Effects of sialidase inhibition by oseltamivir phosphate on platelet recovery and markers of plasma leakage in adults Indonesian patients with dengue (TOTO trial)

The dataset contains the results from a randomised controlled trial assessing the effects of the sialidase inhibitor oseltamivir on the recovery of platelet counts and parameters of plasma leakage in Indonesian adult patients with acute dengue infection (TOTO trial). A total number of 70 patients with a platelet count <70 x 10^9/L and a duration of illness <7 days were randomized between oseltamivir phosphate 75mg BID or placebo for a maximum of five days. Primary outcomes were the time to platelet recovery (platelet count ≥ 100 x 109/l) or discharge from hospital and the course of measures of plasma leakage (measured by daily ultrasound, hematocrit, plasma albumin and syndecan-1 concentrations). A blood count was performed twice daily; maximum follow-up was five days. More details on the trial are given in https://doi.org/10.1186/ISRCTN3522771

Performance of the Sysmex Infection Manager System (IMS) to differentiate between common causes of febrile illness in Southeast Asia

Item does not contain fulltextThis dataset presents the results from a prospective diagnostic study in which the diagnostic performance of the Sysmex Infection Manager System (IMS), which is a novel algorith equipped on a Sysmex hematology analyzer, was tested on a cohort of Indonesian adult patients presenting to a health facility with an acute febrile illness. All patients were evaluated using a structured diagnostic protocol. The total cohort was 600 patients of whom 137 were excluded. The IMS was first trained on the first 200 patients and subsequently validated on the complete cohort consisting of 463 patients. The etiology of the febrile illness was determined using a combination of clinical investigations, as well as a set of laboratory and radiology examinations. The performance of the IMS was compared to that of the biomarkers C-reactive protein (CRP) and procalcitonin (PCT

A novel diagnostic algorithm equipped on an automated hematology analyzer to differentiate between common causes of febrile illness in Southeast Asia

BACKGROUND: Distinguishing arboviral infections from bacterial causes of febrile illness is of great importance for clinical management. The Infection Manager System (IMS) is a novel diagnostic algorithm equipped on a Sysmex hematology analyzer that evaluates the host response using novel techniques that quantify cellular activation and cell membrane composition. The aim of this study was to train and validate the IMS to differentiate between arboviral and common bacterial infections in Southeast Asia and compare its performance against C-reactive protein (CRP) and procalcitonin (PCT). METHODOLOGY/PRINCIPAL FINDINGS: 600 adult Indonesian patients with acute febrile illness were enrolled in a prospective cohort study and analyzed using a structured diagnostic protocol. The IMS was first trained on the first 200 patients and subsequently validated using the complete cohort. A definite infectious etiology could be determined in 190 of 463 evaluable patients (41%), including 89 arboviral infections (81 dengue and 8 chikungunya), 94 bacterial infections (26 murine typhus, 16 salmonellosis, 6 leptospirosis and 46 cosmopolitan bacterial infections), 3 concomitant arboviral-bacterial infections, and 4 malaria infections. The IMS detected inflammation in all but two participants. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the IMS for arboviral infections were 69.7%, 97.9%, 96.9%, and 77.3%, respectively, and for bacterial infections 77.7%, 93.3%, 92.4%, and 79.8%. Inflammation remained unclassified in 19.1% and 22.5% of patients with a proven bacterial or arboviral infection. When cases of unclassified inflammation were grouped in the bacterial etiology group, the NPV for bacterial infection was 95.5%. IMS performed comparable to CRP and outperformed PCT in this cohort. CONCLUSIONS/SIGNIFICANCE: The IMS is an automated, easy to use, novel diagnostic tool that allows rapid differentiation between common causes of febrile illness in Southeast Asia

Effect of oseltamivir phosphate versus placebo on platelet recovery and plasma leakage in adults with dengue and thrombocytopenia; a phase 2, multicenter, double-blind, randomized trial

BACKGROUND: Thrombocytopenia, bleeding and plasma leakage are major complications of dengue. Activation of endogenous sialidases with desialylation of platelets and endothelial cells may underlie these complications. We aimed to assess the effects of the neuraminidase inhibitor oseltamivir on platelet recovery and plasma leakage in dengue. METHODS: We performed a phase 2, double-blind, multicenter, randomized trial in adult dengue patients with thrombocytopenia (<70,000/μl) and a duration of illness ≤ 6 days. Oseltamivir phosphate 75mg BID or placebo were given for a maximum of five days. Primary outcomes were the time to platelet recovery (≥ 100,000/μl) or discharge from hospital and the course of measures of plasma leakage. RESULTS: A total of 70 patients were enrolled; the primary outcome could be assessed in 64 patients (31 oseltamivir; 33 placebo). Time to platelet count ≥100,000/μl (n = 55) or discharge (n = 9) were similar in the oseltamivir and placebo group (3.0 days [95% confidence interval, 2.7 to 3.3] vs. 2.9 days [2.5 to 3.3], P = 0.055). The kinetics of platelet count and parameters of plasma leakage (gall bladder thickness, hematocrit, plasma albumin, syndecan-1) were also similar between the groups. DISCUSSION: In this trial, adjunctive therapy with oseltamivir phosphate had no effect on platelet recovery or plasma leakage parameters. TRIAL REGISTRATION: ISRCTN35227717

Dengue incidence and length of viremia by RT-PCR in a prospective observational community contact cluster study from 2005-2009 in Indonesia.

BACKGROUND: Dengue has become a major global health threat since being recognized three centuries ago. Important gaps remain in understanding the transmission dynamics of dengue virus (DENV) infection. This study reports the results of a prospective observational cluster study that investigated the incidence of symptomatic and asymptomatic infections and length of viremia among close community contacts of hospitalized DENV-infected patients. METHODOLOGY/PRINCIPAL FINDINGS: Between 2005 and 2009, dengue-confirmed cases (n = 97) admitted to Hasan Sadikin Hospital in Bandung, Indonesia, were enrolled as index cases. Subsequently, twenty close community contacts (n = 1928) living with and around the index cases were included and followed up for up to 14 days. Body temperature was measured daily; blood samples were collected every 3-4 days and when reported fever. DENV infection was confirmed using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR), IgM rapid test, and Enzyme-linked Immunosorbent Assay (ELISA). Among the 1928 community contacts, a total of 72 (3.7%) acute DENV infections were diagnosed, which equates to an incidence of 636 cases per 1,000 person-years (95% Confidence interval (CI) 588 to 687 cases per 1,000 person-years). Twenty-nine cases (40%) were symptomatic (22 dengue fever (DF) & 7 dengue hemorrhagic fever (DHF)), and 43 (60%) were asymptomatic. Primary and secondary DENV infections were detected in 18 (25%) and 54 (75%) subjects. Among the RT-PCR positives, viremia was observed as early as seven days before fever onset and converted to negative as late as seven days after the onset of fever. CONCLUSIONS: DENV infections are common among close community contacts of hospitalized dengue patients. The high number of asymptomatic infections and the observation that viremia precedes the onset of fever for up to seven days highlight the importance of unrecognized dengue transmission and the need for improved transmission control

results from a double blind, multicenter, randomized controlled trial.

The dataset contains the results from a randomised controlled trial assessing the effects of the sialidase inhibitor oseltamivir on the recovery of platelet counts and parameters of plasma leakage in Indonesian adult patients with acute dengue infection (TOTO trial). A total number of 70 patients with a platelet count <70 x 10^9/L and a duration of illness <7 days were randomized between oseltamivir phosphate 75mg BID or placebo for a maximum of five days. Primary outcomes were the time to platelet recovery (platelet count ≥ 100 x 109/l) or discharge from hospital and the course of measures of plasma leakage (measured by daily ultrasound, hematocrit, plasma albumin and syndecan-1 concentrations). A blood count was performed twice daily; maximum follow-up was five days. More details on the trial are given in https://doi.org/10.1186/ISRCTN3522771

Performance of the Sysmex Infection Manager System (IMS) to differentiate between common causes of febrile illness in Southeast Asia

This dataset presents the results from a prospective diagnostic study in which the diagnostic performance of the Sysmex Infection Manager System (IMS), which is a novel algorith equipped on a Sysmex hematology analyzer, was tested on a cohort of Indonesian adult patients presenting to a health facility with an acute febrile illness. All patients were evaluated using a structured diagnostic protocol. The total cohort was 600 patients of whom 137 were excluded. The IMS was first trained on the first 200 patients and subsequently validated on the complete cohort consisting of 463 patients. The etiology of the febrile illness was determined using a combination of clinical investigations, as well as a set of laboratory and radiology examinations. The performance of the IMS was compared to that of the biomarkers C-reactive protein (CRP) and procalcitonin (PCT

Desialylation of platelets induced by Von Willebrand Factor is a novel mechanism of platelet clearance in dengue

Thrombocytopenia and platelet dysfunction are commonly observed in patients with dengue virus (DENV) infection and may contribute to complications such as bleeding and plasma leakage. The etiology of dengue-associated thrombocytopenia is multifactorial and includes increased platelet clearance. The binding of the coagulation protein von Willebrand factor (VWF) to the platelet membrane and removal of sialic acid (desialylation) are two well-known mechanisms of platelet clearance, but whether these conditions also contribute to thrombocytopenia in dengue infection is unknown. In two observational cohort studies in Bandung and Jepara, Indonesia, we show that adult patients with dengue not only had higher plasma concentrations of plasma VWF antigen and active VWF, but that circulating platelets had also bound more VWF to their membrane. The amount of platelet-VWF binding correlated well with platelet count. Furthermore, sialic acid levels in dengue patients were significantly reduced as assessed by the binding of Sambucus nigra lectin (SNA) and Maackia amurensis lectin II (MAL-II) to platelets. Sialic acid on the platelet membrane is neuraminidase-labile, but dengue virus has no known neuraminidase activity. Indeed, no detectable activity of neuraminidase was present in plasma of dengue patients and no desialylation was found of plasma transferrin. Platelet sialylation was also not altered by in vitro exposure of platelets to DENV nonstructural protein 1 or cultured DENV. In contrast, induction of binding of VWF to glycoprotein 1b on platelets using the VWF-activating protein ristocetin resulted in the removal of platelet sialic acid by translocation of platelet neuraminidase to the platelet surface. The neuraminidase inhibitor oseltamivir reduced VWF-induced platelet desialylation. Our data demonstrate that excessive binding of VWF to platelets in dengue results in neuraminidase-mediated platelet desialylation and platelet clearance. Oseltamivir might be a novel treatment option for severe thrombocytopenia in dengue infection