Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity
Abstract
:1. Introduction
- Seasonal dependence: it began in winter in the northern hemisphere and both case and death rates were lowest in summer, especially in Europe, and rates began increasing again in July, August, or September in various European countries [10]; it is thus generally inversely correlated with solar UVB doses and vitamin D production [11,12].
- Much of the damage from COVID-19 is thought to be related to the “cytokine storm”, which is manifested as hyperinflammation and tissue damage [16].
- The body’s immune system becomes dysregulated in severe COVID-19 [17].
2. Findings Regarding Vitamin D and COVID-19
2.1. Vitamin D Deficiency Increases the Risk and Severity of COVID-19
2.2. Vitamin D and Treatment of COVID-10
2.3. Vitamin D Helps Immune Cells Produce Antimicrobial Peptides
2.4. Vitamin D Reduces Inflammatory Cytokine Production
2.5. Type II Pneumocytes and Surfactants in the Lungs
2.6. Vitamin D, Angiotensin II, and ACE2 Receptors
2.7. Reduces Risk of Endothelial Dysfunction
2.8. Matrix Metalloproteinase 9
2.9. RAS-Mediated Bradykinin Storm
2.10. Summary: How Vitamin D Might Reduce Risk, Severity, and Death from COVID-19
- Inactivates some viruses by stimulating antiviral mechanisms such as antimicrobial peptides, as discussed in Section 2.3.
- Reduces proinflammatory cytokines through modulating the immune system, as discussed in Section 2.4.
- Increases ACE2 concentrations and reduces risk of death from ensuing ARDS, as discussed in Section 2.5.
- Reduces risk of endothelial dysfunction, as discussed in Section 2.7.
- Reduces MMP-9 concentrations, as discussed in Section 2.8.
- Reduces risk of the bradykinin storm, as discussed in Section 2.9.
2.11. Vitamin D Seasonality and COVID-19
2.12. Racial/Ethnic Disparities
2.13. Vitamin D Reduces Risk of COVID-19 in a Causal Manner
2.14. Other Nutrients That May Augment the Effectiveness of Vitamin D Supplementation
3. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Location | Participants | Outcomes vs. 25(OH)D (ng/mL) | Strengths, Limitations | Reference | |
---|---|---|---|---|---|
1 | UK | 449 C19 patients 348,598 controls from UK Biobank | Incidence for 25(OH)D <10 vs. >10 Univariable OR = 1.37 (1.07–1.76, p = 0.01) Multivariable OR = 0.92 (0.71–1.21, p = 0.56) | Some confounding variables should not be used since they affect 25(OH)D concentrations [19,20] 25(OH)D data were from blood drawn from 2006 to 2010 Participant 25(OH)D concentrations change over time, reducing correlations with disease outcomes [21] | Hastie [22] |
2 | Switzerland | 27 patients PCR+ for SARS-CoV-2; 80 patients PCR– 1377 controls with 25(OH)D measured in same period in 2019 | Patients PCR+ had mean 25(OH)D = 11 vs. 25 for patients PCR– (p = 0.004) Controls had 25(OH)D = 25, not significantly different from patients PCR– (p = 0.08) | PCR+ is for antibodies; may not be active COVID-19 Small number of PCR+ | D’Avolio [23] |
3 | UK, Newcastle upon Tyne | 92 C19, non-ITU; 42 C19, ITU Patients were supplemented with vitamin D3 at doses inversely correlated with baseline 25(OH)D concentration | Non-ITU vs. ITU: 25(OH)D 19 ± 15 vs. 13 ± 7 (p = 0.30) 25(OH)D <20 vs. >20 (p = 0.02) RR for death, 25(OH)D = 0.97 (0.42–2.23, p = 0.94) | Lack of correlation of death with baseline 25(OH)D was likely due to graded supplementation with vitamin D | Panagiotou [24] |
5 | Italy | 42 C19 hospitalized patients; mean age 65 ± 13 years, 88 with ARDS | !L6 for 25(OH)D >30: 80 ± 40 pg/L; for 25(OH)D <10, 240 ± 470 pg/L After 10 days, patients with 25(OH)D <10 had a 50% mortality vs. 5% for 25(OH)D <10 (p = 0.02) | Patients with 25(OH)D <10 ng/mL had a mean age of 74 ± 11 years vs. 63 ± 15 years for patients with 25(OH)D ≥10 ng/mL | Carpagnano [25] |
6 | Korea | 50 C19 patients with PCR+, 150 controls; mean age = 52 ± 20 years | C19 vs. control: 16 (SD 8) vs. 25 (SD 13) (p < 0.001); ≤20, 74% vs. 43% (p = 0.003); ≤10, 24% vs. 7% (p = 0.001) | Strengths: measured B vitamin, folate, selenium and zinc concentrations as well as 25(OH)D Weaknesses: small number of patients; incomplete analysis of data for C19 outcomes | Im [26] |
7 | Russia | 80 C19 patients with community-acquired pneumonia | Severe: 25(OH)D = 12 ± 6 ng/mL; moderate to severe: 25(OH)D = 19 ± 14 ng/mL Death: 25(OH)D = 11 ± 6 ng/mL; discharged: 18 ± 6 ng/mL Obesity rates: 62% for severe, 15% for discharged, p < 0.001 | Strengths: studied the effect of obesity Weaknesses: small numbers | Karonova [27] |
8 | Mexico | 172 hospitalized C19 patients | Mean 25(OH)D = 17 ± 7 ng/mL for hospitalized C19 patients Survivors: mean age = 48 ± 13 years; 25(OH)D = 17 ± 7 ng/mL Death: mean age = 65 ± 12 years; 25(OH)D = 14 ± 6 ng/mL (p value for difference in 25(OH)D = 0.0008) | Weaknesses: survivors were much younger than non-survivors Comorbid factors not reported | Tort [28] |
9 | UK | 105 patients with C19 symptoms; 70 C19 PCR+, 35 PCR–; mean age = 80 ± 10 years | PCR+: 25(OH)D = 11 (8–19); PCR–: 25(OH)D = 21 (13–129) (p = 0.0008) Comorbid diseases were not significantly correlated with ≤12 vs. >12; | PCR+ is for antibodies; may not be active COVID-19 | Baktash [29] |
10 | UK | 656 C19, 203 died from C19; 340,824 controls from UK Biobank | Incidence for 25(OH)D <10 vs. >10 Univariable OR = 1.56 (1.28–1.90, p < 0.0001) Multivariable OR = 1.10 (0.88–1.37, p = 0.40) Death for 25(OH)D <10 ng/mL vs. >10 ng/mL Univariable OR = 1.61 (1.14–2.27, p = 0.0007) Multivariable OR = 1.21 (0.83–1.76, p = 0.31) | Same comments as for earlier UK Biobank study | Hastie [30] |
11 | Germany | 185 C19; median age = 60 years | Multivariable HR for death for 25(OH)D <12: IMV/D, 6.1 (2.8–13.4, p < 0.001); D, 14.7 (4.2–52.2, p < 0.001) | Strengths: HR adjusted for age, gender, and comorbidities Weaknesses: Small number of IMV and deaths | Radujkovic [31] |
12 | Austria | 109 C19 hospitalized patients; mean age = 58 ± 14 years | Mild: 26 ± 12 Moderate: 22 ± 8 Severe: 20 ± 10 (p = 0.12) PTH increased significantly with age (p = 0.001) | The vitamin D finding may have been limited owing to the high mean 25(OH)D concentrations Mild C19 patients had mean age = 46 ± 16 years; moderate and severe patients has mean age = 60 ± 13 years PTH increases with age [32] | Pizzini [33] |
13 | Spain | 80 emergency department patients with a PCR+ test within the past three months; retrospective study | 49 non-severe C19, 25(OH)D = 19 ng/mL; 31 severe C19, 25(OH)D = 13 ng/mL (p = 0.15) For patients under 65 years, 30 non-severe C19, 25(OH)D = 22 (11–31) ng/mL; 10 severe C19, 25(OH)D = 11 (9–12) ng/mL (p = 0.009) Multivariable OR for severe C19 for 25(OH)D <20 ng/mL = 3.2 (95% CI, 0.9 to 11.4, p = 0.07) | Weaknesses: small study; prevalence of advanced chronic kidney disease was higher in severe than non-severe cases (45% vs. 24%, p = 0.054) | Macaya [34] |
14 | China | 62 C19 patients, 80 healthy controls | age, 25(OH)D: controls: 43 years, 29 (23–33) ng/mL; mild/moderate C19: 39 (30–49) years, 23 (18–27) ng/mL; severe/critical C19: 65 (54–69) years, 15 (13–20) ng/mL Multivariate OR for severe/critical C19 for 25(OH)D <20 ng/mL = 15 (1.2 to 187, p = 0.03) | Strengths: many factors measured Weaknesses: the severe/critical patients were much older than mild/moderate patients and controls | Ye [35] |
Location | Participants | Outcomes vs. 25(OH)D (ng/mL) | Strengths, Limitations | Reference | |
---|---|---|---|---|---|
1 | Israel | Data from a hospital in Tel Aviv involving patients who had previous 25(OH)D measurements and were tested for SARS-CoV-2 using PCR 782 patients PCR+ 7025 patients PCR– | Univariate: 20–29 vs. >30: OR = 1.59 (1.24–2.02, p = 0.005); <20 vs. >30, OR = 1.58 (1.13–2.09, p = 0.0002). Multivariate: <30 vs. >30, OR = 1.50 (1.13–1.98, p = 0.001) | Strengths: large number of participants. Weakness: PCR+ is not COVID-19. | Merzon [36] |
2 | US | 489 C19 patients, PCR+; mean age = 49 ± 18 years with 25(OH)D concentrations were from preceding 12 months | 124 <20 vs. 287 >20, RR = 1.77 (1.12–2.81, p = 0.02) | Strengths: this is a retrospective study in which serum 25(OH)D concentrations and vitamin D supplementation history were obtained during the preceding 12 months. | Meltzer [37] |
3 | US | 191,779 patients tested for 25(OH)D and SARS-CoV-2 positivity during the past year by Quest Diagnostics | SARS-CoV-2 positivity for 25(OH)D <20 = 12.5% (95% CI, 12.2–12.8%); positivity for 25(OH)D >55 = 5.9% (95% CI, 5.5–6.4%). For 25(OH)D <20, SARS-CoV-2 positivity rates were: black non-Hispanic, 19%; Hispanic, 16%; white non-Hispanic, 9% | Strengths: large number of participants and is a retrospective study. 25(OH)D concentrations were seasonally adjusted. Weaknesses: SARS-CoV-2 positivity is a precursor to COVID-19, but many with positivity do not develop COVID-19. There may be bias in who was tested since the tests were ordered by physicians. | Kaufman[38] |
Criterion | Evidence | Reference |
---|---|---|
Strength of association | A retrospective study in Chicago found a 77% increased risk of COVID-19 for 25(OH)D <20 ng/mL vs. >20 ng/mL | [37] |
Consistency | Thirteen of 16 observational studies of COVID-19 or SARS-CoV-2 positivity reported inverse correlations with respect to 25(OH)D concentration. Two studies that did not find an inverse association used 25(OH)D values from more than a decade prior to COVID-19 and in the multivariable analysis used some confounding factors that affect 25(OH)D | Table 1 and Table 2 |
Temporality | Four retrospective studies found inverse correlations between serum 25(OH)D and incidence of COVID-19 or SARS-CoV-2 positivity | [34,36,37,38] |
Biological gradient | The large observational study of SARS-CoV-2 positivity found a large decrease as serum 25(OH)D increased from <20 to 50 ng/mL | [38] |
Plausibility | Mechanisms have been proposed to explain how vitamin D reduces risk of SARS-CoV-2 infection and COVID-19 | Discussed in this review |
Coherence with known facts | Serum 25(OH)D concentrations are inversely correlated with risk and outcome of many diseases, also supported by RCTs in several cases | [5,7,8,44,139] |
Experiment | Two intervention studies provide weak experimental support. Many RCTs are either planned or in progress to evaluate the role of vitamin D supplementation on COVID-19 risk and outcomes [18] | [58,59] |
Analogy | Vitamin D supplementation reduces risk of some acute respiratory tract infections | [8] |
Account for confounding factors | Univariate or multivariate regression analyses with confounding factors | [29,31,36,37] |
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Mercola, J.; Grant, W.B.; Wagner, C.L. Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity. Nutrients 2020, 12, 3361. https://doi.org/10.3390/nu12113361
Mercola J, Grant WB, Wagner CL. Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity. Nutrients. 2020; 12(11):3361. https://doi.org/10.3390/nu12113361
Chicago/Turabian StyleMercola, Joseph, William B. Grant, and Carol L. Wagner. 2020. "Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity" Nutrients 12, no. 11: 3361. https://doi.org/10.3390/nu12113361