{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:52:23Z","timestamp":1791244343177,"version":"4.1.0"},"reference-count":50,"publisher":"American Society of Tropical Medicine and Hygiene","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10,4]]},"abstract":"<jats:title>ABSTRACT.<\/jats:title>\n<jats:p>In 2017, Sri Lanka experienced its largest dengue epidemic and reported severe and unusual presentations of dengue with high morbidity. This outbreak was associated with the reemergence of dengue virus-2 (DENV-2), with the responsible strain identified as a variant of the previously circulating DENV-2 cosmopolitan genotype. In this study, we characterized the DENV-2 cosmopolitan genotype from patients during this epidemic. Also, we identified host factors that contributed to the severity of dengue infection in patients infected with this particular virus. Ninety-one acute serum samples from patients at the National Hospital in Kandy were randomly selected. Of these, 40.2% and 48.9% were positive for dengue IgM and IgG, respectively. NS1 antigen levels were significantly higher in primary infections. The severe dengue (SD) and dengue with warning signs (DWWS) groups exhibited significantly higher viral genome and infectivity titers than the dengue without warning signs (DWoWS) group. The highest viremia level was observed in SD patients. As for host cytokine response, interferon \u03b1 (IFN-\u03b1) levels were significantly higher in the DWoWS group than in the DWWS and SD groups, whereas interleukin (IL)-12p40 and tumor necrosis factor \u03b1 (TNF-\u03b1) levels in SD patients were significantly higher than in the other two groups. The TNF-\u03b1, IL-4, and monocyte chemoattractant protein-1 concentrations were positively correlated with NS1 antigen levels. From whole-genome analysis, NS4 had the highest frequency of amino acid variants, followed by the E gene. Our study suggests that viremia levels and immune responses contributed to SD outcomes, and these findings may help in identifying an effective therapeutic strategy against SD infection.<\/jats:p>","DOI":"10.4269\/ajtmh.22-0780","type":"journal-article","created":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T15:22:17Z","timestamp":1694445737000},"page":"917-925","source":"Crossref","is-referenced-by-count":4,"title":["Clinical, Virological, and Immunological Features in Cosmopolitan Genotype DENV-2\u2013Infected Patients during a Large Dengue Outbreak in Sri Lanka in 2017"],"prefix":"10.4269","volume":"109","author":[{"given":"Khine Mya","family":"Nwe","sequence":"first","affiliation":[{"name":"Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mya Myat","family":"Ngwe Tun","sequence":"additional","affiliation":[{"name":"Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan;"},{"name":"Department of Tropical Viral Vaccine Development, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan;"},{"name":"Center for Vaccines and Therapeutic Antibodies for Emerging Infectious Diseases, Shimane University, Izumo, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohitha","family":"Muthugala","sequence":"additional","affiliation":[{"name":"Department of Virology, National Hospital Kandy, Kandy, Sri Lanka;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Nabeshima","sequence":"additional","affiliation":[{"name":"Kenya Research Station, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean Claude","family":"Balingit","sequence":"additional","affiliation":[{"name":"Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan;"},{"name":"Department of Tropical Viral Vaccine Development, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lakmali","family":"Rajamanthri","sequence":"additional","affiliation":[{"name":"Department of Virology, National Hospital Kandy, Kandy, Sri Lanka;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dulani","family":"Jayawardana","sequence":"additional","affiliation":[{"name":"Department of Virology, National Hospital Kandy, Kandy, Sri Lanka;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanthi","family":"Attanayake","sequence":"additional","affiliation":[{"name":"Department of Virology, National Hospital Kandy, Kandy, Sri Lanka;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Inoue","sequence":"additional","affiliation":[{"name":"Kenya Research Station, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Takamatsu","sequence":"additional","affiliation":[{"name":"Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Urano","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Therapeutic Antibodies for Emerging Infectious Diseases, Shimane University, Izumo, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouichi","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Virology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan;"},{"name":"Department of Tropical Viral Vaccine Development, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan;"},{"name":"DEJIMA Infectious Disease Research Alliance, Nagasaki University, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2795","reference":[{"key":"b1","series-title":"Sci Rep","first-page":"13496","article-title":"Evolution, heterogeneity and global dispersal of cosmopolitan genotype of Dengue virus type 2","volume":"11","author":"Yenamandra","year":"2021"},{"key":"b2","series-title":"Indian J Med Microbiol","first-page":"12","article-title":"Molecular studies on dengue viruses detected in patients from central India","volume":"37","author":"Barde","year":"2019"},{"key":"b3","series-title":"Jpn J Infect Dis","first-page":"357","article-title":"Immunogenicity of a candidate DNA vaccine based on the prM\/E genes of a dengue type 2 virus cosmopolitan genotype strain","volume":"68","author":"Putri","year":"2015"},{"key":"b4","series-title":"Viruses","first-page":"1562","article-title":"Dengue\u2013quo tu et quo vadis?","volume":"3","author":"Chen","year":"2011"},{"key":"b5","series-title":"Arch Virol","first-page":"1739","article-title":"Molecular and evolutionary analysis of dengue virus serotype 2 isolates from Korean travelers in 2015","volume":"165","author":"Hwang","year":"2020"},{"key":"b6","series-title":"Annu Rev Microbio","first-page":"649","article-title":"Flavivirus genome organization, expression, and replication","volume":"44","author":"Chambers","year":"1990"},{"key":"b7","series-title":"J Virol","first-page":"6649","article-title":"Role of an arbovirus nonstructural protein in cellular pathogenesis and virus release","volume":"78","author":"Owens","year":"2004"},{"key":"b8","series-title":"J Interferon Cytokine Res","first-page":"421","article-title":"Dengue virus control of type I IFN responses: a history of manipulation and control","volume":"35","author":"Castillo Ramirez","year":"2015"},{"key":"b9","series-title":"Biomed Res Int","first-page":"690835","article-title":"Understanding the dengue viruses and progress towards their control","volume":"2013","author":"Rodriguez-Roche","year":"2013"},{"key":"b10","series-title":"J Clin Virol","first-page":"104304","article-title":"Unusual, neurological and severe dengue manifestations during the outbreak in Sri Lanka, 2017","volume":"125","author":"Ngwe Tun","year":"2020"},{"key":"b11","series-title":"Infect Dis Health","first-page":"114","article-title":"The unprecedented magnitude of the 2017 dengue outbreak in Sri Lanka provides lessons for future mosquito-borne infection control and prevention","volume":"23","author":"Ali","year":"2018"},{"key":"b12","series-title":"Emerg Infect Dis","first-page":"682","article-title":"Severe dengue epidemic, Sri Lanka, 2017","volume":"26","author":"Tissera","year":"2020"},{"key":"b13","series-title":"Viruses","first-page":"34","article-title":"Cytokine signature associated with disease severity in dengue","volume":"11","author":"Patro","year":"2019"},{"key":"b14","series-title":"Front Cell Infect Microbiol","first-page":"317","article-title":"Global epidemiology of dengue outbreaks in 1990\u20132015: a systematic review and meta-analysis","volume":"7","author":"Guo","year":"2017"},{"key":"b15","series-title":"Virology","first-page":"63","article-title":"Phylogenetic relationships and differential selection pressures among genotypes of dengue-2 virus","volume":"298","author":"Twiddy","year":"2002"},{"key":"b16","series-title":"PLoS One","first-page":"e56391","article-title":"Emergence and diversification of dengue 2 cosmopolitan genotype in Pakistan, 2011","volume":"8","author":"Khan","year":"2013"},{"key":"b17","series-title":"PLoS One","first-page":"e27459","article-title":"Circulation of different lineages of dengue virus type 2 in Central America, their evolutionary time-scale and selection pressure analysis","volume":"6","author":"A\u00f1ez","year":"2011"},{"key":"b18","series-title":"Sci Rep","first-page":"9395","article-title":"Cross-serotype interactions and disease outcome prediction of dengue infections in Vietnam","volume":"9","author":"Aguas","year":"2019"},{"key":"b19","series-title":"PLoS Negl Trop Dis","first-page":"1","article-title":"Serotype-specific differences in the risk of dengue hemorrhagic fever: an analysis of data collected in Bangkok, Thailand from 1994 to 2006","volume":"4","author":"Fried","year":"2010"},{"key":"b20","series-title":"J Infect Dis","first-page":"2","article-title":"Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity","volume":"181","author":"Vaughn","year":"2000"},{"key":"b21","series-title":"J Virol Methods","first-page":"15","article-title":"Antibody-capture ELISA for detection of immunoglobulin M antibodies in sera from Japanese encephalitis and dengue hemorrhagic fever patients","volume":"11","author":"Bundo","year":"1985"},{"key":"b22","series-title":"Vector Borne Zoonotic Dis","first-page":"143","article-title":"Evaluation of a dengue IgG indirect enzyme-linked immunosorbent assay and a Japanese encephalitis IgG indirect enzyme-linked immunosorbent assay for diagnosis of secondary dengue virus infection","volume":"10","author":"Inoue","year":"2010"},{"key":"b23","series-title":"PLoS One","first-page":"e0251314","article-title":"Detection of genotype-1 of dengue virus serotype 3 for the first time and complete genome analysis of dengue viruses during the 2018 epidemic in Mandalay, Upper Myanmar","volume":"16","author":"Ngwe Tun","year":"2021"},{"key":"b24","series-title":"J Clin Microbiol","first-page":"5935","article-title":"Development and evaluation of fluorogenic TaqMan reverse transcriptase PCR assays for detection of dengue virus types 1 to 4","volume":"42","author":"Ito","year":"2004"},{"key":"b25","series-title":"Am J Trop Med Hyg","first-page":"1217","article-title":"Clinical, virological, and cytokine profiles of children infected with dengue virus during the outbreak in Southern Vietnam in 2017","volume":"102","author":"Ngwe Tun","year":"2020"},{"key":"b26","series-title":"J Clin Microbiol","first-page":"2107","article-title":"Rapid identification of dengue virus serotypes by using polymerase chain reaction","volume":"29","author":"Morita","year":"1991"},{"key":"b27","series-title":"Nat Biotechnol","first-page":"644","article-title":"Full-length transcriptome assembly from RNA-seq data without a reference genome","volume":"29","author":"Grabherr","year":"2011"},{"key":"b28","series-title":"BMC Bioinformatics","first-page":"421","article-title":"BLAST+: architecture and applications","volume":"10","author":"Camacho","year":"2009"},{"key":"b29","series-title":"Bioinformatics","first-page":"589","article-title":"Fast and accurate long-read alignment with Burrows-Wheeler transform","volume":"26","author":"Li","year":"2010"},{"key":"b30","series-title":"Nucleic Acids Res","first-page":"11189","article-title":"LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets","volume":"40","author":"Wilm","year":"2012"},{"key":"b31","series-title":"Genome Res","first-page":"568","article-title":"VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing","volume":"22","author":"Koboldt","year":"2012"},{"key":"b32","series-title":"Nat Methods","first-page":"772","article-title":"JModelTest 2: more models, new heuristics and parallel computing","volume":"9","author":"Darriba","year":"2012"},{"key":"b33","series-title":"PLoS One","first-page":"e0234508","article-title":"Complete genome analysis and characterization of neurotropic dengue virus 2 cosmopolitan genotype isolated from the cerebrospinal fluid of encephalitis patients","volume":"15","author":"Ngwe Tun","year":"2020"},{"key":"b34","series-title":"Mem Inst Oswaldo Cruz","first-page":"161","article-title":"Primary dengue virus infections induce differential cytokine production in Mexican patients","volume":"111","author":"de la Cruz Hern\u00e1ndez","year":"2016"},{"key":"b35","series-title":"J Infect Dis","first-page":"1292","article-title":"Kinetics of plasma viremia and soluble nonstructural protein 1 concentrations in dengue: differential effects according to serotype and immune status","volume":"203","author":"Duyen","year":"2011"},{"key":"b36","series-title":"Clin Infect Dis","first-page":"1023","article-title":"Slower rates of clearance of viral load and virus-containing immune complexes in patients with dengue hemorrhagic fever","volume":"43","author":"Wang","year":"2006"},{"key":"b37","series-title":"Am J Trop Med Hyg","first-page":"999","article-title":"Dengue serotype-specific differences in clinical manifestation, laboratory parameters and risk of severe disease in adults, Singapore","volume":"92","author":"Yung","year":"2015"},{"key":"b38","series-title":"Malays J Med Sci","first-page":"6","article-title":"Roles and prospects of dengue virus non-structural proteins as antiviral targets: an easy digest","volume":"25","author":"Norazharuddin","year":"2018"},{"key":"b39","series-title":"Membranes (Basel)","first-page":"231","article-title":"Structures and dynamics of dengue virus nonstructural membrane proteins","volume":"12","author":"Li","year":"2022"},{"key":"b40","series-title":"Clin Infect Dis","first-page":"E1074","article-title":"Higher plasma viremia in the febrile phase is associated with adverse dengue outcomes irrespective of infecting serotype or host immune status: an analysis of 5642 Vietnamese cases","volume":"72","author":"Vuong","year":"2021"},{"key":"b41","series-title":"Front Cell Infect Microbiol","first-page":"831281","article-title":"Assessment of the risk of severe dengue using intrahost viral population in dengue virus serotype 2 patients via machine learning","volume":"12","author":"Hung","year":"2022"},{"key":"b42","series-title":"J Clin Virol","first-page":"10","article-title":"Characterization of type I interferon responses in dengue and severe dengue in children in Paraguay","volume":"97","author":"Talarico","year":"2017"},{"key":"b43","series-title":"Trop Med Health","first-page":"137","article-title":"The association of cytokines with severe dengue in children","volume":"42","author":"Mangione","year":"2014"},{"key":"b44","series-title":"Iran J Microbiol","first-page":"202","article-title":"Role of TNF \u03b1, IL-6 and CXCL10 in dengue disease severity","volume":"10","author":"Masood","year":"2018"},{"key":"b45","series-title":"Semin Immunopathol","first-page":"563","article-title":"Immune-mediated cytokine storm and its role in severe dengue","volume":"39","author":"Srikiatkhachorn","year":"2017"},{"key":"b46","series-title":"J Interferon Cytokine Res","first-page":"69","article-title":"Highlights for dengue immunopathogenesis: antibody-dependent enhancement, cytokine storm, and beyond","volume":"38","author":"Kuczera","year":"2018"},{"key":"b47","series-title":"Cytokine","first-page":"175","article-title":"MCP-1 and MIP-1\u03b1 expression in a model resembling early immune response to dengue","volume":"52","author":"Sierra","year":"2010"},{"key":"b48","series-title":"BMC Infect Dis","first-page":"86","article-title":"Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity","volume":"8","author":"Bozza","year":"2008"},{"key":"b49","series-title":"PLoS One","first-page":"e52215","article-title":"Cytokine expression profile of dengue patients at different phases of illness","volume":"7","author":"Rathakrishnan","year":"2012"},{"key":"b50","series-title":"FEMS Immunol Med Microbiol","first-page":"183","article-title":"Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis","volume":"28","author":"Chaturvedi","year":"2000"}],"container-title":["The American Journal of Tropical Medicine and 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