Effect of vitamin D3 supplementation on cellular immunity and inflammatory markers in COVID-19 patients admitted to the ICU

Mikhail V Bychinin, Tatiana V Klypa, Irina A Mandel, Gaukhar M Yusubalieva, Vladimir P Baklaushev, Nadezhda A Kolyshkina, Aleksandr V Troitsky, Mikhail V Bychinin, Tatiana V Klypa, Irina A Mandel, Gaukhar M Yusubalieva, Vladimir P Baklaushev, Nadezhda A Kolyshkina, Aleksandr V Troitsky

Abstract

Vitamin D as an immunomodulator has not been studied in patients with severe COVID-19. This study aimed to estimate the efficacy of vitamin D3 supplementation on cellular immunity and inflammatory markers in patients with COVID-19 admitted to the intensive care unit (ICU). A single-center, double-blind, randomized, placebo-controlled pilot trial was conducted (N = 110). Patients were randomly assigned to receive a weekly oral dose of 60,000 IU of vitamin D3 followed by daily maintenance doses of 5000 IU (n = 55) or placebo (n = 55). Primary outcomes were lymphocyte counts, natural killer (NK) and natural killer T (NKT) cell counts, neutrophil-to-lymphocyte ratio (NLR), and serum levels of inflammatory markers on 7th day of treatment. On day 7, patients in the vitamin D3 group displayed significantly higher NK and NKT cell counts and NLR than those in the placebo group did. The mortality rate (37% vs 50%, P = 0.16), need for mechanical ventilation (63% vs 69%, P = 0.58), incidence of nosocomial infection (60% vs 41%, P = 0.05) did not significantly differ between groups. Vitamin D3 supplementation, compared with placebo, significantly increased lymphocyte counts, but did not translate into reduced mortality in ICU.Trial Registration: ClinicalTrials.gov Identifier: NCT05092698.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
Correlation analysis between the vitamin D and NK/NKT subpopulations of immune cells on admission and on day 7 of stay in the ICU. Baseline levels of vitamin D were positively correlated with NKT cell counts (r = 0.6 (95% CI 0.38; 0.76), P = 0.001), in contrast to NK cells lacking such association (r = 0.26, (95% CI − 0.26; 0.51), P = 0.07) (a,b). On day 7 of treatment, vitamin D levels were positively correlated with NK cell (r = 0.67 (95% CI 0.42; 0.82), P = 0.001) and NKT cell (r = 0.41 (95% CI 0.08; 0.65), P = 0.013) counts (c,d).
Figure 2
Figure 2
Flow diagram of the COVID-VIT trial.

References

    1. Ni Y, et al. Immunological perspectives on the pathogenesis, diagnosis, prevention and treatment of COVID-19. Mol. Biomed. 2021;2:1.
    1. Mazzoni A, et al. Impaired immune cell cytotoxicity in severe COVID-19 Is IL-6 dependent. J. Clin. Investig. 2020;130:4694–4703.
    1. Meckiff BJ, et al. Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19. Cell. 2020;183:1340–1353.
    1. Liu R, et al. Decreased T cell populations contribute to the increased severity of COVID-19. Clin. Chim. Acta. 2020;508:110–114.
    1. Jiang M, et al. T-cell subset counts in peripheral blood can be used as discriminatory biomarkers for diagnosis and severity prediction of coronavirus disease 2019. J. Infect. Dis. 2020;222:198–202.
    1. Charoenngam N, Holick MF. Immunologic effects of vitamin D on human health and disease. Nutrients. 2020;12:2097.
    1. Herr C, Shaykhiev R, Bals R. The role of cathelicidin and defensins in pulmonary inflammatory diseases. Expert Opin. Biol. Ther. 2007;7:1449–1461.
    1. Martens PJ, Gysemans C, Verstuyf A, Mathieu AC. Vitamin D's effect on immune function. Nutrients. 2020;12:1248.
    1. Zhang YP, Wan YD, Sun TW, Kan QC, Wang LX. Association between vitamin D deficiency and mortality in critically ill adult patients: A meta-analysis of cohort studies. Crit. Care. 2014;18:684.
    1. Bychinin MV, et al. Low circulating vitamin D in intensive care unit-admitted COVID-19 patients as a predictor of negative outcomes. J. Nutr. 2021;151:2199–2205.
    1. Gönen MS, 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. 2021;13:4047.
    1. Jolliffe DA, et al. Vitamin D supplementation to prevent acute respiratory infections: A systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol. 2021;9:276–292.
    1. Almerighi C, et al. 1α,25-dihydroxyvitamin D3 inhibits CD40L-induced proinflammatory and immunomodulatory activity in human monocytes. Cytokine. 2009;45(3):190–197.
    1. Entrenas Castillo M, 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. Lakkireddy M, et al. Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease. Sci. Rep. 2021;11:1–8.
    1. Murai IH, 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;325:1053–1060.
    1. Sabico S, 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. 2021;13:2170.
    1. Rastogi A, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: A randomised, placebo-controlled, study (SHADE study) Postgrad. Med. J. 2022;98:87–90.
    1. Sánchez-Zuno GA, et al. Vitamin D levels in COVID-19 outpatients from western Mexico: Clinical correlation and effect of its supplementation. J. Clin. Med. 2021;10:2378.
    1. Varikasuvu SR, et al. COVID-19 and vitamin D (Co-VIVID study): A systematic review and meta-analysis of randomized controlled trials. Expert Rev. Anti Infect Ther. 2022;20:907–913.
    1. Kitajima I, Maruyama I, Matsubara H, Osame M, Igata A. Immune dysfunction in hypophosphatemic vitamin D-resistant rickets: Immunoregulatory reaction of 1 alpha(OH) vitamin D3. Clin. Immunol. Immunopathol. 1989;53:24–31.
    1. Quesada JM, et al. The effect of calcitriol on natural killer cell activity in hemodialyzed patients. J. Steroid Biochem. 1989;34:423–425.
    1. Yu S, Cantorna MT. The vitamin D receptor is required for iNKT cell development. Proc. Natl. Acad. Sci. U.S.A. 2008;105:5207–5212.
    1. Lee GY, et al. Differential effect of dietary vitamin D supplementation on natural killer cell activity in lean and obese mice. J. Nutr. Biochem. 2018;55:178–184.
    1. Weeres MA, et al. The effects of 1,25-dihydroxyvitamin D3 on in vitro human NK cell development from hematopoietic stem cells. J. Immunol. 2014;193:3456–3462.
    1. Lee KN, et al. VDUP1 is required for the development of natural killer cells. Immunity. 2005;22:195–208.
    1. Al-Jaderi Z, Maghazachi AA. Effects of vitamin D3, calcipotriol and FTY720 on the expression of surface molecules and cytolytic activities of human natural killer cells and dendritic cells. Toxins (Basel) 2013;5:1932–1947.
    1. Kalicińska E, et al. Immunosuppression as a hallmark of critical COVID-19: Prospective study. Cells. 2021;10:1293.
    1. Zingaropoli MA, et al. Major reduction of NKT cells in patients with severe COVID-19 pneumonia. Clin. Immunol. 2021;22:108630.
    1. Kim EY, et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat. Med. 2008;14:633–640.
    1. Vabret N, et al. Immunology of COVID-19: Current state of the science. Immunity. 2020;52:910–941.
    1. Vassiliou AG, et al. Vitamin D deficiency correlates with a reduced number of natural killer cells in intensive care unit (ICU) and non-ICU patients with COVID-19 pneumonia. Hellenic J. Cardiol. 2021;62:381–383.
    1. Amrein K, Papinutti A, Mathew E, Vila G, Parekh D. Vitamin D and critical illness: What endocrinology can learn from intensive care and vice versa. Endocr. Connect. 2018;7:304–315.
    1. Krishnan A, et al. Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients. Crit. Care. 2010;14:216.
    1. Hiemstra TF, Casian A, Boraks P, Jayne DR, Schoenmakers I. Plasma exchange induces vitamin D deficiency. QJM. 2014;107:123–130.
    1. Loucera C, et al. Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients. Sci. Rep. 2021;11:23380.
    1. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. Ginde AA, et al. Early high-dose vitamin D3 for critically ill, vitamin D-deficient patients. N. Engl. J. Med. 2019;381:2529–2540.
    1. Tuohimaa P, et al. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: A longitudinal, nested case-control study in the Nordic countries. Int. J. Cancer. 2004;108:104–108.
    1. Sun X, et al. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev. 2020;53:38–42.
    1. Holick MF, et al. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2011;96:1911–1930.
    1. Lips P, et al. Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: A position statement of the European Calcified Tissue Society. Eur. J. Endocrinol. 2019;180:23–54.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj