{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:57:10Z","timestamp":1791385030274,"version":"4.3.3"},"reference-count":58,"publisher":"American Society of Tropical Medicine and Hygiene","issue":"4","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,7]]},"abstract":"<jats:title>ABSTRACT.<\/jats:title>\n                  <jats:p>Yellow fever virus (YFV) remains a major global health threat, driven by climate change, vector expansion, and vaccine shortages. Despite centuries of observation, the pathophysiology of severe yellow fever (YF), specifically the highly lethal \u201cintoxication phase,\" remains poorly understood. Recent clinical data from the 2016\u20132019 S\u00e3o Paulo epidemic and advances in animal models have shifted the understanding of YFV from a purely hepatocentric disease to a complex multiorgan syndrome. Emerging evidence indicates that YFV-induced endothelial damage and hypotension trigger profound intestinal ischemia and mucosal barrier breakdown, which allows gut bacteria to translocate into the portal system. Because the YFV-damaged liver cannot clear these pathogens, secondary polymicrobial sepsis ensues, likely contributing to the high mortality rates observed in severe YF. Our proposed gut-centered framework explains the distinct clinical presentation of YF intoxication. Recognizing secondary sepsis and vascular leakage highlights the urgent need for optimized fluid management, early dialysis, and targeted antimicrobial therapies to improve clinical outcomes.<\/jats:p>","DOI":"10.4269\/ajtmh.26-0276","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T17:38:32Z","timestamp":1786469912000},"page":"694-701","source":"Crossref","is-referenced-by-count":0,"title":["Update on the Pathophysiology of Yellow Fever Intoxication"],"prefix":"10.4269","volume":"115","author":[{"given":"Amaro Nunes","family":"Duarte-Neto","sequence":"first","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeh-Li","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Tropical Medicine, School of Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esper G.","family":"Kallas","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Tropical Medicine, School of Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam L.","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2795","reference":[{"key":"b1","series-title":"Yellow Fever","author":"Hinman","year":"1951"},{"issue":"5","key":"b2","series-title":"PLoS Med","first-page":"e1001638","article-title":"Yellow fever in Africa: Estimating the burden of disease and impact of mass vaccination from outbreak and serological data","volume":"11","author":"Garske","year":"2014"},{"key":"b3","series-title":"Elife","first-page":"e55619","article-title":"The effect of climate change on yellow fever disease burden in Africa","volume":"9","author":"Gaythorpe","year":"2020"},{"issue":"16","key":"b4","series-title":"N Engl J Med","first-page":"1445","article-title":"Yellow Jack\u2019s potential return to the American South","volume":"389","author":"Hotez","year":"2023"},{"issue":"3","key":"b5","series-title":"Lancet Infect Dis","first-page":"241","article-title":"Yellow fever: Is Asia prepared for an epidemic?","volume":"19","author":"Wilder-Smith","year":"2019"},{"issue":"10162","key":"b6","series-title":"Lancet","first-page":"2347","article-title":"Yellow fever: The Pacific should be prepared","volume":"392","author":"Musso","year":"2018"},{"issue":"8","key":"b7","series-title":"Lancet Infect Dis","first-page":"622","article-title":"The revised global yellow fever risk map and recommendations for vaccination, 2010: Consensus of the Informal WHO Working Group on Geographic Risk for Yellow Fever","volume":"11","author":"Jentes","year":"2011"},{"issue":"1","key":"b8","series-title":"Hum Vaccin Immunother","first-page":"1895644","article-title":"Re-thinking yellow fever vaccines: Fighting old foes with new generation vaccines","volume":"18","author":"Montalvo Zurbia-Flores","year":"2022"},{"issue":"2","key":"b9","series-title":"Am J Clin Pathol","first-page":"135","article-title":"Clinical pathology of yellow fever","volume":"25","author":"Elton","year":"1955"},{"issue":"1","key":"b10","series-title":"Ann Anat Pathol (Paris)","first-page":"21","article-title":"[Anatomo-pathological diagnosis of yellow fever (apropos of the epidemic in Upper Volta in 1969)]","volume":"17","author":"Ricosse","year":"1972"},{"key":"b11","series-title":"Adv Virus Res","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/S0065-3527(03)60009-6","article-title":"Pathogenesis and pathophysiology of yellow fever","volume":"60","author":"Monath","year":"2003"},{"issue":"7","key":"b12","series-title":"PLoS Negl Trop Dis","first-page":"e0007625","article-title":"Ultrasound-guided minimally invasive autopsy as a tool for rapid post-mortem diagnosis in the 2018 Sao Paulo yellow fever epidemic: Correlation with conventional autopsy","volume":"13","author":"Duarte-Neto","year":"2019"},{"issue":"5","key":"b13","series-title":"Histopathology","first-page":"638","article-title":"Yellow fever and orthotopic liver transplantation: New insights from the autopsy room for an old but re-emerging disease","volume":"75","author":"Duarte-Neto","year":"2019"},{"key":"b14","series-title":"Public Health Bull","first-page":"151","article-title":"Report on etiology and prevention of yellow fever: Pathological anatomy and histology","volume":"2","author":"Councilman","year":"1890"},{"issue":"2","key":"b15","series-title":"Histopathology","first-page":"195","article-title":"Histopathology of the human liver in yellow fever with special emphasis on the diagnostic role of the Councilman body","volume":"7","author":"Vieira","year":"1983"},{"issue":"2","key":"b16","series-title":"Acta Trop","first-page":"116","article-title":"Reconsideration of histopathology and ultrastructural aspects of the human liver in yellow fever","volume":"94","author":"Quaresma","year":"2005"},{"issue":"1","key":"b17","series-title":"Virology","first-page":"188","article-title":"Differential cytokine responses from primary human Kupffer cells following infection with wild-type or vaccine strain yellow fever virus","volume":"412","author":"Woodson","year":"2011"},{"issue":"1-2","key":"b18","series-title":"Pathol Res Pract","first-page":"177","article-title":"Human fatal yellow fever. Immunohistochemical detection of viral antigens in the liver, kidney and heart","volume":"188","author":"De Brito","year":"1992"},{"key":"b19","series-title":"A Folha M\u00e9dica","first-page":"218","article-title":"Observa\u00e7\u00f5es de 25 casos de febre amarela","volume":"9","author":"Lins","year":"1928"},{"key":"b20","series-title":"Arch Hyg","first-page":"195","article-title":"Contribui\u00e7\u00e3o ao estudo cl\u00ednico da febre amarella","volume":"3","author":"Lins","year":"1929"},{"key":"b21","series-title":"Trans Coll Physicians Phila","first-page":"218","article-title":"Soper, F. L. Yellow fever in the Americas, 1938-1942. Transactions of the College of Physicians of Philadelphia","volume":"10","author":"Soper","year":"1942"},{"key":"b22","series-title":"Yellow Fever","first-page":"385","author":"Kerr","year":"1951"},{"issue":"7","key":"b23","series-title":"Lancet Infect Dis","first-page":"750","article-title":"Predictors of mortality in patients with yellow fever: An observational cohort study","volume":"19","author":"Kallas","year":"2019"},{"issue":"5","key":"b24","series-title":"J Travel Med","first-page":"taz040","article-title":"Severe yellow fever in Brazil: Clinical characteristics and management","volume":"26","author":"Ho","year":"2019"},{"key":"b25","series-title":"Epidemiol Serv Saude","first-page":"e20250739","article-title":"Yellow fever vaccination coverage and knowledge, attitudes and practices: A cross-sectional study during an epizootic event in S\u00e3o Sebasti\u00e3o, Federal District, 2020","volume":"35","author":"de Freitas","year":"2025"},{"key":"b26","series-title":"Rev Saude Publica","first-page":"89","article-title":"Yellow fever: Profile of cases and factors associated with death in a hospital in the State of Rio de Janeiro, 2017\u20132018","volume":"53","author":"Escosteguy","year":"2019"},{"issue":"9","key":"b27","series-title":"J Infect Dis","first-page":"1097","article-title":"Viral kinetics in sylvatic yellow fever cases","volume":"227","author":"Avelino-Silva","year":"2023"},{"issue":"3","key":"b28","series-title":"Kidney Int Rep","first-page":"601","article-title":"Risk factors for acute kidney injury and death in patients infected with the yellow fever virus during the 2018 outbreak in S\u00e3o Paulo, Brazil","volume":"7","author":"Arantes","year":"2022"},{"key":"b29","series-title":"Mem Inst Oswaldo Cruz","first-page":"e190033","article-title":"Lipase and factor V (but not viral load) are prognostic factors for the evolution of severe yellow fever cases","volume":"114","author":"Casadio","year":"2019"},{"key":"b30","series-title":"EBioMedicine","first-page":"105409","article-title":"Yellow fever disease severity and endothelial dysfunction are associated with elevated serum levels of viral NS1 protein and syndecan-1","volume":"109","author":"de Sousa","year":"2024"},{"key":"b31","series-title":"Int J Infect Dis","first-page":"90","article-title":"Clinical profiles and factors associated with mortality in adults with yellow fever admitted to an intensive care unit in Minas Gerais, Brazil","volume":"93","author":"de \u00c1vila","year":"2020"},{"issue":"1","key":"b32","series-title":"J Infect Dis","first-page":"e60","article-title":"Levels of angiopoietin 2 are predictive for mortality in patients infected with yellow fever virus","volume":"230","author":"van de Weg","year":"2024"},{"issue":"21","key":"b33","series-title":"N Engl J Med","first-page":"2059","article-title":"Late-onset relapsing hepatitis associated with yellow fever","volume":"382","author":"Casadio","year":"2020"},{"issue":"12","key":"b34","series-title":"J Med Virol","first-page":"e70099","article-title":"Systems immunology approaches to understanding immune responses in acute infection of yellow fever patients","volume":"96","author":"Gon\u00e7alves","year":"2024"},{"issue":"1","key":"b35","series-title":"Am J Trop Med Hyg","first-page":"180","article-title":"Yellow fever: Factors associated with death in a hospital of reference in infectious diseases, S\u00e3o Paulo, Brazil, 2018","volume":"101","author":"Ribeiro","year":"2019"},{"issue":"3","key":"b36","series-title":"J Infect Dis","first-page":"541","article-title":"Mesenteric ischemia and bacterial translocation precipitate the intoxication phase of yellow fever","volume":"233","author":"Thomazella","year":"2025"},{"issue":"5","key":"b37","series-title":"Br J Haematol","first-page":"455","article-title":"The original haemorrhagic fever: Yellow fever","volume":"17","author":"Dennis","year":"1969"},{"issue":"2","key":"b38","series-title":"Am J Trop Med Hyg","first-page":"431","article-title":"Pathophysiologic correlations in a rhesus monkey model of yellow fever","volume":"30","author":"Monath","year":"1981"},{"issue":"9","key":"b39","series-title":"AMA J Ethics","first-page":"E741","article-title":"Humanity and inhumanity of nonhuman primate research","volume":"26","author":"Weed","year":"2024"},{"issue":"2","key":"b40","series-title":"Ann Trop Med Parasit","first-page":"249","article-title":"Studies on the action of yellow fever virus in mice","volume":"24","author":"Theiler","year":"1930"},{"issue":"51","key":"b41","series-title":"Proc Natl Acad Sci USA","first-page":"32648","article-title":"Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury","volume":"117","author":"Bailey","year":"2020"},{"issue":"8","key":"b42","series-title":"Nat Microbiol","first-page":"1902","article-title":"Amino acid changes in two viral proteins drive attenuation of the yellow fever 17D vaccine","volume":"10","author":"Zhang","year":"2025"},{"issue":"3","key":"b43","series-title":"mBio","first-page":"e00512-22","article-title":"Isolation of a potently neutralizing and protective human monoclonal antibody targeting yellow fever virus","volume":"13","author":"Doyle","year":"2022"},{"issue":"8095","key":"b44","series-title":"Nature","first-page":"173","article-title":"Multiple LDLR family members act as entry receptors for yellow fever virus","volume":"649","author":"Chong","year":"2026"},{"issue":"10","key":"b45","series-title":"J Infect Dis","first-page":"1431","article-title":"Experimental yellow fever virus infection in the Golden Hamster (Mesocricetus auratus). I. Virologic, biochemical, and immunologic studies","volume":"183","author":"Tesh","year":"2001"},{"issue":"2","key":"b46","series-title":"J Virol","first-page":"1462","article-title":"Molecular characterization of a hamster viscerotropic strain of yellow fever virus","volume":"77","author":"McArthur","year":"2003"},{"issue":"304","key":"b47","series-title":"Sci Transl Med","first-page":"304ra141","article-title":"Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination","volume":"7","author":"Beatty","year":"2015"},{"issue":"6525","key":"b48","series-title":"Science","first-page":"194","article-title":"Structural basis for antibody inhibition of flavivirus NS1-triggered endothelial dysfunction","volume":"371","author":"Biering","year":"2021"},{"issue":"11","key":"b49","series-title":"PLoS Pathog","first-page":"e1006673","article-title":"Dengue virus NS1 cytokine-independent vascular leak is dependent on endothelial glycocalyx components","volume":"13","author":"Glasner","year":"2017"},{"issue":"5","key":"b50","series-title":"PLoS Negl Trop Dis","first-page":"e2236","article-title":"Microbial translocation is associated with extensive immune activation in dengue virus infected patients with severe disease","volume":"7","author":"van de Weg","year":"2013"},{"issue":"6","key":"b51","series-title":"Cell Rep","first-page":"1598","article-title":"Flavivirus NS1 triggers tissue-specific vascular endothelial dysfunction reflecting disease tropism","volume":"26","author":"Puerta-Guardo","year":"2019"},{"key":"b52","series-title":"EBioMedicine","first-page":"104810","article-title":"Understanding yellow fever-associated myocardial injury: An autopsy study","volume":"96","author":"Giugni","year":"2023"},{"issue":"2","key":"b53","series-title":"Emerg Infect Dis","first-page":"211","article-title":"Pulmonary complications in fatal yellow fever, Brazil, 2017-2019","volume":"32","author":"Duarte-Neto","year":"2026"},{"key":"b54","article-title":"Gu\u00eda de Manejo Cl\u00ednico del Paciente Grave con Fiebre Amarilla.","year":"2026"},{"issue":"5","key":"b55","series-title":"AJR Am J Roentgenol","first-page":"1392","article-title":"Ultrasound findings and laboratory predictors of early mortality in patients with severe yellow fever","volume":"216","author":"Neves","year":"2021"},{"issue":"3","key":"b56","series-title":"Acta Med Indones","first-page":"193","article-title":"Gallbladder wall thickening for early detection of plasma leakage in dengue infected adult patients","volume":"50","author":"Nainggolan","year":"2018"},{"issue":"2","key":"b57","series-title":"Ultrasound Int Open","first-page":"E76","article-title":"Patterns of gall bladder wall thickening in dengue fever: a mirror of the severity of disease","volume":"3","author":"Parmar","year":"2017"},{"key":"b58","article-title":"Yellow Fever: Region of the Americas.","year":"2025"}],"container-title":["The American Journal of Tropical Medicine and Hygiene"],"original-title":[],"link":[{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/115\/4\/article-p694.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.ajtmh.org\/downloadpdf\/journals\/tpmd\/115\/4\/article-p694.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/www.ajtmh.org\/downloadpdf\/journals\/tpmd\/115\/4\/article-p694.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:24:45Z","timestamp":1791383085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ajtmh.org\/view\/journals\/tpmd\/115\/4\/article-p694.xml"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":58,"journal-issue":{"issue":"4"},"URL":"https:\/\/doi.org\/10.4269\/ajtmh.26-0276","relation":{},"ISSN":["0002-9637","1476-1645"],"issn-type":[{"value":"0002-9637","type":"print"},{"value":"1476-1645","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]}}}