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Effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in patients with moderate to severe COVID-19.
Fernandes, AL, Murai, IH, Reis, BZ, Sales, LP, Santos, MD, Pinto, AJ, Goessler, KF, Duran, CSC, Silva, CBR, Franco, AS, et al
The American journal of clinical nutrition. 2022;(3):790-798
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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 D3 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 D3 (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/m2, of which 109 (54.5%) were male. GM-CSF concentrations showed a significant group-by-time interaction effect (P = 0.04), although the between-group 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 D3, 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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Keeping a Balance During the Pandemic: a Narrative Review on the Important Role of Micronutrients in Preventing Infection and Reducing Complications of COVID-19.
Pinnawala, NU, Thrastardottir, TO, Constantinou, C
Current nutrition reports. 2021;(3):200-210
Abstract
PURPOSE OF REVIEW The SARS-CoV-2 (COVID-19) outbreak has manifested into a major public health concern across the globe, affecting particularly the most vulnerable population groups. Currently, there are various clinical trials being conducted to develop effective treatments. It is estimated that it could take one or more years before these drugs pass all safety tests and concrete results with regard to their effectiveness become available. In addition, despite the recent development of vaccines (licensed for use under conditional licenses) and the commencement of COVID-19 vaccination programs in several countries, there is still a need for safe and novel strategies that may reduce the symptomatology and/or prevent the severe complications associated with COVID-19. Natural compounds previously shown to have antiviral potential should be thoroughly considered and investigated for use in prophylactic treatment of COVID-19 due to their availability and safety. RECENT FINDINGS The current narrative review investigates whether there is evidence in the literature that supplementation with dietary minerals and vitamins may have a role in preventing infection with SARS-CoV-2 or in reducing COVID-19 symptomatology and disease progression. The current evidence from the literature supports that zinc and vitamin C have a potential in reducing the inflammatory response associated with SARS-CoV-2 while folate and vitamin D may have a role in antagonizing the entry of SARs-CoV-2 virus in host calls. Thus, further research should be conducted that could lead to the development of nutritional supplements involving natural and widely available compounds such as zinc, folate, vitamin C, and vitamin D. The latter could be an effective, safe, and inexpensive way to either prevent infection with SARS-CoV-2 and/or lessen the burden of COVID-19 disease.
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A literature review on beneficial role of vitamins and trace elements: Evidence from published clinical studies.
Taheri, S, Asadi, S, Nilashi, M, Ali Abumalloh, R, Ghabban, NMA, Mohd Yusuf, SY, Supriyanto, E, Samad, S
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2021;:126789
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COVID-19 is a kind of SARS-CoV-2 viral infectious pneumonia. This research aims to perform a bibliometric analysis of the published studies of vitamins and trace elements in the Scopus database with a special focus on COVID-19 disease. To achieve the goal of the study, network and density visualizations were used to introduce an overall picture of the published literature. Following the bibliometric analysis, we discuss the potential benefits of vitamins and trace elements on immune system function and COVID-19, supporting the discussion with evidence from published clinical studies. The previous studies show that D and A vitamins demonstrated a higher potential benefit, while Selenium, Copper, and Zinc were found to have favorable effects on immune modulation in viral respiratory infections among trace elements. The principles of nutrition from the findings of this research could be useful in preventing and treating COVID-19.
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"Vitamin D supplementation and COVID-19 treatment: A systematic review and meta-analysis".
Rawat, D, Roy, A, Maitra, S, Shankar, V, Khanna, P, Baidya, DK
Diabetes & metabolic syndrome. 2021;(4):102189
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BACKGROUND Vitamin-D is an immune-modulator which might be linked to disease severity by SARS-CoV-2. METHODS Meta-analysis of RCTs and quasi-experimental studies, evaluating the role of vitamin-D supplementation in COVID patients was done. RESULTS Total 5 studies (3 RCTs and 2 Quasi-experimental) including n = 467 patients were included. Vitamin D didn't reduce mortality (RR 0.55, 95%CI 0.22 to 1.39, p = 0.21), ICU admission rates (RR 0.20, 95% CI 0.01-4.26, p = 0.3) and need for invasive ventilation (RR 0.24, 95% CI 0.01-7.89, p = 0.42). CONCLUSION No significant difference with vitamin-D supplementation on major health related outcomes in COVID-19. Well-designed RCTs are required addressing this topic.
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Does vitamin D supplementation prevent SARS-CoV-2 infection in military personnel? Review of the evidence.
Parsons, IT, Gifford, RM, Stacey, MJ, Lamb, LE, O'Shea, MK, Woods, DR
BMJ military health. 2021;(4):280-286
Abstract
For most individuals residing in Northwestern Europe, maintaining replete vitamin D status throughout the year is unlikely without vitamin D supplementation and deficiency remains common. Military studies have investigated the association with vitamin D status, and subsequent supplementation, with the risk of stress fractures particularly during recruit training. The expression of nuclear vitamin D receptors and vitamin D metabolic enzymes in immune cells additionally provides a rationale for the potential role of vitamin D in maintaining immune homeostasis. One particular area of interest has been in the prevention of acute respiratory tract infections (ARTIs). The aims of this review were to consider the evidence of vitamin D supplementation in military populations in the prevention of ARTIs, including SARS-CoV-2 infection and consequent COVID-19 illness. The occupational/organisational importance of reducing transmission of SARS-CoV-2, especially where infected young adults may be asymptomatic, presymptomatic or paucisymptomatic, is also discussed.
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COVID-19 and IL-6: Why vitamin D (probably) helps but tocilizumab might not.
Silberstein, M
European journal of pharmacology. 2021;:174031
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Interleukin 6 (IL-6), which is involved in the cytokine storm phenomenon, is a therapeutic target in COVID-19, but monoclonal receptor antibody therapeutic agents such as tocilizumab have demonstrated mixed results. Could Vitamin D, which modulates IL-6, be more effective than currently deployed IL-6 antagonists, including tocilizumab, thereby presenting a useful therapeutic option in COVID-19? A narrative review of published trials examining the effect of Vitamin D administration in COVID-19 patients was conducted, and the theoretical basis for the use of tocilizumab as an IL-6 antagonist was compared with the immunomodulatory effect of Vitamin D on IL-6 production. Four of the six included studies reported a positive effect of Vitamin D on outcomes. While tocilizumab non-selectively blocks both anti-inflammatory and pro-inflammatory actions of IL-6, Vitamin D lowers immune cell IL-6 production, potentially reducing pro-inflammatory effects, but does not specifically target IL-6 receptors, avoiding any deleterious effect on the anti-inflammatory actions of IL-6. Vitamin D may have advantages over tocilizumab as an IL-6 immunomodulator, and, given that it is safe if administered under clinical supervision, there is a strong rationale for its use.
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Vitamin supplementation as a potential adjunctive therapeutic approach for COVID-19: biological and clinical plausibility.
Daei Sorkhabi, A, Sarkesh, A, Daei Sorkhabi, A, Entezari-Maleki, T, Rashedi, J, Bannazadeh Baghi, H
Journal of basic and clinical physiology and pharmacology. 2021;(1):55-77
Abstract
The recent pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19) has introduced itself into the human population in the 21st century after the coronavirus diseases SARS-CoV and Middle East respiratory syndrome (MERS-CoV). Major investigations are underway worldwide in the search for pharmaceutical interventions for COVID-19 and many agents are administered in off-label routes. Several cases are under study to check or restrict clinical manifestations of COVID-19. According to the fact that the efficacy of some micro-nutrients like vitamins is proven to treat or prevent infectious diseases because of their antimicrobial and immunomodulatory activity, the potential role of vitamins in the COVID-19 treatment or prevention must be considered.
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Supplementation with vitamin D in the COVID-19 pandemic?
Hadizadeh, F
Nutrition reviews. 2021;(2):200-208
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The coronavirus disease 2019 (COVID-19) pandemic was declared a public health emergency of international concern by the World Health Organization. COVID-19 has high transmissibility and could result in acute lung injury in a fraction of patients. By counterbalancing the activity of the renin-angiotensin system, angiotensin-converting enzyme 2, which is the fusion receptor of the virus, plays a protective role against the development of complications of this viral infection. Vitamin D can induce the expression of angiotensin-converting enzyme 2 and regulate the immune system through different mechanisms. Epidemiologic studies of the relationship between vitamin D and various respiratory infections were reviewed and, here, the postulated mechanisms and clinical data supporting the protective role of vitamin D against COVID-19-mediated complications are discussed.
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Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial.
Murai, IH, Fernandes, AL, Sales, LP, Pinto, AJ, Goessler, KF, Duran, CSC, Silva, CBR, Franco, AS, Macedo, MB, Dalmolin, HHH, et al
JAMA. 2021;(11):1053-1060
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IMPORTANCE The efficacy of vitamin D3 supplementation in coronavirus disease 2019 (COVID-19) remains unclear. OBJECTIVE To investigate the effect of a single high dose of vitamin D3 on hospital length of stay in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS This was a multicenter, double-blind, randomized, placebo-controlled trial conducted in 2 sites in Sao Paulo, Brazil. The study included 240 hospitalized patients with COVID-19 who were moderately to severely ill at the time of enrollment from June 2, 2020, to August 27, 2020. The final follow-up was on October 7, 2020. INTERVENTIONS Patients were randomly assigned to receive a single oral dose of 200 000 IU of vitamin D3 (n = 120) or placebo (n = 120). MAIN OUTCOMES AND MEASURES The primary outcome was length of stay, defined as the time from the date of randomization to hospital discharge. Prespecified secondary outcomes included mortality during hospitalization; the number of patients admitted to the intensive care unit; the number of patients who required mechanical ventilation and the duration of mechanical ventilation; and serum levels of 25-hydroxyvitamin D, total calcium, creatinine, and C-reactive protein. RESULTS Of 240 randomized patients, 237 were included in the primary analysis (mean [SD] age, 56.2 [14.4] years; 104 [43.9%] women; mean [SD] baseline 25-hydroxyvitamin D level, 20.9 [9.2] ng/mL). Median (interquartile range) length of stay was not significantly different between the vitamin D3 (7.0 [4.0-10.0] days) and placebo groups (7.0 [5.0-13.0] days) (log-rank P = .59; unadjusted hazard ratio for hospital discharge, 1.07 [95% CI, 0.82-1.39]; P = .62). The difference between the vitamin D3 group and the placebo group was not significant for in-hospital mortality (7.6% vs 5.1%; difference, 2.5% [95% CI, -4.1% to 9.2%]; P = .43), admission to the intensive care unit (16.0% vs 21.2%; difference, -5.2% [95% CI, -15.1% to 4.7%]; P = .30), or need for mechanical ventilation (7.6% vs 14.4%; difference, -6.8% [95% CI, -15.1% to 1.2%]; P = .09). Mean serum levels of 25-hydroxyvitamin D significantly increased after a single dose of vitamin D3 vs placebo (44.4 ng/mL vs 19.8 ng/mL; difference, 24.1 ng/mL [95% CI, 19.5-28.7]; P < .001). There were no adverse events, but an episode of vomiting was associated with the intervention. CONCLUSIONS AND RELEVANCE Among hospitalized patients with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of a high dose of vitamin D3 for treatment of moderate to severe COVID-19. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04449718.
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High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial (CARED-TRIAL).
Mariani, J, Tajer, C, Antonietti, L, Inserra, F, Ferder, L, Manucha, W
Trials. 2021;(1):111
Abstract
OBJECTIVES To evaluate whether a single high dose of oral cholecalciferol improves the respiratory outcomes as compared with placebo among adults COVID-19 patients at moderate risk of clinical complications. TRIAL DESIGN The CARED trial is an investigator-initiated, multicentre, randomized, parallel, two-arm, sequential, double-blind and placebo-controlled clinical trial. It was planned as a pragmatic trial since the inclusion criteria are broad and the study procedures are as simple as possible, in order to be implemented in the routine clinical practice in general wards in the pandemic setting and a middle-income country context. The sequential design involves two stages. The first stage will assess the effects of vitamin D supplementation on blood oxygenation (physiological effects). The second stage will assess the effects on clinical outcomes. PARTICIPANTS Participants of either gender admitted to general adult wards in 21 hospital sites located in four provinces of Argentina are invited to participate in the study if they meet the following inclusion criteria and none of the exclusion criteria: Inclusion criteria SARS-CoV-2 confirmed infection by RT-PCR; Hospital admission at least 24 hours before; Expected hospitalization in the same site ≥24 hours; Oxygen saturation ≥90% (measured by pulse oximetry) breathing ambient air; Age ≥45 years or at least one of the following conditions: ○ Hypertension; ○ Diabetes; ○ At least moderate COPD or asthma; ○ Cardiovascular disease (history of myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting or valve replacement surgery); ○ Body mass index ≥30; Willingness to sign informed consent (online supplementary material 1 and 2). EXCLUSION CRITERIA Age <18 years; Women in childbearing age; >= 72 hs since current admission; Requirement for a high dose of oxygen (>5 litres/minute) or mechanical ventilation (non-invasive or invasive); History of chronic kidney disease requiring haemodialysis or chronic liver failure; Inability for oral intake. Chronic supplementation with pharmacological vitamin D; Current treatment with anticonvulsants; History of: ○ Sarcoidosis; ○ Malabsorption syndrome; ○ Known hypercalcemia or serum calcium >10.5 mg/dL; Life expectancy <6 months; Known allergy to study medication; Any condition at discretion of investigator impeding to understand the study and give informed consent. INTERVENTION AND COMPARATOR The intervention consists in a single oral dose of 500.000 IU of commercially available cholecalciferol soft gel capsules (5 capsules of 100.000 IU) or matching placebo MAIN OUTCOMES The primary outcome for the first stage is the change in the respiratory Sepsis-related Organ Failure Assessment (SOFAr) score between pre-treatment value and the worst value recorded during the first 7 seven days of hospitalization, the death or discharge, whichever occurs first. The SOFAr score measured as the ratio between the pulse oximetry saturation (SpO2) and FiO2 (27, 28) is used instead of the arterial partial pressure of oxygen (PaO2). SOFAr score is a 4-points scale, with higher values indicating deeper respiratory derangement as follows: 1 PaO2 <400; 2 PaO2 <300; 3 PaO2 <200; 4 PaO2 <100. The primary outcome for the second stage is the combined occurrence of requirement ≥40% of FiO2, invasive or non-invasive ventilation, up to 30 days or hospital discharge. RANDOMISATION A computer-generated random sequence and the treatment assignment is performed through the web-based randomization module available in the electronic data capture system (Castor®). A randomization ratio 1:1, stratified and with permuted blocks was used. Stratification variables were diabetes (yes/no), age (≤60/>60 years) and the site. BLINDING (MASKING): Double-blind was achieved by using placebo soft gel capsules with the same organoleptic properties as the active medication. Central management of the medication is carried out by a pharmacist in charge of packaging the study drug in unblinded fashion, who have no contact with on-site investigators. Medication is packaged in opaque white bottles, each containing five soft gel capsules of the active drug or matching placebo, corresponding to complete individual treatment. Treatment codes are kept under the pharmacist responsibility, and all researchers are unaware of them. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The first stage is planned to include 200 patients (100 per group), the second stage is planned to include 1064 additional patients. The total sample size is 1264 patients. TRIAL STATUS Currently the protocol version is the number 1.4 (from October 13th, 2020). The recruitment is ongoing since August 11th, 2020, and the first subject was enrolled on August 14th. Since then, 21 sites located in four provinces of Argentina were initiated, and 167 patients were recruited by January 11th, 2021. We anticipate to finish the recruitment for the first stage in mid-February, 2021, and in August, 2021 for the second stage. TRIAL REGISTRATION The study protocol is registered in ClinicalTrials.gov (identifier number NCT04411446 ) on June 2, 2020. FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
