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BackgroundDengue is a public health problem in many countries. Rapid diagnosis of dengue can assist patient triage and management. Detection of the dengue viral protein, NS1, represents a new approach to dengue diagnosis.Methodology/Principal FindingsThe sensitivity and specificity of the Platelia NS1 ELISA assay and an NS1 lateral flow rapid test (LFRT) were compared against a gold standard reference diagnostic algorithm in 138 Vietnamese children and adults. Overall, the Platelia NS1 ELISA was modestly more sensitive (82%) than the NS1 LFRT (72%) in confirmed dengue cases. Both ELISA and LFRT assays were more sensitive for primary than secondary dengue, and for specimens collected within 3 days of illness onset relative to later time points. The presence of measurable DENV-reactive IgG and to a lesser extent IgM in the test sample was associated with a significantly lower rate of NS1 detection in both assays. NS1 positivity was associated with the underlying viraemia, as NS1-positive samples had a significantly higher viraemia than NS1-negative samples matched for duration of illness. The Platelia and NS1 LFRT were 100% specific, being negative in all febrile patients without evidence of recent dengue, as well as in patients with enteric fever, malaria, Japanese encephalitis and leptospirosis.Conclusions/SignificanceCollectively, these data suggest NS1 assays deserve inclusion in the diagnostic evaluation of dengue patients, but with due consideration for the limitations in patients who present late in their illness or have a concomitant humoral immune response.

The pathophysiological basis of hemorrhage in dengue infections remains poorly understood, despite the increasing global importance of these infections. A large prospective study of 167 Vietnamese children with dengue shock syndrome documented only minor prolongations of prothrombin and partial thromboplastin times but moderate to severe depression of plasma fibrinogen concentrations. A detailed study of 48 children revealed low plasma concentrations of the anticoagulant proteins C, S, and antithrombin III, which decreased with increasing severity of shock, probably because of capillary leakage. Concurrent increases in the levels of thrombomodulin, tissue factor, and plasminogen activator inhibitor type 1 (PAI-1) indicated increased production of these proteins. Thrombomodulin levels suggestive of endothelial activation correlated with increasing shock severity, whereas PAI-1 levels correlated with bleeding severity. Dengue virus can directly activate plasminogen in vitro. Rather than causing true disseminated intravascular coagulation, dengue infection may activate fibrinolysis primarily, degrading fibrinogen directly and prompting secondary activation of procoagulant homeostatic mechanisms.

Japanese encephalitis (JE) causes at least 10 000 deaths each year. Death is presumed to result from infection, dysfunction and destruction of neurons. There is no antiviral treatment. Seizures and raised intracranial pressure (ICP) are potentially treatable complications, but their importance in the pathophysiology of JE is unknown. Between 1994 and 1997 we prospectively studied patients with suspected CNS infections referred to an infectious disease referral hospital in Ho Chi Minh City, Vietnam. We diagnosed Japanese encephalitis virus (JEV), using antibody detection, culture of serum and CSF, and immunohistochemistry of autopsy material. We observed patients for seizures and clinical signs of brainstem herniation, measured CSF opening pressures (OP) and, on a subset of patients, performed EEGs. Of 555 patients with suspected CNS infections, 144 (26%) were infected with JEV (134 children and 10 adults). Seventeen (12%) patients died and 33 (23%) had severe sequelae. Of the 40 patients with witnessed seizures, 24 (62%) died or had severe sequelae, compared with 26 (14%) of 104 with no witnessed seizures [odds ratio (OR) 4.50, 95% confidence interval (CI) 1.94-10.52, P < 0.0001]. Patients in status epilepticus (n = 25), including 15 with subtle motor seizures, were more likely to die than those with other seizures (P = 0.003). Patients with seizures were more likely to have an elevated CSF OP (P = 0.033) and to develop brainstem signs compatible with herniation syndromes (P < 0.0001). Of 11 patients with CSF OP > or =25 cm, five (46%) died, compared with seven (9%) of 80 patients with lower pressures [OR 8.69, 95% CI 1.73-45.39, P = 0.005). Of the 50 patients with a poor outcome, 35 (70%) had signs compatible with herniation syndromes (including 19 with signs of rostro-caudal progression), compared with nine (10%) of those with better outcomes (P < 0.0001). Of 11 patients with CSF OP > or =25 cm, five (46%) died, compared with seven (9%) of 80 patients with lower pressures (OR 8.69, 95% CI 1.73-45.39, P = 0.005). The combination of coma, multiple seizures, brainstem signs and illness for 7 or more days was an accurate predictor of outcome, correctly identifying 42 (84%) of 50 patients with a poor outcome and 82 (87%) of 94 with a better outcome. These findings suggest that in JE, seizures and raised ICP may be important causes of death. The outcome may be improved by measures aimed at controlling these secondary complications.