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Vitamin D was the only supplement that fought COVID-19 (out of 6) – Oct 2021


Vitamins, supplements and COVID-19: a review of currently available evidence

Drugs Context. 2021;10:2021-6-2. https://doi.org/10.7573/dic.2021-6-2
Lauren L Speakman, Sarah M Michienzi, Melissa E Badowski
Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, IL, USA
 Download the PDF from VitaminDWiki

Background: In the midst of the COVID-19 pandemic, there has been an information overload of health data (both accurate and inaccurate) available to the public. With vitamins and supplements being readily accessible, many have turned to using them in an effort to combat the virus. The purpose of this review was to analyse clinical trials regarding vitamins and supplements for the treatment of COVID-19 infections.

Methods: Articles were identified through a literature search utilizing online databases and bibliographic review.

Results: A total of seven articles were identified for review. All articles evaluated the use of vitamins and supplements for the treatment of COVID-19. Drug therapies included oral vitamin D, intravenous and oral vitamin C, oral vitamin D/magnesium/ vitamin B12, oral zinc, oral combination zinc/ascorbic acid, and intravenous alpha-lipoic acid. The end points of each study varied, including the Sequential Organ Failure Assessment score, mortality, rate of intensive care unit (ICU) admissions, negativity of COVID-19 tests, oxygen requirements, and symptom burden.

Conclusion: Of the vitamins and supplements that were studied, vitamin D presented the most promising data demonstrating significant decreases in oxygen requirements, need for ICU treatment, SARS-CoV-2 RNA test positivity, and mortality. All of these benefits were exhibited in hospitalized patients. Other vitamins and supplements that were evaluated in studies did not demonstrate any statistically significant benefits. Common shortcomings of the articles included generally small sample sizes, varying sites of study (which could determine the virus variant), a lack of standard of care as background therapy, and utilization of doses that were higher than standard.

Introduction

SARS-CoV-2, the virus causing COVID-19, was first reported to the WHO on 31 December 2019 and was declared a global pandemic on 11 March 2020.1-3 To date, there have been more than 229 million reported cases and 4.7 million deaths globally.4
Whilst the fight against the COVID-19 pandemic has persisted for more than 18 months at the time of writing, few therapies have proven effective in the management or prevention of COVID-19 infections, with the exception of vaccines.5-7 Throughout the course of this pandemic, many therapies have been proposed as having utility, with many, but not all of them, falling short of providing meaningful results in clinical trials.8-16 Some proposed therapies have never undergone clinical trials, and medical claims are being made based on theoretical or anecdotal evidence.17 Since the publication of the preceding article that reviewed in-progress studies on vitamins and supplements in COVID-19,18 various vaccines have been developed and used globally, with others in the pipeline.5-7,19-24

The National Institutes of Health (NIH) released and regularly updates a set of guideline recommendations based on evolving evidence. As of this writing, remdesivir is the only formally FDA-approved drug for the treatment of COVID-19 in patients meeting certain criteria,25 including hospitalized patients requiring supplemental oxygen but who do not require high- flow oxygen, ventilatory support or extracorporeal membrane oxygenation.25 Additionally, the NIH recommended against any medication, pre-exposure or post-exposure prophylaxis, for COVID-19.26 The NIH guidelines also stated that there are insufficient data regarding the use of supplements for the treatment of COVID-19.27

For COVID-19 management in the outpatient setting, the NIH recommended bamlanivimab plus etesevimab28 or casirivimab plus imdevimab29 in certain populations as defined by the Emergency Use Authorization (EUA) criteria.30 Previously, bamlanivimab alone had received an EUA in the outpatient setting.31 For COVID-19 management in the inpatient setting, the NIH recommended remdesivir, dexamethasone, and/or tocilizumab, depending on oxygen requirements and risk of disease progression.32 Several other immunomodulators are currently in the pipeline.33 The Infectious Diseases Society of America,34 the Society for Critical Care Medicine35 and the WHO36 have each published their own set of fluid guideline recommendations that are generally in accordance with the NIH recommendations. The CDC did not recommend specific therapies but instead deferred to the NIH guidance.37 Whilst there is no universal standard of care at the time of this publication, most institutions have protocolized COVID-19 management, with recommendations evolving with changing evidence.
With an abundance of news outlets and means of communication, there has been ample misinformation circulating amongst the public regarding the dos and don'ts of combatting this novel virus.17 With vitamins and supplements being readily accessible to the general public without provider oversight, it is important to address their role in this pandemic as there has been much discussion surrounding their use. The purpose of this review was to analyse completed and published clinical trials regarding vitamins and supplements for the treatment and/or prevention of COVID-19 infections.
Methods
We performed a literature search using PubMed, Google Scholar and bibliography review using the National Clinical Trials (NCT) numbers from previous manuscripts and the following search terms: coronavirus/COVID-19/SARS-CoV-2/ COVID and vitamins/supplements. The results were filtered to "clinical trial" and "randomized controlled trial". Both prospective and retrospective studies evaluating the use of vitamins and/or supplements for the prevention or treatment of COVID-19 and published on or before 26 February 2021were included. Studies were excluded if they did not report on an intervention or if complete/final results were not available. This manuscript was exempt from ethics review and Institutional Review Board approval as it did not involve human subject research.
Results
Twenty-seven manuscripts were identified from an initial database search, with six of which qualified for inclusion in this analysis (Figure 1). Reasons for study exclusion were non-interventional study (n=2), erroneous search result (n=11), inability to obtain access to paper (n=1) and study in progress (n=7). An additional China-based study that was not available through online databases was identified through a bibliography review and included in this review, making a total of seven qualifying trials for this paper.
All identified studies involved the treatment of COVID-19 and did not address prophylaxis therapies for COVID-19. The interventions in the studies were oral vitamin D, intravenous (IV) and oral vitamin C, oral combination vitamin D/magnesium/ vitamin B12, oral zinc, oral combination zinc/ascorbic acid, and IV alpha-lipoic acid (ALA), with the majority of the studies investigating the use of vitamin D (n=4). Of the identified trials, two were retrospective, and five were prospective with randomization. Of the randomized trials, three were open- label, one was single-blind, and the other was unspecified. The proposed utility of each of the vitamins and supplements and available data are summarized below and in Table 1.

Vitamin D (cholecalciferol, calcifediol)

Vitamin D has previously been proposed to have antiviral effects, which led to a theoretical benefit of its use as an adjuvant in treating COVID-19 infections.38-43 Several retrospective studies have addressed an observed correlation between low serum vitamin D levels and severity of the course of COVID-19 disease symptoms, which is evaluated later in this paper.44-50 Amongst the vitamin D interventional trials assessed in this review, calcifediol use showed significant decreases in intensive care unit (ICU) admission rates, from 50% without therapy to 2% with therapy (p<0.001).51 Additionally, patients receiving high-dose cholecalciferol showed significantly more negative SARS-CoV-2 tests prior to week 3 (p=0.018).52 A retrospective study involving various dosing strategies of cholecalciferol was associated with decreased risk of COVID-19- related mortality (p<0.001).53 With regard to vitamin D levels, in the SHADE study, the cholecalciferol group had achieved significantly higher vitamin D levels (>50 ng/mL) compared to the placebo group (p<0.001)52 by day 14.52

Vitamin C (ascorbic acid)

Vitamin C, a water-soluble vitamin, plays various roles, including supporting connective tissues through collagen synthesis, wound healing, and enhancing the immune system through its bactericidal properties and antibody boosting.54 It has previously been proposed as having a theoretical benefit in immune defence against COVID-19 infection, based on its known properties and hypothetical, inconsistent evidence supporting its role in symptom mitigation in the common cold.55-57 Additionally, various studies have demonstrated the positive effects of vitamin C against Epstein-Barr virus, enterovirus/ rhinovirus-induced acute respiratory distress syndrome, and severe sepsis and in mechanically ventilated patients with acute respiratory distress syndrome in the ICU.58-66 IV vitamin C was investigated based on variable evidence of its use in critically ill patients and showed no mortality benefit but some symptom management benefit.67 One study involving high-dose vitamin C in the setting of COVID-19 demonstrated a significantly longer hospital stay than the non-vitamin C arm. Additionally, there were no significant differences in mortality or ICU length of stay.68 Vitamin C, alone and in combination with zinc, showed no significant decreases in COVID-19-related symptoms compared to no study intervention.69

Magnesium

Magnesium has previously been shown to increase 25-hydroxyvitamin D levels when they are <30 ng/mL at baseline;70 thus, if vitamin D helps protect against COVID-19, magnesium could in turn also be beneficial. So far, magnesium has only been studied in combination with vitamins B and D. The combination therapy showed significant decreases in oxygen support (including ICU support) (p=0.006); however, there were no significant differences in the outcome of oxygen support, excluding any ICU support.71
See below: Magnesium and Virus in VitaminDWiki

Vitamin B12

Vitamin B12 has been observed to play a fundamental role in gut microbiome,72 which can affect the innate immune response.73 Some data report that SARS-CoV-2 RNA was found in the stool of patients testing positive for COVID-19, implying that there could be involvement of the gut-lung axis in COVID-19 infections.74 Additionally, one study demonstrated that the faecal microbiome of patients testing positive for COVID-19 was significantly altered compared to a control group.75 Similar to magnesium, vitamin B has only been studied in combination with vitamin D and magnesium. As stated above, this combination therapy showed significant decreases in oxygen support (including ICU support) (p=0.006); however, there were no significant differences in the outcome of oxygen support, excluding any ICU support.71

Zinc

The proposed immune-related mechanism of action of zinc is through enhancement of the innate anti-infective properties of basophils, eosinophils, and neutrophils.76 Some weak evidence supports the use of zinc in mitigating symptoms of the common cold.77-80 Additionally, zinc has demonstrated inhibition of RNA polymerase in vitro but this has not been studied in SARS-CoV-2.81,82 Zinc supplementation has been minimally studied in COVID-19; however, one trial demonstrates that zinc, both alone and in combination with vitamin C, showed no significant decreases in COVID-19-related symptoms compared to no study intervention.69
See below: Zinc and Virus in VitaminDWiki

Alpha-lipoic acid

ALA is an anti-inflammatory and antioxidant. It has previously been shown to decrease the levels of serum inflammatory cytokines and inflammatory-related symptoms in patients with acute coronary syndrome, liver transplantation, and kidney-pancreas combined transplantation.83-86 Only one study investigated the use of ALA in COVID-19, and this study demonstrated no significant differences in the Sequential Organ Failure Assessment (SOFA) score by day 7 of therapy or

Vitamin, mineral and nutrient deficiency in COVID-19

Aside from interventional trials involving vitamins and supplements in COVID-19, data have also been published regarding serum levels of vitamins, minerals, and nutrients and their role in COVID-19.89,90 Most of the data involve vitamin D levels. A full review of deficiencies in COVID-19 is beyond the scope of this article, but representative studies are discussed below to better contextualize supplementation in COVID-19. Interested readers can find a more in-depth analysis on this topic in the cited review articles.91-94
Several retrospective studies found a relationship between vitamin D levels and COVID-19 positivity rate. Amongst patients aged >70 years old, one study showed that patients positive for COVID-19 had significantly lower median vitamin D levels compared to those negative for COVID-19 (9.3 ng/mL versus 23.1 ng/mL, respectively; p=0.037).48 Similarly, another study found positive COVID-19 tests were associated with deficient vitamin D status (defined as <20 ng/mL) at the time of testing (relative risk 1.77, 95% CI 1.12-2.81; p=0.02).49 Moreover, a third study demonstrated an association between low vitamin D levels (defined as <30 ng/mL) and an increased likelihood of COVID-19 infection (p<0.001).50
Additional retrospective studies found vitamin D was also related to the severity and outcomes of COVID-19. Amongst patients who were positive for COVID-19, in both inpatient and outpatient settings and equally treated at a single site in Germany, those who had vitamin D deficiency (<12 ng/mL) had significantly higher hospitalization rates (p=0.004), required intensive oxygen therapy (p<0.001), and had significantly higher rates of invasive mechanical ventilation and/or death (p<0.001) or death alone (p<0.001). Insufficient levels of vitamin D (<20 ng/mL) were also associated with higher rates of invasive mechanical ventilation and/or death (p=0.004) or death alone (p=0.2).95 In contrast, another study did not show a difference in mortality between vitamin D deficiency (<30 nmol/L) and replete inpatient adults >65 years old in the United Kingdom. However, vitamin D deficiency was associated with significantly higher ventilation requirements (p=0.042).96 In an Italian study, patients with severe vitamin D deficiency (<10 ng/mL) had higher median respiratory intermediate care unit stays compared to those with vitamin D levels >10 ng/mL (8 versus 12.5 days). Additionally, those with severe vitamin D deficiency had higher mortality rates (50% versus 5%; p=0.019).97
Minimal data exist regarding supplements or vitamins, besides vitamin D; however, there are some data on selenium and potassium. In one study, 64.7% of COVID-19 non-survivors had selenium levels <45.7 pg/L, whereas 39.3% of COVID-19 survivors had these levels. Additionally, the COVID-19 non-survivors had significantly lower selenium serum levels than the survivors (p<0.001).98 In another study of 197 inpatients with COVID-19, those who were normokalaemic (K >3.5 mmol/L) had significantly fewer complications (including respiratory failure, sepsis, liver damage, respiratory distress and cardiac damage) than those with severe hypokalaemia (K <3 mmol/L) (p=0.006). Additionally, normokalaemic patients were less likely to be critically ill compared to severely hypokalaemic patients (p=0.03).99

Discussion

Of the vitamins and supplements that were studied, vitamin D presents the most promising data demonstrating significant decreases in oxygen requirements (p=0.006),71 need for ICU treatment (p<0.001),51 SARS-CoV-2 RNA test positivity (p=0.018)52 and mortality (p<0.001).53 All of these benefits were exhibited in hospitalized patients; no studies were conducted in the outpatient setting to demonstrate similar results. A shortcoming of most of the identified trials is the small sample size, with the exception of a large, retrospective trial evaluating various dosing strategies of cholecalciferol and its impact on COVID-19 mortality.53 The end points of each study varied, including SOFA score, mortality, rate of ICU admissions, negativity of COVID-19 tests, oxygen requirements and symptom burden. Additionally, with each study taking place in different parts of the world, the study populations were likely affected by different virus variants. The lack of a global standard of care meant that background therapy varied from trial to trial. In many instances, the dose of the vitamin or supplement utilized in these trials was higher than standard over-the-counter doses,89,90 making it unlikely that patients would take the doses that were studied in these trials without the supervision of a clinician.

Conclusion

With the lack of large randomized controlled trials, results from the studies to date must be interpreted cautiously. At this time, studies involving vitamins and supplements do not provide enough evidence to justify their use over other established pharmacological therapies and prevention techniques that have been proven for use in COVID-19 management and prevention.
Additionally, current data regarding vitamin D levels and COVID-19 suggest that low vitamin D levels are associated with increased risk of COVID-19 infection as well as with more complications during infection and higher rates of death. However, from these data alone, it cannot be deducted that vitamin D supplementation is beneficial in the setting of COVID-19 infections. More data are needed regarding other vitamins and minerals to deduct further effects of serum levels on COVID-19. Finally, with regard to selenium levels, the challenge for most institutions would be limited access to selenium testing.

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