Risk of bias of the included studies in the meta-analysis
The Cochrane risk of bias tool for RCTs for evaluation of the risk of
bias in Castillo et al25. Data showed in Figure S2.
The risk of bias assessment of the two non-randomized interventional
studies is shown in Table S1. The risk of bias in observational studies
is detailed in Table S2.
Results of the estimated bias coefficient were from 0.014 to 0.141,
giving a P-value > 0.05 for all analyses. Therefore, the
tests provide weak evidence for the presence of publication bias.
DISCUSSION
This is the first systematic review with meta-analysis to show an
association between low plasma vitamin D level and increased risk of
death in inpatients with COVID-19 (1.41-fold). The results of this study
also show an association between low plasma vitamin D levels in COVID-19
patients and increase ICU admission risk (1.76-fold) and ventilation
requirement (3.50-fold).
Vitamin D deficiency is associated with an increased risk of developing
viral and bacterial infections36. Several studies have
linked the reduction of plasma vitamin D levels with increase
respiratory infections37,38, as influenza infection,
and vitamin D supplementation with the decrease of risk of these
infections39–41. Others studies revealed a higher
risk of ICU admission, sepsis, and death in hospitalized patients who
had low levels of vitamin D in pre-admission42,43.
Vitamin D has a role in regulating mineral metabolism, an important role
in the modulation of the immune response, and control the exacerbation
of the cellular immune response36,44,45. Studies
report that critically ill patients with COVID-19 have elevated in
inflammatory cytokines such as IL-1 and IL-6, and chemokines associated
with a Th1 response, corroborating the hypothesis of a cytokine storm in
this disease46,47.Vitamin D regulates feedback control
pathways that serve to decrease potential inflammatory damage from
disproportionate activation of the immune response48
Others authors question the role of the cytokine storm in COVID-19, and
that severity of the disease occurs due to direct viral injury,
endovasculitis, and or viral-induced
immunosuppression49. There is some evidence to support
this question. The less pronounced cytokine elevations in COVID-19 could
reflect a regulated, or inadequate, inflammatory response to infection
from SARS-Cov2. In addition, non-cytokine biomarkers, such D-dimer,
C-reactive protein, and ferritin, are elevated to a similar in patients
with COVID-19 when comparing with patients of another
disorders49,50.
Vitamin D has other roles in regulating the immune system. LL37 peptide,
a component of the innate immune system that acts in the lungs against
SARS-CoV-2, requires sufficient levels of vitamin D to be effective,
which could indicate the preventive effect of vitamin D levels for the
development of respiratory viruses51.
T lymphocytes are directly susceptible to SARS-CoV-2 infection and are
depleted in clinical COVID-1952. Vitamin D modulates
the function of immune cells, such as T and B cells, monocytes, and
dendritic cells, in an interaction between the innate and adaptive
immune systems53. Lachmann et al54conducted an RCT that showed that vitamin D deficiency is associated
with an absolute lower CD4+ T cell count in HIV
patients, however, that vitamin D supplementation increased the absolute
recovery of CD4+ T cell count in these patients.
It has also been previously shown that vitamin D affects on blood
coagulation parameters55. Hejazi et
al56 where the treatment of the deficiency of vitamin
D in patients with thromboembolism resulted in control of events with
the lowest doses of warfarin. Although COVID-19 is a respiratory
disease, many data have pointed to coagulopathy as a marker of mortality
from this disease57. Thus, anticoagulant therapy seems
to be associated with a better prognosis in critically ill patients with
COVID-19 57. Therefore, it is possible to assume that
the sufficient levels of vitamin D may be useful in the anticoagulant
treatment of critically ill patients with COVID-19 or may prevent mild
cases from becoming severe.
SARS- CoV-2 uses the angiotensin-converting enzyme receptor 2 to enter
alveolar epithelial cells, which would lead to the deregulation of the
Renin-Angiotensin System (RAS), accumulating the toxic product
angiotensin II in alveolar cells and causing an acute lung
injury58,59. Vitamin D regulates the balance between
the expression of members of the RAS and their deficiency pointed to
excessive activation of this system60. Therefore,
vitamin D deficiency may exacerbate pulmonary RAS dysregulation induced
by SARS-CoV-2 infection.
This study also showed that regular vitamin D supplementation was
associated with a lower risk of death and vitamin D treatment of
patients with COVID-19 was associated with a lower risk of ICU
admission. Castilho et al and Tan et al showed that administration of
calcifediol and cholecalciferol, respectively, reduced the need for ICU
admission of patients with COVID-19 that requiring hospitalization.
However, treatment with vitamin D in patients already diagnosed with
COVID-19 needs to be further studied.
This study has several strengths. To our knowledge, this is the first
meta-analysis using interventional studies associating vitamin D with
COVID-19 patients, and that included analyzing the risk of mortality in
hospitalized patients. This study informs physicians and patients
regarding the importance of monitoring vitamin D levels. Some
limitations of our study were the small number of interventional
studies, the analysis that used different treatments for vitamin D
supplementation, different cut-off plasma vitamin D levels,
observational design of the selected studies, and sample size.
These results suggest that COVID-19 patients with sufficient plasma
vitamin D levels is decreased risks of death, ICU admission, and
ventilation requirement. However, randomized clinical trials are needed
to confirm the benefits of vitamin D treatment in patients with
COVID-19.
REFERENCES
1. Bogoch II, Watts A, Thomas-Bachli A, Huber C, Kraemer MUG, Khan K.
Pneumonia of unknown aetiology in Wuhan, China: potential for
international spread via commercial air travel. J Travel Med .
2020;2020:1-3. doi:10.1093/jtm/taaa008
2. Lu H, Stratton CW, Tang Y-W. Outbreak of pneumonia of unknown
etiology in Wuhan, China: The mystery and the miracle. J Med
Virol . 2020:92. doi:10.1002/jmv.25678
3. WHO. WHO | Pneumonia of unknown cause – China. WHO.
http://www.who.int/csr/don/05-january-2020-pneumonia-of-unkown-cause-china/en/.
Published 2020. Accessed August 16, 2020.
4. WHO. WHO Coronavirus Disease (COVID-19) Dashboard. WHO.
https://covid19.who.int/. Published 2020. Accessed December 19, 2020.
5. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of
mortality due to COVID-19 based on an analysis of data of 150 patients
from Wuhan, China. Intensive Care Med . 2020:1.
doi:10.1007/s00134-020-05991-x
6. Martineau AR, Jolliffe DA, Greenberg L, et al. Vitamin D
supplementation to prevent acute respiratory infections: Individual
participant data meta-analysis. Health Technol Assess (Rockv) .
2019;23(2):1-44. doi:10.3310/hta23020
7. 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(7):1195-1198.
doi:10.1007/s40520-020-01570-8
8. Isaia G, Diémoz H, Maluta F, et al. Does solar ultraviolet radiation
play a role in COVID-19 infection and deaths? An environmental
ecological study in Italy. Sci Total Environ . 2020;(xxxx):143757.
doi:10.1016/j.scitotenv.2020.143757
9. Norval M, Björn LO, De Gruijl FR. Is the action spectrum for the
UV-induced production of previtamin D 3 in human skin correct?Photochem Photobiol Sci . 2010;9(1):11-17. doi:10.1039/b9pp00012g
10. Brenner H, Holleczek B, Schoettker B. Vitamin D insufficiency and
deficiency and mortality from respiratory diseases in a cohort of older
adults: potential for limiting the death toll during and beyond the
COVID-19 pandemic. 2020. doi:10.1101/2020.06.22.20137299
11. Kerget B, Kerget F, Kiziltunç A, et al. Evaluation of the
relationship of serum vitamin d levels in covid-19 patients with
clinical course and prognosis. Tuberk Toraks . 2020;68(3):227-235.
doi:10.5578/tt.70027
12. Ye K, Tang F, Liao X, et al. Does Serum Vitamin D Level Affect
COVID-19 Infection and Its Severity?-A Case-Control Study. J Am
Coll Nutr . October 2020:1-8. doi:10.1080/07315724.2020.1826005
13. 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;(0123456789).
doi:10.1007/s40618-020-01370-x
14. Hastie CE, Mackay DF, Ho F, et al. Vitamin D concentrations and
COVID-19 infection in UK Biobank. Diabetes Metab Syndr Clin Res
Rev . 2020;14(4):561-565. doi:10.1016/j.dsx.2020.04.050
15. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the
assessment of the quality of nonrandomized studies in meta-analyses.Eur J Epidemiol . 2010;25(9):603-605.
doi:10.1007/s10654-010-9491-z
16. Higgins JP, Savović J, Page MJ, Elbers RG, Sterne JA. Chapter 8:
Assessing risk of bias in a randomized trial | Cochrane
Training. Cochrane.
https://training.cochrane.org/handbook/current/chapter-08. Published
2019. Accessed June 9, 2020.
17. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: A tool for
assessing risk of bias in non-randomised studies of interventions.BMJ . 2016;355:4-10. doi:10.1136/bmj.i4919
18. Higgins JP, Li T, Deeks JJ. Chapter 6: Choosing effect measures and
computing estimates of effect | Cochrane Training. Cochrane.
https://training.cochrane.org/handbook/current/chapter-06. Published
2019. Accessed June 9, 2020.
19. Zhang J. What’s the Relative Risk?: A Method of Correcting the Odds
Ratio in Cohort Studies of Common Outcomes. JAMA J Am Med Assoc .
2008;280(19):1690-1691. doi:10.1001/jama.280.19.1690
20. Abrishami A, Dalili N, Mohammadi Torbati P, et al. Possible
association of vitamin D status with lung involvement and outcome in
patients with COVID-19: a retrospective study. Eur J Nutr .
2020;(0123456789). doi:10.1007/s00394-020-02411-0
21. Alguwaihes AM, Al-Sofiani ME, Megdad M, et al. Diabetes and Covid-19
among hospitalized patients in Saudi Arabia: a single-centre
retrospective study. Cardiovasc Diabetol . 2020;19(1):1-12.
doi:10.1186/s12933-020-01184-4
22. Annweiler C, Hanotte B, Grandin de l’Eprevier C, Sabatier JM, Lafaie
L, Célarier T. Vitamin D and survival in COVID-19 patients: A
quasi-experimental study. J Steroid Biochem Mol Biol .
2020;204(October):1-6. doi:10.1016/j.jsbmb.2020.105771
23. Annweiler G, Corvaisier M, Gautier J, et al. Vitamin d
supplementation associated to better survival in hospitalized frail
elderly covid-19 patients: The geria-covid quasi-experimental study.Nutrients . 2020;12(11):1-12. doi:10.3390/nu12113377
24. Baktash V, Hosack T, Patel N, et al. Vitamin D status and outcomes
for hospitalised older patients with COVID-19. Postgrad Med J .
2020;2:1-6. doi:10.1136/postgradmedj-2020-138712
25. Castillo ME, Costa LME, Vaquero Barrios JM, 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(August).
doi:10.1016/j.jsbmb.2020.105751
26. Cereda E, Bogliolo L, Klersy C, et al. Vitamin D 25OH deficiency in
COVID-19 patients admitted to a tertiary referral hospital. Clin
Nutr . 2020;(xxxx). doi:10.1016/j.clnu.2020.10.055
27. Hernández JL, Nan D, Fernandez-Ayala M, et al. Vitamin D Status in
Hospitalized Patients with SARS-CoV-2 Infection. J Clin Endocrinol
Metab . 2020;XX(Xx):1-11. doi:10.1210/clinem/dgaa733
28. Jain A, Chaurasia R, Sengar NS, Singh M, Mahor S, Narain S. Analysis
of vitamin D level among asymptomatic and critically ill COVID-19
patients and its correlation with inflammatory markers. Sci Rep .
2020;10(1):1-8. doi:10.1038/s41598-020-77093-z
29. Macaya F, Espejo C, Valls A, et al. Interaction between age and
vitamin D deficiency in severe COVID-19 infection. Nutr Hosp .
2020;37(5):1039-1042.
30. Mendy A, Apewokin S, Wells AA, Morrow AL. Diverse Population of
COVID-19 Patients. 2020:1-24.
31. 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. FEBS J .
2020;287(17):3693-3702. doi:10.1111/febs.15495
32. Pizzini A, Aichner M, Sahanic S, et al. Impact of vitamin d
deficiency on covid-19—a prospective analysis from the covild
registry. Nutrients . 2020;12(9):1-9. doi:10.3390/nu12092775
33. Radujkovic A, Hippchen T, Tiwari-Heckler S, Dreher S, Boxberger M,
Merle U. Vitamin D deficiency and outcome of COVID-19 patients.Nutrients . 2020;12(9):1-13. doi:10.3390/nu12092757
34. Smet D De, Smet K De, Herroelen P, Gryspeerdt S. OUP accepted
manuscript. Am J Clin Pathol . 2020;25:1-8.
doi:10.1093/ajcp/aqaa252
35. Tan CW, Ho LP, Kalimuddin S, et al. Cohort study to evaluate effect
of vitamin D, magnesium, and vitamin B12 in combination on severe
outcome progression in older patients with coronavirus (COVID-19).Nutrition . 2020;79-80:111017. doi:10.1016/j.nut.2020.111017
36. Van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin
D3: Basic concepts. In: Journal of Steroid Biochemistry and
Molecular Biology . Vol 97. J Steroid Biochem Mol Biol; 2005:93-101.
doi:10.1016/j.jsbmb.2005.06.002
37. Li W, Cheng X, Guo L, et al. Association between serum
25-hydroxyvitamin D concentration and pulmonary infection in children.Med (United States) . 2018;97(1). doi:10.1097/MD.0000000000009060
38. Juusela M, Pallasaho P, Sarna S, Piirilä P, Lundbäck B, Sovijärvi A.
Bronchial hyperresponsiveness in an adult population in Helsinki:
Decreased FEV1, the main determinant. Clin Respir J .
2013;7(1):34-44. doi:10.1111/j.1752-699X.2012.00279.x
39. Jung HC, Seo MW, Lee S, Kim SW, Song JK. Vitamin D3 supplementation
reduces the symptoms of upper respiratory tract infection during winter
training in vitamin D-insufficient taekwondo athletes: A randomized
controlled trial. Int J Environ Res Public Health . 2018;15(9).
doi:10.3390/ijerph15092003
40. 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. doi:10.1136/bmj.i6583
41. Arihiro S, Nakashima A, Matsuoka M, et al. Randomized Trial of
Vitamin D Supplementation to Prevent Seasonal Influenza and Upper
Respiratory Infection in Patients With Inflammatory Bowel Disease.Inflamm Bowel Dis • . 2019;25(6). doi:10.1093/ibd/izy346
42. Moromizato T, Litonjua AA, Braun AB, Gibbons FK, Giovannucci E,
Christopher KB. Association of low serum 25-hydroxyvitamin D levels and
sepsis in the critically ill. Crit Care Med . 2014;42(1):97-107.
doi:10.1097/CCM.0b013e31829eb7af
43. Braun A, Chang D, Mahadevappa K, et al. Association of low serum
25-hydroxyvitamin D levels and mortality in the critically ill.Crit Care Med . 2011;39(4):671-677.
doi:10.1097/CCM.0b013e318206ccdf
44. Looman KIM, Jansen MAE, Voortman T, et al. The role of vitamin D on
circulating memory T cells in children: The Generation R study.Pediatr Allergy Immunol . 2017;28(6):579-587.
doi:10.1111/pai.12754
45. Wang T-T, Nestel FP, Bourdeau V, et al. Cutting Edge:
1,25-Dihydroxyvitamin D 3 Is a Direct Inducer of Antimicrobial Peptide
Gene Expression . J Immunol . 2004;173(5):2909-2912.
doi:10.4049/jimmunol.173.5.2909
46. Yang Y, Shen C, Li J, et al. Plasma IP-10 and MCP-3 levels are
highly associated with disease severity and predict the progression of
COVID-19. J Allergy Clin Immunol . 2020;146(1):119-127.e4.
doi:10.1016/j.jaci.2020.04.027
47. England JT, Abdulla A, Biggs CM, et al. Weathering the COVID-19
storm: Lessons from hematologic cytokine syndromes. Blood Rev .
May 2020:100707. doi:10.1016/j.blre.2020.100707
48. Bikle DD. Vitamin D and immune function: Understanding common
pathways. Curr Osteoporos Rep . 2009;7(2):58-63.
doi:10.1007/s11914-009-0011-6
49. Leisman DE, Ronner L, Pinotti R, et al. Rapid Review Cytokine
elevation in severe and critical COVID-19: a rapid systematic review,
meta-analysis, and comparison with other inflammatory syndromes.
2020:1233. doi:10.1016/S2213-2600(20)30404-5
50. Mardani R, Alamdary A, Mousavi Nasab S, Gholami R, Ahmadi N, Gholami
A. Association of vitamin D with the modulation of the disease severity
in COVID-19. Virus Res . 2020;289:1-5.
51. Benskin LL. A Basic Review of the Preliminary Evidence That COVID-19
Risk and Severity Is Increased in Vitamin D Deficiency. Front
Public Heal . 2020;8. doi:10.3389/fpubh.2020.00513
52. Wang X, Xu W, Hu G, et al. SARS-CoV-2 infects T lymphocytes through
its spike protein-mediated membrane fusion. Cell Mol Immunol .
2020:1. doi:10.1038/s41423-020-0424-9
53. Greiller CL, Martineau AR. Modulation of the immune response to
respiratory viruses by vitamin D. Nutrients . 2015;7(6):4240-4270.
doi:10.3390/nu7064240
54. Lachmann R, Bevan MA, Kim S, et al. A comparative phase 1 clinical
trial to identify anti-infective mechanisms of vitamin D in people with
HIV infection. 2015. doi:10.1097/QAD.0000000000000666
55. Liu G, Hong T, Yang J. A single large dose of vitamin d could be
used as a means of coronavirus disease 2019 prevention and treatment.Drug Des Devel Ther . 2020;14:3429-3434. doi:10.2147/DDDT.S271754
56. Hejazi ME, Modarresi-Ghazani F, Hamishehkar H, Mesgari-Abbasi M,
Dousti S, Entezari-Maleki T. The Effect of Treatment of Vitamin D
Deficiency on the Level of P-Selectin and hs-CRP in Patients With
Thromboembolism: A Pilot Randomized Clinical Trial. J Clin
Pharmacol . 2017;57(1):40-47. doi:10.1002/jcph.774
57. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment
is associated with decreased mortality in severe coronavirus disease
2019 patients with coagulopathy. J Thromb Haemost .
2020;18(5):1094-1099. doi:10.1111/jth.14817
58. Pfeffer PE, Hawrylowicz CM. Vitamin D and lung disease.Thorax . 2012;67(11):1018-1020. doi:10.1136/thoraxjnl-2012-202139
59. Carter SJ, Baranauskas MN, Fly AD. Considerations for Obesity,
Vitamin D, and Physical Activity Amid the COVID‐19 Pandemic.Obesity . 2020;28(7):1176-1177. doi:10.1002/oby.22838
60. Xu J, Yang J, Chen J, Luo Q, Zhang Q, Zhang H. Vitamin D alleviates
lipopolysaccharide-induced acute lung injury via regulation of the
renin-angiotensin system. Mol Med Rep . 2017;16(5):7432-7438.
doi:10.3892/mmr.2017.7546