Febre amarela, entendendo uma antiga doença: aspectos clinico-epidemiológicos, virológicos e dinâmica evolutiva durante os surtos de 2017 e 2018, em Minas Gerias, Brasil

Abstract

At the end of 2016 and beginning of 2017, Brazil was surprised by cases of yellow fever occurring in the Southeast region, outside the Amazon Basin, which is the endemic region for the yellow fever virus (YFV). In 2018, a new wave of yellow fever cases took place in that same region. These cases occurred mainly in the state of Minas Gerais (MG). With this large number of yellow fever cases, the opportunity arose to study clinical, epidemiological, virological aspects, and the evolutionary dynamics of the YFV of the 2017 and 2018 outbreaks in MG, during the acute and convalescent phase of the disease. After the yellow fever outbreak in 2017 and 2018, the hypothesis arose whether the virus that caused the two yellow fever epidemics in MG would be the same or if a new introduction of YFV in the state had occurred. Epidemiological data together with sequencing data from serum samples from patients with yellow fever showed that the circulating YFV in MG had a unique origin, and are grouped with the South American I genotype, which is the main circulating YFV genotype in Brazil. During the yellow fever outbreak, through a collaboration with the Minas Gerais State Secretary of Health, our research group was asked to genotype 21 suspected cases of adverse events following vaccination with YFV-17DD. After standardization of a genotyping tool based on RT-qPCR and sequencing, it was concluded that none of the cases analyzed came from adverse events following vaccination with YFV-17DD. When analyzing the socio-demographic profile of patients with yellow fever, it was observed that the profile of these patients is in accordance with wild yellow fever and that the accumulated mortality rate was 23.84%. After qualitative and quantitative RT-qPCR analyzes, it was possible to detect YFV RNA from the 4th to the 25th day after the onset of symptoms, thus increasing the YFV molecular detection window. After analyzes during the acute phase of natural YFV infection, no differences in viral load values were observed between patients who died or were discharged, and viral load was not a possible marker of disease prognosis/severity. A group of patients was treated with the antiviral Sofosbuvir during the acute phase of yellow fever. Statistical differences were found in the viral load values between the untreated group with discharge and death outcomes and the treated group. These values indicate a possible action of the antiviral Sofosbuvir on the genomic load of YFV in the group of treated patients. During analyzes of the acute phase of yellow fever, four CSF samples from patients who progressed to death were positive on RT-qPCR for YFV and had antibody neutralization titers against YFV. We also analyzed the cases of eight patients with possible vaccine failure, who had been vaccinated at least one year ago against yellow fever. All eight patients analyzed had YFV infection confirmed by RT-qPCR and six still had detection of anti-YFV IgM and had antibody neutralization titers against YFV. During the analysis of the yellow fever convalescence phase, a group of patients was observed who showed changes in biochemical markers 60 days after the onset of symptoms, a condition called "late-relapsing hepatitis after yellow fever". The values of the liver damage markers AST and ALT during the convalescence phase were analyzed between the group that developed the clinical picture of late hepatitis and the control group. The values are significantly higher in the group with the clinical picture of late-relapsing hepatitis after yellow fever. Of this group of patients with late hepatitis, two urine collected during the convalescence phase were RT-qPCR positive for wild-type YFV. From a patient in the late hepatitis group, wild YFV was detected in the liver biopsy collected during the convalescence phase. These data suggest the possible persistence of the symptoms of yellow fever, the genome and possibly YFV in the convalescence phase in this group of patients. Major outbreaks bring opportunities to study and better understand diseases, their causative agents and their relationship with the population. When we talk about old diseases, which have occurred since centuries past, the breaking of paradigms is necessary in the modern world. The results of this work may provide data for the implementation of public policies, directing new strategies for treatment, prevention and management of yellow fever.