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Involvement of the secosteroid vitamin D in autoimmune rheumatic diseases and COVID-19

Cutolo et al., Nature Reviews Rheumatology, doi:10.1038/s41584-023-00944-2
Mar 2023  
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Vitamin D for COVID-19
8th treatment shown to reduce risk in October 2020
 
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4,100+ studies for 60+ treatments. c19early.org
Review of the role of vitamin D in autoimmune rheumatic diseases and COVID-19. For COVID-19, vitamin D deficiency is associated with increased risk of infection and severe outcomes. Authors discuss the immunomodulatory effects of vitamin D, including enhancing innate antiviral response, downregulating inflammatory cytokines, and shifting T cell responses. Several randomized controlled trials suggest vitamin D supplementation may reduce COVID-19 severity and mortality. Authors find that monitoring vitamin D levels and appropriate supplementation is recommended for ARDs and COVID-19.
Cutolo et al., 28 Mar 2023, peer-reviewed, 4 authors. Contact: mcutolo@unige.it.
This PaperVitamin DAll
Involvement of the secosteroid vitamin D in autoimmune rheumatic diseases and COVID-19
Maurizio Cutolo, Vanessa Smith, Sabrina Paolino, Emanuele Gotelli
Nature Reviews Rheumatology, doi:10.1038/s41584-023-00944-2
Evidence supporting the extra-skeletal role of vitamin D in modulating immune responses is centred on the effects of its final m et ab ol ite, 1 ,2 5-di hy dr ox yvitamin D 3 (1,25(OH) 2 D 3 , also known as calcitriol), which is regarded as a t r u e s t e r o id h o r m o ne. 1,25(OH) 2 D 3 , the active form of vitamin D, can modulate the innate immune system in response to invading pathogens, downregulate inflammatory responses and support the adaptive arm of the immune system. Serum concentrations of its inactive precursor 25-hydroxyvitamin D 3 (25(OH)D 3 , also known as calcidiol) fluctuate seasonally (being lowest in winter) and correlate negatively with the activation of the immune system as well as with the incidence and severity of autoimmune rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. Thus, a low serum concentration of 25(OH)D 3 is considered to be a risk factor for autoimmune rheumatic diseases and vitamin D 3 supplementation seems to improve the prognosis; moreover, long-term vitamin D 3 supplementation seems to reduce their incidence (i.e. rheumatoid arthritis). In the setting of COVID-19, 1,25(OH) 2 D 3 seems to downregulate the early viral phase (SARS-CoV-2 infection), by enhancing innate antiviral effector mechanisms, as well as the later cytokine-mediated hyperinflammatory phase. This Review provides an update of the latest scientific and clinical evidence concerning vitamin D and immune response in autoimmune rheumatic diseases and COVID-19, which justify the need for monitoring of serum 25(OH)D 3 concentrations and for appropriate supplementation following clinical trial-based approaches. Sections Key points • Vitamin D 3 (cholecalciferol) is a prototypical secosteroid, a type of steroid with a 'broken' ring, which originates from cholesterol, as do all steroid hormones (including glucocorticoids, mineralocorticoids and sex hormones). • The activation of vitamin D 3 is accomplished by sequential hydroxylations that produce 25(OH)D 3 (calcidiol) in the liver and then the active metabolite 1,25(OH) 2 D 3 (calcitriol) in the kidney and at extra-renal sites (including immune cells). • 1,25(OH) 2 D 3 modulates the innate immune response against pathogens and invading microorganisms, downregulates the inflammatory response and supports the adaptive arm of the immune system. • Reduced serum concentrations of 25(OH)D 3 are detected in autoimmune rheumatic diseases such as rheumatoid, systemic lupus erythematosus and systemic sclerosis; vitamin D supplementation seems to improve at least the prognosis. • Serum concentrations of vitamin D fluctuate seasonally (being lowest in winter) and correlate negatively with the activation of the immune system and with the incidence and severity of autoimmune rheumatic diseases. • 1,25(OH) 2 D 3 downregulates both the early viral phase of COVID-19, through the enhancement of innate antiviral effector mechanisms, and the later..
Author contributions M.C. and E.G. researched data for the article. V.S. and S.P. made a substantial contribution to discussion of the content. M.C. and E.G. wrote the manuscript. All authors reviewed and/or edited the manuscript before submission. Competing interests M.C. declares that his university laboratory has received funds for research from Amgen, Bristol-Myers Squibb, Boehringer Ingelheim and Pfizer. V.S. declares that she has received funds for research from Boehringer-Ingelheim and Janssen-Cilag. S.P. and E.G. declare no competing interests.
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Disord.', 'key': '944_CR188', 'unstructured': 'Feldthusen, C., Grimby-Ekman, A., Forsblad-d’Elia, H., Jacobsson, L. & ' 'Mannerkorpi, K. Seasonal variations in fatigue in persons with ' 'rheumatoid arthritis: a longitudinal study. BMC Musculoskelet. Disord. ' '17, 59 (2016).', 'volume': '17', 'year': '2016'}, { 'DOI': '10.1136/ard.2010.144402', 'author': 'G Mouterde', 'doi-asserted-by': 'publisher', 'first-page': '1251', 'journal-title': 'Ann. Rheum. Dis.', 'key': '944_CR189', 'unstructured': 'Mouterde, G. et al. Predictors of radiographic progression in the ESPOIR ' 'Cohort: the season of first symptoms may influence the short-term ' 'outcome in early arthritis. Ann. Rheum. Dis. 70, 1251–1256 (2011).', 'volume': '70', 'year': '2011'}, { 'DOI': '10.1038/s41598-020-64284-x', 'author': 'M Herly', 'doi-asserted-by': 'publisher', 'journal-title': 'Sci. Rep.', 'key': '944_CR190', 'unstructured': 'Herly, M. et al. Impact of season on the association between vitamin D ' 'levels at diagnosis and one-year remission in early rheumatoid ' 'arthritis. Sci. Rep. 10, 7371 (2020).', 'volume': '10', 'year': '2020'}, { 'DOI': '10.1016/j.autrev.2017.03.002', 'author': 'J Vojinovic', 'doi-asserted-by': 'publisher', 'first-page': '548', 'journal-title': 'Autoimmun. Rev.', 'key': '944_CR191', 'unstructured': 'Vojinovic, J. et al. European multicentre pilot survey to assess vitamin ' 'D status in rheumatoid arthritis patients and early development of a new ' 'patient reported outcome questionnaire (D-PRO). Autoimmun. Rev. 16, ' '548–554 (2017).', 'volume': '16', 'year': '2017'}, { 'DOI': '10.1038/nrrheum.2011.115', 'author': 'M Cutolo', 'doi-asserted-by': 'publisher', 'first-page': '500', 'journal-title': 'Nat. Rev. Rheumatol.', 'key': '944_CR192', 'unstructured': 'Cutolo, M. Rheumatoid arthritis: circadian and circannual rhythms in RA. ' 'Nat. Rev. Rheumatol. 7, 500–502 (2011).', 'volume': '7', 'year': '2011'}, { 'DOI': '10.1016/j.nutres.2021.05.007', 'author': 'SL Finch', 'doi-asserted-by': 'publisher', 'first-page': '139', 'journal-title': 'Nutr. Res.', 'key': '944_CR193', 'unstructured': 'Finch, S. L. et al. Higher concentrations of vitamin D in Canadian ' 'children with juvenile idiopathic arthritis compared to healthy controls ' 'are associated with more frequent use of vitamin D supplements and ' 'season of birth. Nutr. Res. 92, 139–149 (2021).', 'volume': '92', 'year': '2021'}, { 'DOI': '10.1177/0961203312439640', 'author': 'DJ Birmingham', 'doi-asserted-by': 'publisher', 'first-page': '855', 'journal-title': 'Lupus', 'key': '944_CR194', 'unstructured': 'Birmingham, D. J. et al. Evidence that abnormally large seasonal ' 'declines in vitamin D status may trigger SLE flare in non-African ' 'Americans. Lupus 21, 855–864 (2012).', 'volume': '21', 'year': '2012'}, { 'author': 'F Dall’Ara', 'first-page': '153', 'journal-title': 'Clin. Exp. Rheumatol.', 'key': '944_CR195', 'unstructured': 'Dall’Ara, F. et al. Winter lupus flares are associated with low vitamin ' 'D levels in a retrospective longitudinal study of Italian adult ' 'patients. Clin. Exp. Rheumatol. 33, 153–158 (2015).', 'volume': '33', 'year': '2015'}, { 'DOI': '10.1007/s10067-011-1684-7', 'author': 'B Seriolo', 'doi-asserted-by': 'publisher', 'first-page': '445', 'journal-title': 'Clin. Rheumatol.', 'key': '944_CR196', 'unstructured': 'Seriolo, B., Molfetta, L. & Cutolo, M. Seasonal variations in serum ' 'levels of 25-hydroxyvitamin D in patients with systemic sclerosis. Clin. ' 'Rheumatol. 30, 445–446 (2011).', 'volume': '30', 'year': '2011'}, { 'DOI': '10.1080/14397595.2019.1702238', 'author': 'C Foocharoen', 'doi-asserted-by': 'publisher', 'first-page': '1025', 'journal-title': 'Mod. Rheumatol.', 'key': '944_CR197', 'unstructured': 'Foocharoen, C. et al. Effect of season on clinical outcomes of Thai ' 'systemic sclerosis: analysis of the Thai National Healthcare Database. ' 'Mod. Rheumatol. 30, 1025–1032 (2020).', 'volume': '30', 'year': '2020'}, { 'DOI': '10.1038/s41584-020-00565-z', 'author': 'R Talarico', 'doi-asserted-by': 'publisher', 'first-page': '177', 'journal-title': 'Nat. Rev. Rheumatol.', 'key': '944_CR198', 'unstructured': 'Talarico, R. et al. The impact of COVID-19 on rare and complex ' 'connective tissue diseases: the experience of ERN ReCONNET. Nat. Rev. ' 'Rheumatol. 17, 177–184 (2021).', 'volume': '17', 'year': '2021'}, { 'DOI': '10.1016/S2665-9913(21)00112-0', 'author': 'D Saadoun', 'doi-asserted-by': 'publisher', 'first-page': 'e481', 'journal-title': 'Lancet Rheumatol.', 'key': '944_CR199', 'unstructured': 'Saadoun, D. et al. SARS-CoV-2 outbreak in immune-mediated inflammatory ' 'diseases: the Euro-COVIMID multicentre cross-sectional study. Lancet ' 'Rheumatol. 3, e481–e488 (2021).', 'volume': '3', 'year': '2021'}, { 'DOI': '10.1136/rmdopen-2020-001454', 'author': 'M Cutolo', 'doi-asserted-by': 'publisher', 'journal-title': 'RMD Open', 'key': '944_CR200', 'unstructured': 'Cutolo, M., Paolino, S. & Smith, V. Evidences for a protective role of ' 'vitamin D in COVID-19. RMD Open 6, e001454 (2020).', 'volume': '6', 'year': '2020'}, { 'DOI': '10.1002/jmv.26360', 'author': 'R Munshi', 'doi-asserted-by': 'publisher', 'first-page': '733', 'journal-title': 'J. Med. Virol.', 'key': '944_CR201', 'unstructured': 'Munshi, R. et al. Vitamin D insufficiency as a potential culprit in ' 'critical COVID-19 patients. J. Med. Virol. 93, 733–740 (2021).', 'volume': '93', 'year': '2021'}, { 'DOI': '10.1111/cen.14276', 'author': 'G Panagiotou', 'doi-asserted-by': 'publisher', 'first-page': '508', 'journal-title': 'Clin. Endocrinol.', 'key': '944_CR202', 'unstructured': 'Panagiotou, G. et al. Low serum 25-hydroxyvitamin D (25[OH]D) levels in ' 'patients hospitalized with COVID-19 are associated with greater disease ' 'severity. Clin. Endocrinol. 93, 508–511 (2020).', 'volume': '93', 'year': '2020'}, { 'DOI': '10.1007/s40520-020-01570-8', 'author': 'PC Ilie', 'doi-asserted-by': 'publisher', 'first-page': '1195', 'journal-title': 'Aging Clin. Exp. Res.', 'key': '944_CR203', 'unstructured': '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. 32, 1195–1198 (2020).', 'volume': '32', 'year': '2020'}, { 'DOI': '10.1111/cen.14540', 'author': 'Z Wang', 'doi-asserted-by': 'publisher', 'first-page': '281', 'journal-title': 'Clin. Endocrinol.', 'key': '944_CR204', 'unstructured': 'Wang, Z. et al. Association of vitamin D deficiency with COVID-19 ' 'infection severity: systematic review and meta-analysis. Clin. ' 'Endocrinol. 96, 281–287 (2022).', 'volume': '96', 'year': '2022'}, { 'DOI': '10.1371/journal.pone.0268396', 'author': 'O D’Ecclesiis', 'doi-asserted-by': 'publisher', 'journal-title': 'PLoS One', 'key': '944_CR205', 'unstructured': 'D’Ecclesiis, O. et al. Vitamin D and SARS-CoV2 infection, severity and ' 'mortality: a systematic review and meta-analysis. PLoS One 17, e0268396 ' '(2022).', 'volume': '17', 'year': '2022'}, { 'DOI': '10.3390/nu14102134', 'author': 'B Hosseini', 'doi-asserted-by': 'publisher', 'first-page': '2134', 'journal-title': 'Nutrients', 'key': '944_CR206', 'unstructured': 'Hosseini, B., El Abd, A. & Ducharme, F. M. Effects of vitamin D ' 'supplementation on COVID-19 related outcomes: a systematic review and ' 'meta-analysis. Nutrients 14, 2134 (2022).', 'volume': '14', 'year': '2022'}, { 'author': 'V Borba', 'first-page': '439', 'journal-title': 'Isr. Med. Assoc. J.', 'key': '944_CR207', 'unstructured': 'Borba, V. & Shoenfeld, Y. Vitamin D and immune system function in ' 'patients with COVID-19. Isr. Med. Assoc. J. 24, 439–440 (2022).', 'volume': '24', 'year': '2022'}, { 'author': 'AR Martineau', 'first-page': '356:i6583', 'journal-title': 'BMJ', 'key': '944_CR208', 'unstructured': 'Martineau, A. R. et al. Vitamin D supplementation to prevent acute ' 'respiratory tract infections: systematic review and metaanalysis of ' 'individual participant data. BMJ 15, 356:i6583 (2017).', 'volume': '15', 'year': '2017'}, { 'DOI': '10.1210/clinem/dgab892', 'author': 'HA Dissanayake', 'doi-asserted-by': 'publisher', 'first-page': '1484', 'journal-title': 'J. Clin. Endocrinol. Metab.', 'key': '944_CR209', 'unstructured': 'Dissanayake, H. A. et al. Prognostic and therapeutic role of vitamin D ' 'in COVID-19: systematic review and meta-analysis. J. Clin. Endocrinol. ' 'Metab. 107, 1484–1502 (2022).', 'volume': '107', 'year': '2022'}, { 'author': 'M Cutolo', 'first-page': '383', 'journal-title': 'Clin. Exp. Rheumatol.', 'key': '944_CR210', 'unstructured': 'Cutolo, M., Smith, V. & Paolino, S. Understanding immune effects of ' 'oestrogens to explain the reduced morbidity and mortality in female ' 'versus male COVID-19 patients. Comparisons with autoimmunity and ' 'vaccination. Clin. Exp. Rheumatol. 38, 383–386 (2020).', 'volume': '38', 'year': '2020'}, { 'DOI': '10.1038/s41584-020-0503-4', 'author': 'M Cutolo', 'doi-asserted-by': 'publisher', 'first-page': '628', 'journal-title': 'Nat. Rev. Rheumatol.', 'key': '944_CR211', 'unstructured': 'Cutolo, M. & Straub, R. H. Sex steroids and autoimmune rheumatic ' 'diseases: state of the art. Nat. Rev. Rheumatol. 16, 628–644 (2020).', 'volume': '16', 'year': '2020'}, { 'DOI': '10.1016/B978-0-12-386960-9.00009-5', 'author': 'S Hansdottir', 'doi-asserted-by': 'publisher', 'first-page': '217', 'journal-title': 'Vitam. Horm.', 'key': '944_CR212', 'unstructured': 'Hansdottir, S. & Monick, M. M. Vitamin D effects on lung immunity and ' 'respiratory diseases. Vitam. Horm. 86, 217–237 (2011).', 'volume': '86', 'year': '2011'}, { 'DOI': '10.7861/clinmed.2020-0301', 'author': 'EK Weir', 'doi-asserted-by': 'publisher', 'first-page': 'e107', 'journal-title': 'Clin. Med.', 'key': '944_CR213', 'unstructured': 'Weir, E. K., Thenappan, T., Bhargava, M. & Chen, Y. Does vitamin D ' 'deficiency increase the severity of COVID-19? Clin. Med. 20, e107–e108 ' '(2020).', 'volume': '20', 'year': '2020'}, { 'DOI': '10.1136/jclinpath-2012-201301', 'author': 'JL Waldron', 'doi-asserted-by': 'publisher', 'first-page': '620', 'journal-title': 'J. Clin. Pathol.', 'key': '944_CR214', 'unstructured': 'Waldron, J. L. et al. Vitamin D: a negative acute phase reactant. J. ' 'Clin. Pathol. 66, 620–622 (2013).', 'volume': '66', 'year': '2013'}, { 'DOI': '10.1016/j.chom.2009.08.004', 'author': 'JM Yuk', 'doi-asserted-by': 'publisher', 'first-page': '231', 'journal-title': 'Cell Host Microbe', 'key': '944_CR215', 'unstructured': 'Yuk, J. M. et al. Vitamin D3 induces autophagy in human ' 'monocytes/macrophages via cathelicidin. Cell Host Microbe 6, 231–243 ' '(2009).', 'volume': '6', 'year': '2009'}, { 'DOI': '10.3390/nu7043011', 'author': 'MT Cantorna', 'doi-asserted-by': 'publisher', 'first-page': '3011', 'journal-title': 'Nutrients', 'key': '944_CR216', 'unstructured': 'Cantorna, M. T., Snyder, L., Lin, Y. D. & Yang, L. Vitamin D and ' '1,25(OH)2D regulation of T cells. Nutrients 7, 3011–3021 (2015).', 'volume': '7', 'year': '2015'}, { 'DOI': '10.3892/mmr.2017.7546', 'author': 'J Xu', 'doi-asserted-by': 'publisher', 'first-page': '7432', 'journal-title': 'Mol. Med. Rep.', 'key': '944_CR217', 'unstructured': 'Xu, J. et al. Vitamin D alleviates lipopolysaccharide-induced acute lung ' 'injury via regulation of the renin-angiotensin system. Mol. Med. Rep. ' '16, 7432–7438 (2017).', 'volume': '16', 'year': '2017'}, { 'DOI': '10.3390/biom9110649', 'author': 'S Mohammad', 'doi-asserted-by': 'publisher', 'first-page': '649', 'journal-title': 'Biomolecules', 'key': '944_CR218', 'unstructured': 'Mohammad, S., Mishra, A. & Ashraf, M. Z. Emerging role of vitamin D and ' 'its associated molecules in pathways related to pathogenesis of ' 'thrombosis. Biomolecules 9, 649 (2019).', 'volume': '9', 'year': '2019'}, { 'DOI': '10.3390/nu9090980', 'author': 'F Jiang', 'doi-asserted-by': 'publisher', 'first-page': '1', 'journal-title': 'Nutrients', 'key': '944_CR219', 'unstructured': 'Jiang, F., Yang, Y., Xue, L., Li, B. & Zhang, Z. 1α, 25-dihydroxyvitamin ' 'D3 attenuates TGF-β-induced pro-fibrotic effects in human lung ' 'epithelial cells through inhibition of epithelial-mesenchymal ' 'transition. Nutrients 9, 1–13 (2017).', 'volume': '9', 'year': '2017'}, { 'DOI': '10.1016/j.biopha.2022.112965', 'author': 'M Torres', 'doi-asserted-by': 'publisher', 'first-page': '112965', 'journal-title': 'Biomed. Pharmacother.', 'key': '944_CR220', 'unstructured': 'Torres, M. et al. Changes in the immune response against SARS-CoV-2 in ' 'individuals with severe COVID-19 treated with high dose of vitamin D. ' 'Biomed. Pharmacother. 150, 112965 (2022).', 'volume': '150', 'year': '2022'}, { 'DOI': '10.1007/s00198-018-4520-y', 'author': 'JM Quesada-Gomez', 'doi-asserted-by': 'publisher', 'first-page': '1697', 'journal-title': 'Osteoporos. Int.', 'key': '944_CR221', 'unstructured': 'Quesada-Gomez, J. M. & Bouillon, R. Is calcifediol better than ' 'cholecalciferol for vitamin D supplementation? Osteoporos. Int. 29, ' '1697–1711 (2018).', 'volume': '29', 'year': '2018'}, { 'DOI': '10.3390/biomedicines9050509', 'author': 'J Oristrell', 'doi-asserted-by': 'publisher', 'first-page': '509', 'journal-title': 'Biomedicines', 'key': '944_CR222', 'unstructured': 'Oristrell, J. et al. Association of calcitriol supplementation with ' 'reduced COVID-19 mortality in patients with chronic kidney disease: a ' 'population-based study. Biomedicines 9, 509 (2021).', 'volume': '9', 'year': '2021'}, { 'DOI': '10.1016/j.arcmed.2022.04.003', 'author': 'MA Villasis-Keever', 'doi-asserted-by': 'publisher', 'first-page': '423', 'journal-title': 'Arch. Med. Res.', 'key': '944_CR223', 'unstructured': 'Villasis-Keever, M. A. et al. Efficacy and safety of Vitamin D ' 'supplementation to prevent COVID-19 in frontline healthcare workers. A ' 'randomized clinical trial. Arch. Med. Res. 53, 423–430 (2022).', 'volume': '53', 'year': '2022'}, { 'DOI': '10.1016/j.eprac.2021.09.016', 'author': 'Z Maghbooli', 'doi-asserted-by': 'publisher', 'first-page': '1242', 'journal-title': 'Endocr. Pract.', 'key': '944_CR224', 'unstructured': 'Maghbooli, Z. et al. Treatment with 25-Hydroxyvitamin D3 (calcifediol) ' 'is associated with a reduction in the blood neutrophil-to-lymphocyte ' 'ratio marker of disease severity in hospitalized patients with COVID-19: ' 'a pilot multicenter, randomized, placebo-controlled, double-blinded ' 'clinical trial. Endocr. Pract. 27, 1242–1251 (2021).', 'volume': '27', 'year': '2021'}, { 'DOI': '10.1186/s13063-022-06016-2', 'author': 'F Jaun', 'doi-asserted-by': 'publisher', 'journal-title': 'Trials', 'key': '944_CR225', 'unstructured': 'Jaun, F. et al. High-dose vitamin D substitution in patients with ' 'COVID-19: study protocol for a randomized, double-blind, ' 'placebo-controlled, multi-center study-VitCov Trial. Trials 23, 114 ' '(2022).', 'volume': '23', 'year': '2022'}, { 'DOI': '10.1136/bmjopen-2021-057024', 'author': 'M Legacy', 'doi-asserted-by': 'publisher', 'journal-title': 'BMJ Open', 'key': '944_CR226', 'unstructured': 'Legacy, M. et al. Dietary supplements to reduce symptom severity and ' 'duration in people with SARS-CoV-2: study protocol for a randomised, ' 'double-blind, placebo controlled clinical trial. BMJ Open 12, e057024 ' '(2022).', 'volume': '12', 'year': '2022'}, { 'DOI': '10.3390/biomedicines9111714', 'author': 'TS Chillon', 'doi-asserted-by': 'publisher', 'first-page': '1714', 'journal-title': 'Biomedicines', 'key': '944_CR227', 'unstructured': 'Chillon, T. S. et al. Relationship between vitamin D status and antibody ' 'response to COVID-19 mRNA vaccination in healthy adults. Biomedicines 9, ' '1714 (2021).', 'volume': '9', 'year': '2021'}, { 'DOI': '10.3390/nu13030717', 'author': 'A Sulli', 'doi-asserted-by': 'publisher', 'first-page': '717', 'journal-title': 'Nutrients', 'key': '944_CR228', 'unstructured': 'Sulli, A. et al. Vitamin D and lung outcomes in elderly COVID-19 ' 'patients. Nutrients 213, 717–723 (2021).', 'volume': '213', 'year': '2021'}, { 'DOI': '10.3390/nu13103596', 'author': 'L Borsche', 'doi-asserted-by': 'publisher', 'first-page': '3596', 'journal-title': 'Nutrients', 'key': '944_CR229', 'unstructured': 'Borsche, L., Glauner, B. & von Mendel, J. COVID-19 mortality risk ' 'correlates inversely with vitamin D3 status, and a mortality rate close ' 'to zero could theoretically be achieved at 50 ng/mL 25(OH)D3: results of ' 'a systematic review and meta-analysis. Nutrients 13, 3596 (2021).', 'volume': '13', 'year': '2021'}, { 'DOI': '10.1371/journal.pone.0273078', 'author': 'G Scabbia', 'doi-asserted-by': 'publisher', 'journal-title': 'PLoS One', 'key': '944_CR230', 'unstructured': 'Scabbia, G. et al. Does climate help modeling COVID-19 risk and to what ' 'extent? PLoS One 17, e0273078 (2022).', 'volume': '17', 'year': '2022'}, { 'DOI': '10.1016/j.amsu.2021.102419', 'author': 'K Sharun', 'doi-asserted-by': 'publisher', 'journal-title': 'Ann. Med. Surg.', 'key': '944_CR231', 'unstructured': 'Sharun, K., Tiwari, R. & Dha, K.\xa0COVID-19 and sunlight: Impact on ' 'SARS-CoV-2 transmissibility, morbidity, and mortality. Ann. Med. Surg. ' 'https://doi.org/10.1016/j.amsu.2021.102419 (2021).', 'year': '2021'}, { 'DOI': '10.1210/jc.2004-0682', 'author': 'BW Hollis', 'doi-asserted-by': 'publisher', 'first-page': '3149', 'journal-title': 'J. Clin. Endocrinol. Metab.', 'key': '944_CR232', 'unstructured': 'Hollis, B. W. Editorial: The determination of circulating ' '25-hydroxyvitamin D: no easy task. J. Clin. Endocrinol. Metab. 89, ' '3149–3151 (2004).', 'volume': '89', 'year': '2004'}, { 'DOI': '10.3945/ajcn.111.031070', 'author': 'L Tripkovic', 'doi-asserted-by': 'publisher', 'first-page': '1357', 'journal-title': 'Am. J. Clin. Nutr.', 'key': '944_CR233', 'unstructured': 'Tripkovic, L. et al. Comparison of vitamin D2 and vitamin D3 ' 'supplementation in raising serum 25-hydroxyvitamin D status: a ' 'systematic review and meta-analysis. Am. J. Clin. Nutr. 95, 1357–1364 ' '(2012).', 'volume': '95', 'year': '2012'}, { 'DOI': '10.1016/j.bone.2018.02.024', 'author': 'H Ketha', 'doi-asserted-by': 'publisher', 'first-page': '321', 'journal-title': 'Bone', 'key': '944_CR234', 'unstructured': 'Ketha, H. et al. Comparison of the effect of daily versus bolus dose ' 'maternal vitamin D3 supplementation on the 24,25-dihydroxyvitamin D3 to ' '25-hydroxyvitamin D3 ratio. 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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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