Effect of Cholecalciferol Supplementation on the Clinical Features and Inflammatory Markers in Hospitalized COVID-19 Patients: A Randomized, Open-Label, Single-Center Study
Tatiana L Karonova, Ksenia A Golovatyuk, Igor V Kudryavtsev, Alena T Chernikova, Arina A Mikhaylova, Arthur D Aquino, Daria I Lagutina, Ekaterina K Zaikova, Olga V Kalinina, Alexey S Golovkin, William B Grant, Evgeny V Shlyakhto
Nutrients, doi:10.3390/nu14132602
Recent studies showed that a low 25-hydroxyvitamin D (25(OH)D) level was associated with a higher risk of morbidity and severe course of COVID-19. Our study aimed to evaluate the effects of cholecalciferol supplementation on the clinical features and inflammatory markers in patients with COVID-19. A serum 25(OH)D level was determined in 311 COVID-19 patients. Among them, 129 patients were then randomized into two groups with similar concomitant medication. Group I (n = 56) received a bolus of cholecalciferol at a dose of 50,000 IU on the first and the eighth days of hospitalization. Patients from Group II (n = 54) did not receive the supplementation. We found significant differences between groups with the preferential increase in serum 25(OH)D level and ∆ 25(OH)D in Group I on the ninth day of hospitalization (p < 0.001). The serum 25(OH)D level on the ninth day was negatively associated with the number of bed days (r = −0.23, p = 0.006); we did not observe other clinical benefits in patients receiving an oral bolus of cholecalciferol. Moreover, in Group I, neutrophil and lymphocyte counts were significantly higher (p = 0.04; p = 0.02), while the C-reactive protein level was significantly lower on the ninth day of hospitalization (p = 0.02). Patients with supplementation of 100,000 IU of cholecalciferol, compared to those without supplementation, showed a decrease in the frequencies of CD38++CD27 transitional and CD27−CD38+ mature naive B cells (p = 0.006 and p = 0.02) and an increase in the level of CD27−CD38− DN B cells (p = 0.02). Thus, the rise in serum 25(OH)D level caused by vitamin D supplementation in vitamin D insufficient and deficient patients may positively affect immune status and hence the course of COVID-19.
References
Agraz-Cibrian, Giraldo, Urcuqui-Inchima, 25-Dihydroxyvitamin D3 induces formation of neutrophil extracellular trap-like structures and modulates the transcription of genes whose products are neutrophil extracellular trap-associated proteins: A pilot study, Steroids,
doi:10.1016/j.steroids.2018.11.001Alcala-Diaz, Limia-Perez, Gomez-Huelgas, Martin-Escalante, Cortes-Rodriguez et al., Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study, Nutrients,
doi:10.3390/nu13061760Amrein, Scherkl, Hoffmann, Neuwersch-Sommeregger, Köstenberger et al., deficiency 2.0: An update on the current status worldwide, Eur. J. Clin. Nutr,
doi:10.1038/s41430-020-0558-yAnnweiler, Corvaisier, Gautier, Dubée, Legrand et al., Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study, Nutrients,
doi:10.3390/nu12113377Ao, Kikuta, Ishii, The Effects of Vitamin D on Immune System and Inflammatory Diseases, Biomolecules,
doi:10.3390/biom11111624Berry, Hesketh, Power, Hypponen, Vitamin D status has a linear association with seasonal infections and lung function in British adults, Br. J. Nutr,
doi:10.1017/S0007114511001991Bouillon, Marcocci, Carmeliet, Bikle, White et al., Skeletal and extraskeletal actions of Vitamin D: Current evidence and outstanding questions, Endocr. Rev,
doi:10.1210/er.2018-00126Carpagnano, Di Lecce, Quaranta, Zito, Buonamico et al., Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19, J. Endocrinol. Investig,
doi:10.1007/s40618-020-01370-xChen, Sims, Chen, Gu, Chen et al., Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation, J. Immunol,
doi:10.4049/jimmunol.179.3.1634Chinapaka, Baba, Kandakatla, Author Correction: Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID-19 disease, Sci. Rep,
doi:10.1038/s41598-021-97181-yDankers, Colin, Van Hamburg, Lubberts, Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential, Front. Immunol,
doi:10.3389/fimmu.2016.00697Dissanayake, De Silva, Sumanatilleke, De Silva, Gamage et al., Prognostic and therapeutic role of vitamin D in COVID-19: Systematic review and meta-analysis, J. Clin. Endocrinol. Metab,
doi:10.1210/clinem/dgab892Efird, Anderson, Jindal, Redding, Thompson et al., The Interaction of Vitamin D and Corticosteroids: A Mortality Analysis of 26,508 Veterans Who Tested Positive for SARS-CoV-2, Int. J. Environ. Res. Public Health,
doi:10.3390/ijerph19010447Elamir, Amir, Lim, Rana, Lopez et al., A randomized pilot study using calcitriol in hospitalized COVID-19 patients, Bone,
doi:10.1016/j.bone.2021.116175Gao, Ding, Dong, Zhang, Kursat Azkur et al., Risk factors for severe and critically ill COVID-19 patients: A review, Allergy,
doi:10.1111/all.14657Geldmeyer-Hilt, Heine, Hartmann, Baumgrass, Radbruch et al., 1,25-dihydroxyvitamin D3 impairs NF-κB activation in human naïve B cells, Biochem. Biophys. Res. Commun,
doi:10.1016/j.bbrc.2011.03.078Golovkin, Kalinina, Bezrukikh, Aquino, Zaikova et al., Imbalanced Immune Response of T-Cell and B-Cell Subsets in Patients with Moderate and Severe COVID-19, Viruses,
doi:10.3390/v13101966Gonen, Alaylioglu, Durcan, Ozdemir, Sahin et al., Rapid and Effective Vitamin D Supplementation May Present Better Clinical Outcomes in COVID-19 (SARS-CoV-2) Patients by Altering Serum INOS1, IL1B, IFNg, Cathelicidin-LL37, and ICAM1, Nutrients,
doi:10.3390/nu13114047Grant, Anouti, Boucher, Dursun, Gezen-Ak et al., A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health, Nutrients
Gusev, Sarapultsev, Solomatina, Chereshnev, SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19, Int. J. Mol. Sci,
doi:10.3390/ijms23031716Hanley, Sutter, Goodman, Du, Sekiguchi et al., Circulating B cells in type 1 diabetics exhibit fewer maturation-associated phenotypes, Clin. Immunol,
doi:10.1016/j.clim.2017.09.021Hayes, Hubler, Moore, Barta, Praska et al., Vitamin D Actions on CD4(+) T Cells in Autoimmune Disease, Front. Immunol,
doi:10.3389/fimmu.2015.00100Heine, Niesner, Chang, Steinmeyer, Zügel et al., 1,25-dihydroxyvitamin D(3) promotes IL-10 production in human B cells, Eur. J. Immunol,
doi:10.1002/eji.200838216Karonova, Andreeva, Golovatuk, Bykova, Simanenkova et al., Low 25(OH)D Level Is Associated with Severe Course and Poor Prognosis in COVID-19, Nutrients,
doi:10.3390/nu13093021Karonova, Kudryavtsev, Golovatyuk, Aquino, Kalinina et al., Vitamin D Status and Immune Response in Hospitalized Patients with Moderate and Severe COVID-19, Pharmaceuticals,
doi:10.3390/ph15030305Kaufman, Niles, Kroll, Bi, Holick, SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels, PLoS ONE,
doi:10.1371/journal.pone.0239252Kaya, Pamukçu, Yakar, The role of vitamin D deficiency on COVID-19: A systematic review and meta-analysis of observational studies, Epidemiol. Health,
doi:10.4178/epih.e2021074Kazemi, Mohammadi, Aghababaee, Golzarand, Clark et al., Association of Vitamin D status with SARS-CoV-2 infection or COVID-19 severity: A systematic review and meta-analysis, Adv. Nutr,
doi:10.1093/advances/nmab012Khammissa, Fourie, Motswaledi, Ballyram, Lemmer et al., The Biological Activities of Vitamin D and Its Receptor in Relation to Calcium and Bone Homeostasis, Cancer, Immune and Cardiovascular Systems, Skin Biology, and Oral Health, BioMed Res. Int,
doi:10.1155/2018/9276380Kudryavtsev, Arsentieva, Batsunov, Korobova, Khamitova et al., Alterations in B Cell and Follicular T-Helper Cell Subsets in Patients with Acute COVID-19 and COVID-19 Convalescents, Curr. Issues Mol. Biol,
doi:10.3390/cimb44010014Kudryavtsev, Kalinina, Bezrukikh, Melnik, Golovkin, The significance of phenotyping and quantification of plasma extracellular vesicles levels using high-sensitivity flow cytometry during covid-19 treatment, Viruses
Kudryavtsev, Rubinstein, Golovkin, Kalinina, Vasilyev et al., Dysregulated Immune Responses in SARS-CoV-2-Infected Patients: A Comprehensive Overview, Viruses,
doi:10.3390/v14051082Lakkireddy, Gadiga, Malathi, Karra, Raju et al., None
Ling, Broad, Murphy, Pappachan, Pardesi-Newton 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,
doi:10.3390/nu12123799Maghbooli, Sahraian, Jamalimoghadamsiahkali, Asadi, Zarei 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. Off. J. Am. Coll. Endocrinol. Am. Assoc. Clin. Endocrinol,
doi:10.1016/j.eprac.2021.09.016Mangge, Kneihsl, Schnedl, Sendlhofer, Curcio et al., Immune Responses against SARS-CoV-2-Questions and Experiences, Biomedicines,
doi:10.3390/biomedicines9101342Mazziotti, Formenti, Frara, Doga, Giustina, Vitamin D and Glucocorticoid-Induced Osteoporosis, Front. Horm. Res,
doi:10.1159/000486078Mercola, Grant, Wagner, Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity, Nutrients,
doi:10.3390/nu12113361Murai, Fernandes, Sales, Pinto, Goessler 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,
doi:10.1001/jama.2020.26848Murdaca, Tonacci, Negrini, Greco, Borro et al., Emerging role of vitamin D in autoimmune diseases: An update on evidence and therapeutic implications, Autoimmun. Rev,
doi:10.1016/j.autrev.2019.102350Oristrell, Oliva, Casado, Subirana, Domínguez et al., Vitamin D supplementation and COVID-19 risk: A population-based, cohort study, J. Endocrinol. Investig,
doi:10.1007/s40618-021-01639-9Pludowski, Holick, Grant, Konstantynowicz, Mascarenhas et al., Vitamin D supplementation guidelines, J. Steroid Biochem. Mol. Biol,
doi:10.1016/j.jsbmb.2017.01.021Rastogi, Bhansali, Khare, Suri, Yaddanapudi et al., Short term, high-dose vitamin D supplementation for COVID-19 disease: A randomised, placebo-controlled, study (SHADE study), Postgrad. Med. J,
doi:10.1136/postgradmedj-2020-139065Rolf, Muris, Hupperts, Damoiseaux, Vitamin D effects on B cell function in autoimmunity, Ann. N. Y. Acad. Sci,
doi:10.1111/nyas.12440Sabico, Enani, Sheshah, Aljohani, Aldisi et al., Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial, Nutrients,
doi:10.3390/nu13072170Seal, Bertenthal, Carey, Grunfeld, Bikle et al., Association of Vitamin D Status and COVID-19-Related Hospitalization and Mortality, J. Gen. Intern. Med,
doi:10.1007/s11606-021-07170-0Shafqat, Shafqat, Salameh, Kashir, Alkattan et al., Mechanistic Insights Into the Immune Pathophysiology of COVID-19
Shah, Varna, Sharma, Mavalankar, Does vitamin D supplementation reduce COVID-19 severity?: A systematic review, QJM Int. J. Med,
doi:10.1093/qjmed/hcac040Shuwa, Shaw, Knight, Wemyss, Mcclure et al., Alterations in T and B cell function persist in convalescent COVID-19 patients, Med,
doi:10.1016/j.medj.2021.03.013Soliman, Abdelaziz, Fathy, Impact of Vitamin D Therapy on the Progress COVID-19: Six Weeks Follow-Up Study of Vitamin D Deficient Elderly Diabetes Patients, Proc. Singap. Healthc,
doi:10.1177/20101058211041405Taefehshokr, Taefehshokr, Heit, Mechanisms of Dysregulated Humoral and Cellular Immunity by SARS-CoV-2, Pathogens,
doi:10.3390/pathogens9121027Terrier, Derian, Schoindre, Chaara, Geri et al., Restoration of regulatory and effector T cell balance and B cell homeostasis in systemic lupus erythematosus patients through vitamin D supplementation, Arthritis Res. Ther,
doi:10.1186/ar4060Todosenko, Vulf, Yurova, Khaziakhmatova, Mikhailova et al., Causal Links between Hypovitaminosis D and Dysregulation of the T Cell Connection of Immunity Associated with Obesity and Concomitant Pathologies, Biomedicines,
doi:10.3390/biomedicines9121750Torres, Casado, Vigón, Rodríguez-Mora, Mateos 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,
doi:10.1016/j.biopha.2022.112965Xu, Yang, Chen, Luo, Zhang et al., Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the renin-angiotensin system, Mol. Med. Rep,
doi:10.3892/mmr.2017.7546DOI record:
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"DOI": "10.3892/mmr.2017.7546",
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{
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},
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},
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"DOI": "10.3390/v13101966",
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"DOI": "10.1016/j.clim.2017.09.021",
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"DOI": "10.3390/nu12113377",
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"DOI": "10.3390/ijerph19010447",
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},
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},
{
"DOI": "10.1093/qjmed/hcac040",
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},
{
"DOI": "10.1001/jama.2020.26848",
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"DOI": "10.3390/nu12123799",
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"DOI": "10.1016/j.biopha.2022.112965",
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},
{
"DOI": "10.3390/nu13114047",
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"DOI": "10.3390/nu13061760",
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"DOI": "10.1007/s40618-021-01639-9",
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"DOI": "10.1177/20101058211041405",
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"DOI": "10.1159/000486078",
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"doi-asserted-by": "publisher",
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},
{
"DOI": "10.1096/fj.01-0433rev",
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"key": "ref35"
},
{
"DOI": "10.3390/biom11111624",
"doi-asserted-by": "publisher",
"key": "ref36"
},
{
"DOI": "10.3389/fimmu.2015.00100",
"doi-asserted-by": "publisher",
"key": "ref37"
},
{
"DOI": "10.3390/biomedicines9121750",
"doi-asserted-by": "publisher",
"key": "ref38"
},
{
"DOI": "10.1016/j.bbrc.2011.03.078",
"doi-asserted-by": "publisher",
"key": "ref39"
},
{
"DOI": "10.4049/jimmunol.179.3.1634",
"doi-asserted-by": "publisher",
"key": "ref40"
},
{
"DOI": "10.1002/eji.200838216",
"doi-asserted-by": "publisher",
"key": "ref41"
},
{
"DOI": "10.1111/nyas.12440",
"doi-asserted-by": "publisher",
"key": "ref42"
},
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