Dong Thi Hoai Tam

Fluid Replacement in Dengue Shock Syndrome: A Randomized, Double-Blind Comparison of Four Intravenous-Fluid Regimens

Dengue hemorrhagic fever and dengue shock syndrome (DSS) are major causes of childhood morbidity and mortality in many tropical countries. Increased intravascular permeability leading to shock is the cardinal feature of DSS. Fluid resuscitation to counteract massive plasma leakage is the mainstay of treatment. A double-blind, randomized trial comparing four intravenous-fluid regimens for acute resuscitation of 50 children with DSS was conducted. Colloids (dextran 70 or the protein digest gelafundin 35,000) restored cardiac index and blood pressure and normalized hematocrit more rapidly than crystalloids (Ringers lactate or 0.9%-weight/volume saline). Dextran 70 provided the most rapid normalization of the hematocrit and restoration of the cardiac index, without adverse effects, and may be the preferred solution for acute resuscitation in DSS. Further large-scale double-blind trials are required to provide an evidence-based approach to the management of DSS.

Noninvasive Measurement of Microvascular Leakage in Patients with Dengue Hemorrhagic Fever

Dengue shock syndrome (DSS) is a potentially lethal complication of dengue virus infection associated with hypotension and leakage of plasma water into the extravascular space. To determine whether the underlying pathophysiology of DSS is distinct from that in milder forms of the disease, we assessed microvascular permeability, by use of strain gauge plethysmography, in Vietnamese children with DSS (n=19), or dengue hemorrhagic fever (DHF) without shock (n=16), and in healthy control children (n=15). At admission and after fluid resuscitation, the mean coefficient of microvascular permeability (K(f)) for the patients with dengue was approximately 50% higher than that for the control patients (P=.02). There was no significant difference in K(f) between the 2 groups of patients with dengue; this suggests the same underlying pathophysiology. We hypothesize that in patients with DSS, the fluctuations in K(f) are larger than those in patients with DHF, which leads to short-lived peaks of markedly increased microvascular permeability and consequent hemodynamic shock.

Clinical Characteristics of Dengue Shock Syndrome in Vietnamese Children: A 10-Year Prospective Study in a Single Hospital

We present the clinical features, management, and outcomes for 1719 Vietnamese children with dengue shock syndrome enrolled in a 10-year prospective study in a single center, to provide the first comprehensive description of this increasingly important disorder.

A Prognostic Model for Development of Profound Shock among Children Presenting with Dengue Shock Syndrome

Purpose To identify risk factors and develop a prediction model for the development of profound and recurrent shock amongst children presenting with dengue shock syndrome (DSS) Methods We analyzed data from a prospective cohort of children with DSS recruited at the Paediatric Intensive Care Unit of the Hospital for Tropical Disease in Ho Chi Minh City, Vietnam. The primary endpoint was “profound DSS”, defined as ≥2 recurrent shock episodes (for subjects presenting in compensated shock), or ≥1 recurrent shock episodes (for subjects presenting initially with decompensated/hypotensive shock), and/or requirement for inotropic support. Recurrent shock was evaluated as a secondary endpoint. Risk factors were pre-defined clinical and laboratory variables collected at the time of presentation with shock. Prognostic model development was based on logistic regression and compared to several alternative approaches. Results The analysis population included 1207 children of whom 222 (18%) progressed to “profound DSS” and 433 (36%) had recurrent shock. Independent risk factors for both endpoints included younger age, earlier presentation, higher pulse rate, higher temperature, higher haematocrit and, for females, worse hemodynamic status at presentation. The final prognostic model for “profound DSS” showed acceptable discrimination (AUC=0.69 for internal validation) and calibration and is presented as a simple score-chart. Conclusions Several risk factors for development of profound or recurrent shock among children presenting with DSS were identified. The score-chart derived from the prognostic models should improve triage and management of children presenting with DSS in dengue-endemic areas.

The value of daily platelet counts for predicting dengue shock syndrome: Results from a prospective observational study of 2301 Vietnamese children with dengue

Background Dengue is the most important mosquito-borne viral infection to affect humans. Although it usually manifests as a self-limited febrile illness, complications may occur as the fever subsides. A systemic vascular leak syndrome that sometimes progresses to life-threatening hypovolaemic shock is the most serious complication seen in children, typically accompanied by haemoconcentration and thrombocytopenia. Robust evidence on risk factors, especially features present early in the illness course, for progression to dengue shock syndrome (DSS) is lacking. Moreover, the potential value of incorporating serial haematocrit and platelet measurements in prediction models has never been assessed. Methodology/Principal findings We analyzed data from a prospective observational study of Vietnamese children aged 5–15 years admitted with clinically suspected dengue to the Hospital for Tropical Diseases in Ho Chi Minh City between 2001 and 2009. The analysis population comprised all children with laboratory-confirmed dengue enrolled between days 1–4 of illness. Logistic regression was the main statistical model for all univariate and multivariable analyses. The prognostic value of daily haematocrit levels and platelet counts were assessed using graphs and separate regression models fitted on each day of illness. Among the 2301 children included in the analysis, 143 (6%) progressed to DSS. Significant baseline risk factors for DSS included a history of vomiting, higher temperature, a palpable liver, and a lower platelet count. Prediction models that included serial daily platelet counts demonstrated better ability to discriminate patients who developed DSS from others, than models based on enrolment information only. However inclusion of daily haematocrit values did not improve prediction of DSS. Conclusions/Significance Daily monitoring of platelet counts is important to help identify patients at high risk of DSS. Development of dynamic prediction models that incorporate signs, symptoms, and daily laboratory measurements, could improve DSS prediction and thereby reduce the burden on health services in endemic areas.

Genetic variants of MICB and PLCE1 and associations with the laboratory features of dengue.

BackgroundA 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.MethodsThis 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.ResultsThe 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.DiscussionThe 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 registrationISRCTN ISRCTN03147572. Registered 24th July 2012.

Nonannual seasonality of influenza-like illness in a tropical urban setting

In temperate and subtropical climates, respiratory diseases exhibit seasonal peaks in winter. In the tropics, with no winter, peak timings are irregular.

Reply to Halstead and Sayce et al

To the Editor—We agree with Dr Halstead that the findings of our trial of early corticosteroid therapy in Vietnamese children and young adults with dengue add an interesting perspective to the long-running debate on the mechanisms underlying disease pathogenesis [1, 2]. The absence of any adverse effects of prednisolone therapy on the virological safety parameters assessed, together with the lack of a reduction in the frequency of shock or other complications, brings into question the concept of an immunopathogenic storm being causally responsible for the microvascular dysfunction. However, we caution against overinterpreting the clinical trial results as representing definitive evidence against a role for T cells or any other immunological mechanisms. Instead, we believe our results emphasize how little we understand about the disease processes responsible for these complications and hope that these results will trigger more expansive efforts in dengue pathogenesis research. Detailed examination of serial measurements of immunological events in study participants will be published elsewhere (manuscript in preparation), but it is clear that the pharmacological “footprint” of prednisolone therapy in this trial was less than anticipated. Perhaps earlier therapy, or higher treatment doses, might have elicited a greater effect on clinical and laboratory end points, but given the dysglycemia encountered with the 2 mg/kg dosage regimen, the latter option would not be feasible for large-scale intervention in the community. The potential role of dengue nonstructural protein 1 (NS1) in pathogenesis is an important area to consider, but is not without difficulties. Importantly, there are conflicting data on the relationship between concentrations of secreted NS1, plasma viremia, immune status, and clinical disease severity [3–5]. In particular, plasma levels of dengue virus 2–associated NS1 are often low or undetectable in both human studies and mouse models [4, 6], yet dengue virus 2 is well established as a cause of severe disease. Secondly, kinetic studies reveal that although plasma levels of NS1 are often high in early disease, the protein may also persist for several weeks after infection without causing clinical complications [7], suggesting that if NS1 is important in pathogenesis, other factors must also be operating to influence outcome. We agree that complement activation, possibly exacerbated by NS1, is probably important and is a relatively poorly researched area of dengue pathogenesis. Sayce and colleagues describe data from a series of experiments that investigate dexamethasone as a dengue therapeutic in primary monocyte-derived macrophages from dengue-naive donors [8]. They observed a significant but transient decrease in viral load on day 1 with dexamethasone treatment, concomitant with a relative reduction in levels of selected inflammatory cytokines, and they comment that the effectiveness of treatment with steroids may depend critically on time of drug administration. However, interpretation of these results in terms of overall disease pathogenesis is difficult, because the true relevance of isolated cell culture systems to human disease processes is doubtful. The idea of combined antiviral and immunomodulatory therapy is certainly one avenue that may be worth pursuing, particularly if it is possible to initiate the combined therapy very early in the disease evolution. Efforts directed toward improving dengue rapid diagnostics suitable for use early in the febrile phase, together with research to identify risk factors associated with subsequent progression to severe disease, are important if this strategy is to be considered. In the end, if a simple, safe, and effective therapy or combination of therapies does become available, it is crucial that prompt intervention targeted toward high-risk groups is a realistic possibility. Finally, although the mechanisms underlying microvascular dysfunction in dengue are almost certainly multifactorial, it is hoped that the recent momentum in clinical intervention trials will eventually lead to improved treatment options for patients with dengue as well as insights into pathogenesis [2, 7, 9, 10].