Update on the Pathophysiology of Yellow Fever Intoxication

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 "intoxication phase," remains poorly understood. Recent clinical data from the 2016-2019 São 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.