Commentary: Myths and facts on vitamin D amidst the COVID-19 pandemic

Abstract

“It is not the Answer that Enlightens but the Question.”Eugene Ionescu COVID-SARS-2 pandemic has struck and spread at light speed, reaching 6 continents within 3 months, transforming our societies globally [[1]Fauci A.S. Lane H.C. Redfield R.R. Covid-19 - navigating the uncharted.N Engl J Med. 2020; 382: 1268-1269Crossref PubMed Scopus (969) Google Scholar]. In <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]COVID-19 dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU).https://coronavirus.jhu.edu/map.htmlDate accessed: May 22, 2020Google Scholar]. Disease severity and mortality rates are higher in the elderly, African Americans, patients with diabetes mellitus, chronic lung and cardiovascular diseases [[3]Yancy C.W. COVID-19 and African Americans.JAMA. Apr 15 2020; https://doi.org/10.1001/jama.2020.6548. Online ahead of printCrossref PubMed Google Scholar,[4]CDC COVID-19 Response Team Severe outcomes among patients with coronavirus disease 2019 (COVID-19) - United States, February 12–March 16, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 343-346Crossref PubMed Scopus (1322) Google Scholar], 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 and 50 nmol/L (8–20 ng/mL), causes calcium malabsorption, secondary hyperparathyroidism, accelerated bone loss, osteoporosis and fractures in adults [[5]Bouillon R. Marcocci C. Carmeliet G. Bikle D. White J.H. Dawson-Hughes B. et al.Skeletal and Extraskeletal actions of vitamin D: current evidence and outstanding questions.Endocr Rev. 2019; 40: 1109-1151Crossref PubMed Scopus (394) Google Scholar]. 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]Bouillon R. Marcocci C. Carmeliet G. Bikle D. White J.H. Dawson-Hughes B. et al.Skeletal and Extraskeletal actions of vitamin D: current evidence and outstanding questions.Endocr Rev. 2019; 40: 1109-1151Crossref PubMed Scopus (394) Google Scholar]. Both can be prevented with daily supplements of 400–800 IU of vitamin D, provided calcium intake is adequate. In elderly or institutionalized subjects, vitamin D at doses of 800–2000 IU/day, co-administered with calcium, reduces the risk of hip fractures by 15–30%, and of other non-vertebral fractures by 20% [5Bouillon R. Marcocci C. Carmeliet G. Bikle D. White J.H. Dawson-Hughes B. et al.Skeletal and Extraskeletal actions of vitamin D: current evidence and outstanding questions.Endocr Rev. 2019; 40: 1109-1151Crossref PubMed Scopus (394) Google Scholar, 6El-Hajj Fuleihan G. Bouillon R. Clarke B. Chakhtoura M. Cooper C. McClung M. et al.Serum 25-hydroxyvitamin D levels: variability, knowledge gaps, and the concept of a desirable range.J Bone Miner Res. 2015; 30: 1119-1133Crossref PubMed Scopus (130) Google Scholar, 7Chakhtoura M. Chamoun N. Rahme M. El-Hajj Fuleihan G. 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.Bone. 2020; 131: 115112Crossref PubMed Scopus (13) Google Scholar]. These doses are within ranges recommended by major organizations pre-COVID times. Ecological studies suggest that high latitudes (>+30°N), and winter season, risk factors for low vitamin D, are associated with higher mortality rates in COVID-19 infections [[8]Ilie P.C. Stefanescu S. Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.Aging Clin Exp Res. May 6 2020; ([online ahead of print]): 1-4https://doi.org/10.1007/s40520-020-01570-8Crossref PubMed Scopus (445) Google Scholar,[9]Rhodes J.M. Subramanian S. Laird E. Kenny R.A. Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity.Aliment Pharmacol Ther. Apr 20 2020; https://doi.org/10.1111/apt.15777. Online ahead of printCrossref Google Scholar]. 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]Garg M. Al-Ani A. Mitchell H. Hendy P. Christensen B. 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.Aliment Pharmacol Ther. Apr 30 2020; https://doi.org/10.1111/apt.15796. Online ahead of printCrossref Google Scholar]. 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]Palaiodimos L. Kokkinidis D.G. Li W. Karamanis D. Ognibene J. Arora S. et al.Severe obesity is associated with higher in-hospital mortality in a cohort of patients with COVID-19 in the Bronx, New York.Metabolism. 2020; 108: 154262Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar,[12]Simonnet A. Chetboun M. Poissy J. Raverdy V. Noulette J. Duhamel A. et al.High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation.Obesity (Silver Spring). Apr 9 2020; ([online ahead of print])https://doi.org/10.1002/oby.22831Crossref PubMed Scopus (1168) Google Scholar]. However, although BMI is a known predictor of vitamin D status [13Bell N.H. Vitamin D-endocrine system.J Clin Invest. 1985; 76: 1-6Crossref PubMed Scopus (96) Google Scholar, 14Rafiq S. Jeppesen P.B. Body mass index, vitamin D, and type 2 diabetes: a systematic review and meta-analysis.Nutrients. 2018; 10Crossref Scopus (61) Google Scholar, 15Pereira-Santos M. Costa P.R. Assis A.M. Santos C.A. Santos D.B. Obesity and vitamin D deficiency: a systematic review and meta-analysis.Obes Rev. 2015; 16: 341-349Crossref PubMed Scopus (481) Google Scholar], hypovitaminosis D in this population may be explained by poor lifestyle habits, vitamin D sequestration in adipose tissue, and altered metabolism [[16]Bassatne A. Chakhtoura M. Saad R. El-Hajj Fuleihan G. Vitamin D supplementation in obesity and during weight loss: a review of randomized controlled trials.Metabolism. 2019; 92: 193-205Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. 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 [17Darling A.L. Ahmadi K.R. Ward K.A. Harvey N.C. Alves A.C. Dunn-Waters D.K. et al.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 (n 723).MedRxiv. 2020; ([online ahead of print])https://doi.org/10.1101/2020.04.29.20084277Crossref Google Scholar, 18Hastie C.E. Mackay D.F. Ho F. Celis-Morales C.A. Katikireddi S.V. Niedzwiedz C.L. et al.Vitamin D concentrations and COVID-19 infection in UK Biobank.Diabetes Metab Syndr. 2020; 14: 561-565Crossref PubMed Scopus (300) Google Scholar, 19D’Avolio A. Avataneo V. Manca A. Cusato J. De Nicolò A. Lucchini R. et al.25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2.Nutrients. 2020; 12PubMed Google Scholar, 20De Smet D. De Smet K. Herroelen P. Gryspeerdt S. Martens G.A. Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics.MedRxiv. 2020; ([online ahead of print])https://doi.org/10.1101/2020.05.01.20079376Crossref Scopus (0) Google Scholar]. Two are non-peer-reviewed papers [[17]Darling A.L. Ahmadi K.R. Ward K.A. Harvey N.C. Alves A.C. Dunn-Waters D.K. et al.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 (n 723).MedRxiv. 2020; ([online ahead of print])https://doi.org/10.1101/2020.04.29.20084277Crossref Google Scholar,[20]De Smet D. De Smet K. Herroelen P. Gryspeerdt S. Martens G.A. Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics.MedRxiv. 2020; ([online ahead of print])https://doi.org/10.1101/2020.05.01.20079376Crossref Scopus (0) Google Scholar]. In the case of UK Biobank studies samples were collected in 2006–2010 [[17]Darling A.L. Ahmadi K.R. Ward K.A. Harvey N.C. Alves A.C. Dunn-Waters D.K. et al.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 (n 723).MedRxiv. 2020; ([online ahead of print])https://doi.org/10.1101/2020.04.29.20084277Crossref Google Scholar,[18]Hastie C.E. Mackay D.F. Ho F. Celis-Morales C.A. Katikireddi S.V. Niedzwiedz C.L. et al.Vitamin D concentrations and COVID-19 infection in UK Biobank.Diabetes Metab Syndr. 2020; 14: 561-565Crossref PubMed Scopus (300) Google Scholar], while studies from Switzerland and Belgium did not characterize controls, nor adjusted for other predictors [[19]D’Avolio A. Avataneo V. Manca A. Cusato J. De Nicolò A. Lucchini R. et al.25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2.Nutrients. 2020; 12PubMed Google Scholar,[20]De Smet D. De Smet K. Herroelen P. Gryspeerdt S. Martens G.A. Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics.MedRxiv. 2020; ([online ahead of print])https://doi.org/10.1101/2020.05.01.20079376Crossref Scopus (0) Google Scholar]. 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]Pham H. Rahman A. Majidi A. Waterhouse M. Neale R.E. Acute respiratory tract infection and 25-hydroxyvitamin D concentration: a systematic review and meta-analysis.Int J Environ Res Public Health. 2019; 16Crossref Scopus (69) Google Scholar]. 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]Cao Y. Liu X. Xiong L. Cai K. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: a systematic review and meta-analysis.J Med Virol. Apr 3 2020; ([online ahead of print])https://doi.org/10.1002/jmv.25822Crossref Scopus (210) Google Scholar]. They reflect an immune and inflammatory response, involving both T-cells and B-cells, to the acute phase of the viral infection [[23]Tay M.Z. Poh C.M. Rénia L. MacAry P.A. Ng L.F.P. The trinity of COVID-19: immunity, inflammation and intervention.Nat Rev Immunol. Apr 28 2020; ([online ahead of print])https://doi.org/10.1038/s41577-020-0311-8Crossref PubMed Scopus (2321) Google Scholar]. 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 IFN-γ 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]Tay M.Z. Poh C.M. Rénia L. MacAry P.A. Ng L.F.P. The trinity of COVID-19: immunity, inflammation and intervention.Nat Rev Immunol. Apr 28 2020; ([online ahead of print])https://doi.org/10.1038/s41577-020-0311-8Crossref PubMed Scopus (2321) Google Scholar]. 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 [23Tay M.Z. Poh C.M. Rénia L. MacAry P.A. Ng L.F.P. The trinity of COVID-19: immunity, inflammation and intervention.Nat Rev Immunol. Apr 28 2020; ([online ahead of print])https://doi.org/10.1038/s41577-020-0311-8Crossref PubMed Scopus (2321) Google Scholar, 24Grant W.B. Lahore H. McDonnell S.L. Baggerly C.A. French C.B. Aliano J.L. et al.Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.Nutrients. 2020; 12Crossref PubMed Scopus (1087) Google Scholar, 25Sundaram M.E. Coleman L.A. Vitamin D and influenza.Adv Nutr. 2012; 3: 517-525Crossref PubMed Scopus (53) Google Scholar]. 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 [26Greiller C.L. Martineau A.R. Modulation of the immune response to respiratory viruses by vitamin D.Nutrients. 2015; 7: 4240-4270Crossref PubMed Scopus (272) Google Scholar, 27Hansdottir S. Monick M.M. Lovan N. Powers L. Gerke A. Hunninghake G.W. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state.J Immunol. 2010; 184: 965-974Crossref PubMed Scopus (259) Google Scholar, 28Gruber-Bzura B.M. Vitamin D and influenza-prevention or therapy?.Int J Mol Sci. 2018; 19: 2419Crossref Scopus (128) Google Scholar]. Other anti-inflammatory effects of vitamin D include modulation of macrophage chemotactic protein1, interleukin 8, type 1 interferon, TNF-α and lowering of oxygen reactive species [[26]Greiller C.L. Martineau A.R. Modulation of the immune response to respiratory viruses by vitamin D.Nutrients. 2015; 7: 4240-4270Crossref PubMed Scopus (272) Google Scholar,[29]Calton E.K. Keane K.N. Newsholme P. Soares M.J. The impact of vitamin D levels on inflammatory status: a systematic review of immune cell studies.PLoS One. 2015; 10e0141770Crossref PubMed Scopus (226) Google Scholar]. The efficacy of vitamin D trials in patients with influenza infections is not well established [[25]Sundaram M.E. Coleman L.A. Vitamin D and influenza.Adv Nutr. 2012; 3: 517-525Crossref PubMed Scopus (53) Google Scholar,[27]Hansdottir S. Monick M.M. Lovan N. Powers L. Gerke A. Hunninghake G.W. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state.J Immunol. 2010; 184: 965-974Crossref PubMed Scopus (259) Google Scholar,[28]Gruber-Bzura B.M. Vitamin D and influenza-prevention or therapy?.Int J Mol Sci. 2018; 19: 2419Crossref Scopus (128) Google Scholar]. Prevention trials, mostly conducted in the pediatric age group, are negative [[28]Gruber-Bzura B.M. Vitamin D and influenza-prevention or therapy?.Int J Mol Sci. 2018; 19: 2419Crossref Scopus (128) Google Scholar,30Goncalves-Mendes N. Talvas J. Dualé C. Guttmann A. Corbin V. Marceau G. et al.Impact of vitamin D supplementation on influenza vaccine response and immune functions in deficient elderly persons: a randomized placebo-controlled trial.Front Immunol. 2019; 10: 65Crossref PubMed Scopus (80) Google Scholar, 31Loeb M. Dang A.D. Thiem V.D. Thanabalan V. Wang B. Nguyen N.B. et al.Effect of Vitamin D supplementation to reduce respiratory infections in children and adolescents in Vietnam: a randomized controlled trial.Influenza Other Respi Viruses. 2019; 13: 176-183Crossref PubMed Scopus (50) Google Scholar, 32Zhou J. Du J. Huang L. Wang Y. Shi Y. Lin H. Preventive effects of vitamin D on seasonal influenza A in infants: a multicenter, randomized, open, controlled clinical trial.Pediatr Infect Dis J. 2018; 37: 749-754Crossref PubMed Scopus (0) Google Scholar, 33Aglipay M. Birken C.S. Parkin P.C. Loeb M.B. Thorpe K. Chen Y. et al.Effect of high-dose vs standard-dose wintertime vitamin D supplementation on viral upper respiratory tract infections in young healthy children.JAMA. 2017; 318: 245-254Crossref PubMed Scopus (93) Google Scholar, 34Principi N. Marchisio P. Terranova L. Zampiero A. Baggi E. Daleno C. et al.Impact of vitamin D administration on immunogenicity of trivalent inactivated influenza vaccine in previously unvaccinated children.Hum Vaccin Immunother. 2013; 9: 969-974Crossref PubMed Scopus (36) Google Scholar, 35Urashima M. Mezawa H. Noya M. Camargo Jr., C.A. Effects of vitamin D supplements on influenza A illness during the 2009 H1N1 pandemic: a randomized controlled trial.Food Funct. 2014; 5: 2365-2370Crossref PubMed Google Scholar, 36Urashima M. Segawa T. Okazaki M. Kurihara M. Wada Y. Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren.Am J Clin Nutr. 2010; 91: 1255-1260Crossref PubMed Scopus (673) Google Scholar, 37Kriesel J.D. Spruance J. Calcitriol (1,25-dihydroxy-vitamin D3) coadministered with influenza vaccine does not enhance humoral immunity in human volunteers.Vaccine. 1999; 17: 1883-1888Crossref PubMed Scopus (60) Google Scholar]. 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]Yamshchikov A.V. Desai N.S. Blumberg H.M. Ziegler T.R. Tangpricha V. Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials.Endocr Pract. 2009; 15: 438-449Crossref PubMed Scopus (237) Google Scholar]. 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]Martineau A.R. Jolliffe D.A. Hooper R.L. Greenberg L. Aloia J.F. Bergman P. et al.Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.BMJ. 2017; 356: i6583Crossref PubMed Scopus (1116) Google Scholar]. 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]Langlois P.L. Szwec C. D’Aragon F. Heyland D.K. Manzanares W. Vitamin D supplementation in the critically ill: a systematic review and meta-analysis.Clin Nutr. 2018; 37: 1238-1246Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar], while it was associated with a 30% reduction in mortality compared to placebo, in another [[41]Putzu A. Belletti A. Cassina T. Clivio S. Monti G. Zangrillo A. et al.Vitamin D and outcomes in adult critically ill patients. A systematic review and meta-analysis of randomized trials.J Crit Care. 2017; 38: 109-114Crossref PubMed Scopus (72) Google Scholar]. Finally, the most recent randomized trial of 1360 ICU patients reported that early administration of 540,000 IU of vitamin D3 did not improve 90-day mortality [[42]The National Heart L, and Blood Institute PETAL Clinical Trials Network Early high-dose vitamin D3 for critically ill, vitamin D–deficient patients.N Engl J Med. 2019; 381: 2529-2540Crossref PubMed Scopus (130) Google Scholar]. 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. We screened the Cochrane database, the 2019 Novel Coronavirus Research Compendium (NCRC) on pharmaceutical interventions [[43]2019 Novel Coronavirus Research Compendium (NCRC).https://ncrc.jhsph.edu/Date accessed: May 22, 2020Google Scholar], WHO primary trial registries [[44]Primary registries in the WHO Registry Network.https://www.who.int/ictrp/network/primary/en/Date accessed: May 22, 2020Google Scholar], and ClinicalTrials.Gov [[45]ClinicalTrials.Gov Registry.https://clinicaltrials.gov/Date accessed: May 22, 2020Google Scholar], for vitamin D supplementation trials in COVID-19 individuals. None is completed yet. Eight identified trials aim at prevention or treatment and span 1–12 weeks. Two ongoing prevention trials evaluate the effect of vitamin D supplementation, alone (1600 IU on day 1 and 800 IU on days 2–5) or in combination with Zinc and Plaquenil (vitamin D dose not provided), on COVID-19 infection risk in health care providers, high risk, or institutionalized individuals. A third compares vitamin D3 1000 IU/day given for 2 months, to placebo, on both infection and complication rates. Three controlled trials explore the effect of vitamin D supplementation in COVID-19 positive patients on mortality, as a primary outcome, hospital complications, time to recovery and inflammatory markers, as secondary outcomes. The vitamin D arms consist of vitamin D (25,000 IU, single oral dose), the active vitamin D (Calcifediol 266 μg, 2 capsules day 1 and 1 capsule on days 3, 7, 14, 21, 28), or 2 vitamin D doses (400,000 IU or 50,000 IU in a single oral dose) compared to each other. One trial compares a vitamin D analogue (Ergocalciferol 1.25 μg daily) to vitamin D3 1000 IU daily, for 3 weeks, on symptoms recovery. One study investigates the efficacy of vitamin D 50,000 IU weekly for 2 weeks, with or without aspirin, in reducing the risk of hospitalization for COVID-19 patients. What are optimal doses of the sunshine vitamin in COVID-19 times? Vitamin D3 supplementation, daily or weekly, at daily equivalent doses of 1000–4000 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]El-Hajj Fuleihan G. Bouillon R. Clarke B. Chakhtoura M. Cooper C. McClung M. et al.Serum 25-hydroxyvitamin D levels: variability, knowledge gaps, and the concept of a desirable range.J Bone Miner Res. 2015; 30: 1119-1133Crossref PubMed Scopus (130) Google Scholar], not exceeding the upper tolerable level [[46]Ross A.C. Manson J.E. Abrams S.A. Aloia J.F. Brannon P.M. Clinton S.K. et al.The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know.J Clin Endocrinol Metab. 2011; 96: 53-58Crossref PubMed Scopus (2962) Google Scholar]. It is based on clear evidence for efficacy in fracture risk reduction and possibly falls in institutionalized individuals [[7]Chakhtoura M. Chamoun N. Rahme M. El-Hajj Fuleihan G. 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.Bone. 2020; 131: 115112Crossref PubMed Scopus (13) Google Scholar], an important consideration in frail COVID-19 patients. It is also well aligned with recommendations from the Center for Evidence Based Medicine [[47]Center for Evidence Based Medicine https://www.cebm.net/covid-19/vitamin-d-a-rapid-review-of-the-evidence-for-treatment-or-prevention-in-covid-19/Date accessed: May 22, 2020Google Scholar]. Alternative guidance has been proposed. Preventive doses of vitamin D3 of 10,000 IU/day for 4 weeks followed by 5000 IU/day to reach a target 25(OH)D level of 100–150 nmol/L [[24]Grant W.B. Lahore H. McDonnell S.L. Baggerly C.A. French C.B. Aliano J.L. et al.Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.Nutrients. 2020; 12Crossref PubMed Scopus (1087) Google Scholar], and treatment doses >6000 IU/day in deficient individuals to reach a similar level and reduce disease progression [[48]Ebadi M. Montano-Loza A.J. Perspective: improving vitamin D status in the management of COVID-19.Eur J Clin Nutr. 2020; : 1-4PubMed Google Scholar], 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]Grant W.B. Lahore H. McDonnell S.L. Baggerly C.A. French C.B. Aliano J.L. et al.Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.Nutrients. 2020; 12Crossref PubMed Scopus (1087) Google Scholar]. The latter is based on indirect evidence derived from a single study in tuberculosis patients [[48]Ebadi M. Montano-Loza A.J. Perspective: improving vitamin D status in the management of COVID-19.Eur J Clin Nutr. 2020; : 1-4PubMed Google Scholar]. However, loading doses do not seem to have added beneficial effect on acute respiratory infections [[39]Martineau A.R. Jolliffe D.A. Hooper R.L. Greenberg L. Aloia J.F. Bergman P. et al.Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.BMJ. 2017; 356: i6583Crossref PubMed Scopus (1116) Google Scholar], may adversely affect fall and fracture outcomes [[49]Sanders K.M. Stuart A.L. Williamson E.J. Simpson J.A. Kotowicz M.A. Young D. et al.Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial.JAMA. 2010; 303: 1815-1822Crossref PubMed Scopus (1078) Google Scholar,[50]Bischoff-Ferrari H.A. Dawson-Hughes B. Orav E.J. Staehelin H.B. Meyer O.W. Theiler R. et al.Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial.JAMA Intern Med. 2016; 176: 175-183Crossref PubMed Scopus (373) Google Scholar], and possibly other COVID-19 respiratory outcomes. Major gaps are to be filled before making solid recommendations. The role of vitamin D supplementation in COVID-19 patients, to enhance disease resistance or as adjuvant therapy, awaits results of well-designed experimental studies. Independent associations between low vitamin D and COVID-19 morbidity and mortality need to be established first. This can be achieved with observational studies with low selection bias, adjusted analyses, and 25(OH)D level measurements using gold standard assays. Initiation time, dosing regimens and vitamin D preparations can only be determined through randomized controlled trials. Considering the relatively small number of subjects in current trials, additional multicenter trials would be needed. Investigators should ideally consider protocols of current studies to define dosing regimens and primary outcomes. This would enable individual patient meta-analyses and shed much needed light to strengthen the evidence on the role of vitamin D in these dark COVID-19 times. None for Marlene Chakhtoura and Ghada El-Hajj Fuleihan, Nicola Napoli receives research funds from Abiogen. The authors thank Drs Aya Bassatne, Maya Basbous, Ola El-Zein, and Mrs Maya Rahme for their contributions to the literature search and screening of relevant papers retrieved.