondary dengue infections
The lack of adequate tools to predict whether a patient infected with dengue virus will progress with the benign form or with life-threatening disease has often resulted in a large number of unnecessary and costly hospitalizations, which during dengue outbreaks have led to a public health crisis by creating a shortage of hospital beds [5]
Summary
Dengue virus (DENV) is a member of the family Flaviviridae, genus Flavivirus, with four antigenically distinct serotypes (DENV-1 to DENV-4). Infection with this virus is a growing public health concern in tropical and subtropical regions of the world, with an estimated incidence of 50–100 million cases per year [1]. Dengue virus infection in humans causes a large spectrum of illness ranging from mild sub-clinical disease to a severe and occasionally fatal hemorrhagic clinical form, the dengue hemorrhagic fever (DHF) [2]. Dengue virus infection causes a wide spectrum of illness, ranging from sub-clinical to severe disease. A strict definition of primary versus secondary dengue infections requires a combination of several tests performed at different stages of the disease, which is not practical
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