Comparative Histopathology of Yellow Fever in New and Old World Non-Human Primates: Hepatic and Extrahepatic Lesions in Susceptible Species

Yellow fever virus (YFV) causes a systemic, frequently fatal infection in susceptible non-human primates (NHPs), which serve as important hosts and sentinels of viral circulation. However, susceptibility and pathological outcomes differ markedly between New World and Old World species. This narrative review comparatively examines the hepatic and extrahepatic histopathological spectrum of lesions associated with YFV infection in NHPs and explores their implications for pathogenesis, surveillance, conservation, and outbreak preparedness. Relevant historical and contemporary studies were identified through a targeted literature search focusing on comparative pathology, host susceptibility, viral tropism, and tissue injury in naturally and experimentally infected primates. The liver is the principal target organ, with characteristic findings including midzonal hepatocellular necrosis, Councilman bodies, microvesicular steatosis, sinusoidal congestion, hemorrhage, and relatively limited inflammatory infiltration. Reported extrahepatic lesions involve the spleen, lymph nodes, kidneys, lungs, heart, and central nervous system, although their frequency and severity remain inconsistently documented across primate species. Highly susceptible Neotropical primates, particularly Alouatta spp., generally develop high viral burdens, extensive multiorgan damage, and high mortality. Although several African Old World primate species exhibit relatively mild or subclinical infections, severe disease has been documented in experimentally infected Asian macaques, highlighting substantial heterogeneity in susceptibility within both New World and Old World primate groups. Histopathology remains essential for investigating primate epizootics, although diagnostic accuracy improves when integrated with immunohistochemistry, reverse-transcription polymerase chain reaction, in situ hybridization, and genomic methods. Standardized protocols for necropsy, sampling, lesion scoring, and reporting are needed to improve interspecies and interregional comparisons. Comparative primate pathology can strengthen early-warning surveillance, guide human vaccination strategies, support wildlife conservation, and advance integrated One Health preparedness.