{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:36:13Z","timestamp":1760060173734,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CDC Grant","award":["200-2017-93142","5TD43TW010923"],"award-info":[{"award-number":["200-2017-93142","5TD43TW010923"]}]},{"name":"Fogarty International Center","award":["200-2017-93142","5TD43TW010923"],"award-info":[{"award-number":["200-2017-93142","5TD43TW010923"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Historically, DENV-4 has been rarely associated with epidemics and has been less well-studied than DENV-1 to -3. Epidemic dengue struck several South and Central American countries in 2022, with Nicaragua reporting the highest incidence. In an acute febrile illness (AFI) cohort enrolled from June to September 2022, 58 (34%) of 172 patients had PCR-confirmed dengue, of which 46 (79%) were serotyped as DENV-4. In this cohort, acute dengue, as a proportion of AFI, increased from 8% in June to a peak of 58% in August. Genome sequencing and phylogenetic analysis identified a lineage of DENV-4 Genotype IIb (GIIb) with six amino acid substitutions on the surface-exposed regions of the envelope (E) protein as compared to a reference sequence from 2005. Indeed, two of these mutations appear to be novel and located at G172E or near N174K, an antigenic epitope on domain I. Most (90%, 43\/48) DENV-4 patients had pre-existing DENV IgG (secondary dengue), at the acute phase. Secondary dengue was associated with the male sex (prevalence ratio (PR)), 6.88) and being younger than 11 years of age (PR, 8.38). Further analysis showed no association between past Zika exposure and DENV-4 acute illness in older subjects (\u226512 years of age). In conclusion, our study describes an epidemic of DENV-4 in Le\u00f3n, Nicaragua, associated with a novel lineage of genotype GIIb, which contains two amino acid changes not observed in DENV-4 before 2022.<\/jats:p>","DOI":"10.3390\/v17081113","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T13:30:38Z","timestamp":1755091838000},"page":"1113","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acute Febrile Illness Associated with an Emerging Dengue 4 GIIb Variant Causing Epidemic in Le\u00f3n, Nicaragua 2022"],"prefix":"10.3390","volume":"17","author":[{"given":"Omar","family":"Zepeda","sequence":"first","affiliation":[{"name":"Centro de Investigaci\u00f3n de Enfermedades Tropicales (CIET), Faculty of Microbiology, University of Costa Rica, San Jos\u00e9 11501-2060, Costa Rica"},{"name":"Department of Microbiology and Immunology, School of Medicine, The University of North Carolina, Chapel Hill, NC 27559, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwing C.","family":"Cuadra","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, The University of North Carolina, Chapel Hill, NC 27559, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel O.","family":"Espinoza","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yerun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4226-873X","authenticated-orcid":false,"given":"Hern\u00e1n","family":"Vanegas","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias M\u00e9dicas, Universidad Nacional Aut\u00f3noma de Nicaragua (UNAN-Le\u00f3n), Le\u00f3n 21000, Nicaragua"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis","family":"Domeracki","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7964-3575","authenticated-orcid":false,"given":"Rodrigo A.","family":"Mora-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n de Enfermedades Tropicales (CIET), Faculty of Microbiology, University of Costa Rica, San Jos\u00e9 11501-2060, Costa Rica"},{"name":"Research Center on Surgery and Cancer, CICICA, Universidad de Costa Rica, San Jos\u00e9 11501-2060, Costa Rica"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5942-1534","authenticated-orcid":false,"given":"Anne","family":"Piantadosi","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesse J.","family":"Waggoner","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Armando J.","family":"Matute","sequence":"additional","affiliation":[{"name":"Hospital Escuela Oscar Danilo Rosales Arguello, Departamento de Medicina Interna, Facultad de Ciencias M\u00e9dicas, Universidad Nacional Aut\u00f3noma de Nicaragua (UNAN-Le\u00f3n), Le\u00f3n 21000, Nicaragua"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1736-1350","authenticated-orcid":false,"given":"Lakshmanane","family":"Premkumar","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, The University of North Carolina, Chapel Hill, NC 27559, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aravinda M.","family":"de Silva","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, The University of North Carolina, Chapel Hill, NC 27559, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7974-1933","authenticated-orcid":false,"given":"Matthew H.","family":"Collins","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan E.","family":"Reller","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9819-870X","authenticated-orcid":false,"given":"Filem\u00f3n","family":"Bucardo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, School of Medicine, The University of North Carolina, Chapel Hill, NC 27559, USA"},{"name":"Department of Family Medicine, School of Medicine, The University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/S0140-6736(18)32560-1","article-title":"Dengue","volume":"393","author":"Ooi","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1179\/2046904712Z.00000000052","article-title":"The Revised WHO Dengue Case Classification: Does the System Need to Be Modified?","volume":"32","author":"Hadinegoro","year":"2012","journal-title":"Paediatr. 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