








key: cord-329321-usqjkj89
authors: Chakhtoura, M.; Napoli, N.; Fuleihan, G. El Hajj
title: Myths and Facts on Vitamin D Amidst the COVID-19 Pandemic()
date: 2020-05-26
journal: Metabolism
DOI: 10.1016/j.metabol.2020.154276
sha: 
doc_id: 329321
cord_uid: usqjkj89

nan

Covid-SARS-2 pandemic has struck and spread at light speed, reaching 6 continents within 3 months, transforming our societies globally [1] . In less than 6 months numbers rose exponentially to 5,159,674 cases and 335,4186 fatalities (6.5%); a third roughly are in the US (May 22, 2020) [2] . Disease severity and mortality rates are higher in the elderly, African Americans, patients with diabetes mellitus, chronic lung and cardiovascular diseases [3, 4] , all groups with low vitamin D levels. Should we supplement patients with vitamin D? We examine the biological plausibility and evidence for a role of vitamin D in COVID-19 patients, and provide a framework for guidance on supplementation, based on a rigorous and systematic approach. We interrogated the Systematic Reviews database Epistemonikos, and four medical databases including Cochrane.

The beneficial role of the sunshine vitamin on musculoskeletal health is undisputed. Vitamin D insufficiency, a serum 25-Hydroxy vitamin D [25(OH)D] between 20-50 nmol/L (8-20 ng/ml), causes calcium malabsorption, secondary hyperparathyroidism, accelerated bone loss, osteoporosis and fractures in adults [5] . Deficiency, a serum 25(OH)D < 20 nmol/L, decreases the serum calcium-phosphate product, and leads to rickets in children and osteomalacia in adults [5] . Both can be prevented with daily supplements of 400-800IU of vitamin D, provided calcium intake is adequate. In elderly or institutionalized subjects, vitamin D at doses of 800-2,000 IU/day, co-administered with calcium, reduces the risk of hip fractures by 15-30%, and of other non-vertebral fractures by 20% [5] [6] [7] . These doses are within ranges recommended by major organizations pre-COVID times.

Ecological studies suggest that high latitudes (>+30ºN), and winter season, risk factors for low vitamin D, are associated with higher mortality rates in COVID-19 infections [8] [9] . Several exceptions exist and are likely explained by other contributing factors such as population age, density and ethnicity, lifestyle factors, and social distancing measures [10] . Obesity is a risk factor to all non-communicable diseases, and an increasing number of reports identify obesity as a risk factor for COVID-19 related morbidity and mortality [11] [12] . However, although BMI is a known predictor of vitamin D status [13] [14] [15] , hypovitaminosis D in this population may be explained by poor lifestyle habits, vitamin D sequestration in adipose tissue, and altered metabolism [16] . Retrospective case-control studies reveal inverse associations between serum 25(OH)D level and the risk of COVID -19 infection or severity. They all suffer from major limitations [17] [18] [19] [20] . Two are non-peer-reviewed papers [17, 20] . In the case of UK biobank studies samples were collected in 2006-2010 [17, 18] , while studies from Switzerland and Belgium did not characterize controls, nor adjusted for other predictors [19, 20] . Clear support for causality between serum 25(OH)D levels and COVID-19 therefore remains elusive.

Hypovitaminosis D increases the risk for viral respiratory infections [21] . The most feared complications, in a report of over 46,000 COVID-19 patients, were bilateral pneumonias (76%), acute respiratory distress syndrome (ARDS) with ICU admissions (29%), and multi-organ failure (8.5%) [22] .

of the viral infection [23] . SARS-CoV-2, infects respiratory epithelial cells through the ACE2 receptor, triggers pyroptosis, the release of pro-inflammatory cytokines such as IL6, and chemokines. These attract monocytes, macrophages, and T cells, the latter producing IFNγ further contributing to inflammation. In an immune-compromised host, this progresses to the cytokine storm, which coupled with the production of non-neutralizing antibodies by B cells, leads to further organ damage [23] . Vitamin D modulates innate and adaptive immunity, through the Vitamin D Receptor (VDR) and CYP27B1, the enzyme converting it to the active metabolite calcitriol, both of which are expressed in immune cells [23] [24] [25] . The effect of vitamin D on immunity and viral respiratory diseases has been tested. Vitamin D metabolites do not consistently influence replication or clearance of respiratory viruses, nor antibody titers to vaccination, but they decrease the expression of cytokines induced by the viral infection, including IL6, TNF-α and IFN-β [26] [27] [28] . Other anti-inflammatory effects of vitamin D include modulation of macrophage chemotactic protein1, interleukin 8, type 1 interferon, TNFα and lowering of oxygen reactive species [26, 29] . The efficacy of vitamin D trials in patients with influenza infections is not well established [25, 27, 28] . Prevention trials, mostly conducted in the pediatric age group, are negative [28, [30] [31] [32] [33] [34] [35] [36] [37] . However, two systematic reviews of controlled trials showed promising results. The first investigating the effectiveness of vitamin D in the prevention or treatment of infectious diseases reported that the strongest evidence was in reducing the risk of acute respiratory illness and influenza [38] . More recently, an individual patient meta-analysis of 25 trials, of over 11,000 participants, showed vitamin D supplementation to reduce the risk of acute respiratory infections, including viral, by 12% in all participants. This effect was noted with daily or weekly doses (by 19%), but not bolus doses, and was most pronounced in patients with serum 25(OH)D levels below 50 nmol/L (20 ng/ml) [39] . The evidence from trials in critically ill patients is also mixed. Vitamin D had no significant effects on mortality, ventilation, or length to stay in one meta-analysis [40] , while it was associated with a 30% reduction in mortality compared to placebo, in another [41] . Finally, the most recent randomized trial of 1,360 ICU patients reported that early administration of 540,000 IU of vitamin D3 did not improve 90 day mortality [42] . Differences in inclusion criteria, diseases treated, baseline 25(OH)D levels, and regimens used (doses, regimens, and formulations), in trials included in these 2 meta-analyses may explain opposing results.

J o u r n a l P r e -p r o o f (NCRC) on pharmaceutical interventions [43] , WHO primary trial registries [44] , and ClinicalTrials.Gov What are optimal doses of the sunshine vitamin in COVID-19 times? Vitamin D3 supplementation, daily or weekly, at daily equivalent doses of 1,000-4,000 IU, is advisable. The wide range targets a desirable 25 (OH) > 75 nmol/L (30 ng/ml). Both accommodate the anticipated higher needs across the lifespan incurred by lockdown measures, immobilization, and hospitalization. They also allow flexibility in tailoring doses to individual needs, factoring in considerations such as prevention or treatment, baseline risks, COVID-19 status and health care settings. Importantly, our approach is anchored in abundant safety data across the life course [6] , not exceeding the upper tolerable level [46] . It is based on clear evidence for efficacy in fracture risk reduction and possibly falls in institutionalized individuals [7] , an important consideration in frail COVID-19 patients. It is also well aligned with recommendations from the Center for Evidence Based Medicine [47] . Alternative guidance has been proposed. Preventive doses of vitamin D3 of 10,000 IU/d for 4 weeks followed by 5,000 IU/day to reach a target 25(OH)D level of 100-150 nmol/L [24] , and treatment doses >6,000 IU/day in deficient individuals to reach a similar level and reduce disease progression [48] , are suggested. The former is based on a publication on the role of vitamin D in influenza and pneumonia, and a target level associated with a reduction in viral respiratory infections in one observational study [24] . The latter is based on indirect evidence derived from a single study in tuberculosis patients [48] . However, loading doses do not seem to have added beneficial effect on acute respiratory infections [39] , may adversely affect fall and fracture outcomes [49, 50] , and possibly other COVID-19 respiratory outcomes. Major gaps are to be 

References 17 and 20 are from pre-print, non-peer reviewed papers. They were not used as evidence to derive specific guidance in this commentary

Covid-19 -Navigating the Uncharted

COVID-19 and African Americans

Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) -United States

Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions

Serum 25-Hydroxyvitamin D levels: Variability, Knowledge Gaps, and the Concept of a Desirable Range

Impact of vitamin D supplementation on falls and fractures-A critical appraisal of the quality of the evidence and an overview of the available guidelines

The Role of Vitamin D in the Prevention of Coronavirus Disease

Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity

Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North-supports vitamin D as a factor determining severity. Authors' reply

Severe obesity is associated with higher in-hospital mortality in a cohort of patients with COVID-19 in the

High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation. Obesity (Silver Spring)

Vitamin D-endocrine system

Body Mass Index, Vitamin D, and Type 2 Diabetes: A Systematic Review and Meta-Analysis

Obesity and vitamin D deficiency: a systematic review and meta-analysis

Vitamin D supplementation in obesity and during weight loss: A review of randomized controlled trials

Vitamin D status, body mass index, ethnicity and COVID-19: Initial analysis of the first-reported UK Biobank COVID-19 positive cases (n 580) compared with negative controls

Vitamin D concentrations and COVID-19 infection in UK Biobank

25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2

Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics

Acute Respiratory Tract Infection and 25-Hydroxyvitamin D Concentration: A Systematic Review and Meta-Analysis

Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: A systematic review and meta-analysis

The trinity of COVID-19: immunity, inflammation and intervention

Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths

Vitamin D and Influenza. Advances in Nutrition

Modulation of the immune response to respiratory viruses by vitamin D

Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state

Vitamin D and Influenza-Prevention or Therapy?

The Impact of Vitamin D Levels on Inflammatory Status: A Systematic Review of Immune Cell Studies

Impact of Vitamin D Supplementation on Influenza Vaccine Response and Immune Functions in Deficient Elderly Persons: A Randomized Placebo-Controlled Trial

Effect of Vitamin D supplementation to reduce respiratory infections in children and adolescents in Vietnam: A randomized controlled trial. Influenza Other Respir Viruses

Preventive Effects of Vitamin D on Seasonal Influenza A in Infants: A Multicenter, Randomized, Open, Controlled Clinical Trial

Effect of High-Dose vs Standard-Dose Wintertime Vitamin D Supplementation on Viral Upper Respiratory Tract Infections in Young Healthy Children

Impact of vitamin D administration on immunogenicity of trivalent inactivated influenza vaccine in previously unvaccinated children

Effects of vitamin D supplements on influenza A illness during the 2009 H1N1 pandemic: a randomized controlled trial

Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren

Calcitriol (1,25-dihydroxy-vitamin D3) coadministered with influenza vaccine does not enhance humoral immunity in human volunteers

Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Vitamin D supplementation in the critically ill: A systematic review and meta-analysis

Vitamin D and outcomes in adult critically ill patients. A systematic review and meta-analysis of randomized trials

The National Heart L, and Blood Institute PETAL Clinical Trials Network. Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients

Primary Registries in the WHO Registry Network

The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know

Perspective: improving vitamin D status in the management of COVID-19

Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial

Monthly High-Dose Vitamin D Treatment for the Prevention of Functional Decline: A Randomized Clinical Trial



