Correlation of Plasma 25(OH)D3 and Vitamin D Binding Protein Levels with COVID-19 Severity and Outcome in Hospitalized Patients.

BACKGROUND: The Coronavirus Disease-19 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been declared a worldwide pandemic. The severity of COVID-19 varies greatly across infected individuals. Possible factors may include plasma levels of 25(OH)D and vitamin D binding protein (DBP), as both are involved in the host immune response. Other possible nutrition-related factors include malnutrition and/or obesity which disrupt the optimal host immune response to infections. Current literature shows inconsistent evidence about the association of plasma 25(OH)D3 and DBP on infection severity and clinical outcomes. OBJECTIVES: This study aimed to measure plasma 25(OH)D3 and DBP in hospitalized COVID-19 cases and assess their correlation with infection severity, inflammatory markers, and clinical outcome. METHODS: 167 patients were included in this analytical cross-sectional study, of which 81 were critical and 86 were non-critical hospitalized COVID-19 patients. Plasma levels of 25(OH)D3, DBP, and the inflammatory cytokines, IL-6, IL-8, IL-10, and TNF-α were assessed using the Enzyme-linked Immunosorbent Assay (ELISA). Information regarding biochemical and anthropometrical indices, hospital length of stay (LoS), and illness outcome was obtained from the medical records. RESULTS: Plasma 25(OH)D3 level was found to be significantly lower in critical compared to non-critical patients (Median = 8.38 (IQR = 2.33) vs. 9.83 (IQR = 3.03) nmol/L, respectively; p < 0.001), and it positively correlated with hospital LoS. However, plasma 25(OH)D3 did not correlate with mortality or any of the inflammatory markers. DBP on the other hand correlated positively with mortality (rs = 0.188, p = 0.015) and hospital LoS (rs = 0.233, p = 0.002). DBP was significantly higher in critical than non-critical patients (Median = 1262.18 (IQR = 463.66) vs. 1153.35 (IQR = 418.46) ng/mL, respectively; p < 0.001). Furthermore, IL-6 and IL-8 were significantly higher in critical than non-critical patients. However, no differences were found in IL-10, TNF-α, IL-10/TNF-α, TNF-α/IL-10, IL-6/IL-10, or CRP between groups. CONCLUSION: The current study found that critical COVID-19 patients had lower 25(OH)D3 than non-critical patients, yet, levels were found to be suboptimal in both groups. Further, critical patients had higher DBP levels as compared to non-critical patients. This finding may encourage future research to unravel the effects of this understudied protein that appears to have significant associations with inflammation, even though the precise mechanism is unknown.

Immunotherapy with GcMAF revisited - A critical overview of the research of Nobuto Yamamoto.

This overview describes the research of Nobutu Yamamoto (Philadelphia) concerning immunotherapy with GcMAF for patients with cancer and for patients infected with pathogenic envelope viruses. GcMAF (Group-specific component Macrophage-Activating Factor) is a mammalian protein with an incredible potency to directly activate macrophages. Since the late 1980s Yamamoto's investigations were published in numerous journals but in order to understand the details of his research, a minute survey of many of his patents was required. But even then, regrettably, a precise description of his experiments was sometimes lacking. This overview tries to summarize all of Yamamoto's research on GcMAF, as well as some selected more recent papers from other investigators, who tried to verify and/or reproduce Yamamoto's reports. In my opinion the most important result of the GcMAF research deserves widespread renewed attention: human GcMAF injections (100 ng per week, intramuscular or intravenous) can help to cure patients with a great variety of cancers as well as patients infected with pathogenic envelope viruses like the human immunodeficiency virus 1 (HIV-1), influenza, measles and rubella (and maybe also SARS-CoV-2). From Yamamoto's data it can be calculated that GcMAF is a near-stoichiometric activator of macrophages. Yamamoto monitored the progress of his immunotherapy via the serum level of an enzyme called nagalase (α-N-acetylgalactosaminidase activity at pH 6). I have extensively discussed the properties and potential catalytic site of this enzyme activity in an Appendix entitled: "Search for the potential active site of the latent α-N-acetylgalactosaminidase activity in the glycoproteins of some envelope viruses".

Vitamin D, vitamin D-binding protein, free vitamin D and COVID-19 mortality in hospitalized patients.

BACKGROUND: Vitamin D deficiency has been associated with worse coronavirus disease 2019 (COVID-19) outcomes, but circulating 25-hydroxyvitamin D [25(OH)D] is largely bound to vitamin D-binding protein (DBP) or albumin, both of which tend to fall in illness, making the 25(OH)D status hard to interpret. Because of this, measurements of unbound ("free") and albumin-bound ("bioavailable") 25(OH)D have been proposed. OBJECTIVES: We aimed to examine the relationship between vitamin D status and mortality from COVID-19. METHODS: In this observational study conducted in Liverpool, UK, hospitalized COVID-19 patients with surplus sera available for 25(OH)D analysis were studied. Clinical data, including age, ethnicity, and comorbidities, were extracted from case notes. Serum 25(OH)D, DBP, and albumin concentrations were measured. Free and bioavailable 25(OH)D were calculated. Relationships between total, free, and bioavailable 25(OH)D and 28-day mortality were analyzed by logistic regression. RESULTS: There were 472 patients with COVID-19 included, of whom 112 (23.7%) died within 28 days. Nonsurvivors were older (mean age, 73 years; range, 34-98 years) than survivors (mean age, 65 years; range, 19-95 years; P = 0.003) and were more likely to be male (67%; P = 0.02). The frequency of vitamin D deficiency [25(OH)D < 50 nmol/L] was similar between nonsurvivors (71/112; 63.4%) and survivors (204/360; 56.7%; P = 0.15) but, after adjustments for age, sex, and comorbidities, increased odds for mortality were present in those with severe deficiency [25(OH)D < 25 nmol/L: OR, 2.37; 95% CI, 1.17-4.78] or a high 25(OH)D (≥100 nmol/L; OR, 4.65; 95% CI, 1.51-14.34) compared with a 25(OH)D value of 50-74 nmol/L (reference). Serum DBP levels were not associated with mortality after adjustments for 25(OH)D, age, sex, and comorbidities. Neither free nor bioavailable 25(OH)D values were associated with mortality. CONCLUSIONS: Vitamin D deficiency, as commonly defined by serum 25(OH)D levels (<50 nmol/L), is not associated with increased mortality from COVID-19, but extremely low (<25 nmol/L) and high (>100 nmol/L) levels may be associated with mortality risks. Neither free nor bioavailable 25(OH)D values are associated with mortality risk. The study protocol was approved by the London-Surrey Research Ethics Committee (20/HRA/2282).

Vitamin D-related polymorphisms and vitamin D levels as risk biomarkers of COVID-19 disease severity.

Vitamin D is a fundamental regulator of host defences by activating genes related to innate and adaptive immunity. Previous research shows a correlation between the levels of vitamin D in patients infected with SARS-CoV-2 and the degree of disease severity. This work investigates the impact of the genetic background related to vitamin D pathways on COVID-19 severity. For the first time, the Portuguese population was characterized regarding the prevalence of high impact variants in genes associated with the vitamin D pathways. This study enrolled 517 patients admitted to two tertiary Portuguese hospitals. The serum concentration of 25 (OH)D, was measured in the hospital at the time of patient admission. Genetic variants, 18 variants, in the genes AMDHD1, CYP2R1, CYP24A1, DHCR7, GC, SEC23A, and VDR were analysed. The results show that polymorphisms in the vitamin D binding protein encoded by the GC gene are related to the infection severity (p = 0.005). There is an association between vitamin D polygenic risk score and the serum concentration of 25 (OH)D (p = 0.04). There is an association between 25 (OH)D levels and the survival and fatal outcomes (p = 1.5e-4). The Portuguese population has a higher prevalence of the DHCR7 RS12785878 variant when compared with its prevalence in the European population (19% versus 10%). This study shows a genetic susceptibility for vitamin D deficiency that might explain higher severity degrees in COVID-19 patients. These results reinforce the relevance of personalized strategies in the context of viral diseases.Trial registration: NCT04370808.

Authors' reply: the biologic importance of the vitamin D binding protein polymorphism in pediatric COVID-19 patients.

What is Known? • Vitamin D has multiple roles in the immune system that can modulate the body reaction to an infection • Vitamin D binding protein (DBP) is the key transport protein which, along with albumin, binds over 99% of the circulating vitamin D metabolites What is New? • Lower 25 OH vitamin D levels were associated with higher inflammation markers, suggesting an important role of vitamin D in the clinical course of COVID-19 in children and adolescents probably by regulating the systemic inflammatory response • Further studies are warranted to investigate the possible causal association of DBP levels and polymorphism with vitamin D status (total and bioavailable vitamin D) in COVID-19 patients.

Human gene polymorphisms and their possible impact on the clinical outcome of SARS-CoV-2 infection.

The SARS-CoV-2 pandemic has become one of the most serious health concerns globally. Although multiple vaccines have recently been approved for the prevention of coronavirus disease 2019 (COVID-19), an effective treatment is still lacking. Our knowledge of the pathogenicity of this virus is still incomplete. Studies have revealed that viral factors such as the viral load, duration of exposure to the virus, and viral mutations are important variables in COVID-19 outcome. Furthermore, host factors, including age, health condition, co-morbidities, and genetic background, might also be involved in clinical manifestations and infection outcome. This review focuses on the importance of variations in the host genetic background and pathogenesis of SARS-CoV-2. We will discuss the significance of polymorphisms in the ACE-2, TMPRSS2, vitamin D receptor, vitamin D binding protein, CD147, glucose-regulated protein 78 kDa, dipeptidyl peptidase-4 (DPP4), neuropilin-1, heme oxygenase, apolipoprotein L1, vitamin K epoxide reductase complex 1 (VKORC1), and immune system genes for the clinical outcome of COVID-19.

The role of DBP gene polymorphisms in the prevalence of new coronavirus disease 2019 infection and mortality rate.

Since December 2019, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has given rise to emerging respiratory infections with pandemic diffusion. The vitamin D binding protein (DBP) with emphasis on its regulation of total and free vitamin D metabolite levels participate in various clinical conditions. The main goal of this study was to evaluate if there was any association between the DBP gene polymorphism at rs7041 and rs4588 loci and the prevalence of COVID-19 and its mortality rates caused among populations of 10 countries including Turkey. Positive significant correlations were found between the prevalence (per million) and mortality rates (per million), and GT genotype (P < .05) while there was a negative significant correlation between prevalence (per million) and mortality rates (per million), and TT genotype at rs7041 locus among all populations (P < .05). However, no significant correlation was found at rs4588 locus. GT genotype was found to confer this susceptibility to the populations of Germany, Mexico, Italy, Czech, and Turkey. The variations in the prevalence of COVID-19 and its mortality rates among countries may be explained by Vitamin D metabolism differed by the DBP polymorphisms of rs7041 and rs4588.