Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study)
Ashu Rastogi, Anil Bhansali, Niranjan Khare, Vikas Suri, Narayana Yaddanapudi, Naresh Sachdeva, G D Puri, Pankaj Malhotra
Postgraduate Medical Journal, doi:10.1136/postgradmedj-2020-139065
Background Vitamin D has an immunomodulatory role but the effect of therapeutic vitamin D supplementation in SARS-CoV-2 infection is not known. Aim Effect of high dose, oral cholecalciferol supplementation on SARS-CoV-2 viral clearance. Design Randomised, placebo-controlled. Participants Asymptomatic or mildly symptomatic SARS-CoV-2 RNA positive vitamin D deficient (25(OH) D<20 ng/ml) individuals. Intervention Participants were randomised to receive daily 60 000 IU of cholecalciferol (oral nano-liquid droplets) for 7 days with therapeutic target 25(OH) D>50 ng/ml (intervention group) or placebo (control group). Patients requiring invasive ventilation or with significant comorbidities were excluded. 25(OH)D levels were assessed at day 7, and cholecalciferol supplementation was continued for those with 25(OH)D <50 ng/ml in the intervention arm. SARS-CoV-2 RNA and inflammatory markers fibrinogen, D-dimer, procalcitonin and (CRP), ferritin were measured periodically. Outcome measure Proportion of patients with SARS-CoV-2 RNA negative before day-21 and change in inflammatory markers. Results Forty SARS-CoV-2 RNA positive individuals were randomised to intervention (n=16) or control (n=24) group. Baseline serum 25(OH)D was 8.6 (7.1 to 13.1) and 9.54 (8.1 to 12.5) ng/ml (p=0.730), in the intervention and control group, respectively. 10 out of 16 patients could achieve 25(OH)D>50 ng/ml by day-7 and another two by day-14 [day-14 25(OH)D levels 51.7 (48.9 to 59.5) ng/ml and 15.2 (12.7 to 19.5) ng/ml (p<0.001) in intervention and control group, respectively]. 10 (62.5%) participants in the intervention group and 5 (20.8%) participants in the control arm (p<0.018) became SARS-CoV-2 RNA negative. Fibrinogen levels significantly decreased with cholecalciferol supplementation (intergroup difference 0.70 ng/ml; P=0.007) unlike other inflammatory biomarkers. Conclusion Greater proportion of vitamin D-deficient individuals with SARS-CoV-2 infection turned SARS-CoV-2 RNA negative with a significant decrease in fibrinogen on high-dose cholecalciferol supplementation. Trial register number NCT04459247.
Competing interests None declared. Patient consent for publication Not required. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available upon reasonable request. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peerreviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/ or omissions arising from translation and adaptation or otherwise. This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the COVID-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, noncommercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained. What is already known on the subject ► Vitamin-D has immunomodulatory effect and may reduce susceptibility and severity of viral infections but its role in SARS-CoV-2 infection is not known.
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References
Amrein, Sourij, Wagner, Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double-blind, placebo-controlled pilot study, Crit Care,
doi:10.1186/cc10120Arboleda, Urcuqui-Inchima, Vitamin D supplementation: a potential approach for COVID-19 therapeutics?, Front Immunol,
doi:10.3389/fimmu.2020.01523Camargo, Martineau, Vitamin D to prevent COVID-19: recommendations for the design of clinical trials, Febs J,
doi:10.1111/febs.15534Castillo, Costa, Barrios, 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,
doi:10.1016/j.jsbmb.2020.105751Dixon, Barker, Mckinnon, Positive correlation between circulating cathelicidin antimicrobial peptide (hCAP18/LL-37) and 25-hydroxyvitamin D levels in healthy adults, BMC Res Notes,
doi:10.1186/1756-0500-5-575Illie, Stefanescu, Smith, The role of vitamin D in the prevention of coronavirus disease infection and mortality, Aging Clin Exp Res,
doi:10.1007/s40520-020-01570-8Jing, Liu, Zhang, Household secondary attack rate of COVID-19 and associated determinants in Guangzhou, China: a retrospective cohort study [published online ahead of print, 2020 Jun 17, Lancet Infect Dis,
doi:10.1016/S1473-3099(20)30471-0Kearns, Alvarez, Tangpricha, Large, single-dose, oral vitamin D supplementation in adult populations: a systematic review, Endocr Pract,
doi:10.4158/EP13265.RAMaghbooli, Sahraian, Ebrahimi, 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,
doi:10.1371/journal.pone.0239799Martineau, Jolliffe, Hooper, Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data, BMJ,
doi:10.1136/bmj.i6583Merzon, Tworowski, Gorohovski, Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study, Febs J,
doi:10.1111/febs.15495Sanders, Monogue, Jodlowski, Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review, JAMA,
doi:10.1001/jama.2020.6019Tellioglu, Basaran, Guzel, Efficacy and safety of high dose intramuscular or oral cholecalciferol in vitamin D deficient/insufficient elderly, Maturitas,
doi:10.1016/j.maturitas.2012.04.011Zdrenghea, Makrinioti, Bagacean, Vitamin D modulation of innate immune responses to respiratory viral infections, Rev Med Virol,
doi:10.2174/18715281113129990046Zeng, Huang, Guo, Association of inflammatory markers with the severity of COVID-19: a meta-analysis
Zeng, Yu, Chen, Longitudinal changes of inflammatory parameters and their correlation with disease severity and outcomes in patients with COVID-19 from Wuhan, China, Crit Care,
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Vitamin '
'D has an immunomodulatory role but the effect of therapeutic vitamin D supplementation in '
'SARS-CoV-2 infection is not '
'known.</jats:p></jats:sec><jats:sec><jats:title>Aim</jats:title><jats:p>Effect of high dose, '
'oral cholecalciferol supplementation on SARS-CoV-2 viral '
'clearance.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Randomised, '
'placebo-controlled.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>Asymptomatic '
'or mildly symptomatic SARS-CoV-2 RNA positive vitamin D deficient (25(OH)D&lt;20 ng/ml) '
'individuals.</jats:p></jats:sec><jats:sec><jats:title>Intervention</jats:title><jats:p>Participants '
'were randomised to receive daily 60 000 IU of cholecalciferol (oral nano-liquid droplets) for '
'7 days with therapeutic target 25(OH)D&gt;50 ng/ml (intervention group) or placebo '
'(control group). Patients requiring invasive ventilation or with significant comorbidities '
'were excluded. 25(OH)D levels were assessed at day 7, and cholecalciferol supplementation was '
'continued for those with 25(OH)D &lt;50 ng/ml in the intervention arm. SARS-CoV-2 RNA and '
'inflammatory markers fibrinogen, D-dimer, procalcitonin and (CRP), ferritin were measured '
'periodically.</jats:p></jats:sec><jats:sec><jats:title>Outcome '
'measure</jats:title><jats:p>Proportion of patients with SARS-CoV-2 RNA negative before day-21 '
'and change in inflammatory '
'markers.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Forty '
'SARS-CoV-2 RNA positive individuals were randomised to intervention (n=16) or control (n=24) '
'group. Baseline serum 25(OH)D was 8.6 (7.1 to 13.1) and 9.54 (8.1 to 12.5) ng/ml (p=0.730), '
'in the intervention and control group, respectively. 10 out of 16 patients could achieve '
'25(OH)D&gt;50 ng/ml by day-7 and another two by day-14 [day-14 25(OH)D levels 51.7 (48.9 '
'to 59.5) ng/ml and 15.2 (12.7 to 19.5) ng/ml (p&lt;0.001) in intervention and control '
'group, respectively]. 10 (62.5%) participants in the intervention group and 5 (20.8%) '
'participants in the control arm (p&lt;0.018) became SARS-CoV-2 RNA negative. Fibrinogen '
'levels significantly decreased with cholecalciferol supplementation (intergroup difference '
'0.70 ng/ml; P=0.007) unlike other inflammatory '
'biomarkers.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Greater '
'proportion of vitamin D-deficient individuals with SARS-CoV-2 infection turned SARS-CoV-2 RNA '
'negative with a significant decrease in fibrinogen on high-dose cholecalciferol '
'supplementation.</jats:p></jats:sec><jats:sec><jats:title>Trial register '
'number</jats:title><jats:p>NCT04459247.</jats:p></jats:sec>',
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'article-title': 'Temporal dynamics in viral shedding and transmissibility of COVID-19',
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'in Guangzhou, China: a retrospective cohort study [published online '
'ahead of print, 2020 Jun 17]',
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'doi-asserted-by': 'crossref',
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'article-title': 'Association of vitamin D status and other clinical characteristics with '
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'volume': '287',
'author': 'Merzon',
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'journal-title': 'Febs J'},
{ 'key': '2023041705590501800_',
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'article-title': 'Vitamin D supplementation to prevent acute respiratory tract '
'infections: systematic review and meta-analysis of individual '
'participant data',
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'doi-asserted-by': 'crossref',
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'article-title': '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',
'volume': '203',
'author': 'Entrenas Castillo',
'year': '2020',
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'DOI': '10.1016/j.ijid.2020.04.061',
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