Coronavirus Vitamin D

By Ronald Steriti, ND, PhD
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Vitamin D, D-Binding Protein and Free Vitamin D

A study examined the relationship between vitamin D status and mortality from COVID-19.
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 25(OH)D status hard to interpret. Because of this, measurement of unbound "free" and albumin-bound "bioavailable" 25(OH) D has been proposed.
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 co-morbidities 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.
Four hundred and seventy-two patients with COVID-19 were included, of whom 112 (23.7%) died within 28 days. Non-survivors were older (mean age 73, [range 34-98]) than survivors (65, [19-95]; P = 0.003) and more likely male (67%; P = 0.02).
The frequency of vitamin D deficiency (25(OH)D <50nmol/L) was similar between non-survivors (71/112 [63.4%]) and survivors (204/360 [56.7%]; P = 0.15) but, after adjustment for age, sex and co-morbidities, increased odds for mortality were present in those with severe deficiency (25(OH)D <25nmol/L), OR 2.37 (95% CI 1.17, 4.78), or high 25(OH)D (≥100nmol/L), OR 4.65 (95% CI 1.51, 14.34) compared with 25(OH)D 50-74 nmol/L (reference).
Serum DBP levels were not associated with mortality after adjustment for 25(OH)D, age, sex and co-morbidities. Neither free nor bioavailable 25(OH)D were associated with mortality.
Vitamin D deficiency as commonly defined by serum 25 (OH)D levels (<50nmol/L) is not associated with increased mortality from COVID-19 but extreme low (<25nmol/L) and high (>100nmol/L) levels may be associated with risk. Neither free nor bioavailable 25(OH) D associate with risk. (Subramanian et al., 2022)

COVID-19 Associated Rhinocerebral Mucormycosis

A study determined whether low serum vitamin D level is a risk factor for development of Rhinocerebral mucormycosis in COVID-19 afflicted patients.
A case control study was conducted in a tertiary care hospital utilizing the archived records of COVID-19 afflicted Rhinocerebral mucormycosis cases and age and gender matched controls.
The mean value (± standard deviation) of vitamin D level in patients with Mucormycosis was 19.65 ± 13.07 ng/ml and in control subjects it was 27.88 ± 18.04 ng/ml.There was a significant difference between groups (p = 0.02).
Low Vitamin D level may be implicated as a risk factor for the advent of mucormycosis in a COVID-19 afflicted patient. Vitamin D supplements may be provided to such patients to achieve normal serum levels. (Popli et al., 2022)

A Single High Dose of Vitamin D3, Negative

A study investigated 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.
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 two hospitals in Sao Paulo, Brazil. Of 240 randomized patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200 000 IU of vitamin D3 (n = 101) or placebo (n = 99).
The primary outcome was hospital length of stay, that has been published in our previous study. The prespecified secondary outcomes were serum levels of interleukin-1β, interleukin-6, interleukin-10, tumor necrosis factor alpha (TNF-α) and 25-hydroxyvitamin D. The post-hoc exploratory secondary outcomes were interleukin-4, interleukin-12p70, interleukin-17A, interferon gamma (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-8, interferon-inducible protein-10 (IP-10), macrophage inflammatory protein-1 beta (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), growth factor vascular endothelial (VEGF), and leukocytes count. Generalized estimating equations (GEE) for repeated measures, with Bonferroni's adjustment, were used for testing all outcomes.
The study included 200 patients with a mean (SD) age 55.5 (14.3) years and body mass index (BMI) 32.2 (7.1) kg/m2, of which 109 (54.5%) were male. GM-CSF levels showed a significant group by time interaction effect (P = 0.04), although between-group difference at post-intervention after Bonferroni's adjustment was not significant. No significant effects were observed for the other outcomes.
The findings do not support the use of a single dose of 200 000 IU of vitamin D3, compared to placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. (Fernandes et al., 2022)

Daily High Dose Oral Vitamin D Therapy on Inflammatory Markers

A study published in Scientific Reports investigated the impact of Pulse D therapy in reducing the inflammatory markers of COVID-19. The Gandhi Medical College, Hospital Secunderabad in collaboration with Nizam’s Institute of Medical Sciences, Hyderabad, India conducted the study.
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 randomized 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.
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.
Adjunctive Pulse D therapy can be added safely to the existing treatment protocols of COVID-19 for improved outcomes. (Lakkireddy et al., 2021)

Single High-Dose Vitamin D3 in Severely Deficient, Negative

An ancillary analysis of a multicenter, double-blinded, randomized, placebo-controlled trial investigated the effect of a single high dose of vitamin D3 on the length of hospital stay of patients with severe 25-hydroxyvitamin D deficiency and COVID-19.
The primary outcome was length of hospital stay, defined as the total number of days that patients remained hospitalized from the date of randomization until the date of hospital discharge. Secondary outcomes included serum levels of 25-hydroxyvitamin D, mortality during hospitalization, number of patients admitted to the intensive care unit, and number of patients who required mechanical ventilation.
Thirty-two patients were included in the study. The mean (SD) age was 58.5 (15.6) years, body mass index was 30.8 (8.6) kg/m2, and 25-hydroxyvitamin D level was 7.8 (1.6) ng/mL.
No significant difference was observed in the median interquartile range of length of hospital stay between the vitamin D3 group (6.0 [4.0-18.0] days) versus placebo (9.5 [6.3-15.5] days) (log-rank p=0.74; hazard ratio, 1.13 [95% confidence interval (CI), 0.53-2.40]; p=0.76).
Vitamin D3 significantly increased serum 25-hydroxyvitamin D levels in the vitamin D3 group compared with that in the placebo group (between-group difference, 23.9 ng/mL [95% CI, 17.7-30.1]; p<0.001).
A dose of 200.000 IU of vitamin D3 did not significantly reduce the length of hospital stay of patients with severe 25-hydroxyvitamin D deficiency and COVID-19. (Murai et al., 2021)

Rapid and Effective Vitamin D Supplementation

A study published in Nutrients evaluated the effectiveness of vitamin D3 supplementation in COVID-19. The Istanbul University-Cerrahpasa, Turkey conducted the study.
The study retrospectively analyzed the data of 867 COVID-19 cases. Then, a prospective study was conducted, including 23 healthy individuals and 210 cases. A total of 163 cases had vitamin D supplementation, and 95 were followed for 14 days. Clinical outcomes, routine blood biomarkers, serum levels of vitamin D metabolism, and action mechanism-related parameters were evaluated.
Serum 25OHD levels increased significantly to above 30 ng/mL within two weeks. COVID-19 cases (no comorbidities, no vitamin D treatment, 25OHD <30 ng/mL) had 1.9-fold increased risk of having hospitalization longer than 8 days compared with the cases with comorbidities and vitamin D treatment. Having vitamin D treatment decreased the mortality rate by 2.14 times. The correlation analysis of specific serum biomarkers with 25OHD indicated that the vitamin D action in COVID-19 might involve regulation of INOS1, IL1B, IFNg, cathelicidin-LL37, and ICAM1.
Vitamin D treatment shortened hospital stay and decreased mortality in COVID-19 cases, even in the existence of comorbidities. Vitamin D supplementation is effective on various target parameters; therefore, it is essential for COVID-19 treatment. (Gönen et al., 2021)

2-Week 5000 IU versus 1000 IU Vitamin D3

A multi-center randomized clinical trial aims to determine the effects of 5000 IU versus 1000 IU daily oral vitamin D3 supplementation in the recovery of symptoms and other clinical parameters among mild to moderate COVID-19 patients with sub-optimal vitamin D status.
A total of 69 reverse transcriptase polymerase chain reaction (RT-PCR) SARS-CoV-2 positive adults who were hospitalized for mild to moderate COVID-19 disease were allocated to receive once daily for 2 weeks either 5000 IU oral vitamin D3 (n = 36, 21 males; 15 females) or 1000 IU oral vitamin D3 (standard control) (n = 33, 13 males; 20 females). Anthropometrics were measured and blood samples were taken pre- and post-supplementation. Fasting blood glucose, lipids, serum 25(OH)D, and inflammatory markers were measured. COVID-19 symptoms were noted on admission and monitored until full recovery.
Vitamin D supplementation for 2 weeks caused a significant increase in serum 25(OH)D levels in the 5000 IU group only (adjusted p = 0.003). Within-group comparisons also showed a significant decrease in BMI and IL-6 levels overtime in both groups (p-values < 0.05) but was not clinically significant in between-group comparisons. Kaplan-Meier survival analysis revealed that the 5000 IU group had a significantly shorter time to recovery (days) than the 1000 IU group in resolving cough, even after adjusting for age, sex, baseline BMI, and D-dimer (6.2 ± 0.8 versus 9.1 ± 0.8; p = 0.039), and ageusia (loss of taste) (11.4 ± 1.0 versus 16.9 ± 1.7; p = 0.035).
A 5000 IU daily oral vitamin D3 supplementation for 2 weeks reduces the time to recovery for cough and gustatory sensory loss among patients with sub-optimal vitamin D status and mild to moderate COVID-19 symptoms. The use of 5000 IU vitamin D3 as an adjuvant therapy for COVID-19 patients with suboptimal vitamin D status, even for a short duration, is recommended. (Sabico et al., 2021)

High-Dose Vitamin D3 (Cholecalciferol) Booster Therapy

A study published in Nutrients determined whether COVID-19 mortality was affected by serum 25-hydroxyvitamin D (25(OH)D) levels, vitamin D status, or cholecalciferol therapy, and to elucidate any other predictors of COVID-19 mortality. The University of Manchester and Leicester General Hospital, UK conducted the study.
Patients hospitalized with COVID-19 were opportunistically recruited from three UK hospitals, and their data were collected retrospectively. Logistic regression was used to determine any relationships between COVID-19 mortality and potential predictors, including 25(OH)D levels and cholecalciferol booster therapy.
A total of 986 participants with COVID-19 were studied, of whom 151 (16.0%) received cholecalciferol booster therapy. High-dose booster therapy was approximately ≥ 280,000 IU in a time period of up to 7 weeks. Patients received cholecalciferol booster therapy if they were recognized as being either vitamin D insufficient (serum 25(OH)D 25–50 nmol/L) or deficient as part of routine clinical care.
In the primary cohort of 444 patients, cholecalciferol booster therapy was associated with a reduced risk of COVID-19 mortality, following adjustment for potential confounders (OR|adj| 0.13, 95% CI 0.05-0.35, p < 0.001). This finding was replicated in a validation cohort of 541 patients (OR|adj| 0.38, 95% CI 0.17-0.84, p = 0.018).
In this observational study, treatment with cholecalciferol booster therapy, regardless of baseline serum 25(OH)D levels, appears to be associated with a reduced risk of mortality in acute in-patients admitted with COVID-19. (Ling et al., 2020)

GERIA-COVID, Hospitalized Frail Elderly Patients

A quasi-experimental study published in Nutrients determined whether bolus vitamin D supplementation taken either regularly over the preceding year or after the diagnosis of COVID-19 was effective in improving survival among hospitalized frail elderly COVID-19 patients. The University of Angers and University Hospital, Angers, France conducted the study.
Seventy-seven patients consecutively hospitalized for COVID-19 in a geriatric unit were included. Intervention groups were participants regularly supplemented with vitamin D over the preceding year (Group 1), and those supplemented with vitamin D after COVID-19 diagnosis (Group 2). The comparator group involved participants having received no vitamin D supplements (Group 3). Outcomes were 14-day mortality and highest (worst) score on the ordinal scale for clinical improvement (OSCI) measured during COVID-19 acute phase. Potential confounders were age, gender, functional abilities, undernutrition, cancer, hypertension, cardiomyopathy, glycated hemoglobin, number of acute health issues at admission, hospital use of antibiotics, corticosteroids, and pharmacological treatments of respiratory disorders.
Group 1 was defined as all COVID-19 patients who had received oral boluses of vitamin D supplements over the preceding year. Bolus included the doses of 50,000 IU vitamin D3 per month, or the doses of 80,000 IU or 100,000 IU vitamin D3 every 2−3 months.
The three groups (n = 77; mean ± SD, 88 ± 5years; 49% women) were similar at baseline (except for woman proportion, p = 0.02), as were the treatments used for COVID-19. In Group 1 (n = 29), 93.1% of COVID-19 participants survived at day 14, compared to 81.2% survivors in Group 2 (n = 16) (p = 0.33) and 68.7% survivors in Group 3 (n = 32) (p = 0.02). While considering Group 3 as reference (hazard ratio (HR) = 1), the fully-adjusted HR for 14-day mortality was HR = 0.07 (p = 0.017) for Group 1 and HR = 0.37 (p = 0.28) for Group 2. Group 1 had longer survival time than Group 3 (log-rank p = 0.015), although there was no difference between Groups 2 and 3 (log-rank p = 0.32). Group 1, but not Group 2 (p = 0.40), was associated with lower risk of OSCI score ≥5 compared to Group 3 (odds ratio = 0.08, p= 0.03).
Regular bolus vitamin D supplementation was associated with less severe COVID-19 and better survival in frail elderly. (Annweiler et al., 2020)

Calcifediol (25-OH Vitamin D) and Best Available Therapy

A study published in the Journal of Steroid Biochemistry and Molecular Biology evaluated the effect of calcifediol treatment, on Intensive Care Unit Admission and Mortality rate among Spanish patients hospitalized for COVID-19. The Hospital Universitario Reina Sofía, Universidad de Córdoba, Spain conducted the study.
A parallel pilot randomized open label, double-masked clinical trial was conducted at Reina Sofia University Hospital, Córdoba Spain. The study included 76 consecutive patients hospitalized with COVID-19 infection, clinical picture of acute respiratory infection, confirmed by a radiographic pattern of viral pneumonia and by a positive SARS-CoV-2 PCR with CURB65 severity scale (recommending hospital admission in case of total score > 1).
All hospitalized patients received as best available therapy the same standard care, (per hospital protocol), of a combination of hydroxychloroquine (400 mg every 12 h on the first day, and 200 mg every 12 h for the following 5 days), azithromycin (500 mg orally for 5 days. Eligible patients were allocated at a 2 calcifediol:1 no calcifediol ratio through electronic randomization on the day of admission to take oral calcifediol (0.532 mg), or not. Patients in the calcifediol treatment group continued with oral calcifediol (0.266 mg) on day 3 and 7, and then weekly until discharge or ICU admission. Outcomes of effectiveness included rate of ICU admission and deaths.
Of 50 patients treated with calcifediol, one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50 %) p value X^2^ Fischer test p < 0.001. Univariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment versus without Calcifediol treatment: 0.02 (95 %CI 0.002-0.17). Multivariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment vs Without Calcifediol treatment ICU (adjusting by Hypertension and T2DM): 0.03 (95 %CI: 0.003-0.25). Of the patients treated with calcifediol, none died, and all were discharged, without complications. The 13 patients not treated with calcifediol, who were not admitted to the ICU, were discharged. Of the 13 patients admitted to the ICU, two died and the remaining 11 were discharged.
This pilot study demonstrated that administration of a high dose of Calcifediol or 25-hydroxyvitamin D, a main metabolite of vitamin D endocrine system, significantly reduced the need for ICU treatment of patients requiring hospitalization due to proven COVID-19. Calcifediol seems to be able to reduce severity of the disease. (Entrenas Castillo et al., 2020)

Vitamin D, A Clinical Case Series

Four vitamin D deficient patients diagnosed with COVID-19 in April 2020 were provided with either cholecalciferol of 1000 IU daily (standard dose) or ergocalciferol 50,000 IU daily for 5 days (high dose) as part of supplementation.
Patients that received a high dose of vitamin D supplementation achieved normalization of vitamin D levels and improved clinical recovery evidenced by shorter lengths of stay, lower oxygen requirements, and a reduction in inflammatory marker status. (Ohaegbulam et al., 2020)

 

References

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