Vitamin D and COVID-19: Do Latest Studies Support Supplementation?
To date, research on vitamin D supplementation and COVID-19 outcomes has been limited, so the PEN Team reviewed two recent studies on vitamin D and COVID-19 to see what, if anything, has changed.
Conversations continue on social media about the potential role of vitamin D supplementation in the prevention and treatment of COVID-19. The PEN Team noticed that a common rationale was that patients with COVID-19 tended to have lower vitamin D status (25(OH)D levels). We decided to take a look at two recent studies that reported this connection to determine if the results support vitamin D supplementation to improve COVID-19 outcomes.
First, we looked at an observational study by De Smet et al. that noted that patients with COVID-19 had progressively lower 25(OH)D levels with more severe COVID respiratory disease (1). The study authors also observed that those with vitamin D deficiency were almost four times more likely to die (adjusted odds ratio [OR] 3.87; 95% confidence interval [CI], 1.30 to 11.55). Vitamin D deficiency was prevalent among the patients with COVID-19 infections, more so among the men (67%) than among the women (47%). These researchers adjusted for several variables that are risk factors for COVID-19 mortality (age, ethnicity, chronic lung disease, coronary artery disease/hypertension, diabetes and extent of lung damage).
From other vitamin D research, we know that the marker for vitamin D status (25(OH)D) can be lowered by infections (2). Therefore, low 25(OH)D levels may not reflect poor vitamin D status in a person with an infection. De Smet et al. were not able to determine whether what looked like a vitamin D deficiency was actually a nutritional deficiency or whether the COVID-19 infection lowered the participants 25(OH)D, making these patients appear to have a vitamin D deficiency (1). For this reason, this observational study does not provide evidence that vitamin D supplementation would be helpful for improving outcomes of a COVID-19 infection.
The second study we examined was a randomized control trial of vitamin D supplementation in people with mild symptomatic and asymptomatic COVID-19 infections. Rastogi et al. randomized 40 people with mild COVID-19 infections to 60,000 IU/day of vitamin D3 or placebo for seven days (3). The researchers observed that more participants in the intervention group became COVID-19 RNA negative before day 21 compared to participants in the control arm (62.5% versus 20.8%, P<0.018). Vitamin D supplementation lowered fibrinogen levels significantly but not the other inflammatory markers (SARS-CoV-2 RNA, D-dimer, procalcitonin CRP and ferritin). These researchers only reported differences in indirect markers (3) and did not report World Health Organization-recommended patient-important outcomes (patient survival and patient health care system use over the course of clinical illness) (4). The PEN Team thinks that this trial does not answer the question of whether vitamin D supplementation improves COVID-19 outcomes.
What This Means
After reviewing these studies, the PEN Team has two key questions:
1. What is the relationship between vitamin D deficiency and COVID-19 severity?
2. What is the impact of vitamin D supplementation on patient-important outcomes, such as disease severity, hospitalization and death?
Before dietitians can make recommendations on the use of vitamin D supplementation to improve COVID-19 outcomes, randomized control trials examining the prevention of COVID-19 (including severe COVID-19) and the treatment of COVID-19 with patient-important outcomes are needed.
- De Smet D, De Smet K, Herroelen P, Gryspeerdt S, Martens GA. Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality. Am J Clin Pathol. 2020 Nov 25:aqaa252. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717135/
- Hernández-Álvarez E, Pérez-Barrios C, Blanco-Navarro I, Pérez-Sacristán B, Donoso-Navarro E, Silvestre RA, et al. Association between 25-OH-vitamin D and C-reactive protein as a marker of inflammation and cardiovascular risk in clinical practice. Ann Clin Biochem. 2019 Jul;56(4):502-7. Available from: https://pubmed.ncbi.nlm.nih.gov/31043057/
- 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: a randomised, placebo-controlled, study (SHADE study). Postgrad Med J. 2020 Nov 12:postgradmedj-2020-139065. Abstract available from: https://pubmed.ncbi.nlm.h.gov/33184146/
- WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020 Aug;20(8):e192-e197. Abstract available from https://pubmed.ncbi.nlm.nih.gov/32539990/
Supplements Associated with Liver Injury
With the increased use of herbal and dietary supplements worldwide, there has also been an increase in reports of liver injury attributable to their use (1). “Herbal and dietary supplement-related liver injury now accounts for 20% of cases of hepatotoxicity in the US” with rates of hepatotoxicity from herbal and dietary supplements in Europe ranging between 13-16% of cases and Asian countries reporting even higher rates. Anabolic steroids, green tea extract and supplements with multiple ingredients are the products most commonly linked to the hepatotoxicity in the US. See: Liver Injury from Herbal and Dietary Supplements.
Dietitians may also find this open access article on the hepatotoxicity of dietary supplements to be of interest. A literature search was performed in PubMed to identify English and Spanish case reports, case series and clinical reviews published from 1984 to 2015 that described reports of liver injury associated with dietary supplement and/or herbal product use (2). Products examined included: anabolic steroids, green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang as well as multi-ingredient products Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™. They found that the prevalence of herbal and dietary supplement-induced liver injury is increasing worldwide.
Hepatotoxicity can result in anything from mildly uncomfortable symptoms, such as nausea and vomiting to, in extreme circumstances, complete liver failure. Dietary supplements are not benign substances and their safe use requires awareness of potential side-effects.
This information reminds dietitians to be sure to delve into their clients' use of supplements, paying specific attention to the type of product used and whether people are taking the recommended amounts or using them in ways that put them at risk for adverse events. Staying abreast of the literature on efficacy of dietary supplements as well as their safety is critical. A good place to start is the PEN® System. There are more than 190 practice questions and 35 background documents identified in the search for dietary supplements.
- Navarro V, Khan I, Björnsson E, Seeff LB, Serrano J, Hoofnagle JH. Liver injury from herbal and dietary supplements. Hepatology. 2016 Sep 27 [Epub ahead of print]. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/27677775
- García-Cortés M, Mercedes Robles-Díaz M, Aida Ortega-Alonso A, Medina-Caliz I, Andrade RJ. Hepatotoxicity by dietary supplements: a tabular listing and clinical characteristics. Int J Mol Sci. 2016;17(4):537. Abstract available from: https://www.ncbi.nlm.nih.gov/pubmed/27070596