Vitamine D et virus?

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Low Circulating Vitamin D in Intensive Care Unit–Admitted COVID-19 Patients as a Predictor of Negative Outcomes
Mikhail V Bychinin, The Journal of Nutrition, 2021

Background
Vitamin D deficiency has been associated with an increased risk of respiratory infections.

Objectives
The study aimed to evaluate the serum 25-hydroxyvitamin D [25(OH)D] concentration in patients admitted to the intensive care unit (ICU) as a predictor of coronavirus disease 2019 (COVID-19) mortality.

Methods
A single-center retrospective observational study was conducted. Forty adult patients (50% men) with confirmed COVID-19 who were admitted to the ICU were enrolled. The primary endpoint was mortality at day 60. Serum 25(OH)D concentration was measured on the day of admission to the ICU. We used the Mann–Whitney test, Fisher's exact test, Kaplan–Meier analysis, and receiver operator characteristic (ROC) analysis to assess serum 25(OH)D concentration as a predictor of COVID-19 mortality.

Results
All 40 patients had a low median (IQR) serum 25(OH)D concentration at admission [12 (9–15) ng/mL]. The median (IQR) serum 25(OH)D concentration was greater in survivors [13.3 (10.0–17.1) ng/mL, n = 22] than in nonsurvivors [9.6 (7.9–14.2) ng/mL; n = 18], P = 0.044. The area under the ROC curve was 0.69 (95% CI: 0.52, 0.86; P = 0.044). The 60-d mortality rate of those with serum 25(OH)D concentrations ≤9.9 ng/mL (n = 14, 71%) tended to be greater than that of those with concentrations >9.9 ng/mL (n = 26, 31%) (P = 0.065), and they had a 5.6-fold higher risk of death (OR: 5.63; 95% CI: 1.35, 23.45; P = 0.018).

Conclusions
The ICU patients had a low serum 25(OH)D concentration. Serum 25(OH)D concentrations ≤9.9 ng/mL on admission can be used to predict in-hospital mortality in patients with COVID-19.

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Traduction de l'étude

Vitamine D à faible circulation dans les unités de soins intensifs - Patients admis au COVID-19 comme prédicteur de résultats négatifs
Mikhail V Bychinin, Le Journal de la Nutrition, 2021

Arrière-plan
Une carence en vitamine D a été associée à un risque accru d'infections respiratoires.

Objectifs
L'étude visait à évaluer la concentration sérique de 25-hydroxyvitamine D [25 (OH) D] chez les patients admis à l'unité de soins intensifs (USI) en tant que prédicteur de la mortalité par coronavirus 2019 (COVID-19).

Méthodes
Une étude observationnelle rétrospective monocentrique a été menée. Quarante patients adultes (50% d'hommes) avec COVID-19 confirmé qui ont été admis à l'USI ont été recrutés. Le critère d'évaluation principal était la mortalité au jour 60. La concentration sérique de 25 (OH) D a été mesurée le jour de l'admission à l'USI. Nous avons utilisé le test de Mann-Whitney, le test exact de Fisher, l'analyse de Kaplan-Meier et l'analyse des caractéristiques de l'opérateur du récepteur (ROC) pour évaluer la concentration sérique de 25 (OH) D comme prédicteur de la mortalité par COVID-19.

Résultats
Les 40 patients avaient une faible concentration sérique médiane (IQR) de 25 (OH) D à l'admission [12 (9–15) ng / mL]. La concentration sérique médiane (IQR) de 25 (OH) D était plus élevée chez les survivants [13,3 (10,0–17,1) ng / mL, n = 22] que chez les non-survivants [9,6 (7,9–14,2) ng / mL; n = 18], p = 0,044. L'aire sous la courbe ROC était de 0,69 (IC à 95%: 0,52, 0,86; P = 0,044). Le taux de mortalité à 60 jours des personnes ayant des concentrations sériques de 25 (OH) D ≤ 9,9 ng / mL (n = 14, 71%) avait tendance à être supérieur à celui de ceux dont les concentrations étaient> 9,9 ng / mL (n = 26, 31 %) (P = 0,065), et ils avaient un risque de décès 5,6 fois plus élevé (OR: 5,63; IC à 95%: 1,35, 23,45; P = 0,018).

Conclusions
Les patients en soins intensifs avaient une faible concentration sérique de 25 (OH) D. Des concentrations sériques de 25 (OH) D ≤ 9,9 ng / mL à l'admission peuvent être utilisées pour prédire la mortalité à l'hôpital chez les patients atteints de COVID-19.

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Genetically predicted serum vitamin D and COVID-19: a Mendelian randomisation study
Bonnie K Patchen BMJ Nutrition, Prevention & Health 2021

Abstract
Objectives To investigate causality of the association of serum vitamin D with the risk and severity of COVID-19 infection.

Design Two-sample Mendelian randomisation study.

Setting Summary data from genome-wide analyses in the population-based UK Biobank and SUNLIGHT Consortium, applied to meta-analysed results of genome-wide analyses in the COVID-19 Host Genetics Initiative.

Participants 17 965 COVID-19 cases including 11 085 laboratory or physician-confirmed cases, 7885 hospitalised cases and 4336 severe respiratory cases, and 1 370 547 controls, primarily of European ancestry.

Exposures Genetically predicted variation in serum vitamin D status, instrumented by genome-wide significant single nucleotide polymorphisms (SNPs) associated with serum vitamin D or risk of vitamin D deficiency/insufficiency.

Main outcome measures Susceptibility to and severity of COVID-19 infection, including severe respiratory infection and hospitalisation.

Results Mendelian randomisation analysis, sufficiently powered to detect effects comparable to those seen in observational studies, provided little to no evidence for an effect of genetically predicted serum vitamin D on susceptibility to or severity of COVID-19 infection. Using SNPs in loci related to vitamin D metabolism as genetic instruments for serum vitamin D concentrations, the OR per SD higher serum vitamin D was 1.04 (95% CI 0.92 to 1.18) for any COVID-19 infection versus population controls, 1.05 (0.84 to 1.31) for hospitalised COVID-19 versus population controls, 0.96 (0.64 to 1.43) for severe respiratory COVID-19 versus population controls, 1.15 (0.99 to 1.35) for COVID-19 positive versus COVID-19 negative and 1.44 (0.75 to 2.78) for hospitalised COVID-19 versus non-hospitalised COVID-19. Results were similar in analyses using SNPs with genome-wide significant associations with serum vitamin D (ie, including SNPs in loci with no known relationship to vitamin D metabolism) and in analyses using SNPs with genome-wide significant associations with risk of vitamin D deficiency or insufficiency.

Conclusions These findings suggest that genetically predicted differences in long-term vitamin D nutritional status do not causally affect susceptibility to and severity of COVID-19 infection, and that associations observed in previous studies may have been driven by confounding. These results do not exclude the possibility of low-magnitude causal effects or causal effects of acute responses to therapeutic doses of vitamin D.

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Traduction de l'étude

Vitamine D et COVID-19 sériques génétiquement prédites: une étude de randomisation mendélienne
Bonnie K Patchen BMJ Nutrition, Prévention & Santé 2021

Abstrait
Objectifs Étudier la causalité de l'association de la vitamine D sérique avec le risque et la gravité de l'infection au COVID-19.

Conception Étude de randomisation mendélienne à deux échantillons.

Paramètres Résumé des données d'analyses à l'échelle du génome de la UK Biobank et du consortium SUNLIGHT basé sur la population, appliquées aux résultats méta-analysés d'analyses à l'échelle du génome dans le cadre de la COVID-19 Host Genetics Initiative.

Participants 17 965 cas de COVID-19 dont 11 085 cas confirmés en laboratoire ou par le médecin, 7885 cas hospitalisés et 4336 cas respiratoires sévères et 1 370 547 témoins, principalement d'origine européenne.

Expositions Variation génétiquement prédite du statut sérique en vitamine D, instrumentée par des polymorphismes mononucléotidiques (SNP) significatifs à l'échelle du génome associés à la vitamine D sérique ou au risque de carence / insuffisance en vitamine D.

Principaux critères de jugement Sensibilité et gravité de l'infection au COVID-19, y compris infection respiratoire sévère et hospitalisation.

Résultats L'analyse de randomisation mendélienne, suffisamment puissante pour détecter des effets comparables à ceux observés dans les études observationnelles, a fourni peu ou pas de preuves d'un effet de la vitamine D sérique génétiquement prédite sur la sensibilité ou la gravité de l'infection au COVID-19. En utilisant des SNP dans des locus liés au métabolisme de la vitamine D comme instruments génétiques pour les concentrations sériques de vitamine D, le RC par SD plus élevé de vitamine D sérique était de 1,04 (IC à 95% 0,92 à 1,18) pour toute infection au COVID-19 par rapport aux témoins de la population, 1,05 (0,84 à 1,18). 1,31) pour le COVID-19 hospitalisé par rapport aux témoins de la population, 0,96 (0,64 à 1,43) pour le COVID-19 respiratoire sévère par rapport aux témoins de la population, 1,15 (0,99 à 1,35) pour le COVID-19 positif par rapport au COVID-19 négatif et 1,44 (0,75 à 2,78) pour le COVID-19 hospitalisé versus le COVID-19 non hospitalisé. Les résultats étaient similaires dans les analyses utilisant des SNP avec des associations significatives à l'échelle du génome avec la vitamine D sérique (c'est-à-dire, y compris les SNP dans des locus sans relation connue avec le métabolisme de la vitamine D) et dans les analyses utilisant des SNP avec des associations significatives à l'échelle du génome avec le risque de carence en vitamine D ou insuffisance.

Conclusions Ces résultats suggèrent que les différences génétiquement prédites dans l'état nutritionnel à long terme de la vitamine D n'affectent pas de manière causale la sensibilité et la gravité de l'infection au COVID-19, et que les associations observées dans les études précédentes peuvent avoir été induites par des facteurs de confusion. Ces résultats n'excluent pas la possibilité d'effets causals de faible magnitude ou d'effets causaux de réponses aiguës à des doses thérapeutiques de vitamine D.

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Assessment of the Association of Vitamin D Level With SARS-CoV-2 Seropositivity Among Working-Age Adults
Yonghong Li, JAMA Netw Open. 2021;4(5):e2111634.

Key Points
Question Are low levels of vitamin D independently associated with the risk of SARS-CoV-2 seropositivity?

Findings In this cohort study of 18 148 individuals whose vitamin D levels were measured before the COVID-19 pandemic, low levels of vitamin D were associated with SARS-CoV-2 seropositivity in unadjusted univariable analysis. However, after adjusting for potentially confounding factors, including age, sex, race/ethnicity, education, body mass index, blood pressure, smoking status, and geographical location, vitamin D level was not associated with SARS-CoV-2 seropositivity.

Meaning Although SARS-CoV-2–seropositive individuals did have lower vitamin D levels than seronegative individuals, low vitamin D levels were not independently associated with the risk of seropositivity.

Abstract
Importance Low vitamin D levels have been reported to be associated with increased risk of SARS-CoV-2 infection. Independent, well-powered studies could further our understanding of this association.

Objective To examine whether low levels of vitamin D are associated with SARS-CoV-2 seropositivity, an indicator of previous infection.

Design, Setting, and Participants This is a cohort study of employees and spouses who elected to be tested for SARS-CoV-2 IgG as part of an annual employer-sponsored health screening program conducted in August to November 2020. This program includes commonly assessed demographic, biometric, and laboratory variables, including total vitamin D measurement. Baseline (prepandemic) levels of vitamin D and potential confounders were obtained from screening results from the previous year (September 2019 to January 2020). Data analysis was performed from December 2020 to March 2021.

Exposures Low total serum 25-hydroxyvitamin D, defined as either less than 20 ng/mL or less than 30 ng/mL.

Main Outcomes and Measures The main outcome was SARS-CoV-2 seropositivity, as determined with US Food and Drug Administration emergency use–authorized assays. The association of SARS-CoV-2 seropositivity with vitamin D levels was assessed by multivariable logistic regression analyses and propensity score analyses.

Results The 18 148 individuals included in this study had test results for SARS-CoV-2 IgG in 2020 and vitamin D levels from the prepandemic and pandemic periods. Their median (interquartile range) age was 47 (37-56) years, 12 170 (67.1%) were women, 900 (5.0%) were seropositive, 4498 (24.8%) had a vitamin D level less than 20 ng/mL, and 10 876 (59.9%) had a vitamin D level less than 30 ng/mL before the pandemic. In multivariable models adjusting for age, sex, race/ethnicity, education, body mass index, blood pressure, smoking status, and geographical location, SARS-CoV-2 seropositivity was not associated with having a vitamin D level less than 20 ng/mL before (odds ratio [OR], 1.04; 95% CI, 0.88-1.22) or during (OR, 0.93; 95% CI, 0.79-1.09) the pandemic; it was also not associated with having a vitamin D level less than 30 ng/mL before (OR, 1.09; 95% CI, 0.93-1.27) or during (OR, 1.05; 95% CI, 0.91-1.23) the pandemic. Similar results were observed in propensity score analyses. SARS-CoV-2 seropositivity was associated with obesity (OR, 1.26; 95% CI, 1.08-1.46), not having a college degree (OR, 1.40; 95% CI, 1.21-1.62), and Asian (OR, 1.46; 95% CI, 1.13-1.87), Black (OR, 2.74; 95% CI, 2.25-3.34), Hispanic (OR, 2.65; 95% CI, 2.15-3.27), American Indian or Alaska Native, and Native Hawaiian or other Pacific Islander (OR, 2.01; OR, 1.54-2.62) race/ethnicity, and was inversely associated with high blood pressure (OR, 0.82; 95% CI, 0.70-0.96), smoking (OR, 0.60; 95% CI, 0.47-0.78), and residing in the US Northeast (OR, 0.75; 95% CI, 0.62-0.92) and West (OR, 0.54; 95% CI, 0.44-0.67).

Conclusions and Relevance In this cohort study, SARS-CoV-2 seropositivity was not associated with low levels of vitamin D independently of other risk factors.

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Discussion
In this study, low vitamin D levels were not independently associated with SARS-CoV-2 seropositivity in a cohort of working-age adults. SARS-CoV-2–seropositive individuals did have lower vitamin D levels than seronegative individuals, both before and during the pandemic, which is consistent with other reports.6,11 However, low levels of vitamin D were not associated with SARS-CoV-2 seropositivity after adjusting for age, sex, race/ethnicity, education, BMI, blood pressure, smoking status, and geographical location. As expected, vitamin D deficiency and insufficiency were more common in individuals who had a BMI greater than or equal to 30, who did not have a college degree, or who were younger, current smokers, hypertensive, or Asian, Black, Hispanic, American Indian or Alaska Native, and Native Hawaiian or other Pacific Islander race/ethnicity.

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Traduction de l'étude

Évaluation de l'association du taux de vitamine D avec la séropositivité du SRAS-CoV-2 chez les adultes en âge de travailler
Yonghong Li, JAMA Netw Open. 2021; 4 (5): e2111634.

Points clés
Question Les faibles niveaux de vitamine D sont-ils indépendamment associés au risque de séropositivité au SRAS-CoV-2?

Résultats Dans cette étude de cohorte portant sur 18148 personnes dont les niveaux de vitamine D ont été mesurés avant la pandémie de COVID-19, de faibles niveaux de vitamine D étaient associés à la séropositivité du SRAS-CoV-2 dans une analyse univariée non ajustée. Cependant, après ajustement pour tenir compte des facteurs de confusion potentiels, notamment l'âge, le sexe, la race / l'origine ethnique, l'éducation, l'indice de masse corporelle, la pression artérielle, le tabagisme et la situation géographique, le taux de vitamine D n'était pas associé à la séropositivité du SRAS-CoV-2.

Signification Bien que les personnes séropositives au SRAS-CoV-2 aient des taux de vitamine D inférieurs à ceux des personnes séronégatives, de faibles taux de vitamine D n'étaient pas indépendamment associés au risque de séropositivité.

Abstrait
Importance De faibles taux de vitamine D sont associés à un risque accru d'infection par le SRAS-CoV-2. Des études indépendantes et bien puissantes pourraient approfondir notre compréhension de cette association.

Objectif Examiner si de faibles niveaux de vitamine D sont associés à la séropositivité du SRAS-CoV-2, un indicateur d'une infection antérieure.

Conception, milieu et participants Il s'agit d'une étude de cohorte d'employés et de conjoints qui ont choisi de subir un test de dépistage du SRAS-CoV-2 IgG dans le cadre d'un programme annuel de dépistage de la santé parrainé par l'employeur et mené d'août à novembre 2020. les variables démographiques, biométriques et de laboratoire, y compris la mesure de la vitamine D totale. Les niveaux de base (prépandémique) de vitamine D et les facteurs de confusion potentiels ont été obtenus à partir des résultats du dépistage de l'année précédente (septembre 2019 à janvier 2020). L'analyse des données a été réalisée de décembre 2020 à mars 2021.

Expositions Faible teneur totale en 25-hydroxyvitamine D sérique, définie comme étant inférieure à 20 ng / mL ou inférieure à 30 ng / mL.

Principaux résultats et mesures Le principal résultat était la séropositivité du SRAS-CoV-2, tel que déterminé par les tests autorisés pour l'utilisation d'urgence de la Food and Drug Administration des États-Unis. L'association de la séropositivité du SRAS-CoV-2 avec les niveaux de vitamine D a été évaluée par des analyses de régression logistique multivariée et des analyses de score de propension.

Résultats Les 18148 personnes incluses dans cette étude avaient des résultats de tests pour les IgG anti-SRAS-CoV-2 en 2020 et les niveaux de vitamine D des périodes prépandémique et pandémique. Leur âge médian (intervalle interquartile) était de 47 (37-56) ans, 12170 (67,1%) étaient des femmes, 900 (5,0%) étaient séropositifs, 4498 (24,8%) avaient un taux de vitamine D inférieur à 20 ng / mL, et 10876 (59,9%) avaient un taux de vitamine D inférieur à 30 ng / mL avant la pandémie. Dans les modèles multivariables ajustés en fonction de l'âge, du sexe, de la race / origine ethnique, du niveau de scolarité, de l'indice de masse corporelle, de la tension artérielle, du tabagisme et de la situation géographique, la séropositivité au SRAS-CoV-2 n'était pas associée à un taux de vitamine D inférieur à 20 ng / mL avant (rapport de cotes [OR], 1,04; IC à 95%, 0,88-1,22) ou pendant (OR, 0,93; IC à 95%, 0,79-1,09) la pandémie; il n'était pas non plus associé à un taux de vitamine D inférieur à 30 ng / mL avant (OR, 1,09; IC à 95%, 0,93-1,27) ou pendant (OR, 1,05; IC à 95%, 0,91-1,23) la pandémie. Des résultats similaires ont été observés dans les analyses de score de propension. La séropositivité au SRAS-CoV-2 était associée à l'obésité (OR, 1,26; IC à 95%, 1,08-1,46), sans diplôme universitaire (OR, 1,40; IC à 95%, 1,21-1,62), et asiatique (OR, 1,46; IC à 95%, 1,13-1,87), Noir (OR, 2,74; IC à 95%, 2,25-3,34), Hispanique (OR, 2,65; IC à 95%, 2,15-3,27), Amérindien ou natif d'Alaska et Hawaïen ou autre Origine ethnique des îles du Pacifique (OR, 2,01; OR, 1,54-2,62), et était inversement associée à l'hypertension artérielle (OR, 0,82; IC à 95%, 0,70-0,96), au tabagisme (OR, 0,60; IC à 95%, 0,47 -0,78) et résidant dans le nord-est des États-Unis (OR, 0,75; IC à 95%, 0,62-0,92) et dans l'Ouest (OR, 0,54; IC à 95%, 0,44-0,67).

Conclusions et pertinence Dans cette étude de cohorte, la séropositivité SRAS-CoV-2 n'était pas associée à de faibles niveaux de vitamine D indépendamment des autres facteurs de risque.

Discussion

Dans cette étude, de faibles taux de vitamine D n'étaient pas indépendamment associés à la séropositivité du SRAS-CoV-2 dans une cohorte d'adultes en âge de travailler. Les personnes séropositives au SRAS-CoV-2 avaient des taux de vitamine D inférieurs à ceux des personnes séronégatives, à la fois avant et pendant la pandémie, ce qui concorde avec d'autres rapports.6,11 Cependant, de faibles taux de vitamine D n'étaient pas associés au SRAS-CoV- 2 séropositivité après ajustement en fonction de l'âge, du sexe, de la race / origine ethnique, du niveau de scolarité, de l'IMC, de la tension artérielle, du tabagisme et de la situation géographique. Comme prévu, la carence et l'insuffisance en vitamine D étaient plus fréquentes chez les personnes qui avaient un IMC supérieur ou égal à 30, qui n'avaient pas de diplôme universitaire ou qui étaient plus jeunes, fumeurs actuels, hypertendus ou asiatiques, noirs, hispaniques, américains. Indiens ou indigènes de l'Alaska, et hawaïens ou autres races / ethnies indigènes des îles du Pacifique

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A key role for vitamin D binding protein in COVID-19?
Marijn M. Speeckaert European Journal of Nutrition volume 60, pages2259–2260 (2021)

With interest, we read the paper of Abrishami et al. [1], which investigated the possible association of vitamin D status with lung involvement and outcome in patients with coronavirus disease 2019 (COVID-19). Higher 25-hydroxyvitamin D concentrations were associated with significantly less extent of total lung involvement, whereas a link was found between vitamin D deficiency and a significantly increased risk of mortality. We would like to highlight the importance of the polymorphic vitamin D binding protein (DBP), the major carrier of vitamin D, which plays probably an underestimated role in the pathogenesis of COVID-19.

DBP is a serum α2-globulin with a molecular weight of 52–59 kDa. Under normal physiological conditions, nearly all (85–90%) circulating vitamin D compounds are tightly bound to DBP, which has a great influence on the vitamin D pharmacokinetic. Only 10–15% of the circulating vitamin D is associated with albumin, whereas < 1% of circulating vitamin D is present in its free form. The latter two form the bioavailable fraction of vitamin D [2]. Apart from its specific sterol binding capacity, DBP exerts several other important biological functions such as macrophage activation, enhancement of the leukocyte chemotactic activity of activated complement peptides, actin scavenging, and fatty acid transport. DBP is also characterized by a considerable polymorphism with three well-known alleles [DBP 1F (fast), DBP 1S (slow), and DBP 2], which are determined by two single-nucleotide polymorphisms (SNPs), rs7041 and rs4588. The DBP 1F-proteins have a faster migration rate than those encoded by DBP 1S. The DBP phenotype determines the median plasma concentration of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, being highest in DBP 1–1, intermediate in DBP 1–2, and lowest in DBP 2–2 [3]. The blood DBP concentration shows a similar pattern [4], and a positive correlation has been observed between serum 1,25-dihydroxyvitamin D and DBP concentrations in healthy women [5].

Although the exact pathophysiology of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is not completely clear, different clinical stages of the disease have been identified, in which DBP can play a role. The early pathogenesis of COVID-19 pneumonia is characterized by a widespread endothelialitis affecting multiple organ systems. More specifically, viral inclusion bodies are detected within endothelial cells with apoptosis, inflammatory cell infiltration, and microvascular thrombosis. This is often accompanied by systemic inflammation with elevated concentrations of C-reactive protein, cytokines, and fibrinogen [6]. SARS-CoV can induce apoptosis and actin reorganization in mammalian cells under stressed conditions. During cell death and lung tissue injury, the release of globular actin (G-actin) in the extracellular compartment results in polymerization into filamentous actin (F-actin). An increased amount of F-actin is directly responsible for the aggregation of platelets in vitro and may lead to clogging of microvessels, reducing the flow of blood and generation of thrombus in the blood vessels. DBP and gelsolin are members of the extracellular actin scavenger system, which cleave actin and inhibit repolymerisation. However, elevated concentrations and/or prolonged exposure to DBP-actin complexes may induce endothelial cell injury and death, particularly in the lung microvasculature [7].

During a later phase of COVID-19, a disproportionate immune response may lead to cytokine storm syndrome, resulting in damage to the lung parenchyma, pneumonitis, acute respiratory distress syndrome (ARDS), viral septic shock, and death [6]. A 30% reduction in plasma DBP concentration, which is accompanied by lower circulating levels of 1,25-dihydroxyvitamin D, has been measured in patients with ARDS. This may be explained by either reduced production or increased losses of DBP or may be determined by the DBP phenotype [8]. DBP has also been detected in the bronchoalveolar lavage fluid of ARDS patients. DBP-release at sites of endothelial injury exerts a chemotactic effect on complement derived C5a and C5a des Arg. This leads to the attraction, aggregation, and activation of monocytes and neutrophils, generating an oxidative burst [2]. The competition of vitamin D metabolites for the same binding site on DBP may inhibit this chemotaxis, which may influence the course and outcome of COVID-19. DBP has also been identified as a good prognostic marker in septic patients. Lower serum DBP levels were associated with a higher risk of in-hospital mortality [9]. Therefore, we suggest exploring the value of DBP as a prognostic biomarker in patients with a SARS-CoV-2 infection [2, 9].

Finally, we have recently demonstrated the importance of the DBP polymorphism in COVID-19. More in detail, the frequency of the DBP 1 allele (a mixture of DBP 1F and DBP 1S) in 55 countries was compared with the prevalence and mortality data of COVID-19. The DBP 1 allele frequency was associated with a lower prevalence and mortality [10]. This could be partly explained by the potential protective effects of vitamin D, as higher concentrations of vitamin D metabolites are measured in patients with the DBP 1–1 phenotype [3].

In conclusion, future studies should explore the relationship between vitamin D, DBP, and COVID-19.

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Serum vitamin D binding protein level, but not serum total, bioavailable, free vitamin D, is higher in 30-days survivors than in nonsurvivors with sepsis
Yoo, Jung-Wan Medicine: June 19, 2020 - Volume 99 - Issue 25 - p e20756

The prognostic value of 3 types (total, bioavailable, and free) of 25-hydroxy vitamin D [25(OH)D] and vitamin D binding protein (VDBP) in patients with sepsis is unknown. The aim of this study was to evaluate the association of levels of those 3 types of 25(OH) D and VDBP with 30-day mortality in patients with sepsis. From March to December 2018, patients diagnosed with sepsis and admitted to the medical intensive care unit were enrolled, prospectively. We measured total 25(OH)D and VDBP levels, performed GC genotyping for the polymorphisms rs4588 and rs7041, and calculated bioavailable and free 25(OH)D levels.

Total, bioavailable, and free 25(OH)D levels did not differ in 30-days nonsurvivors and survivors. Serum VDBP level was significantly higher in survivors than nonsurvivors (138.6 ug/mL vs 108.2 ug/mL, P = .023) and was associated with 30-day mortality in univariate but not multivariate analysis. VDBP polymorphisms and allele frequencies were not statistically different between the groups. Serum VDBP level was significantly higher in survivors than nonsurvivors over 30-days mortality in septic patients. However, 3 types (total, bioavailable, and free) of 25(OH)D levels did not differ between the survivors and nonsurvivors group.

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Vitamin D binding protein polymorphism and COVID-19
Marijn M. Speeckaert, J Med Virol 12 September 2020

With interest, we read the paper of Batur et al.,1 which investigated the influence of the vitamin D binding protein (DBP) gene polymorphisms on the prevalence and mortality rate of coronavirus disease 2019 (COVID-19). The GT genotype at rs7041 showed a positive correlation with prevalence and mortality rates of COVID-19, whereas a negative correlation was observed with the TT genotype. No significant correlation was found between the prevalence and mortality data, and the polymorphism at the rs4588 locus. The authors concluded that the difference in susceptibility for and mortality due to COVID-19 among the selected countries might be explained by the presence of vitamin D deficiency due to a different vitamin D metabolism, orchestrated by the DBP polymorphisms of rs7041 and rs4588. However, previous research in healthy, white, premenopausal women showed that the less frequent TT genotype was associated with lower plasma 25-hydroxyvitamin D concentrations in comparison with the more prevalent GG and GT genotypes.2 Besides, the study of Batur et al. included data of only 10 countries.

Human DBP is a highly polymorphic protein with three major circulating DBP alleles, which are defined by the genetic polymorphisms rs7041 and rs4588: DBP1F [rs7041-T (ASP), rs4588-C (Thr)], DBP1S [rs7041-G (ASP), rs4588-C (Thr)], and DBP2 [rs7041-T (ASP), rs4588-A (Lys)].3 The DBP1 allele (DBP1F and DBP1S) encodes an anodal and a cathodal band: DBP1a [pI 4.84 (DBP1F), pI 4.85 (DBP1S)] and DBP1c [pI 4.94 (DBP1F), pI 4.95 (DBP1S)]. DBP1F proteins show a faster migration rate in comparison with DBP1S. The posttranslational difference between the DBP1a and DBP1c isoforms is explained by a single N-acetyl-neuraminic acid residue in DBP1a, which is absent in DBP1c. The DBP2 allele encodes one single band (pI 5.1).4 Subjects with white skin have a relatively lower frequency of the DBP1F allele and a higher frequency (50%–60%) of the DBP1S allele. In comparison with populations of African ancestry, which have a high DBP1F allele frequency, a markedly higher DBP2 allele frequency is observed in Caucasians.5 The median plasma concentration of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D is partly determined by the DBP phenotype.6 The potential role of vitamin D and vitamin D-related genes polymorphisms in the prevention and treatment of patients with a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is currently the topic of several studies and ongoing trials.7, 8 Although only limited data about vitamin D status and COVID-19 are available, a higher prevalence of vitamin D deficiency in patients with severe COVID-19 has been published.9, 10 Multiple mechanisms have been proposed to support the hypothesis that vitamin D deficiency is a risk factor for the disease and/or its adverse outcome.10 Besides the systemic synthesis of vitamin D, there is increasing evidence that local, extra-renal vitamin D metabolism may be critical for its immunomodulatory effects. The induction of nonspecific responses could strengthen the role of vitamin D as an inhibitor of virus entry by interacting with the angiotensin-converting enzyme-2 (ACE2) receptor, which serves as the entry point for SARS-CoV-2. Although not yet proven, vitamin D could also potentially modulate the virus replication via interaction with both host cell and virus factors: for example, inhibition of endoplasmic reticulum stress. Furthermore, vitamin D could improve the efficacy of the host response impact by influencing both innate and adaptive immune responses (natural killer cells and T lymphocytes). Finally, vitamin D might also play a key role in the uncontrolled cytokine storm through inhibition of inflammatory responses, increasing ACE2 expression, decreasing the neutrophil to lymphocyte ratio, and inhibition of complement.8

In contrast to the study of Batur et al.,1 which explored the influence of the DBP genotypes, we wanted to investigate the influence of the DBP phenotypes in patients with a SARS-CoV-2 infection. We compared the frequency of the DBP1 allele [a mixture of DBP1F (fast) and DBP1S (slow)] in 55 countries (Table 1) with the prevalence and mortality data of COVID-19, taking into account the time interval since the start of the infection in each country.

The time interval since the start of the infection in each country was recorded to synchronize the data. In a univariate model, the correlation between COVID-19 prevalence and the DBP1 allele frequency was significant: log (prevalence; no. of cases/106 inhabitants) = 15.64 − 7.22 (DBP1 allele frequency, %) + 0.54 (date of the first case, days since January 1, 2020), r² = 0.116; p = .04. Similarly, the DBP1 allele frequency correlated negatively with COVID-19 mortality: log (mortality; no. of cases/106 inhabitants) = 20.91–10.24 (DBP1 allele frequency, %);− 0.11 (date of first case, days since January 1, 2020), r² = 0.156; p = .01.

The association between the DBP1 allele frequency and a lower prevalence and mortality due to a SARS-CoV-2 infection could be partly explained by the potential protective effects of vitamin D, as already described in the paper of Batur et al.1 In a study with healthy, white, premenopausal women, the median plasma concentration of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were highest in DBP 1-1 subjects, intermediate in DBP 2-1 individuals, and lowest in the DBP 2-2 group.11 However, rs7041 and rs4588 explain only 9.9% of the 25-hydroxyvitamin D concentrations. A genome-wide meta-analysis has identified four additional SNPs, which affect the concentration of 25-hydroxyvitamin D: rs2282679 (DBP), rs10741657 (near CYP2R1), rs12785878 (near DHCR7), and rs6013897 (at CYP24A1).12

In conclusion, DBP1 carriers might be less susceptible to infection of and mortality due to COVID-19. Further research should focus on the interaction between DBP and its polymorphisms, vitamin D, and SARS-CoV-2 infection.

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The role of DBP gene polymorphisms in the prevalence of new coronavirus disease 2019 infection and mortality rate
Lutfiye Karcioglu Batur J Med Virol . 2021 Mar;93(3):1409-1413.

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.

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Possible association of vitamin D status with lung involvement and outcome in patients with COVID-19: a retrospective study
Alireza Abrishami, European Journal of Nutrition volume 60, pages2249–2257 (2021)

Vitamin D deficiency has been reported as a key factor in the development of infectious diseases such as respiratory tract infections and inflammatory processes like acute respiratory distress syndrome. However, the impact of vitamin D on the severity and outcome of COVID-19 is still not fully known. Herein, we aimed to evaluate the prognostic role of serum vitamin D concentration on the extent of lung involvement and final outcome in patients with COVID-19.

Methods
Seventy-three subjects with confirmed diagnosis of COVID-19 were investigated in this study. The patients had been admitted to our academic hospital from February 28, 2020 to April 19, 2020. Demographic and clinical data, serum 25(OH)D levels, and findings of initial chest computed tomography were recorded. Linear and binary logistic regression, cox regression and ROC curve tests were used for statistical analysis.

Results
The mean age of patients was 55.18 ± 14.98 years old; 46.4% were male. Mean serum 25(OH)D concentration was significantly lower in the deceased (13.83 ± 12.53 ng/ mL compared with discharged patients (38.41 ± 18.51 ng/mL) (P < 0.001). Higher levels of 25(OH)D were associated with significantly less extent of total lung involvement (β = − 0.10, P = 0.004). In addition, vitamin D deficiency [25(OH) D < 25 ng/mL] was associated with a significant increase in the risk of mortality (hazard ratio = 4.15, P = 0.04).

Conclusion
This study suggests that serum vitamin D status might provide useful information regarding the clinical course, extent of lung involvement and outcome of patients with COVID-19. However, further studies with larger sample size are needed to confirm these findings.

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Traduction de l'étude

Association possible du statut en vitamine D avec une atteinte pulmonaire et des résultats chez les patients atteints de COVID-19: une étude rétrospective
Alireza Abrishami, European Journal of Nutrition volume 60, pages2249-2257 (2021)

Une carence en vitamine D a été signalée comme un facteur clé dans le développement de maladies infectieuses telles que les infections des voies respiratoires et les processus inflammatoires comme le syndrome de détresse respiratoire aiguë. Cependant, l'impact de la vitamine D sur la gravité et le résultat du COVID-19 n'est toujours pas entièrement connu. Ici, nous avons cherché à évaluer le rôle pronostique de la concentration sérique de vitamine D sur l'étendue de l'atteinte pulmonaire et le résultat final chez les patients atteints de COVID-19.

Méthodes
Soixante-treize sujets avec un diagnostic confirmé de COVID-19 ont été étudiés dans cette étude. Les patients avaient été admis dans notre hôpital universitaire du 28 février 2020 au 19 avril 2020. Les données démographiques et cliniques, les taux sériques de 25 (OH) D et les résultats de la tomodensitométrie thoracique initiale ont été enregistrés. Des tests de régression logistique linéaire et binaire, de régression cox et de courbe ROC ont été utilisés pour l'analyse statistique.

Résultats
L'âge moyen des patients était de 55,18 ± 14,98 ans; 46,4% étaient des hommes. La concentration sérique moyenne de 25 (OH) D était significativement plus faible chez les personnes décédées (13,83 ± 12,53 ng / mL par rapport aux patients sortants (38,41 ± 18,51 ng / mL) (P <0,001). Des taux plus élevés de 25 (OH) D étaient associés à une atteinte pulmonaire totale significativement moindre (β = - 0,10, P = 0,004). De plus, une carence en vitamine D [25 (OH) D <25 ng / mL] était associée à une augmentation significative du risque de mortalité (hazard ratio = 4,15, P = 0,04).

Conclusion
Cette étude suggère que le statut sérique en vitamine D pourrait fournir des informations utiles concernant l'évolution clinique, l'étendue de l'atteinte pulmonaire et les résultats des patients atteints de COVID-19. Cependant, d'autres études avec une plus grande taille d'échantillon sont nécessaires pour confirmer ces résultats.

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Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease
Maheshwar Lakkireddy, Scientific Reports volume 11, Article number: 10641 (2021)

COVID 19 is known to cause immune dysregulation and vitamin D is a known immunomodulator. This study aims to objectively investigate the impact of Pulse D therapy in reducing the inflammatory markers of COVID-19. Consented COVID-19 patients with hypovitaminosis D were evaluated for inflammatory markers (N/L ratio, CRP, LDH, IL6, Ferritin) along with vitamin D on 0th day and 9th/11th day as per their respective BMI category. Subjects were randomised into VD and NVD groups. VD group received Pulse D therapy (targeted daily supplementation of 60,000 IUs of vitamin D for 8 or 10 days depending upon their BMI) in addition to the standard treatment. NVD group received standard treatment alone. Differences in the variables between the two groups were analysed for statistical significance.

Eighty seven out of one hundred and thirty subjects have completed the study (VD:44, NVD:43). Vitamin D level has increased from 16 ± 6 ng/ml to 89 ± 32 ng/ml after Pulse D therapy in VD group and highly significant (p < 0.01) reduction of all the measured inflammatory markers was noted. Reduction of markers in NVD group was insignificant (p > 0.05). The difference in the reduction of markers between the groups (NVD vs VD) was highly significant (p < 0.01).

Therapeutic improvement in vitamin D to 80–100 ng/ml has significantly reduced the inflammatory markers associated with COVID-19 without any side effects. Hence, adjunctive Pulse D therapy can be added safely to the existing treatment protocols of COVID-19 for improved outcomes.

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Traduction de l'étude

Impact de la thérapie orale quotidienne à haute dose de vitamine D sur les marqueurs inflammatoires chez les patients atteints de la maladie COVID 19
Maheshwar Lakkireddy, Scientific Reports volume 11, numéro d'article: 10641 (2021)

Le COVID 19 est connu pour provoquer une dérégulation immunitaire et la vitamine D est un immunomodulateur connu. Cette étude vise à étudier objectivement l'impact de la thérapie Pulse D sur la réduction des marqueurs inflammatoires du COVID-19. Les patients COVID-19 consentants atteints d'hypovitaminose D ont été évalués pour les marqueurs inflammatoires (rapport N / L, CRP, LDH, IL6, ferritine) ainsi que la vitamine D le 0ème jour et le 9ème / 11ème jour selon leur catégorie d'IMC respective. Les sujets ont été randomisés en groupes VD et NVD. Le groupe VD a reçu une thérapie Pulse D (supplémentation quotidienne ciblée de 60 000 UI de vitamine D pendant 8 ou 10 jours selon leur IMC) en plus du traitement standard. Le groupe NVD a reçu un traitement standard seul. Les différences dans les variables entre les deux groupes ont été analysées pour leur signification statistique.

Quatre-vingt-sept sujets sur cent trente ont terminé l'étude (VD: 44, NVD: 43). Le taux de vitamine D est passé de 16 ± 6 ng / ml à 89 ± 32 ng / ml après traitement par Pulse D dans le groupe VD et une réduction hautement significative (p <0,01) de tous les marqueurs inflammatoires mesurés a été notée. La réduction des marqueurs dans le groupe NVD était insignifiante (p> 0,05). La différence de réduction des marqueurs entre les groupes (NVD vs VD) était très significative (p <0,01).

L'amélioration thérapeutique de la vitamine D à 80-100 ng / ml a considérablement réduit les marqueurs inflammatoires associés au COVID-19 sans aucun effet secondaire. Par conséquent, la thérapie d'appoint Pulse D peut être ajoutée en toute sécurité aux protocoles de traitement existants du COVID-19 pour de meilleurs résultats.