{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:47:21Z","timestamp":1791488841612,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.pntd.0010051","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T00:00:00Z","timestamp":1643068800000}}],"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T00:00:00Z","timestamp":1641513600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMW (the Netherlands Organisation for Health Research and Development","doi-asserted-by":"crossref","award":["451001005"],"award-info":[{"award-number":["451001005"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>We performed a phase 2, double-blind, multicenter, randomized trial in adult dengue patients with thrombocytopenia (&lt;70,000\/\u03bcl) and a duration of illness \u2264 6 days. Oseltamivir phosphate 75mg BID or placebo were given for a maximum of five days. Primary outcomes were the time to platelet recovery (\u2265 100,000\/\u03bcl) or discharge from hospital and the course of measures of plasma leakage.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p>A total of 70 patients were enrolled; the primary outcome could be assessed in 64 patients (31 oseltamivir; 33 placebo). Time to platelet count \u2265100,000\/\u03bcl (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],<jats:italic>P<\/jats:italic>= 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.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Discussion<\/jats:title><jats:p>In this trial, adjunctive therapy with oseltamivir phosphate had no effect on platelet recovery or plasma leakage parameters.<\/jats:p><\/jats:sec><jats:sec id=\"sec005\"><jats:title>Trial registration<\/jats:title><jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/doi.org\/10.1186\/ISRCTN35227717\" xlink:type=\"simple\">ISRCTN35227717<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pntd.0010051","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T18:36:07Z","timestamp":1641580567000},"page":"e0010051","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["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"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6168-4758","authenticated-orcid":true,"given":"Rahajeng N.","family":"Tunjungputri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4858-2498","authenticated-orcid":true,"given":"Silvita Fitri","family":"Riswari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Setyo G.","family":"Pramudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Kuntjoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3745-8229","authenticated-orcid":true,"given":"Bachti","family":"Alisjahbana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry Galuh","family":"Nugraha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1833-3391","authenticated-orcid":true,"given":"Andre","family":"van der Ven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Hussein","family":"Gasem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6056-157X","authenticated-orcid":true,"given":"Quirijn","family":"de Mast","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,1,7]]},"reference":[{"key":"pntd.0010051.ref001","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/S1473-3099(16)00146-8","article-title":"The global economic burden of dengue: a systematic analysis","volume":"16","author":"DS Shepard","year":"2016","journal-title":"The Lancet infectious diseases"},{"key":"pntd.0010051.ref002","article-title":"Dengue: guidelines for diagnosis, treatment, prevention and control","author":"World Health Organization","year":"2009"},{"key":"pntd.0010051.ref003","article-title":"Dengue: guideline for diagnosis, treatment, prevention and control\u2014New edition.,","author":"World Health Organization","year":"2009"},{"key":"pntd.0010051.ref004","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1080\/09537100701426604","article-title":"Thrombocytopenia in patients with dengue virus infection in the Brazilian Amazon.","volume":"18","author":"MP Mourao","year":"2007","journal-title":"Platelets"},{"key":"pntd.0010051.ref005","doi-asserted-by":"crossref","first-page":"e0005859","DOI":"10.1371\/journal.pntd.0005859","article-title":"Clinical and epidemiologic characteristics of dengue and other etiologic agents among patients with acute febrile illness, Puerto Rico, 2012\u20132015.","volume":"11","author":"KM Tomashek","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0010051.ref006","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1111\/j.1365-3156.2008.02151.x","article-title":"Clinical and laboratory features that distinguish dengue from other febrile illnesses in endemic populations","volume":"13","author":"JA Potts","year":"2008","journal-title":"Trop Med Int Health"},{"key":"pntd.0010051.ref007","first-page":"145","article-title":"Thrombocytopenia in dengue fever.","volume":"4","author":"KI Schexneider","year":"2005","journal-title":"Curr Hematol Rep"},{"key":"pntd.0010051.ref008","doi-asserted-by":"crossref","first-page":"4958","DOI":"10.1182\/blood-2007-11-123620","article-title":"Inflammation induces hemorrhage in thrombocytopenia","volume":"111","author":"T Goerge","year":"2008","journal-title":"Blood"},{"key":"pntd.0010051.ref009","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1073\/pnas.0711200105","article-title":"Platelets prevent IFN-alpha\/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus","volume":"105","author":"M Iannacone","year":"2008","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"pntd.0010051.ref010","doi-asserted-by":"crossref","first-page":"24316","DOI":"10.1073\/pnas.2007642117","article-title":"Hemostasis vs. homeostasis: Platelets are essential for preserving vascular barrier function in the absence of injury or inflammation","volume":"117","author":"S Gupta","year":"2020","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"pntd.0010051.ref011","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.4269\/ajtmh.2007.77.1135","article-title":"Lack of efficacy of high-dose intravenous immunoglobulin treatment of severe thrombocytopenia in patients with secondary dengue virus infection","volume":"77","author":"EM Dimaano","year":"2007","journal-title":"Am J Trop Med Hyg"},{"key":"pntd.0010051.ref012","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1093\/cid\/cis655","article-title":"Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: a randomized, placebo-controlled trial","volume":"55","author":"DT Tam","year":"2012","journal-title":"Clin Infect Dis"},{"key":"pntd.0010051.ref013","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1016\/S0140-6736(17)30269-6","article-title":"Prophylactic platelet transfusion plus supportive care versus supportive care alone in adults with dengue and thrombocytopenia: a multicentre, open-label, randomised, superiority trial.","volume":"389","author":"DC Lye","year":"2017","journal-title":"Lancet"},{"key":"pntd.0010051.ref014","doi-asserted-by":"crossref","first-page":"313842","DOI":"10.1155\/2015\/313842","article-title":"Thrombocytopenia in dengue: interrelationship between virus and the imbalance between coagulation and fibrinolysis and inflammatory mediators.","volume":"2015","author":"EL De Azeredo","year":"2015","journal-title":"Mediators Inflamm"},{"key":"pntd.0010051.ref015","doi-asserted-by":"crossref","first-page":"S68","DOI":"10.1016\/S0049-3848(16)30370-X","article-title":"Platelet clearance by the hepatic Ashwell-Morrell receptor: mechanisms and biological significance","volume":"141","author":"KM Hoffmeister","year":"2016","journal-title":"Thrombosis research"},{"key":"pntd.0010051.ref016","doi-asserted-by":"crossref","first-page":"e1007500","DOI":"10.1371\/journal.ppat.1007500","article-title":"Desialylation of platelets induced by Von Willebrand Factor is a novel mechanism of platelet clearance in dengue.","volume":"15","author":"SF Riswari","year":"2019","journal-title":"PLoS pathogens"},{"key":"pntd.0010051.ref017","doi-asserted-by":"crossref","first-page":"e1005738","DOI":"10.1371\/journal.ppat.1005738","article-title":"Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability.","volume":"12","author":"H Puerta-Guardo","year":"2016","journal-title":"PLoS pathogens"},{"key":"pntd.0010051.ref018","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1099\/jgv.0.001319","article-title":"Increased serum sialic acid is associated with morbidity and mortality in a murine model of dengue disease","volume":"100","author":"DA Espinosa","year":"2019","journal-title":"The Journal of general virology"},{"key":"pntd.0010051.ref019","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.4049\/jimmunol.178.5.2651","article-title":"Cutting edge: oseltamivir decreases T cell GM1 expression and inhibits clearance of respiratory syncytial virus: potential role of endogenous sialidase in antiviral immunity","volume":"178","author":"ML Moore","year":"2007","journal-title":"The Journal of Immunology"},{"key":"pntd.0010051.ref020","doi-asserted-by":"crossref","first-page":"E94","DOI":"10.1002\/ajh.23953","article-title":"Sialidase inhibition to increase platelet counts: A new treatment option for thrombocytopenia","volume":"90","author":"AJ Jansen","year":"2015","journal-title":"Am J Hematol"},{"key":"pntd.0010051.ref021","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1080\/09537104.2020.1714576","article-title":"Evaluating the effects of oseltamivir phosphate on platelet counts: a retrospective review.","volume":"31","author":"H Shaim","year":"2020","journal-title":"Platelets"},{"key":"pntd.0010051.ref022","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1080\/09537104.2018.1513476","article-title":"Multirefractory primary immune thrombocytopenia; targeting the decreased sialic acid content.","volume":"30","author":"N Revilla","year":"2019","journal-title":"Platelets"},{"key":"pntd.0010051.ref023","doi-asserted-by":"crossref","first-page":"495","DOI":"10.3109\/09537104.2014.948838","article-title":"Successful treatment with oseltamivir phosphate in a patient with chronic immune thrombocytopenia positive for anti-GPIb\/IX autoantibody.","volume":"26","author":"L Shao","year":"2015","journal-title":"Platelets"},{"key":"pntd.0010051.ref024","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1111\/fcp.12213","article-title":"Unexpected platelets elevation in a patient with idiopathic thrombocytopenia treated with oseltamivir for influenza infection","volume":"30","author":"P Bigot","year":"2016","journal-title":"Fundam Clin Pharmacol"},{"key":"pntd.0010051.ref025","doi-asserted-by":"crossref","first-page":"e289","DOI":"10.1016\/S2352-3026(21)00030-2","article-title":"Dexamethasone plus oseltamivir versus dexamethasone in treatment-naive primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial","volume":"8","author":"L Sun","year":"2021","journal-title":"The Lancet Haematology"},{"key":"pntd.0010051.ref026","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s13045-017-0476-1","article-title":"Platelet desialylation is a novel mechanism and a therapeutic target in thrombocytopenia during sepsis: an open-label, multicenter, randomized controlled trial.","volume":"10","author":"MF Li","year":"2017","journal-title":"J Hematol Oncol"},{"key":"pntd.0010051.ref027","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s13045-015-0216-3","article-title":"Desialylation is associated with apoptosis and phagocytosis of platelets in patients with prolonged isolated thrombocytopenia after allo-HSCT","volume":"8","author":"XH Zhang","year":"2015","journal-title":"J Hematol Oncol"},{"key":"pntd.0010051.ref028","doi-asserted-by":"crossref","first-page":"e1006673","DOI":"10.1371\/journal.ppat.1006673","article-title":"Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components.","volume":"13","author":"DR Glasner","year":"2017","journal-title":"PLoS Pathog"},{"key":"pntd.0010051.ref029","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1016\/j.cellsig.2013.08.008","article-title":"A novel epidermal growth factor receptor-signaling platform and its targeted translation in pancreatic cancer.","volume":"25","author":"AM Gilmour","year":"2013","journal-title":"Cellular signalling"},{"key":"pntd.0010051.ref030","doi-asserted-by":"crossref","first-page":"3484","DOI":"10.1128\/AAC.00344-08","article-title":"Limited inhibitory effects of oseltamivir and zanamivir on human sialidases","volume":"52","author":"K Hata","year":"2008","journal-title":"Antimicrobial agents and chemotherapy"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0010051","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T00:00:00Z","timestamp":1643068800000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0010051","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,15]],"date-time":"2024-09-15T21:55:54Z","timestamp":1726437354000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0010051"}},"subtitle":[],"editor":[{"given":"Anita K.","family":"McElroy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,1,7]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0010051","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0010051","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,7]]}}}