Does the plasma vitamin D level affect the severity of infection in COVID-19 patients of different age groups?
Year 2022,
Volume: 15 Issue: 3, 499 - 512, 01.07.2022
Dilek Güvenç
,
Aynur Atilla
,
Bahattin Avcı
,
Vedide Rezan Uslu
,
Sedat Gökmen
,
Fatih Temocin
,
Tuba Kuruoğlu
Abstract
Purpose: SARS-CoV-2 has caused an on-going global pandemic of COVID-19 disease. Vitamin-D has an immunomodulatory effect on the disease by suppressing the adaptive immune system which can lead to a cytokine storm, and boosting the innate immune system. This study evaluated the relationship between both the clinical characteristics of COVID-19 patients and the severity of their infections, and their serum Vitamin D levels.
Material and Methods: Forty COVID-19 patients from the period April to July, 2020, and 46 healthy subjects from a similar period in 2019, were included. Serum Vitamin-D level, Clinical findings, comorbidities, chest computed tomography findings, hematological and serum biochemistry analyzes of the patients were evaluated.
Results: COVID-19 patients had a significantly lower mean serum 25(OH) Vitamin-D level (12·86 ± 6·27 ng/mL) than healthy subjects (25·4 ± 12·7 ng/mL) (p<<0·001). The prevalence of Vitamin D deficiency in COVID-19 patients was high, not only in the elderly, but also in middle age and young patients. Ground-glass opacification and paving stone sign were the most frequent patterns observed in chest-computed tomography (CT) images. There was a significant negative relationship between Vitamin-D deficiency and C-reactive protein (CRP) level (p=0·0243). In addition, a high CRP level was associated with abnormal CT findings (p=0·001).
Conclusion: The authors conclude that determining the Vitamin-D level in COVID-19 patients and administering it at the appropriate dosage can reduce the severity and progression of COVID-19 disease by contributing to the regulation of the cytokine storm and pulmonary inflammatory response.
References
- 1. Wang C, Han J. Will the COVID-19 pandemic end with the Delta and Omicron variants? : Springer; 2022. p. 1-11.
- 2. Al-Quteimat OM, Amer AM. The impact of the COVID-19 pandemic on cancer patients. Am J Clin Oncol. 2020;43:452-455. doi: https://doi.org/10.1097/COC.0000000000000712.
- 3. Daneshkhah A, Agrawal V, Eshein A, Subramanian H, Roy H, Backman V. Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients. Aging Clin Exp Res. 2020;32:2141-2158. doi: 10.1007/s40520-020-01677-y.
- 4. Zdrenghea MT, Makrinioti H, Bagacean C, Bush A, Johnston SL, Stanciu LA. Vitamin D modulation of innate immune responses to respiratory viral infections. Rev Med Virol. 2017;27:e1909. doi: https://doi.org/10.1002/rmv.1909.
- 5. Alpdemir M, Alpdemir MF. Meta Analysis Vitamin D deficiency status in Turkey: A meta-analysis. Int J Med Biochem. 2019;2:118-131. doi: https://doi.org/10.14744/ijmb.2019.04127.
- 6. Çubukçu M, Recai A, Müderrisoğlu S. Samsun İlinde D Vitamini Düzeylerinin Yaş, Cinsiyet ve Mevsimsel Özelliklere Göre Değerlendirilmesi. Ankara Medical Journal. 2019;19:769-775. doi: https://doi.org/10.17098/amj.652002.
- 7. Hughes D, Norton R. Vitamin D and respiratory health. Clin Exp Immunol. 2009;158:20-25. doi: https://doi.org/10.1111/j.1365-2249.2009.04001.x.
- 8. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. The American journal of clinical nutrition. 2010;91:1255-1260. doi: https://doi.org/10.3945/ajcn.2009.29094.
- 9. Loeb M, Dang AD, Thiem VD, et al. Effect of Vitamin D supplementation to reduce respiratory infections in children and adolescents in Vietnam: A randomized controlled trial. Influenza Other Respi Viruses. 2019;13:176-183. doi: https://doi.org/10.1111/irv.12615.
- 10. Teymoori‐Rad M, Shokri F, Salimi V, Marashi SM. The interplay between vitamin D and viral infections. Rev Med Virol. 2019;29:e2032. doi: https://doi.org/10.1002/rmv.2032.
- 11. Aranow C. Vitamin D and the immune system. J Investig Med. 2011;59:881-886. doi: http://dx.doi.org/10.2310/JIM.0b013e31821b8755.
- 12. Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients. 2013;5:2502-2521. doi: https://doi.org/10.3390/nu5072502.
- 13. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet. 2020;395:565-574. doi: https://doi.org/10.1016/S0140-6736(20)30251-8.
- 14. Burrell LM, Johnston CI, Tikellis C, Cooper ME. ACE2, a new regulator of the renin–angiotensin system. Trends Endocrinol Metab. 2004;15:166-169. doi: https://doi.org/10.1016/j.tem.2004.03.001.
- 15. Parekh D, Dancer RC, Scott A, et al. Vitamin D to prevent lung injury following esophagectomy—a randomized, placebo-controlled trial. Crit Care Med. 2018;46:e1128. doi: https://doi.org/10.1097/CCM.0000000000003405.
- 16. Dancer RC, Parekh D, Lax S, et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax. 2015;70:617-624. doi: http://dx.doi.org/10.1136/thoraxjnl-2014-206680.
- 17. Mitchell F. Vitamin-D and COVID-19: do deficient risk a poorer outcome? The Lancet. Diabetes & Endocrinology. 2020;8:570. doi: https://doi.org/10.1016/S2213-8587(20)30183-2.
- 18. Ministry of Health. COVID-19 (SARS-CoV-2 Infection) Treatment for Adult Patients 2020 [cited 2020 October 14]. Available from: https://covid19.saglik.gov.tr/Eklenti/39061/0/covid-19rehberieriskinhastatedavisipdf.pdf.
- 19. Singh S, Kaur R, Singh RK. Revisiting the role of vitamin D levels in the prevention of COVID-19 infection and mortality in European countries post infections peak. Aging Clin Exp Res. 2020;32:1609-1612. doi: https://doi.org/10.1007/s40520-020-01619-8.
- 20. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of vitamin D status and other clinical characteristics with COVID-19 test results. JAMA network open. 2020;3:e2019722-e2019722. doi: https://doi.org/10.1001/jamanetworkopen.2020.19722.
- 21. Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res. 2020;32:1195–1198. doi: https://doi.org/10.1007/s40520-020-01570-8.
- 22. Merzon E, Tworowski D, Gorohovski A, et al. Low plasma 25 (OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study. The FEBS journal. 2020;287:3693-3702. doi: https://doi.org/10.1111/febs.15495.
- 23. Karahan S, Katkat F. Impact of Serum 25 (OH) Vitamin D Level on Mortality in Patients with COVID-19 in Turkey. J Nutr Health Aging. 2020:1-8. doi: https://doi.org/10.1007/s12603-020-1479-0.
- 24. Hastie CE, Mackay DF, Ho F, et al. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020;114:561-565. doi: https://doi.org/10.1016/j.dsx.2020.04.050.
- 25. Ojeda A, Cuñat T, Calvo A. Diagnosis of vitamin D deficiency in patients admitted in ICU with COVID 19 disease. J Biomed Res Rev. 2020;3:1-4.
- 26. Zhao J, Gao H-Y, Feng Z-Y, Wu Q-J. A retrospective analysis of the clinical and epidemiological characteristics of COVID-19 patients in Henan Provincial People’s Hospital, Zhengzhou, China. Frontiers in Medicine. 2020;7:286. doi: https://doi.org/10.3389/fmed.2020.00286.
- 27. D’Avolio A, Avataneo V, Manca A, et al. 25-hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2. Nutrients. 2020;12:1359. doi: https://doi.org/10.3390/nu12051359.
- 28. Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF. SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One. 2020;15:e0239252. doi: https://doi.org/10.1371/journal.pone.0239252.
- 29. Coster D, Wasserman A, Fisher E, et al. Using the kinetics of C-reactive protein response to improve the differential diagnosis between acute bacterial and viral infections. Infection. 2020;48:241-248. doi: https://doi.org/10.1007/s15010-019-01383-6.
- 30. Wang G, Wu C, Zhang Q, et al., editors. C-Reactive Protein Level May Predict the Risk of COVID-19 Aggravation. Open Forum Infectious Diseases; 2020: Oxford University Press US.
- 31. Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem. 2004;279:48487-48490. doi: https://doi.org/10.1074/jbc.R400025200.
- 32. Kruit A, Zanen P. The association between vitamin D and C-reactive protein levels in patients with inflammatory and non-inflammatory diseases. Clin Biochem. 2016;49:534-537. doi: https://doi.org/10.1016/j.clinbiochem.2016.01.002.
- 33. Liefaard MC, Ligthart S, Vitezova A, et al. Vitamin D and C-reactive protein: a Mendelian randomization study. PLoS One. 2015;10:e0131740. doi: https://doi.org/10.1371/journal.pone.0131740.
- 34. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi: https://doi.org/10.1136/bmj.i6583.
- 35. Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M. Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Front Physiol. 2014;5:151. doi: https://doi.org/10.3389/fphys.2014.00151.
- 36. Adorini L, Penna G. Dendritic cell tolerogenicity: a key mechanism in immunomodulation by vitamin D receptor agonists. Hum Immunol. 2009;70:345-352. doi: https://doi.org/10.1016/j.humimm.2009.01.016.
- 37. Xiong Y, Liu Y, Cao L, et al. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerging microbes & infections. 2020;9:761-770. doi: https://doi.org/10.1080/22221751.2020.1747363.
- 38. Aygun H. Vitamin D can prevent COVID-19 infection-induced multiple organ damage. Naunyn-schmiedeberg's Archives of Pharmacology. 2020;393:1157–1160 doi: https://doi.org/10.1007/s00210-020-01911-4.
- 39. Carpagnano GE, Di Lecce V, Quaranta VN, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest. 2020;9:1-7. doi: https://doi.org/10.1007/s40618-020-01370-x.
- 40. Liu K-C, Xu P, Lv W-F, Qiu X-H, Yao J-L, Jin-Feng G. CT manifestations of coronavirus disease-2019: a retrospective analysis of 73 cases by disease severity. Eur J Radiol. 2020;126:108941. doi: https://doi.org/10.1016/j.ejrad.2020.108941.
- 41. De Smet D, De Smet K, Herroelen P, Gryspeerdt S, Martens G. Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality. Am J Clin Pathol. 2021;155:381-388. doi: 10.1093/ajcp/aqaa252.
- 42. Mardani R, Vasmehjani AA, Zali F, et al. Laboratory parameters in detection of COVID-19 patients with positive RT-PCR; a diagnostic accuracy study. Archives of Academic Emergency Medicine. 2020;8:e43.
- 43. Deng X, Liu B, Li J, Zhang J, Zhao Y, Xu K. Blood biochemical characteristics of patients with coronavirus disease 2019 (COVID-19): a systemic review and meta-analysis. Clinical Chemistry and Laboratory Medicine (CCLM). 2020;58:1172-1181. doi: https://doi.org/10.1515/cclm-2020-0338.
- 44. Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clinical Chemistry and Laboratory Medicine (CCLM). 2020;58:1131-1134. doi: https://doi.org/10.1515/cclm-2020-0198.
- 45. Tan CW, Ho LP, Kalimuddin S, et al. A cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients. Nutrition. 2020;79-80:111017. doi: https://doi.org/10.1016/j.nut.2020.111017.
- 46. Castillo ME, Costa LME, Barrios JMV, 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. The Journal of steroid biochemistry and molecular biology. 2020;203:105751. doi: https://doi.org/10.1016/j.jsbmb.2020.105751.
- 47. Sassi F, Tamone C, D'Amelio P. Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients. 2018;10:1656. doi: 10.3390/nu10111656. PubMed PMID: 30400332; PubMed Central PMCID: PMCPMC6266123.
- 48. Szymczak-Pajor I, Śliwińska A. Analysis of association between vitamin D deficiency and insulin resistance. Nutrients. 2019;11:794. doi: https://doi.org/10.3390/nu11040794.
Plazma D vitamini düzeyi farklı yaş gruplarındaki COVID-19 hastalarında enfeksiyonun şiddetini etkiler mi?
Year 2022,
Volume: 15 Issue: 3, 499 - 512, 01.07.2022
Dilek Güvenç
,
Aynur Atilla
,
Bahattin Avcı
,
Vedide Rezan Uslu
,
Sedat Gökmen
,
Fatih Temocin
,
Tuba Kuruoğlu
Abstract
Amaç: SARS-CoV-2, devam eden küresel COVID-19 pandemisine sebep olmuştur. D vitamini, sitokin fırtınasına yol açabilen adaptif immun yanıtı baskılayarak ve doğuştan gelen immun yanıtı güçlendirerek immunmodulatör etki oluşturur. Bu çalışmada, COVID-19 hastalarının klinik özellikleri, enfeksiyonlarının şiddeti ve serum D vitamini düzeyleri arasındaki ilişki değerlendiridi.
Gereç ve Yöntem: Nisan-Temmuz 2020 döneminde 40 COVID-19 hastası ve 2019'daki aynı döneme ait 46 sağlıklı denek çalışmaya dahil edildi. Hastaların serum D vitamini düzeyi, klinik bulgular, komorbiditeler, akciğere ait bilgisayarlı tomografi bulguları, hematolojik ve serum biyokimya analizleri değerlendirildi.
Bulgular: COVID-19 hastalarının ortalama serum 25(OH) D Vitamini düzeyi (12.86 ± 6.27 ng/mL) sağlıklı deneklere (25.4 ± 12.7 ng/mL) göre anlamlı derecede düşük belirlenmiştir (p<<0.001). COVID-19 hastalarında D vitamini eksikliği prevalansı sadece yaşlılarda değil orta yaş ve genç hastalarda da yüksek bulunmuştur. Göğüs bilgisayarlı tomografi (BT) görüntülerinde en sık gözlenen paternler buzlu cam opaklaşması ve kaldırım taşı görüntüsü olmuştur. Vitamin D eksikliği ile C-reaktif protein (CRP) düzeyi arasında negatif ilişki belirlenmiştir (p=0.0243). Ayrıca yüksek CRP düzeyinin anormal BT bulguları ile ilişkili olduğu saptanmıştır (p=0.001).
Sonuç: COVID-19 hastalarında D vitamini seviyesinin belirlenmesi ve uygun dozda uygulanmasının sitokin fırtınasının ve pulmoner inflamatuar yanıtın düzenlenmesine katkıda bulunarak COVID-19 hastalığının şiddetini ve ilerlemesini azaltabileceği sonucuna varılmıştır.
References
- 1. Wang C, Han J. Will the COVID-19 pandemic end with the Delta and Omicron variants? : Springer; 2022. p. 1-11.
- 2. Al-Quteimat OM, Amer AM. The impact of the COVID-19 pandemic on cancer patients. Am J Clin Oncol. 2020;43:452-455. doi: https://doi.org/10.1097/COC.0000000000000712.
- 3. Daneshkhah A, Agrawal V, Eshein A, Subramanian H, Roy H, Backman V. Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients. Aging Clin Exp Res. 2020;32:2141-2158. doi: 10.1007/s40520-020-01677-y.
- 4. Zdrenghea MT, Makrinioti H, Bagacean C, Bush A, Johnston SL, Stanciu LA. Vitamin D modulation of innate immune responses to respiratory viral infections. Rev Med Virol. 2017;27:e1909. doi: https://doi.org/10.1002/rmv.1909.
- 5. Alpdemir M, Alpdemir MF. Meta Analysis Vitamin D deficiency status in Turkey: A meta-analysis. Int J Med Biochem. 2019;2:118-131. doi: https://doi.org/10.14744/ijmb.2019.04127.
- 6. Çubukçu M, Recai A, Müderrisoğlu S. Samsun İlinde D Vitamini Düzeylerinin Yaş, Cinsiyet ve Mevsimsel Özelliklere Göre Değerlendirilmesi. Ankara Medical Journal. 2019;19:769-775. doi: https://doi.org/10.17098/amj.652002.
- 7. Hughes D, Norton R. Vitamin D and respiratory health. Clin Exp Immunol. 2009;158:20-25. doi: https://doi.org/10.1111/j.1365-2249.2009.04001.x.
- 8. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. The American journal of clinical nutrition. 2010;91:1255-1260. doi: https://doi.org/10.3945/ajcn.2009.29094.
- 9. Loeb M, Dang AD, Thiem VD, et al. Effect of Vitamin D supplementation to reduce respiratory infections in children and adolescents in Vietnam: A randomized controlled trial. Influenza Other Respi Viruses. 2019;13:176-183. doi: https://doi.org/10.1111/irv.12615.
- 10. Teymoori‐Rad M, Shokri F, Salimi V, Marashi SM. The interplay between vitamin D and viral infections. Rev Med Virol. 2019;29:e2032. doi: https://doi.org/10.1002/rmv.2032.
- 11. Aranow C. Vitamin D and the immune system. J Investig Med. 2011;59:881-886. doi: http://dx.doi.org/10.2310/JIM.0b013e31821b8755.
- 12. Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients. 2013;5:2502-2521. doi: https://doi.org/10.3390/nu5072502.
- 13. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet. 2020;395:565-574. doi: https://doi.org/10.1016/S0140-6736(20)30251-8.
- 14. Burrell LM, Johnston CI, Tikellis C, Cooper ME. ACE2, a new regulator of the renin–angiotensin system. Trends Endocrinol Metab. 2004;15:166-169. doi: https://doi.org/10.1016/j.tem.2004.03.001.
- 15. Parekh D, Dancer RC, Scott A, et al. Vitamin D to prevent lung injury following esophagectomy—a randomized, placebo-controlled trial. Crit Care Med. 2018;46:e1128. doi: https://doi.org/10.1097/CCM.0000000000003405.
- 16. Dancer RC, Parekh D, Lax S, et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax. 2015;70:617-624. doi: http://dx.doi.org/10.1136/thoraxjnl-2014-206680.
- 17. Mitchell F. Vitamin-D and COVID-19: do deficient risk a poorer outcome? The Lancet. Diabetes & Endocrinology. 2020;8:570. doi: https://doi.org/10.1016/S2213-8587(20)30183-2.
- 18. Ministry of Health. COVID-19 (SARS-CoV-2 Infection) Treatment for Adult Patients 2020 [cited 2020 October 14]. Available from: https://covid19.saglik.gov.tr/Eklenti/39061/0/covid-19rehberieriskinhastatedavisipdf.pdf.
- 19. Singh S, Kaur R, Singh RK. Revisiting the role of vitamin D levels in the prevention of COVID-19 infection and mortality in European countries post infections peak. Aging Clin Exp Res. 2020;32:1609-1612. doi: https://doi.org/10.1007/s40520-020-01619-8.
- 20. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of vitamin D status and other clinical characteristics with COVID-19 test results. JAMA network open. 2020;3:e2019722-e2019722. doi: https://doi.org/10.1001/jamanetworkopen.2020.19722.
- 21. Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res. 2020;32:1195–1198. doi: https://doi.org/10.1007/s40520-020-01570-8.
- 22. Merzon E, Tworowski D, Gorohovski A, et al. Low plasma 25 (OH) vitamin D level is associated with increased risk of COVID‐19 infection: an Israeli population‐based study. The FEBS journal. 2020;287:3693-3702. doi: https://doi.org/10.1111/febs.15495.
- 23. Karahan S, Katkat F. Impact of Serum 25 (OH) Vitamin D Level on Mortality in Patients with COVID-19 in Turkey. J Nutr Health Aging. 2020:1-8. doi: https://doi.org/10.1007/s12603-020-1479-0.
- 24. Hastie CE, Mackay DF, Ho F, et al. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020;114:561-565. doi: https://doi.org/10.1016/j.dsx.2020.04.050.
- 25. Ojeda A, Cuñat T, Calvo A. Diagnosis of vitamin D deficiency in patients admitted in ICU with COVID 19 disease. J Biomed Res Rev. 2020;3:1-4.
- 26. Zhao J, Gao H-Y, Feng Z-Y, Wu Q-J. A retrospective analysis of the clinical and epidemiological characteristics of COVID-19 patients in Henan Provincial People’s Hospital, Zhengzhou, China. Frontiers in Medicine. 2020;7:286. doi: https://doi.org/10.3389/fmed.2020.00286.
- 27. D’Avolio A, Avataneo V, Manca A, et al. 25-hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2. Nutrients. 2020;12:1359. doi: https://doi.org/10.3390/nu12051359.
- 28. Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF. SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One. 2020;15:e0239252. doi: https://doi.org/10.1371/journal.pone.0239252.
- 29. Coster D, Wasserman A, Fisher E, et al. Using the kinetics of C-reactive protein response to improve the differential diagnosis between acute bacterial and viral infections. Infection. 2020;48:241-248. doi: https://doi.org/10.1007/s15010-019-01383-6.
- 30. Wang G, Wu C, Zhang Q, et al., editors. C-Reactive Protein Level May Predict the Risk of COVID-19 Aggravation. Open Forum Infectious Diseases; 2020: Oxford University Press US.
- 31. Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem. 2004;279:48487-48490. doi: https://doi.org/10.1074/jbc.R400025200.
- 32. Kruit A, Zanen P. The association between vitamin D and C-reactive protein levels in patients with inflammatory and non-inflammatory diseases. Clin Biochem. 2016;49:534-537. doi: https://doi.org/10.1016/j.clinbiochem.2016.01.002.
- 33. Liefaard MC, Ligthart S, Vitezova A, et al. Vitamin D and C-reactive protein: a Mendelian randomization study. PLoS One. 2015;10:e0131740. doi: https://doi.org/10.1371/journal.pone.0131740.
- 34. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi: https://doi.org/10.1136/bmj.i6583.
- 35. Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M. Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Front Physiol. 2014;5:151. doi: https://doi.org/10.3389/fphys.2014.00151.
- 36. Adorini L, Penna G. Dendritic cell tolerogenicity: a key mechanism in immunomodulation by vitamin D receptor agonists. Hum Immunol. 2009;70:345-352. doi: https://doi.org/10.1016/j.humimm.2009.01.016.
- 37. Xiong Y, Liu Y, Cao L, et al. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerging microbes & infections. 2020;9:761-770. doi: https://doi.org/10.1080/22221751.2020.1747363.
- 38. Aygun H. Vitamin D can prevent COVID-19 infection-induced multiple organ damage. Naunyn-schmiedeberg's Archives of Pharmacology. 2020;393:1157–1160 doi: https://doi.org/10.1007/s00210-020-01911-4.
- 39. Carpagnano GE, Di Lecce V, Quaranta VN, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest. 2020;9:1-7. doi: https://doi.org/10.1007/s40618-020-01370-x.
- 40. Liu K-C, Xu P, Lv W-F, Qiu X-H, Yao J-L, Jin-Feng G. CT manifestations of coronavirus disease-2019: a retrospective analysis of 73 cases by disease severity. Eur J Radiol. 2020;126:108941. doi: https://doi.org/10.1016/j.ejrad.2020.108941.
- 41. De Smet D, De Smet K, Herroelen P, Gryspeerdt S, Martens G. Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality. Am J Clin Pathol. 2021;155:381-388. doi: 10.1093/ajcp/aqaa252.
- 42. Mardani R, Vasmehjani AA, Zali F, et al. Laboratory parameters in detection of COVID-19 patients with positive RT-PCR; a diagnostic accuracy study. Archives of Academic Emergency Medicine. 2020;8:e43.
- 43. Deng X, Liu B, Li J, Zhang J, Zhao Y, Xu K. Blood biochemical characteristics of patients with coronavirus disease 2019 (COVID-19): a systemic review and meta-analysis. Clinical Chemistry and Laboratory Medicine (CCLM). 2020;58:1172-1181. doi: https://doi.org/10.1515/cclm-2020-0338.
- 44. Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clinical Chemistry and Laboratory Medicine (CCLM). 2020;58:1131-1134. doi: https://doi.org/10.1515/cclm-2020-0198.
- 45. Tan CW, Ho LP, Kalimuddin S, et al. A cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients. Nutrition. 2020;79-80:111017. doi: https://doi.org/10.1016/j.nut.2020.111017.
- 46. Castillo ME, Costa LME, Barrios JMV, 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. The Journal of steroid biochemistry and molecular biology. 2020;203:105751. doi: https://doi.org/10.1016/j.jsbmb.2020.105751.
- 47. Sassi F, Tamone C, D'Amelio P. Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients. 2018;10:1656. doi: 10.3390/nu10111656. PubMed PMID: 30400332; PubMed Central PMCID: PMCPMC6266123.
- 48. Szymczak-Pajor I, Śliwińska A. Analysis of association between vitamin D deficiency and insulin resistance. Nutrients. 2019;11:794. doi: https://doi.org/10.3390/nu11040794.