Showing papers by "Renan P. Souza published in 2021"

Association between ACE2 and TMPRSS2 nasopharyngeal expression and COVID-19 respiratory distress.

Abstract: ACE2 and TMPRSS2 are key players on SARS-CoV-2 entry into host cells. However, it is still unclear whether expression levels of these factors could reflect disease severity. Here, a case-control study was conducted with 213 SARS-CoV-2 positive individuals where cases were defined as COVID-19 patients with respiratory distress requiring oxygen support (N = 38) and controls were those with mild to moderate symptoms of the disease who did not need oxygen therapy along the entire clinical course (N = 175). ACE2 and TMPRSS2 mRNA levels were evaluated in nasopharyngeal swab samples by RT-qPCR and logistic regression analyzes were applied to estimate associations with respiratory outcomes. ACE2 and TMPRSS2 levels positively correlated with age, which was also strongly associated with respiratory distress. Increased nasopharyngeal ACE2 levels showed a protective effect against this outcome (adjOR = 0.30; 95% CI 0.09-0.91), while TMPRSS2/ACE2 ratio was associated with risk (adjOR = 4.28; 95% CI 1.36-13.48). On stepwise regression, TMPRSS2/ACE2 ratio outperformed ACE2 to model COVID-19 severity. When nasopharyngeal swabs were compared to bronchoalveolar lavages in an independent cohort of COVID-19 patients under mechanical ventilation, similar expression levels of these genes were observed. These data suggest nasopharyngeal TMPRSS2/ACE2 as a promising candidate for further prediction models on COVID-19.

Epidemic Spread of SARS-CoV-2 Lineage B.1.1.7 in Brazil

Abstract: The emergence of diverse lineages harboring mutations with functional significance and potentially enhanced transmissibility imposes an increased difficulty on the containment of the SARS-CoV-2 pandemic [...].

Systematic review of host genetic association with Covid-19 prognosis and susceptibility: What have we learned in 2020?

Abstract: Biomarker identification may provide strategic opportunities to understand disease pathophysiology, predict outcomes, improve human health, and reduce healthcare costs. The highly heterogeneous Covid-19 clinical manifestation suggests a complex interaction of several different human, viral and environmental factors. Here, we systematically reviewed genetic association studies evaluating Covid-19 severity or susceptibility to SARS-CoV-2 infection following PRISMA recommendations. Our research comprised papers published until December 31st , 2020, in PubMed and BioRXiv databases focusing on genetic association studies with Covid-19 prognosis or susceptibility. We found 20 eligible genetic association studies, of which 11 assessed Covid-19 outcome and 14 evaluated infection susceptibility (five analyzed both effects). Q-genie assessment indicated moderate quality. Five large-scale association studies (GWAS, whole-genome, or exome sequencing) were reported with no consistent replication to date. Promising hits were found on the 3p21.31 region and ABO locus. Candidate gene studies examined ACE1, ACE2, TMPRSS2, IFITM3, APOE, Furin, IFNL3, IFNL4, HLA, TNF-ɑ genes, and ABO system. The most evaluated single locus was the ABO, and the most sampled region was the HLA with three and five candidate gene studies, respectively. Meta-analysis could not be performed. Available data showed the need for further reports to replicate claimed associations.

Report 46: Factors driving extensive spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals

Abstract: The SARS-CoV-2 Gamma variant spread rapidly across Brazil, causing substantial infection and death waves. We use individual-level patient records following hospitalisation with suspected or confirmed COVID-19 to document the extensive shocks in hospital fatality rates that followed Gamma's spread across 14 state capitals, and in which more than half of hospitalised patients died over sustained time periods. We show that extensive fluctuations in COVID-19 in-hospital fatality rates also existed prior to Gamma's detection, and were largely transient after Gamma's detection, subsiding with hospital demand. Using a Bayesian fatality rate model, we find that the geographic and temporal fluctuations in Brazil's COVID-19 in-hospital fatality rates are primarily associated with geographic inequities and shortages in healthcare capacity. We project that approximately half of Brazil's COVID-19 deaths in hospitals could have been avoided without pre-pandemic geographic inequities and without pandemic healthcare pressure. Our results suggest that investments in healthcare resources, healthcare optimization, and pandemic preparedness are critical to minimize population wide mortality and morbidity caused by highly transmissible and deadly pathogens such as SARS-CoV-2, especially in low- and middle-income countries. Note: The following manuscript has appeared as 'Report 46 - Factors driving extensive spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals' at https://spiral.imperial.ac.uk:8443/handle/10044/1/91875 . One sentence summary: COVID-19 in-hospital fatality rates fluctuate dramatically in Brazil, and these fluctuations are primarily associated with geographic inequities and shortages in healthcare capacity.

Dengue virus infection induces inflammation and oxidative stress on the heart.

Abstract: Objective Dengue fever is one of the most important arboviral diseases in the world, and its severe forms are characterised by a broad spectrum of systemic and cardiovascular hallmarks. However, much remains to be elucidated regarding the pathogenesis triggered by Dengue virus (DENV) in the heart. Herein, we evaluated the cardiac outcomes unleashed by DENV infection and the possible mechanisms associated with these effects. Methods A model of an adapted DENV-3 strain was used to infect male BALB/c mice to assess haemodynamic measurements and the functional, electrophysiological, inflammatory and oxidative parameters in the heart. Results DENV-3 infection resulted in increased systemic inflammation and vascular permeability with consequent reduction of systolic blood pressure and increase in heart rate. These changes were accompanied by a decrease in the cardiac output and stroke volume, with a reduction trend in the left ventricular end-systolic and end-diastolic diameters and volumes. Also, there was a reduction trend in the calcium current density in the ventricular cardiomyocytes of DENV-3 infected mice. Indeed, DENV-3 infection led to leucocyte infiltration and production of inflammatory mediators in the heart, causing pericarditis and myocarditis. Moreover, increased reactive oxygen species generation and lipoperoxidation were also verified in the cardiac tissue of DENV-3 infected mice. Conclusions DENV-3 infection induced a marked cardiac dysfunction, which may be associated with inflammation, oxidative stress and electrophysiological changes in the heart. These findings provide new cardiac insights into the mechanisms involved in the pathogenesis triggered by DENV, contributing to the research of new therapeutic targets for clinical practice.

Blockade of Interleukin Seventeen (IL-17A) with Secukinumab in Hospitalized COVID-19 patients - the BISHOP study.

Abstract: Background Patients with severe COVID-19 seem to have a compromised antiviral response and hyperinflammation. Neutrophils are critical players in COVID-19 pathogenesis. IL-17A plays a major role in protection against extracellular pathogens and neutrophil attraction and activation. We hypothesized that secukinumab, an anti-IL17A monoclonal antibody, could mitigate the deleterious hyperinflammation in COVID-19. Methods BISHOP was an open-label, single-center, phase-II controlled trial. Fifty adults hospitalized Covid-19 patients, confirmed by a positive SARS-CoV-2 RT-PCR, were randomized 1:1 to receive 300mg of secukinumab subcutaneously at day-0 (group A) plus standard of care (SoC: antiviral drugs, antimicrobials, corticosteroids, and/or anticoagulants) or SoC alone (group B). A second dose of 300mg of secukinumab could be administered on day-7, according to staff judgment. The primary endpoint was ventilator-free days at day-28 (VFD-28). Secondary efficacy and safety outcomes were also explored. Findings An intention-to-treat analysis showed no difference in VFD-28: 23.7 (95%CI 19.6-27.8) in group A vs. 23.8 (19.9-27.6) in group B, p=0.62; There was also no difference in hospitalization time, intensive care unit demand, the incidence of circulatory shock, acute kidney injury, fungal or bacterial co-infections, and severe adverse events. Pulmonary thromboembolism was less frequent in group A (4.2% vs. 26.2% p=0.04). There was one death in each group. Viral clearance, defined by the viral load fold change (2-ΔΔCT) in upper airways, between day-0 and day-7, was also similar: 0.17 (0.05-0.56) in group A vs. 0.24 (0.10-0.57) in group B. Interpretation The efficacy of secukinumab in the treatment of Covid19 was not demonstrated. No difference between groups in adverse events and no unexpected events were observed. Funding Novartis Brazil supported this research providing expert input in the development of the project, drug supply, data management, and monitoring.

Common Dysregulation of Innate Immunity Pathways in Human Primary Astrocytes Infected With Chikungunya, Mayaro, Oropouche, and Zika Viruses.

Abstract: Arboviruses pose a major threat throughout the world and represent a great burden in tropical countries of South America. Although generally associated with moderate febrile illness, in more severe cases they can lead to neurological outcomes, such as encephalitis, Guillain-Barre syndrome, and Congenital Syndromes. In this context astrocytes play a central role in production of inflammatory cytokines, regulation of extracellular matrix, and control of glutamate driven neurotoxicity in the central nervous system. Here, we presented a comprehensive genome-wide transcriptome analysis of human primary astrocytes infected with Chikungunya, Mayaro, Oropouche, or Zika viruses. Analyses of differentially expressed genes (DEGs), pathway enrichment, and interactomes have shown that Alphaviruses up-regulated genes related to elastic fiber formation and N-glycosylation of glycoproteins, with down-regulation of cell cycle and DNA stability and chromosome maintenance genes. In contrast, Oropouche virus up-regulated cell cycle and DNA maintenance and condensation pathways while down-regulated extracellular matrix, collagen metabolism, glutamate and ion transporters pathways. Zika virus infection only up-regulated eukaryotic translation machinery while down-regulated interferon pathways. Reactome and integration analysis revealed a common signature in down-regulation of innate immune response, antiviral response, and inflammatory cytokines associated to interferon pathway for all arboviruses tested. Validation of interferon stimulated genes by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) corroborated our transcriptome findings. Altogether, our results showed a co-evolution in the mechanisms involved in the escape of arboviruses to antiviral immune response mediated by the interferon (IFN) pathway.

Seroprevalence, prevalence, and genomic surveillance: monitoring the initial phases of the SARS-CoV-2 pandemic in Betim, Brazil

Abstract: The Covid-19 pandemic has created an unprecedented need for epidemiological monitoring using diverse strategies. We conducted a project combining prevalence, seroprevalence, and genomic surveillance approaches to describe the initial pandemic stages in Betim City, Brazil. We collected 3239 subjects in a population-based age-, sex- and neighbourhood-stratified, household, prospective; cross-sectional study divided into three surveys 21 days apart sampling the same geographical area. In the first survey, overall prevalence (participants positive in serological or molecular tests) reached 0.46% (90% CI 0.12% - 0.80%), followed by 2.69% (90% CI 1.88% - 3.49%) in the second survey and 6.67% (90% CI 5.42% - 7.92%) in the third. The underreporting reached 11, 19.6, and 20.4 times in each survey, respectively. We observed increased odds to test positive in females compared to males (OR 1.88 95% CI 1.25 - 2.82), while the single best predictor for positivity was ageusia/ anosmia (OR 8.12, 95% CI 4.72 - 13.98). Thirty-five SARS-CoV-2 genomes were sequenced, of which 18 were classified as lineage B.1.1.28, while 17 were B.1.1.33. Multiple independent viral introductions were observed. Integration of multiple epidemiological strategies was able to describe Covid-19 dispersion in the city adequately. Presented results have helped local government authorities to guide pandemic management.