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  • Publication
    An evidence-based algorithm for early prognosis of severe dengue in the outpatient setting.
    (2016-12-28) Nguyen, MT ; Simmons, Cameron ; Ho, TN ; Nguyen, VVC ; Nguyen, TH ; Ha, MT ; Ta, VT ; Nguyen, LDH ; Phan, L ; Han, KQ ; Duong, THK ; Tran, NBC ; Bridget, W ; Wolbers, M ; Simmons, CP
    BACKGROUND: Early prediction of severe dengue could significantly assist patient triage and case management METHODS: We prospectively investigated 7563 children with ≤3 days of fever recruited in the outpatient departments of six hospitals in southern Vietnam between 2010 and 2013. The primary endpoint of interest was severe dengue (2009 WHO Guidelines) and pre-defined risk variables were collected at the time of enrolment to enable prognostic model development. RESULTS: The analysis population comprised 7544 patients, of whom 2060 (27.3%) had laboratory-confirmed dengue and nested amongst these were 117 (1.5%) severe cases. In the multivariate logistic model a history of vomiting, lower platelet count, elevated aspartate aminotransferase (AST), positivity in the NS1 rapid test and viremia magnitude were all independently associated with severe dengue. The final prognostic model (Early Severe Dengue identifier- ESDI) included history of vomiting, platelet count, AST level and NS1 rapid test status. CONCLUSIONS: The ESDI had acceptable performance features (AUC= 0.95, sensitivity 87% (95%CI: 80-92%), specificity 88% (95%CI: 87-89%), positive predictive value 10% (95%CI: 9-12%), negative predictive value of 99.8% (95%CI: 99.6-99.9%)) in the population of all 7563 enrolled children. A score-chart, for routine clinical use, was derived from the prognostic model and could improve triage and management of children presenting with fever in dengue endemic areas.
  • Publication
    Genetic variants of MICB and PLCE1 and associations with the laboratory features of dengue
    (2017-06-09) Simmons, Cameron
    BACKGROUND: A previous genome-wide association study identified 2 susceptibility loci for severe dengue at MICB rs3132468 and PLCE1 rs3740360 and further work showed these mutations to be also associated with less severe clinical presentations. The aim of this study was to determine if these specific loci were associated with laboratory features of dengue that correlate with clinical severity with the aim of elucidating the functional basis of these genetic variants. METHODS: This was a case-only analysis of laboratory-confirmed dengue patients obtained from 2 prospective cohort studies and 1 randomised clinical trial in Vietnam (Trial registration: ISRCTN ISRCTN03147572. Registered 24th July 2012). 2742 dengue cases were successfully genotyped at MICB rs3132468 and PLCE1 rs3740360. Laboratory variables were compared between genotypes and stratified by DENV serotype. RESULTS: The analysis showed no association between MICB and PLCE1 genotype and early viraemia level, platelet nadir, white cell count nadir, or maximum haematocrit in both overall analysis and in analysis stratified by serotype. DISCUSSION: The lack of an association between genotype and viremia level may reflect the sampling procedures within the included studies. The study findings mean that the functional basis of these mutations remains unclear. TRIAL REGISTRATION: ISRCTN ISRCTN03147572 . Registered 24th July 2012.
  • Publication
    The Host Protein Reticulon 3.1A Is Utilized by Flaviviruses to Facilitate Membrane Remodelling
    (2017-11-07) Simmons, Cameron
    Flaviviruses are enveloped, positive-sensed single-stranded RNA viruses that remodel host membranes, incorporating both viral and host factors facilitating viral replication. In this study, we identified a key role for the membrane-bending host protein Reticulon 3.1 (RTN3.1A) during the replication cycle of three flaviviruses: West Nile virus (WNV), Dengue virus (DENV), and Zika virus (ZIKV). We observed that, during infection, RTN3.1A is redistributed and recruited to the viral replication complex, a recruitment facilitated via the WNV NS4A protein, however, not DENV or ZIKV NS4A. Critically, small interfering RNA (siRNA)-mediated knockdown of RTN3.1A expression attenuated WNV, DENV, and ZIKV replication and severely affected the stability and abundance of the NS4A protein, coinciding with a significant alternation and reduction of viral membrane structures in the endoplasmic reticulum. These observations identified a crucial role of RTN3.1A for the viral remodelling of host membranes during efficient flavivirus replication and the stabilization of viral proteins within the endoplasmic reticulum.
  • Publication
    Recent advances in dengue pathogenesis and clinical management
    (2015-12-10) Simmons, Cameron
    This review describes and commentates on recent advances in the understanding of dengue pathogenesis and immunity, plus clinical research on vaccines and therapeutics. We expand specifically on the role of the dermis in dengue virus infection, the contribution of cellular and humoral immune responses to pathogenesis and immunity, NS1 and mechanisms of virus immune evasion. Additionally we review a series of therapeutic intervention trials for dengue, as well as recent clinical research aimed at improving clinical diagnosis, risk prediction and disease classification.
  • Publication
    Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study
    (2016-09-01) Simmons, Cameron
    BACKGROUND: The hallmark of severe dengue is increased microvascular permeability, but alterations in the microcirculation and their evolution over the course of dengue are unknown. METHODS: We conducted a prospective observational study to evaluate the sublingual microcirculation using side-stream dark-field imaging in patients presenting early (<72 hours after fever onset) and patients hospitalized with warning signs or severe dengue in Vietnam. Clinical findings, microvascular function, global hemodynamics assessed with echocardiography, and serological markers of endothelial activation were determined at 4 time points. RESULTS: A total of 165 patients were enrolled. No difference was found between the microcirculatory parameters comparing dengue with other febrile illnesses. The proportion of perfused vessels (PPV) and the mean flow index (MFI) were lower in patients with dengue with plasma than those without leakage (PPV, 88.1% vs 90.6% [P = .01]; MFI, 2.1 vs 2.4 [P = .007]), most markedly during the critical phase. PPV and MFI were correlated with the endothelial activation markers vascular cell adhesion molecule 1 (P < .001 for both) and angiopoietin 2 (P < .001 for both), negatively correlated. CONCLUSIONS: Modest microcirculatory alterations occur in dengue, are associated with plasma leakage, and are correlate with molecules of endothelial activation, angiopoietin 2 and vascular cell adhesion molecule 1.