The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis

Aya Bassatne, Maya Basbous, Marlene Chakhtoura, Ola El Zein, Maya Rahme, Ghada El-Hajj Fuleihan, Aya Bassatne, Maya Basbous, Marlene Chakhtoura, Ola El Zein, Maya Rahme, Ghada El-Hajj Fuleihan

Abstract

Background: Disease severity and mortality rates due to COVID-19 infection are greater in the elderly and chronically ill patients, populations at high risk for vitamin D deficiency. Vitamin D plays an important role in immune function and inflammation. This systematic review and meta-analysis assesses the impact of vitamin D status and supplementation on COVID-19 related mortality and health outcomes.

Methods: We searched four databases until December 18th 2020, and trial registries until January 20th 2021. Two reviewers screened the studies, collected data, assessed the risk of bias, and graded the evidence for each outcome across studies, independently and in duplicate. Pre-specified outcomes of interest were mortality, ICU admission, invasive and non-invasive ventilation, hospitalization, time of hospital stay, disease severity and SARS-CoV-2 positivity. We only included data from peer-reviewed articles in our primary analyses.

Results: We identified 31 peer-reviewed observational studies. In our primary analysis, there was a positive trend between serum 25(OH)D level <20 ng/ml and an increased risk of mortality, ICU admission, invasive ventilation, non-invasive ventilation or SARS-CoV-2 positivity. However, these associations were not statistically significant. Mean 25(OH)D levels was 5.9 ng/ml (95% CI [-9.5, -2.3]) significantly lower in COVID-19 positive, compared to negative patients. The certainty of the evidence was very low. We identified 32 clinical trial protocols, but only three have published results to-date. The trials administer vitamin D doses of 357 to 60,000 IU/day, from one week to 12 months. Eight megatrials investigate the efficacy of vitamin D in outpatient populations. A pilot trial revealed a significant decrease in ICU admission with calcifediol, compared to placebo (OR = 0.003), but the certainty of the evidence was unclear. Another small trial showed that supplementation with cholecalciferol, 60,000 IU/day, decreased fibrinogen levels, but did not have an effect on D-dimer, procalcitonin and CRP levels, compared to placebo. The third trial did not find any effect of vitamin D supplementation on COVID-19 related health outcomes.

Conclusion: While the available evidence to-date, from largely poor-quality observational studies, may be viewed as showing a trend for an association between low serum 25(OH)D levels and COVID-19 related health outcomes, this relationship was not found to be statistically significant. Calcifediol supplementation may have a protective effect on COVID-19 related ICU admissions. The current use of high doses of vitamin D in COVID-19 patients is not based on solid evidence. It awaits results from ongoing trials to determine the efficacy, desirable doses, and safety, of vitamin D supplementation to prevent and treat COVID-19 related health outcomes.

Keywords: COVID-19; Hospitalization; ICU admission; Mortality; Vitamin D.

Conflict of interest statement

Declaration of competing interest The authors declare no conflict of interest.

Copyright © 2021. Published by Elsevier Inc.

Figures

Fig. 1
Fig. 1
Flow diagram of articles related to coronaviruses and vitamin D. 1 We did not find any articles related to SARS or MERS and Vitamin D.
Fig. 2
Fig. 2
Forest plots of the association between serum 25(OHD) levels

Fig. 3

Forest plot for the mean…

Fig. 3

Forest plot for the mean difference in 25(OH)D levels (ng/ml) between COVID-19 infected…

Fig. 3
Forest plot for the mean difference in 25(OH)D levels (ng/ml) between COVID-19 infected and non-infected patients.
Fig. 3
Fig. 3
Forest plot for the mean difference in 25(OH)D levels (ng/ml) between COVID-19 infected and non-infected patients.

References

    1. World Health Organization (WHO) Coronavirus disease (COVID-19) pandemic. 2020. Available from.
    1. Wang L., Wang Y., Ye D., Liu Q. Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence. Int J Antimicrob Agents. 2020;55(6):105948.
    1. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y., et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507–513.
    1. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.
    1. Team C Severe outcomes among patients with coronavirus disease 2019 (COVID-19)-United States, February 12–March 16, 2020. Morb Mortal Wkly Rep. 2020;69(12):343–346.
    1. Mahase E. Covid-19: why are age and obesity risk factors for serious disease? BMJ. 2020;371:m4130.
    1. Tramontana F., Napoli N., El-Hajj Fuleihan G., Strollo R. The D-side of COVID-19: musculoskeletal benefits of vitamin D and beyond. Endocrine. 2020;69(2):237–240.
    1. Anker M.S., Landmesser U., von Haehling S., Butler J., Coats A.J.S., Anker S.D. Weight loss, malnutrition, and cachexia in COVID-19: facts and numbers. J Cachexia Sarcopenia Muscle. 2021;12(1):9–13.
    1. Di Filippo L., De Lorenzo R., D’Amico M., Sofia V., Roveri L., Mele R., et al. COVID-19 is associated with clinically significant weight loss and risk of malnutrition, independent of hospitalisation: a post-hoc analysis of a prospective cohort study. Clin Nutr. 2020 [S0261-5614(20)30589-6]. Online ahead of print.
    1. Roth D.E., Abrams S.A., Aloia J., Bergeron G., Bourassa M.W., Brown K.H., et al. Global prevalence and disease burden of vitamin D deficiency: a roadmap for action in low- and middle-income countries. Ann N Y Acad Sci. 2018;1430(1):44–79.
    1. Bouillon R., Carmeliet G. Vitamin D insufficiency: definition, diagnosis and management. Best Pract Res Clin Endocrinol Metab. 2018;32(5):669–684.
    1. Vanlint S. Vitamin D and obesity. Nutrients. 2013;5(3):949–956.
    1. 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;12(4):988.
    1. 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. 2020;32(7):1195–1198.
    1. 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. 2020;51(12):1434–1437.
    1. 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. 2018;40(4):1109–1151.
    1. Aranow C. Vitamin D and the immune system. J Investig Med. 2011;59(6):881–886.
    1. Greiller C.L., Martineau A.R. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients. 2015;7(6):4240–4270.
    1. 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. 2020;20(6):363–374.
    1. 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
    1. Jolliffe D., Camargo C.A., Sluyter J., Aglipay M., Aloia J., Bergman P., et al. Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials. medRxiv. 2020
    1. Chakhtoura M., Napoli N., El Hajj Fuleihan G. Commentary: myths and facts on vitamin D amidst the COVID-19 pandemic. Metabolism. 2020;109:154276.
    1. Grant W.B., Lahore H., Rockwell M.S. The benefits of vitamin D supplementation for athletes: better performance and reduced risk of COVID-19. Nutrients. 2020;12(12):3741.
    1. National Health Service Vitamin D. Available from.
    1. Griffin G., Hewison M., Hopkin J., Kenny R.A., Quinton R., Rhodes J., et al. Preventing vitamin D deficiency during the COVID-19 pandemic: UK definitions of vitamin D sufficiency and recommended supplement dose are set too low. Clin Med (Lond) 2021;21(1):e48–e51.
    1. National Institute for Health and Care Excellence (NICE) COVID-19 rapid evidence summary: vitamin D for COVID-19. 2020. Available from.
    1. ASBMR, Endocrine Society, ECTS, NOF, IOF Joint guidance on vitamin D in the era of COVID-19 from the ASBMR, AACE, Endocrine Society, ECTS, NOF, and IOF. 2020. Available from.
    1. World Health Organization (WHO) World Health Organization. 2020. Available from.
    1. World Health Organization (WHO) COVID-19 Global literature on coronavirus disease. 2020. Available from.
    1. World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) 2020. Available from.
    1. Wells G.A., Shea B., O'Connell D., Peterson j., Welch V., Losos M., Tugwell P. The Ottawa Hospital Research Institute; 2000. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available from.
    1. Higgins J.P.T., Altman D.G., Gøtzsche P.C., Jüni P., Moher D., Oxman A.D., et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
    1. McMasterUniversity Grade Pro GDT. Available from.
    1. Cochrane Cochrane handbook for systematic reviews of interventions. 2019. Available from.
    1. Maghbooli Z., Sahraian M.A., Ebrahimi M., Pazoki M., Kafan S., Tabriz H.M., et al. Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PLoS One. 2020;15(9)
    1. Каронова Т., Андреева А., Вашукова М. Уровень 25 (ОН) D в сыворотке крови у больных COVID-19. Журнал инфектологии. 2020;12(3):21–27.
    1. Baktash V., Hosack T., Patel N., Shah S., Kandiah P., Van Den Abbeele K., et al. Vitamin D status and outcomes for hospitalised older patients with COVID-19. Postgrad Med J. 2020;138712
    1. Im J.H., Je Y.S., Baek J., Chung M.-H., Kwon H.Y., Lee J.-S. Nutritional status of patients with coronavirus disease 2019 (COVID-19) Int J Infect Dis. 2020;100:390–393.
    1. Radujkovic A., Hippchen T., Tiwari-Heckler S., Dreher S., Boxberger M., Merle U. Vitamin D deficiency and outcome of COVID-19 patients. Nutrients. 2020;12(9):2757.
    1. Carpagnano G.E., Di Lecce V., Quaranta V.N., Zito A., Buonamico E., Capozza E., et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Investig. 2020:1–7.
    1. Abrishami A., Dalili N., Mohammadi Torbati P., Asgari R., Arab-Ahmadi M., Behnam B., et al. Possible association of vitamin D status with lung involvement and outcome in patients with COVID-19: a retrospective study. Eur J Nutr. 2020:1–9.
    1. Cereda E., Bogliolo L., Klersy C., Lobascio F., Masi S., Crotti S., et al. Vitamin D 25OH deficiency in COVID-19 patients admitted to a tertiary referral hospital. Clin Nutr. 2020 [S0261-5614(20)30601-4]. Online ahead of print.
    1. Hernandez J.L., Nan D., Fernandez-Ayala M., Garcia-Unzueta M., Hernandez-Hernandez M.A., Lopez-Hoyos M., et al. Vitamin D status in hospitalized patients with SARS-CoV-2 infection. J Clin Endocrinol Metab. 2021;106(3):e1343. e135.
    1. Karahan S., Katkat F. Impact of serum 25(OH) vitamin D level on mortality in patients with COVID-19 in Turkey. J Nutr Health Aging. 2020:1–8.
    1. Luo X., Liao Q., Shen Y., Li H., Cheng L. Vitamin D deficiency is inversely associated with COVID-19 incidence and disease severity in Chinese people. J Nutr. 2021;1 51(1):98–103.
    1. Anjum S., Suleman S., Afridi S., Yasmeen G., Ikram Shah M., Afridi S. Examine the association between severe Vitamin D deficiency and mortality in patients with Covid-19. Pakistan Journal of Medical and Health Sciences. 2020;14(3):1184–1186.
    1. Jain A., Chaurasia R., Sengar N.S., Singh M., Mahor S., Narain S. Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Sci Rep. 2020;10(1):1–8.
    1. Vassiliou A.G., Jahaj E., Pratikaki M., Orfanos S.E., Dimopoulou I., Kotanidou A. Low 25-hydroxyvitamin D levels on admission to the intensive care unit may predispose COVID-19 pneumonia patients to a higher 28-day mortality risk: a pilot study on a Greek ICU cohort. Nutrients. 2020;12(12):3773.
    1. Annweiler G., Corvaisier M., Gautier J., Dubée V., Legrand E., Sacco G., et al. Vitamin D supplementation associated to better survival in hospitalized frail elderly COVID-19 patients: the GERIA-COVID quasi-experimental study. Nutrients. 2020;12(11):3377.
    1. Arvinte C., Singh M., Marik P.E. Serum levels of vitamin C and vitamin D in a cohort of critically ill COVID-19 patients of a North American community hospital intensive care unit in May 2020: a pilot study. Medicine in Drug Discovery. 2020;8:100064.
    1. Hamza A., Ahmed M., Ahmed K., Durrani A.B. Role of vitamin D in pathogenesis and severity of coronavirus disease 2019 (COVID-19) infection. Pakistan Journal of Medical and Health Sciences. 2020;14(2):462–465.
    1. Ling S.F., Broad E., Murphy R., Pappachan J.M., Pardesi-Newton S., Kong M.F., et al. High-dose cholecalciferol booster therapy is associated with a reduced risk of mortality in patients with COVID-19: a cross-sectional multi-centre observational study. Nutrients. 2020;12(12):3799.
    1. De Smet D., De Smet K., Herroelen P., Gryspeerdt S., Martens G.A. Serum 25(OH)D level on hospital admission associated with COVID-19 stage and mortality. Am J Clin Pathol. 2020
    1. Angelidi A.M., Belanger M.J., Lorinsky M.K., Karamanis D., Chamorro-Pareja N., Ognibene J., et al. Vitamin D status is associated with in-hospital mortality and mechanical ventilation: a cohort of COVID-19 hospitalized patients. Mayo Clin Proc. 2021 Elsevier.
    1. Tan C.W., Ho L.P., Kalimuddin S., Cherng B.P.Z., Teh Y.E., Thien S.Y., et al. A cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients. medRxiv. 2020
    1. Merzon E., Tworowski D., Gorohovski A., Vinker S., Golan Cohen A., Green I., et al. Low plasma 25 (OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study. FEBS J. 2020;287(17):3693–3702.
    1. Macaya F., Espejo Paeres C., Valls A., Fernandez-Ortiz A., Gonzalez Del Castillo J., Martin-Sanchez F.J., et al. Interaction between age and vitamin D deficiency in severe COVID-19 infection. Nutr Hosp. 2020;37(5):1039–1042.
    1. Ye K., Tang F., Liao X., Shaw B.A., Deng M., Huang G., et al. Does serum vitamin D level affect COVID-19 infection and its severity?-a case-control study. J Am Coll Nutr. 2020:1–8.
    1. Kerget B., Kerget F., Kiziltunc A., Kocak A.O., Araz O., Yilmazel Ucar E., et al. Evaluation of the relationship of serum vitamin D levels in COVID-19 patients with clinical course and prognosis. Tuberkuloz ve Toraks. 2020;68(3):227–235.
    1. Meltzer D.O., Best T.J., Zhang H., Vokes T., Arora V., Solway J. Association of vitamin D deficiency and treatment with COVID-19 incidence. JAMA Netw Open. 2020;3(9)
    1. Abdollahi A., Sarvestani H.K., Rafat Z., Ghaderkhani S., Mahmoudi-Aliabadi M., Jafarzadeh B., et al. The association between the level of serum 25(OH) vitamin D, obesity, and underlying diseases with the risk of developing COVID-19 infection: a case-control study of hospitalized patients in Tehran. Iran Journal of Medical Virology. 2020;26726
    1. Mardani R., Alamdary A., Nasab S.M., Gholami R., Ahmadi N., Gholami A. Association of vitamin D with the modulation of the disease severity in COVID-19. Virus Res. 2020;289:198148.
    1. D'Avolio A., Avataneo V., Manca A., Cusato J., De Nicolo A., Lucchini R., et al. 25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2. Nutrients. 2020;12(5):1359.
    1. Raisi-Estabragh Z., McCracken C., Bethell M.S., Cooper J., Cooper C., Caulfield M.J., et al. Greater risk of severe COVID-19 in Black, Asian and Minority Ethnic populations is not explained by cardiometabolic, socioeconomic or behavioural factors, or by 25(OH)-vitamin D status: study of 1326 cases from the UK Biobank. J Public Health (Oxf) 2020;42(3):451–460.
    1. 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(4):561–565.
    1. PLoSOne Editors Expression of concern: vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PLoS One. 2020;15(10)
    1. Castillo M.E., Entrenas Costa L.M., Vaquero Barrios J.M., Alcalá Díaz J.F., Miranda J.L., Bouillon R., et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: a pilot randomized clinical study. J Steroid Biochem Mol Biol. 2020;203:105751.
    1. 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 [postgradmedj-2020-139065]. Online ahead of print.
    1. Murai I.H., Fernandes A.L., Sales L.P., Pinto A.J., Goessler K.F., Duran C.S., et al. Effect of a single high dose of vitamin D3 on hospital length of stay in patients with moderate to severe COVID-19: a randomized clinical trial. JAMA. 2021;17:2021. doi: 10.1001/jama.2020.26848. Published online February.
    1. Quesada-Gomez J.M., Entrenas-Castillo M., Bouillon R. Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: revised Ms SBMB 2020_166. J Steroid Biochem Mol Biol. 2020;202:105719.
    1. Bilezikian J.P., Bikle D., Hewison M., Lazaretti-Castro M., Formenti A.M., Gupta A., et al. Mechanisms in endocrinology: vitamin D and COVID-19. Eur J Endocrinol. 2020
    1. Mok C.K., Ng Y.L., Ahidjo B.A., Hua Lee R.C., Choy Loe M.W., Liu J., et al. Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis. bioRxiv. 2020
    1. Cannell J.J., Vieth R., Umhau J.C., Holick M.F., Grant W.B., Madronich S., et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134(6):1129–1140.
    1. Grant W.B. Vitamin D supplementation could reduce the risk of type A influenza infection and subsequent pneumonia. Pediatr Infect Dis J. 2010;29(10):987.
    1. Thacher T.D. Vitamin D and COVID-19. Mayo Clin Proc. 2021 doi: 10.1016/j.mayocp.2021.02.014.
    1. Kostoglou-Athanassiou I., Pantazi E., Kontogiannis S., Kousouris D., Mavropoulos I., Athanassiou P. Vitamin D in acutely ill patients. J Int Med Res. 2018;46(10):4246–4257.
    1. Thurnham D. Plasma 25-hydroxy-cholecalciferol (Vitamin D) is depressed by inflammation: implications and parallels with other micronutrients. Sight and Life. 2011;25(2):38–47.
    1. Reid D., Toole B.J., Knox S., Talwar D., Harten J., O'Reilly D.S.J., et al. The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty. Am J Clin Nutr. 2011;93(5):1006–1011.
    1. Quraishi S.A., Camargo C.A., Jr. Vitamin D in acute stress and critical illness. Curr Opin Clin Nutr Metab Care. 2012;15(6):625–634.
    1. Dirks N.F., Ackermans M.T., Lips P., de Jongh R.T., Vervloet M.G., de Jonge R., et al. The when, what & how of measuring vitamin D metabolism in clinical medicine. Nutrients. 2018;10(4):482.
    1. Smolders J., van den Ouweland J., Geven C., Pickkers P., Kox M. Letter to the editor: vitamin D deficiency in COVID-19: mixing up cause and consequence. Metabolism. 2021;115:154434.
    1. Chakhtoura M., El Hajj Fuleihan G. Reply to Vitamin D deficiency in COVID-19: mixing up cause and consequence. Metabolism. 2021;115:154462.
    1. Di Filippo L., Formenti A.M., Giustina A. Hypocalcemia: the quest for the cause of a major biochemical feature of COVID-19. Endocrine. 2020;70(3):463–464.
    1. Yang C., Ma X., Wu J., Han J., Zheng Z., Duan H., et al. Low serum calcium and phosphorus and their clinical performance in detecting COVID-19 patients. J Med Virol. 2021;93(3):1639–1651.
    1. Di Filippo L., Formenti A.M., Rovere-Querini P., Carlucci M., Conte C., Ciceri F., et al. Hypocalcemia is highly prevalent and predicts hospitalization in patients with COVID-19. Endocrine. 2020;68(3):475–478.
    1. Pereira M., Dantas Damascena A., Galvão Azevedo L.M., de Almeida Oliveira T., da Mota Santana J. Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2020:1–9.
    1. Henrina J., Lim M.A., Pranata R. COVID-19 and misinformation: how an infodemic fuelled the prominence of vitamin D. Br J Nutr. 2021;125(3):359–360.
    1. Lanham-New S.A., Webb A.R., Cashman K.D., Buttriss J.L., Fallowfield J.L., Masud T., et al. Vitamin D and SARS-CoV-2 virus/COVID-19 disease. BMJ Nutrition, Prevention &amp. Health. 2020;3(1):106–110.

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