Wild-type Yellow fever virus in cerebrospinal fluid from fatal cases in Brazil, 2018

Abstract

Yellow fever virus (YFV) is the causative agent of yellow fever (YF), a hemorrhagic and viscerotropic acute disease. Severe YF has been described in approximately 15-25% of YF patients, with 20-50% of severe YF cases being fatal. Here we analyzed cerebrospinal fluid (CSF) samples collected during the YF outbreak in Brazil in 2018, aiming to investigate CNS neuroinvasion in fatal YFV cases. YFV RNA was screened by RT-qPCR targeting the 3'UTR region of the YFV genome in CSF. CSF samples were tested for the presence of anti-YFV IgM and neutralizing antibodies, coupled with routine laboratory examinations. Among the 13 patients studied, we detected anti-YFV IgM in CSF from eight patients and YFV RNA in CSF from five patients. YFV RNA genomic load in CSF samples ranged from 1.75×103 to 5.42×103 RNA copies/mL. We genotyped YFV from three CSF samples that grouped with other YFV samples from the 2018 outbreak in Brazil within the South-American I genotype. Even though descriptions of neurologic manifestations due to wild type YFV (WT-YFV) infection are rare, since the last YF outbreak in Brazil in 2017-2018, a few studies have demonstrated WT-YFV RNA in CSF samples from YF fatal cases. Serological tests indicated the presence of IgM and neutralizing antibodies against YFV in CSF samples from two patients. Although the presence of viral RNA, IgM and neutralizing antibodies in CSF samples could indicate neuroinvasiveness, further studies are needed to better elucidate the role of YFV neuroinvasion and possible impacts in disease pathogenesis.

Keywords: Yellow fever virus; central nervous system; cerebrospinal fluid; neurotropic; wild-type Yellow fever virus; yellow fever.

FIGURE 1

Maximum Likelihood tree of Yellow fever virus. The maximum clade credibility tree inferred using Yellow fever virus (YFV) sequences (187 nt) is shown (corresponding to position 9046 to 9232 compared to the YFV nucleotide sequence, GenBank accession number KY885001). The bootstrap values (1.000 replicates) are represented by circles drawn in scale in the nodes. Bootstrap values higher than 75 are indicated. Sequences generated in this study are highlighted in pink. The clade containing samples from the genotype South-American I is represented in black. The clade containing samples from genotype South-American II is represented in green. For clarity purposes, some branches representing different genotypes were collapsed and colored as follows: West African I and II (light blue), Angola (dark blue), and East/Central African (orange), respectively. The tree was reconstructed using the nucleotide substitution model kimura 2-parameters with 4-categories gamma distribution. The analysis was performed using MEGA7 and the tree was visualized and edited in FigTree v1.4.4.