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Supplementation of the population during the COVID-19 pandemic with vitamins and micronutrients – how much evidence is needed?

DOI: https://doi.org/10.4414/smw.2021.20522
Publication Date: 19.05.2021
Swiss Med Wkly. 2021;151:w20522

Schuetz Philippab, Gregoriano Claudiaa, Keller Ulrichb

a Department of Internal Medicine, Kantonsspital Aarau, Switzerland

b University of Basel, Switzerland

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a global pandemic with severe respiratory disease and high morbidity and mortality [1]. In turn, there has been an unprecedented research effort to improve the understanding of pathophysiological mechanisms, risk factors, diagnostic tests, and measures for effective prevention and treatment of COVID-19. Age and age-related vulnerabilities – such as malnutrition and frailty – have emerged as the major risk factors for adverse clinical outcome and mortality in patients with COVID-19 [2]. Higher age is a general risk factor in most illnesses, but it is possible that the high fatality rate among the elderly frail population may be explained – at least in part – by deficiencies in specific vitamins and micronutrients, which are vital for a well-functioning immune system.

Over the last decades, many preclinical and observational studies have provided evidence that vitamins and micronutrients play an important role in the efficient functioning of the immune system. As a consequence, deficiencies in these vitamins and micronutrients may reduce the immune response of patients and increase their vulnerability to infections and to have more severe courses once infected. Vitamin C, for example, is an essential vitamin that cannot be synthesised by humans as a result of loss of a key enzyme in the biosynthetic pathway [3]. Severe vitamin C deficiency results in scurvy, which is characterised by weakening of collagenous structures, poor wound healing and impaired immunity with high susceptibility to fatal infections such as pneumonia [4]. Similarly, vitamin D has been shown to influence susceptibility to and severity of infection via multiple mechanisms with a direct impact on production of the antimicrobial peptide cathelicidin and different cytokines via the innate and adaptive immune system, as well as via the NFκB (nuclear factor kappa-light-chain-enhancer of activated B-cells) pathways [5].

One straight-forward “public health” approach would be to start vitamin and micronutrient supplementation of the entire population at risk to reduce the risk for deficiencies and thereby reduce vulnerabilities. Such an approach may be most suitable for interventions with high clinical efficacy, a high proportion of the population showing benefit, proof of safety and overall low treatment costs. Recently, several researchers from Switzerland have published a call for action to consider supplementation of high-risk groups with micronutrients and vitamins as a strategy to diminish adverse health consequences of COVID-19 in the Swiss population [6]. Clearly, supplements and vitamins are over-the-counter medications with excellent safety data and relatively low treatment costs. Still, to be a valuable public health strategy, evidence of clinical efficacy of broad vitamin and micronutrient supplementation of the population in question is needed. Whether this is the case for vitamins and micronutrients in the face of the COVID-19 pandemic needs further exploration and will be discussed in this brief review.

Deficiencies of specific micronutrients and risk of infections

There is evidence from preclinical and observational clinical studies that specific vitamins and micronutrients play a major role in immunity, and that deficiencies are related to higher risks for infection and adverse clinical outcomes [6]. Indeed, there is wide consensus about the importance of several vitamins (vitamins A, B6, B9, B12, C, D and E), trace elements (zinc, iron, selenium and copper) and omega-3 long-chain polyunsaturated fatty acids (n-3 PUFA) for a well-functioning immune system [7]. As yet, these relationships are best documented for vitamin D and vitamin C [35]. Because deficiencies in vitamins and micronutrients are rarely isolated, but mostly in conjunction with general malnutrition and thus deficiencies in multiple nutrients, interpretation of studies regarding single compounds is challenging.

Vitamin D deficiencies in Switzerland

In Switzerland, there is a high number of patients with vitamin and micronutrient deficiencies, particularly among the elderly population. It has been estimated by the Swiss Federal Office of Public Health that large parts of the Swiss population have inadequate serum 25-hydroxy-vitamin D (25(OH)D) concentrations, particularly among the elderly, frail population. For example, a recent clinical multicentre study found that 60% of multimorbid medical inpatients had deficient vitamin D levels (<50 nmol/l) on admission and 25% were severely deficient (<25 nmol/l) [8]. In this study, vitamin D deficiency was associated with a 30% increase in mortality risk in a statistical regression model adjusted for demographics and comorbidities. Similar to other observational studies, however, the study could not allow causal inference and thus provide proof that supplementation with vitamin D would be effective in reducing excess mortality in patients with deficient levels. Several other studies have also confirmed that the vitamin D status of the Swiss population is inadequate for vulnerable populations groups (e.g., pregnant women, older adults, multimorbid patients), particularly during the winter season. For other vitamins and micronutrients, intake and levels in the general population have not been studied extensively recently.

Evidence from observational trials

In light of their important role regarding immune function, deficient levels of specific vitamins and micronutrients may increase the risk of acquiring an infection and of adverse outcome among infected patients. Most research looking at associations of vitamin and micronutrient deficiencies and clinical outcome was done in the years before COVID-19; however, today there are also several studies investigating levels of vitamins, mainly vitamins D and C, in COVID-19 patients. Table 1 provides an overview of currently published observational studies (upper part of the table) on the association of vitamin and micronutrient deficiencies and clinical outcomes in the population of patients with COVID-19. These studies, from several countries, suggest that for COVID-19 such associations are also present, particularly for vitamins D and C, although there is some heterogeneity among studies and some studies have not reported significant findings. This heterogeneity may be due to various reasons including differences in patient populations, differences in analytical methods, low number of patients in some studies (resulting in low power) and differences in outcomes assessed. As an important limitation of all observational research, levels of vitamins and micronutrients are strongly correlated with age, malnutrition and burden of chronic illnesses, and confounding is a major issue in this type of observational research.

Table 1

Overview of recent trials investigating the role of vitamins and other micronutrients in patients with COVID-19.

First author [Reference]Study designSample sizeLocationInvestigated nutrientInterventionTreatment outcome
Arvinte [9]Observational21USAVitamin C and vitamin DNone↓serum levels of vitamin C and vitamin D in most critically ill patients. Older age and ↓vitamin C level appeared co-dependent risk factors for mortality
Ling [10]Observational444UKVitamin DNoneCholecalciferol booster therapy was associated with a reduced risk of COVID-19 mortality
Mendy [11]Observational689USAVitamin DNoneVitamin D deficiency was associated with hospitalisation and/or disease severity
Merzon [12]Observational782IsraelVitamin DNoneLow plasma 25(OH)D levels appeared to be an independent risk factor for COVID-19 infection and hospitalisation
Raisi-Estabragh [13]Observational1326UKVitamin DNoneNo important relation between the 25(OH)D status adjusted for the season and COVID-19 positivity
Chiscano-Camon [14]Observational18SpainVitamin CNoneUndetectable vitamin C in more than 90% of the patients with ARDS
Hastie [15]Observational449UKVitamin DNoneNo potential link between vitamin D concentrations and risk of COVID-19 infection
Carpagnano [16]Observational42ItalyVitamin DNoneSignificantly greater mortality risk due to COVID-19 in patients with severe vitamin D deficiency
Fasano [17]Observational105ItalyVitamin DNoneCOVID-19 patients were more likely to be vitamin D non-supplemented than unaffected patients
Tan [18]Observational43SingaporeVitamin D, magnesium, vitamin B12NoneA vitamin D / magnesium / vitamin B12 combination in older COVID-19 patients was associated with a significant reduction in the proportion of patients with clinical deterioration requiring oxygen
Jamali Moghadam Siahkali [19]Randomised controlled trial60IranVitamin C1.5 g vitamin C intravenously every 6 h for 5 days vs placeboNo significantly better outcomes in high-dose vitamin C treated patients
Zhang [20]Randomised controlled trial54ChinaVitamin CHigh-dose intravenous (24 g/d) vitamin C vs. placeboNo change in ventilation-free days; ↑PaO2/FiO2; ↓interleukin-6; ↓28-day mortality in patients with SOFA scores ≥3
Thomas [21]Randomised-controlled trial214USAVitamin C and zinc10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents or standard of careNo difference in the duration of symptoms among the four groups
Entrenas Castillo [22]Randomised-controlled trial76SpainVitamin DOral calcifediol at an initial dose of 0.532 mg, followed by 0.266 mg on days 3 and 7, and then weeklyAdministration of a high dose of calcifediol or 25(OH)D significantly reduced the need of hospitalisation in patients with COVID-19
Murai [23]Randomised-controlled trial240BrazilVitamin DSingle oral dose of 200,000 IU of vitamin D3 vs placeboA single high dose of vitamin D3 did not significantly reduce hospital length of stay compared with placebo

25(OH)D = 25-hydroxy vitamin D; ARDS = acute respiratory distress syndrome; PaO2/FiO2 = ratio of arterial oxygen partial pressure to fractional inspired oxygen

Evidence from treatment trials

Clearly, observational studies are prone to bias, and interventional research is needed to understand clinical effects of vitamins and micronutrients – including the effect size and potential side effects. Among the different vitamins and micronutrients discussed, vitamin D and vitamin C had been studied most extensively regarding their role in the management of respiratory tract infections in the years before COVID-19 and generated the strongest evidence regarding efficacy and safety. A Cochrane meta-analysis focusing on the role of oral vitamin C for the prevention and treatment of common colds, which was updated in 2020 with a total of 30 randomised and nonrandomised trials, reported no consistent effect of daily supplementation with vitamin C in large doses to prevent colds, but modest benefits in reducing duration of cold symptoms [24]. The effect was more consistent in subjects on continuous supplementation and in those performing strenuous exercise. For vitamin D, a very recent updated systematic review and meta-analysis of individual participant data in 2021 investigated the effects of supplementation to prevent acute respiratory tract infections based on 43 eligible randomised controlled trials and a total of 48,488 participants [25]. According to the analysis, vitamin D supplementation reduced the relative risk of acute respiratory tract infection by about 8% (61.3% vs 62.3%) with the strongest effects in patients receiving daily or weekly boluses. There is also interventional research showing that a nutritional support strategy including micronutrients among other reduces adverse outcomes and mortality among malnourished patients [26], but it remains unclear whether micronutrients or support with protein and calories was the main driver of effects.

Most importantly, a number of randomised controlled trials have recently investigated effects of vitamin C and vitamin D supplementation and/or treatment on the risk for COVID-19 infection, as well as treatment courses of infected patients (table 1, lower part). These trials, however, ranging from 54 to 240 patients, did not report significant benefits except for one very small Spanish pilot study [22]. This parallel pilot randomised open-label, double-masked clinical trial found significant differences in the risk for intensive care unit (ICU) admission of patients receiving vitamin D vs not receiving vitamin D (50% vs 2%). None of these trials selected patients with deficient vitamin D levels before beginning the supplementation, the group of patients most likely to benefit from treatment.

Clearly, there are today insufficient data from randomised trials regarding the clinical benefits of vitamin and micronutrient supplementation overall, and more specifically regarding COVID-19. Importantly, however, when looking at the trial registration database (https://clinicaltrials.gov/), there is a high number of registered trials currently planned or ongoing (table 2), which will likely improve our understanding of the role of vitamins and micronutrients in the near future and provide more definite evidence regarding clinical benefits.

Table 2

Registered trials evaluating the possible role of vitamin D and other micronutrients in the COVID-19 pandemic.

Trial IDTitleStatusStudy designPlanned timeframeLocation
Vitamin D
NCT04386044Investigating the Role of Vitamin D in the Morbidity of COVID-19 PatientsNot yet recruitingObservational trial2020–2021UK
NCT04628000Baseline Vitamin D Deficiency and COVID-19 Disease SeverityRecruitingObservational trial2020–2022USA
NCT04482673Vitamin D Supplementation in the Prevention and Mitigation of COVID-19 InfectionRecruitingInterventional randomised clinical trial2020–2021USA
NCT04407286Vitamin D Testing and Treatment for COVID 19CompletedInterventional clinical trial2020USA
NCT04535791Efficacy of Vitamin D Supplementation to Prevent the Risk of Acquiring COVID-19 in Healthcare WorkersRecruitingInterventional randomised clinical trial2020–2021Mexico
NCT04738760Clinical Outcomes of High Dose Vitamin D Versus Standard Dose in COVID-19 Egyptian PatientsRecruitingObservational trial2020–2021Egypt
NCT04449718Vitamin D Supplementation in Patients With COVID-19CompletedInterventional randomised clinical trial2020Brazil
NCT04370808VITACOV: Vitamin D Polymorphisms and Severity of COVID-19 InfectionNot yet recruitingObservational trial2020–2021Portugal
NCT04403932Increased Risk of Severe Coronavirus Disease 2019 in Patients With Vitamin D DeficiencyCompletedObservational trial2020Spain
NCT04483635PRevention of COVID-19 With Oral Vitamin D Supplemental Therapy in Essential healthCare TeamsRecruitingInterventional randomised clinical trial2021Canada
NCT04363840The LEAD COVID-19 Trial: Low-risk, Early Aspirin and Vitamin D to Reduce COVID-19 HospitalizationsNot yet recruitingInterventional randomised clinical trial2020 
NCT04536298Vitamin D and COVID-19 TrialRecruitingInterventional randomised clinical trial2020–2021USA
NCT04793243Vitamin D3 Levels in COVID-19 Outpatients From Western MexicoCompletedInterventional randomised clinical trial2020Mexico
NCT04487951N-terminal Pro B-type Natriuretic Peptide and Vitamin D Levels as Prognostic Markers in COVID-19 PneumoniaRecruitingObservational trial2020–2021Egypt
NCT04334005Vitamin D on Prevention and Treatment of COVID-19Not yet recruitingInterventional randomised clinical trial2020Spain
NCT04525820High Dose Vitamin-D Substitution in Patients With COVID-19: a Randomized Controlled, Multi Center StudyRecruitingInterventional randomised clinical trial2020–2021Switzerland
NCT04709744Impact of Vitamin D Level and Supplement on SLE Patients During COVID-19 PandemicCompletedObservational trial2020Egypt
NCT04636086Effect of Vitamin D on Hospitalized Adults With COVID-19 InfectionRecruitingInterventional randomised clinical trial2020–2021Belgium
NCT04385940Vitamin D and COVID-19 ManagementNot yet recruitingInterventional randomised clinical trial2020 
NCT04459247Short Term, High Dose Vitamin D Supplementation for COVID-19Active, not recruitingInterventional randomised clinical trial2020India
NCT04519034Vitamin D Status and Immune-inflammatory Status in Different UK Populations With COVID-19 InfectionNot yet recruitingObservational trial2020UK
NCT03188796The VITDALIZE Study: Effect of High-dose Vitamin D3 on 28-day Mortality in Adult Critically Ill PatientsRecruitingInterventional randomised clinical trialOctober 10, 2017Austria, Belgium
NCT04733625The Effect of Vitamin D Therapy on Morbidity and Mortality in Patients With SARS-CoV 2 InfectionCompletedInterventional randomised clinical trial2020Egypt
NCT04394390Do Vitamin D Levels Really Correlated With Disease Severity in COVID-19 Patients?Enrolling by invitationObservational trial2020Turkey
NCT04579640Trial of Vitamin D to Reduce Risk and Severity of COVID-19 and Other Acute Respiratory InfectionsActive, not recruitingInterventional randomised clinical trial2020–2021UK
NCT04344041COvid-19 and Vitamin D Supplementation: a Multicenter Randomized Controlled Trial of High Dose Versus Standard Dose Vitamin D3 in High-risk COVID-19 Patients (CoVitTrial)RecruitingInterventional randomised clinical trial2020–2021France
NCT04435119Covid-19 and Vitamin D in Nursing-homeCompletedObservational trial2020France
NCT04411446Cholecalciferol to Improve the Outcomes of COVID-19 PatientsRecruitingInterventional randomised clinical trial2020Argentina
NCT04552951Effect of Vitamin D on Morbidity and Mortality of the COVID-19RecruitingInterventional randomised clinical trial2020Spain
NCT04621058Efficacy of Vitamin D Treatment in Mortality Reduction Due to COVID-19.RecruitingInterventional randomised clinical trial2020–2021Spain
NCT04476680Reducing Asymptomatic Infection With Vitamin D in Coronavirus DiseaseNot yet recruitingInterventional randomised clinical trial2020–2021UK
NCT04476745The Effect of D3 on Selected Cytokines Involved in Cytokine Storm in the Covid-19 Uninfected Jordanian PeopleEnrolling by invitationInterventional randomised clinical trial2020–2021Jordan
NCT04386850Oral 25-hydroxyvitamin D3 and COVID-19RecruitingInterventional randomised clinical trial2020–2021Iran
Vitamin C
NCT04401150Lessening Organ Dysfunction With VITamin C - COVID-19RecruitingInterventional randomised clinical trial2020–2022Canada
NCT04664010Efficacy and Safety of High-dose Vitamin C Combined With Chinese Medicine Against Coronavirus Pneumonia (COVID-19)Active, not recruitingInterventional randomised clinical trial2020–2021China
NCT04530539The Effect of Melatonin and Vitamin C on COVID-19RecruitingInterventional randomised clinical trial2020–2021USA
NCT04363216Pharmacologic Ascorbic Acid as an Activator of Lymphocyte Signaling for COVID-19 TreatmentNot yet recruitingInterventional randomised clinical trial2020–2021 
NCT04710329High-Dose Vitamin C Treatment in Critically Ill COVID-19 PatientsCompletedObservational trial2021Turkey
NCT04357782Administration of Intravenous Vitamin C in Novel Coronavirus Infection (COVID-19) and Decreased OxygenationCompletedInterventional clinical trial2020USA
NCT04323514Use of Ascorbic Acid in Patients With COVID 19RecruitingInterventional clinical trial2020–2021Italy
NCT04682574Role of Mega Dose of Vitamin C in Critical COVID-19 PatientsRecruitingInterventional randomised clinical trial2020–2021Pakistan
NCT04344184SAFEty Study of Early Infusion of Vitamin C for Treatment of Novel Coronavirus Acute Lung Injury (SAFE EVICT CORONA-ALI)RecruitingInterventional randomised clinical trial2020–2021USA
Zinc     
NCT04542993Can SARS-CoV-2 Viral Load and COVID-19 Disease Severity be Reduced by Resveratrol-assisted Zinc TherapyActive, not recruitingInterventional randomised clinical trial2020–2022USA
NCT04621461Placebo Controlled Trial to Evaluate Zinc for the Treatment of COVID-19 in the Outpatient SettingCompletedInterventional randomised clinical trial2020–2021USA
NCT04551339Zinc Versus Multivitamin Micronutrient Supplementation in the Setting of COVID-19Enrolling by invitationInterventional randomised clinical trial2020–2021USA
Omega-3
NCT04647604Resolving Inflammatory Storm in COVID-19 Patients by Omega-3 Polyunsaturated Fatty Acids -RecruitingInterventional randomised clinical trial2020–2021Sweden
NCT04553705Omega-3, Nigella Sativa, Indian Costus, Quinine, Anise Seed, Deglycyrrhizinated Licorice, Artemisinin, Febrifugine on Immunity of Patients With (COVID-19)RecruitingInterventional randomised clinical trial2020Saudi Arabia
NCT04483271The Effect of Omega-3 on Selected Cytokines Involved in Cytokine StormEnrolling by invitationInterventional randomised clinical trial2020–2021Jordan
Different nutrients
NCT04641195Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in IndiaNot yet recruitingInterventional randomised clinical trial2021–2022India
NCT04407572Evaluation of the Relationship Between Zinc Vitamin D and b12 Levels in the Covid-19 Positive Pregnant WomenCompletedObservational trial2020Turkey
NCT04335084A Study of Hydroxychloroquine, Vitamin C, Vitamin D, and Zinc for the Prevention of COVID-19 InfectionRecruitingInterventional randomised clinical trial2020–2021USA
NCT04395768International ALLIANCE Study of Therapies to Prevent Progression of COVID-19RecruitingInterventional randomised clinical trial2020–2021Australia
NCT04780061Dietary Supplements for COVID-19Not yet recruitingInterventional randomised clinical trialJul 05Canada
NCT04468139The Study of Quadruple Therapy Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected With COVID-19RecruitingInterventional clinical trial2020Saudi Arabia
NCT04558424RCT, Double Blind, Placebo to Evaluate the Effect of Zinc and Ascorbic Acid Supplementation in COVID-19 Positive Hospitalized Patients in BSMMUNot yet recruitingInterventional randomised clinical trial2020–2021Bangladesh
NCT04342728Coronavirus 2019 (COVID-19)- Using Ascorbic Acid and Zinc SupplementationCompletedInterventional randomised clinical trial2020–2021USA

Conclusions and implications for patient care

Before answering the question regarding usefulness of supplementation of the population during a pandemic with vitamins and micronutrients as a public health strategy to reduce COVID-19 associated morbidity, it is important to define the level of evidence that is needed.Although there is evidence from preclinical and observational studies linking different vitamins and micronutrients to a well-functioning immune system, interventional research has been rather disappointing and/or lacking. A major problem is the fact that previous trials did not select patients according to the degree of deficiency, and a beneficial effect of supplementation in a person with normal or high levels cannot necessarily be expected. One could argue that it is reasonable to select an entire group of subjects at risk for acquiring severe COVID-19 for supplementation without knowing their level of deficiency, even if only those with deficiency would benefit – particularly if supplementation does not cause harm and is at low treatment cost. Many physicians would follow such a pragmatic view, whereas others prefer a more puristical attitude and would like to wait for more solid trial-based evidence. This dilemma cannot be resolved at the present time. It is not uncommon for public health measures that recommendations are based mainly on observational studies instead of randomised controlled trials, as such trials are challenging, expensive and time consuming. Examples are the recommended reduction of dietary salt or of added sugar. Such a strategy makes sense if most of the experimental and observational evidence points toward a beneficial effect, show little or no risk, low cost, and randomised intervention trials are not feasible in free-living populations. Such a strategy may also be appropriate during times of a pandemic where time is most precious.

The strongest evidence today is available for vitamin D, with large and high quality trials and meta-analyses from such trials proving effectiveness for prevention of respiratory infections, particularly in patients with deficient levels, receiving daily or weekly boluses. Whether these effects remain true for COVID-19 is currently uncertain. There is no evidence for harm when using vitamin D in doses up to 2000 units per day. For larger doses, however, an increase in falls and other adverse outcomes is possible. Importantly, a significant proportion of elderly patients in Switzerland and other countries do have deficient levels. And this group of subjects is also the one with the highest risk for a severe course of COVID-19.

One (theoretical) concern with improving immune function through supplementation of vitamins and micronutrients is a possible overstimulation of the inflammatory response, which has been shown to be a main driver for COVID-associated pneumonitis and associated mortality and morbidity. There is today, however, no data suggesting that micronutrients and vitamins would do any harm in COVID-19. Importantly, there are many trials currently planned and ongoing, which will increase our current understanding of the role of vitamins and micronutrients for prevention and treatment of COVID-19. Pending results of such trials, it would seem premature to strongly recommend multiple supplementations of high doses of different micronutrients and vitamins to the overall population. For vitamin D, however, the currently recommended supplementation of 800 units per day for the vulnerable population should be underscored, based on possible beneficial effect on COVID-19, besides its proven effects on bone and muscle. Such a recommendation has clearly more upsides than downsides and may alleviate the heavy burden of this devastating disease [27]. In addition, it is time to conduct high-quality trials to better understand whether and which supplementation for which group of subjects is indeed effective in improving immune defence and thereby lowering the burden of COVID-19. Specifically, this includes observational studies looking at the level of different vitamins and micronutrients in different populations to better understand at-risk groups, as well as interventional research to understand which vitamins and micronutrients (in what doses) provide most benefits. Only time will tell whether early implementation of such a public health strategy, as promoted by Berger and colleagues [6], will in the end save lives, and to what costs.

Potential competing interests

PS reports grants from Nestle Health Science, Abbott Nutrition, bioMerieux, Thermofisher and Roche Diagnostics (all paid to the Institution). CG and UK report no conflicts of interest.

Credits

Header image: © Merlin7125 | Dreamstime.com

Correspondence

Prof. Philipp Schuetz, MD, MPH, Department of Internal Medicine, Kantonsspital Aarau, Tellstrasse H7, CH-5001 Aarau, Philipp.Schuetz[at]unibas.ch

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