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Flavivirus infection as dengue and yellow fever persists as a terrible menace to pandemics, due to Aedes prevalence in the Americas. Yellow fever is characterized by hepatocyte damage, with steatosis, apoptosis and necrosis, mainly in the midzonal region of the liver, but the injury mechanism has not been studied at the light of recent knowledge, such as the advances in cell death mechanisms, inflammatory response and cytokine cell expression tools. We studied 53 human liver paraffin embedded blocks from patients who died with yellow fever, all with histological demonstration of higher prevalence of apoptosis over necrosis and mild disproportionate inflammatory response. Viral antigens were found most frequently in hepatocytes from the midzonal area than other lobule areas, as detected by specific immunohistochemistry. Infiltrating cell subpopulations showed mainly CD4+ T lymphocytes, with small numbers of CD8+ cytotoxic lymphocytes, CD20+ B lymphocytes, NKT+ cells and S100+ dendritic cells in the sites of inflammation, as compared to normal and leptospirosis liver blocks. Some cells expressed TNF-alpha and IFN-gamma, but a much more intense proportion of TGF-beta expressing cells were found, suggesting both a Th1 and Th3 patterns of immune response in yellow fever. Most affected hepatocyte presented apoptosis markers that appear at the cell death main pathway in this infection. Viral antigens, which production could interfere in hepatocyte biology, could induce the activation of apoptosis cascade, but TGF-beta was also an apoptosis promoter. Our finding supports the key effect of the yellow fever virus in hepatocyte injury, resulting in prevalence of apoptosis over necrosis, aside from a TGF-beta action induced by the inflammatory response.

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Seventy-seven human cases of sylvatic yellow fever were reported in Brazil during the period January-June 2000. The first cases were reported 1 week after New Year's day and originated at Chapada dos Veadeiros, a tourist canyon site in Goiás state, near Brasília, the Brazilian capital. The laboratory procedures used for diagnoses included serology with an IgM capture assay and plaque reduction neutralization test, virus isolation in suckling mice and C6/36 cells, and immunohistochemistry. All cases were diagnosed by at least two different laboratory procedures, with the exception of the first three fatal cases, which were diagnosed on the basis of clinical and epidemiological information. The cases were reported in eight Brazilian states as follows: Goiás with 64.9% (50 cases); Amazonas (1); Bahia (10); Distrito Federal (1); Mato Grosso (4); Minas Gerais (2); Pará (1); São Paulo (2); and Tocantins (6). Patient ages were within the following ranges: 13-74 years old (mean 34.3), 64 (84.4%) were male, especially agricultural workers (n = 30), but tourists (n = 11), carpenters (n = 4), fishermen (n = 4), students (n = 3), truck drivers (n = 3), and other people (n = 22) were also sickened. The case fatality rate was 50.6% (39/77). In Bahia state, a serologic survey that was carried out has suggested a symptomatic/asymptomatic coefficient of 1:4. Field studies developed in Distrito Federal, Goiás, and São Paulo states showed that Haemagogus janthinomys was the mosquito species associated with the transmission. A single strain was also obtained from Aedes scapularis in Bahia. Epizootic occurrence (monkey mortality) was observed in 49 municipalities mainly in Goiás state, where 40 municipalities made reports, 21 of which also diagnosed human cases. Data obtained by the National Institute of Meteorology in Brazil showed an increase in temperature and rain in December 1999 and the first 3 months of 2000 in Goiás and surrounding states, which perhaps has contributed to the intense and widespread transmission of the yellow fever virus. The relatively small number of cases probably reflects the extensive use of yellow fever 17D-vaccine during the last 3 years, in which about 45 million doses were used. During the last months of 1999, 16 and 11 yellow fever cases were reported in Tocantins and Goiás states, respectively. It is noteworthy that the last reported autochthonous cases of sylvatic yellow fever in São Paulo and Bahia, both states outside the endemic/enzootic area, had occurred in 1953 and 1948, respectively.