Effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in patients with moderate to severe COVID-19
Alan L Fernandes, Igor H Murai, Bruna Z Reis, Lucas P Sales, Mayara D Santos, Ana J Pinto, Karla F Goessler, Camila Sc Duran, Carla Br Silva, André S Franco, Marina B Macedo, Henrique Hh Dalmolin, Janaina Baggio, Guilherme Gm Balbi, Leila Antonangelo, Valeria F Caparbo, Bruno Gualano, Rosa Mr Pereira
The American Journal of Clinical Nutrition, doi:10.1093/ajcn/nqab426
Background: The modulating effect of vitamin D on cytokine concentrations in severe coronavirus disease 2019 (COVID-19) remains unknown. Objectives: We aimed to investigate the effect of a single high dose of vitamin D 3 on cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. Methods: This is a post hoc, ancillary, and exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients with moderate to severe COVID-19 were recruited from 2 hospitals in São Paulo, Brazil. Of 240 randomly assigned patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200,000 IU vitamin D 3 (n = 101) or placebo (n = 99). The primary outcome was hospital length of stay, which has been published in our previous study. The prespecified secondary outcomes were serum concentrations of IL-1β, IL-6, IL-10, TNF-α, and 25-hydroxyvitamin D. The post hoc exploratory secondary outcomes were IL-4, IL-12p70, IL-17A, IFN-γ , granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IFN-inducible protein-10 (IP-10), macrophage inflammatory protein-1β (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and leukocyte count. Generalized estimating equations for repeated measures, with Bonferroni's adjustment, were used for testing all outcomes. Results: The study included 200 patients with a mean ± SD age of 55.5 ± 14.3 y and BMI of 32.2 ± 7.1 kg/m 2 , of which 109 (54.5%) were male. GM-CSF concentrations showed a significant group-by-time interaction effect (P = 0.04), although the betweengroup difference at postintervention after Bonferroni's adjustment was not significant. No significant effects were observed for the other outcomes. Conclusions: The findings do not support the use of a single dose of 200,000 IU vitamin D 3 , compared with placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. This trial was registered at clinicaltrials.gov as NCT04449718.
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'abstract': '<jats:p>The pandemic dissemination of the SARS-CoV-2 led, on the one hand, to a worldwide '
'effort to develop mechanistic-based therapeutics and vaccines, and on the other hand, the '
'searching for determining the spreaders and the mechanisms of transmission. Melatonin, a '
'multitask molecule, orchestrates defense responses by allowing the proper mounting, duration, '
'and magnitude of innate immune responses. Melatonin is synthesized on demand by '
'immune-competent cells and constitutively by resident macrophages such as alveolar '
'macrophages. Here we investigated whether the expression of genes relevant to virus invasion '
'and infection varies according to a genic index (MEL-Index) that estimates the capacity of '
'the lung to synthesize melatonin. A COVID-19-Signature composed of 455 genes of 288 human '
'lungs (GTEX, UCSD) was correlated with MEL-Index by Pearson correlation test, gene-set '
'enrichment analysis, and networking tool that integrates the connectivity between the most '
'expressed genes, allowing us to compare the same set of genes under different states. The '
'three independent procedures point to a negative relationship between MEL-Index and '
'SARS-CoV-2 infection. The entry in epithelial AT2 cells should be hampered by a positive '
'correlation\xa0TMRPSS2\xa0\xa0and a negative correlation with the coding gene for furin, '
'suggesting dysfunctional processing in virus spike. Moreover, MEL-Index also negatively '
'correlates with the genes that codify the proteins of multi-molecular receptor complex CD147, '
'the gateway in macrophages, and other immune cells. In summary, the perspective that lung and '
'respiratory tract melatonin could be a natural protective factor opens new epidemiological '
'and pharmacological perspectives, as high MEL-Index scores could be predictive of '
'asymptomatic carriers, and nasal administrated melatonin could prevent evolution of '
'presymptomatic carriers.</jats:p>',
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