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| Author(s): |
Mateus Vailant Thomazella
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2023-05-05 |
| Examining board members: |
Esper Georges Kallas;
Gabriel da Rocha Fernandes;
Keity Souza Santos;
Alice Tung Wan Song
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| Advisor: | Esper Georges Kallas |
| Abstract | |
Yellow fever (YF) is an infectious disease with acute manifestations and a broad clinical spectrum caused by YF virus (YFV). Between 2017 and 2019, an outbreak of YF occurred in São Paulo, Brazil, with more than 600 cases and a mortality rate of approximately 35%. Little is known about the factors related to disease severity; however, it was recently shown that neutrophil count is independently associated with death. Additionally, evidence suggests an association between microbial translocation and severe dengue. Therefore, this study aimed to investigate the occurrence of microbial translocation and its association with neutrophil count as a factor associated with the severity of sylvatic YFV infection. To achieve these goals, peripheral blood samples were collected from patients diagnosed with yellow fever between 2018 and 2019 during the acute (time of hospital admission, n=90) and convalescent (n=16) phases of infection. Blood samples from individuals recently vaccinated against YF17DD (14 days after vaccination, n=10) and non-infected donors without recent vaccination (n=30) were used as controls. Plasma levels of markers related to microbial translocation and intestinal damage were quantified using immunoenzymatic assays (sCD14, LBP, EndoCAb IgM, and I-FABP) or quantitative PCR (16S DNA). The plasma microbiological profile was also evaluated by sequencing bacterial 16S DNA. Functional and phenotypic analyses of neutrophils were performed on blood samples from patients admitted in 2019 by quantifying the production of reactive oxygen species (ROS) (Dihydrorhodamine-123 oxidation method) and evaluating the expression of cell surface markers CD66b, CD11b, CD16, and CD14 (multiparametric flow cytometry), respectively. Results were compared between the infected and control groups. Data obtained from samples from the acute phase of the infection were analyzed considering the clinical outcome (death, n=27; or survivor, n=63), laboratory data, and the Model for End-stage Liver Disease (MELD) score. The neutrophil count, neutrophil/lymphocyte ratio, and MELD score were significantly elevated in the deceased patients. The levels of sCD14, LBP, 16S rRNA, and I-FABP were significantly elevated in individuals infected in the acute phase compared with those in the other control groups. Based on the clinical outcomes, deceased patients had higher levels of sCD14, LBP, and I-FABP than survivors and convalescents. No significant differences were observed in the microbiological composition between the survivor, deceased, and convalescent groups; however, a slight reduction in bacterial diversity was observed compared with the deceased and survivor groups. Additionally, bacterial diversity was negatively correlated with neutrophil count and MELD score. No differences were observed in the ROS production between the infected and control groups. Increased CD66b expression and decreased CD14 expression have been observed in neutrophils from infected individuals. Taken together, these results suggest that patients with YF disease who died had more liver and intestinal damage, with impairment of the gut-liver axis and the occurrence of microbial translocation, characterized by changes in markers related to this process (AU) | |
| FAPESP's process: | 19/13713-1 - Investigation of high neutrophil count in peripheral blood of patients with acute Yellow Fever |
| Grantee: | Mateus Vailant Thomazella |
| Support Opportunities: | Scholarships in Brazil - Doctorate |