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  Commentary     July 2021  

Vitamin-D Supplementation in COVID-19: Existing Evidence and Gap in Literature

By Muhammad Abbas Abid1, Hafsa Majid1, Aysha Habib Khan1

Affiliations

  1. Department of Pathology and Laboratory Medicine, The Aga Khan University, Karachi, Pakistan

ABSTRACT
Review of literature on effectiveness of vitamin D in COVID-19 infection demonstrated a positive effect in COVID-19 patients. However, the studies are limited either due to small sample size or are conducted in a select subset of patients. Gaps on proof-of-concept or a cause-effect relationship related to the use of vitamin D in COVID-19 infection still exist. COVID-19 related benefits of vitamin D have not been validated and are still hypothetical. Administration of high amounts of vitamin D, without clinical indication, could result in toxicity and harmful consequences. Large, multi-centre, placebo-controlled clinical trials in patients with varying severity of COVID-19 infection are needed to establish the role of vitamin D supplementation as an inexpensive therapeutic tool to fight the ongoing pandemic. Administration of vitamin D in already sufficient population should be held until concrete evidence is being established.

Key Words: COVID-19, Vitamin D, Knowledge gap, Literature review, Clinical trials, Update.

INTRODUCTION

The severity and mortality of coronavirus disease 2019 (COVID-19) has shown wide variations globally, with countries located more northerly in the northern hemisphere reported to have higher mortality. An estimated increase of 4.4% in mortality for every 1-degree latitude north of 28 degrees north has been reported. One possible explanation proposed for this geographic disparity is the impact of vitamin D on the immune system.1

Studies from other regions of the world have also demonstrated positive correlation between vitamin D deficiency and COVID-19 severity. A study from Iran reported higher mortality in patients with lower 25-(OH)D levels.2 Similar results were reported from other South Asian countries including India.3 Similarly, a study from Africa shows that lower vitamin D levels were significantly associated with higher blood levels of inflammatory markers, higher CT chest severity score, and longer disease duration.4

Certain vitamin D receptor (VDR) gene alleles are associated with increased susceptibility to respiratory infections due to their role in the immune system.

The active vitamin D metabolite, calcitriol, has been shown to suppress the inflammatory cytokines of macrophages along with respiratory epithelial cells to various pathogens and respiratory viruses.5 A preclinical study on mouse models showed that vitamin D (calcitriol) supplementation improved outcomes of H5N1 driven lipopolysaccharide (LPS) induced lung injury and acute respiratory distress syndrome (ARDS).5 So, the proposed effects of vitamin D include activation of VDR signalling pathway to generate beneficial effects in ARDS by reducing the cytokine/chemokine storm, renin-angiotensin system (RAS), modulating neutrophil activity, and by preserving the integrity of the pulmonary epithelial barrier, stimulating epithelial repair and reducing coagulability.6 A computational model using combined molecular docking, molecular dynamics simulations and binding free energy studies to explore the possible role of vitamin D3 in inhibiting the SARS-CoV-2 receptor binding domain (RBD) from binding to angiotensin-converting enzyme 2 (ACE2), showed that vitamin D3 and its derivatives can be promising adjuvant therapy for COVID-19.7

Hence, there is evidence showing vitamin D deficiency as an independent risk factor for COVID-19. But these findings cannot be expanded to include the hypothesis that vitamin D could serve as a possible treatment for COVID-19. Huge knowledge gaps exist in both literature and understanding about the effects of vitamin D status before contracting the infection or treatment with vitamin D to reduce morbidity and mortality.

The possibility that vitamin D could impact the natural course of COVID-19 at multiple steps, led to an increasing interest in understanding the effects of vitamin D in different complications of COVID-19.

Table I: Details of the Vitamin-D trials in COVID-19 patients.

Author

Country

Date published

Study design

Population type

Sample size

Treatment group size

Treatment given

Dose of vitamin D

Results

Limitations

Annweiler et al.

France

October, 2020

Quasi experimental

Geriatric

66

57

Bolus vitamin D3

80,000 IU every 2-3 months

Less severe COVID-19 and
↑ survival rate

Small sample size

Only nursing home residents

Less robust than RCT

Not placebo-controlled

Not randomized

Annweiler et al.

France

November, 2020

Quasi experimental

Geriatric

77

45

Bolus vitamin D3

50,000 IU every month

or

80,000, 100,000 IU every 2-3 months

Less severe COVID-19 and
↑ survival rate

Small sample size

Only hospitalized frail elderly patients

Less robust than RCT

Not placebo-controlled

Castillo
et al.

Spain

October, 2020

Pilot randomized clinical trial

All ages

76

50

Oral Calcifediol

0.532mg at admission, followed by 0.266 weekly

↓ ICU treatment need

Small sample size

Not double blind

Not placebo-controlled

Tan
et al.

Singapore

September, 2020

Cohort observational

>50 years

43

17

Oral vitamin D, magnesium, vitamin b12

1000 IU daily

↓ Clinical deterioration

Small sample size

Retrospective cohort design

Not randomized

Rastogi
et al.

India

November, 2020

RCT

36-51

40

16

Oral Cholecalciferol

60,000 IU daily for 7 days

Quicker seronegativity. Significant
↓ fibrinogen

Small sample size. Short duration. Mildly symptomatic or asymptomatic population.

RCT = Randomised controlled trial; 25 (OH) D = 25-hydroxyvitamin D (Pubmed: March 11, 2021.

The National Institute of Health (NIH) clinical trials database (www.clinicaltrials.gov) has 39 registered clinical trials (as on December 1st, 2020) of vitamin D in COVID-19 patients. Only three of these trials have been completed. A search of PubMed (March 11, 2021) with search terms “COVID-19, vitamin D” and “COVID-19, 25 (OH)D” produced 482 and 4 results, respectively. Only five studies reported the results of intervention with vitamin D in COVID-19 patients.

One quasi-experimental study with 66 subjects from a French nursing home reported decreased severity of COVID-19 and higher survival rates in patients receiving vitamin D supplementation prior to or during the COVID-19 infection.8 The same group presented similar results in another quasi-experimental study with vitamin D supplementation in 77 patients of COVID-19 in a geriatric unit.9 A randomised pilot study consisting of 76 subjects showed that administration of bolus vitamin D3 significantly reduced admissions to the intensive care unit (ICU) among hospitalised COVID-19 patients.6 Another study on cohort of 43 patients, 17 of whom received a combination of vitamin D, magnesium, and vitamin B12 and demonstrated a significant reduction in clinical deterioration and the need for supplemental oxygen and ICU admission.10 Rastogi et al. performed a short-term, high-dose vitamin D, randomised, placebo-controlled trial. They reported significantly quicker COVID-19 seronegative results in the intervention arm with significant reduction in fibrinogen levels.11 Although all five studies demonstrate a positive effect of vitamin D in COVID-19 patients, these studies are limited either due to small sample size or were conducted in a select subset of patients. The characteristics of these studies are outlined in Table I. Other studies, suggesting a positive correlation in vitamin D deficiency and mortality and severity of COVID-19, are retrospective and exhibit inherent biases.

A recent study from Spain, the Barna-COVIDIOL study, was published as a preprint with The Lancet Infectious Diseases, on January 22 2021. The study reported that 36 of 551 (6.5%) patients treated with calcifediol at admission died, compared with 57 of 379 (15%) controls who did not receive calcifediol (p = .001). Similarly, of the calcifediol-treated patients, 30 (5.4%) required admission to ICU, compared with 80 of 379 controls (21.1%; p <.0001). However, the study met with a raft of criticism due to a lack of detail regarding methodology, specifically the randomization process, and was eventually removed from Lancet server. HYPERLINK \l "12 This preprint was a first, large-scale, randomized controlled trial, reporting the impact of vitamin D in COVID-19 patients and reported that vitamin D (calcifediol, [25(OH)D3]) administration in patients hospitalized with COVID-19 reduced mortality significantly.

Gaps in knowledge exist regarding the association that vitamin D administration will result in improvement of COVID-19 patients; and the notion that vitamin D could be used for the treatment of COVID-19 patients is still a hypothesis. No study, to date, has established proof-of-concept or demonstrated a cause-effect relationship including reports from Pakistan. Furthermore, vitamin D is not a harmless drug. Administration of high amounts of vitamin D without clinical correlation could result in toxicity and harmful consequences. Care in vitamin D replacement is warranted to avoid abnormalities in the calcium-vitamin D-parathyroid hormone (PTH) axis. Food sources and lifestyle factors should be encouraged. This will aid in improving the immune system, while also providing long-term health benefits till the time evidence is established regarding the role of vitamin D in the management of COVID-19.

This also calls for large, multi-centre, placebo-controlled clinical trials that study COVID-19 patients with different severity of the disease. Randomised clinical trial documentation of vitamin D supplementation being associated with a positive outcome in COVID-19 patients would provide an inexpensive and accessible addition to current treatment protocols that is easy to disseminate to a larger population considerably rapidly as compared to other more complex interventions. Furthermore, the possible improvement of COVID-19 patients is just one aspect served by vitamin D. Its overall benefit on individuals’ and the community’s general well being is substantial.

As the COVID-19 related benefits of vitamin D have not been validated yet, so its supplementation to replace preexisting deficiency should be the cornerstone in patients suffering from COVID-19. Administration of vitamin D in already sufficient population should be held until concerte evidence has been established. Prospective, community-based studies are needed urgently to establish the efficacy of vitamin D supplementation as an inexpensive therapeutic tool to fight the ongoing pandemic.

ETHICAL APPROVAL: 
Not applicable.

PATIENTS CONSENT: 
Not applicable

CONFLICT OF INTEREST:
The authors declared no conflict of interest.

AUTHORS CONTRIBUTION:
MAA: Literature search, and write-up.
HM: Literature search, and review.
AHK: Idea, literature search, review and critical input.

REFERENCES

  1. Rhodes JM, Subramanian S, Laird E, Griffin G, Kenny RA. Perspective: Vitamin D deficiency and COVID‐19 severity– plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis. J Intern Med 2021; 289(1):97-115. doi: 10.1111/joim.13149.
  2. Shakeri H, Azimian A, Ghasemzadeh-Moghaddam H, Safdari M, Haresabadi M, Daneshmand. Evaluation of the relationship between serum levels of zinc, vitamin B12, vitamin D, and clinical outcomes in patients with COVID-19. J Med Virol 2021. doi: 10.1002/jmv.27277.
  3. Nimavat N, Singh S, Singh P, Singh SK, Sinha N. Vitamin D deficiency and COVID-19: A case-control study at a tertiary care hospital in India. Ann Med Surg 2021; 68:102661. doi: 10.1016/j.amsu.2021.102661.
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  6. Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcalá Díaz JF, López Miranda F. ''Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomised clinical study." J Steroid Biochem Mol Biol 2020; 203:105751. doi: 10.1016/j.jsbmb.2020.105751.
  7. Song Y, Qayyum S, Greer RA, Slominski RM, Raman C, Slominski AT, et al. Vitamin D3 and its hydroxyderivatives as promising drugs against COVID-19: A computational study. J Biomol Struct Dyn 2021; 1-17. doi: 10.1080/ 07391102.2021.1964601.
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  11. Rastogi A, Bhansali A, Khare N, Suri V, Yaddanapudi  N, Sachdeva N, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: S randomised, placebo-controlled, study (SHADE study). Postgrad Med J 2020; postgradmedj-2020-139065. doi: 10.1136/ postgradmedj-2020-139065.
  12. 12. Nogues X, Ovejero D, Pineda-Moncusí M, Bouillon R, Arenas D,  Pascual J, et al. Calcifediol treatment and COVID-19-related outcomes. J Clin Endocrinol Metab 2021;  dgab405. doi: 10.1210/clinem/dgab405.