Abstract: nutrients Article 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 1, *, Ksenia A. Golovatyuk 1 , Igor V. Kudryavtsev 1,2 , Alena T. Chernikova 1 , Arina A. Mikhaylova 1 , Arthur D. Aquino 1 , Daria I. Lagutina 1 , Ekaterina K. Zaikova 1 , Olga V. Kalinina 1 , Alexey S. Golovkin 1 , William B. Grant 3 and Evgeny V. Shlyakhto 1 1 2 3 * Citation: Karonova, T.L.; Golovatyuk, K.A.; Kudryavtsev, I.V.; Chernikova, A.T.; Mikhaylova, A.A.; Aquino, A.D.; Lagutina, D.I.; Zaikova, E.K.; Kalinina, O.V.; Golovkin, A.S.; et al. Effect of Cholecalciferol Supplementation on the Clinical Features and Inflammatory Markers in Hospitalized COVID-19 Patients: A Randomized, Open-Label, Single-Center Study. Nutrients 2022, 14, 2602. https://doi.org/10.3390/ nu14132602 Academic Editor: Sara Baldassano Received: 31 May 2022 Accepted: 21 June 2022 Published: 23 June 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Almazov National Medical Research Centre, 197341 Saint Petersburg, Russia; ksgolovatiuk@gmail.com (K.A.G.); igorek1981@yandex.ru (I.V.K.); arabicaa@gmail.com (A.T.C.); armikhaylova@yandex.ru (A.A.M.); akino97@bk.ru (A.D.A.); daria.lagutina.i@yandex.ru (D.I.L.); catherine3452@yandex.ru (E.K.Z.); olgakalinina@mail.ru (O.V.K.); golovkin_a@mail.ru (A.S.G.); shlyakhto_ev@almazovcentre.ru (E.V.S.) Institute of Experimental Medicine, 197376 Saint Petersburg, Russia Sunlight, Nutrition, and Health Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA; williamgrant08@comcast.net Correspondence: karonova@mail.ru Abstract: 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. Keywords: COVID-19;..