Intriguing results from an observational study
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. 2020:1-4. doi: 10.1007/s40520-020-01570-8 [Epub ahead of print].
The aim of this study was to determine whether there is an association between mean levels of circulating vitamin D in various countries with diagnosis or death from COVID 19.
Investigators obtained mean levels of vitamin D from existing published literature. They obtained the number of cases of COVID-19 per million population in each of the European countries and mortality caused by this disease per million population up until April 8, 2020.
Investigators carried out statistical analyses using the Pearson Correlation Coefficient Calculator.
Mean vitamin D levels (average 56.79 nmol/L) were negatively correlated with the number of cases of COVID-19 in each country and so were the mean vitamin D levels with the number of deaths caused by COVID-19 (average 80.42, STDEV 94.61, r(20)-value = −0.4378; P=0.05).
The idea that vitamin D supplementation could have protective action against pulmonary infections dates back to French publications in the 1940s that suggested application for treating tuberculosis.1-3 In 2016, John Cannell proposed that vitamin D was the “ ‘seasonal stimulus’ intimately associated with solar radiation [that] explained the remarkable seasonality of epidemic influenza,” an idea that Robert Hope-Simpson had pioneered in his 1981 article and subsequent 1992 book.4,5 Hope-Simpson was a highly respected epidemiologist, famous for correlating shingles with herpes zoster infections during childhood.6 Influenza outbreaks displayed such a distinct seasonal variability that Hope-Simpson theorized that something in ultraviolet light (UV) exposure lowered incidence. Cannell connected UV exposure with vitamin D production and suggested that vitamin D was protective. This conclusion seemed so obvious that they were surprised that no one had thought of it sooner. Since then vitamin D and its potential to prevent or ameliorate influenza and upper respiratory infections has been studied extensively.
The data has not proven as conclusive as we had assumed it would be.
Studies have reported consistent associations between low vitamin D and susceptibility to acute respiratory tract infections. This led to multiple randomized clinical trials to see whether vitamin D supplementation influenced the course of acute respiratory infection. By 2017, 5 separate meta-analyses had been published aggregating data from up to 15 primary trials. Two of these studies reported significant protective effects.7,8 Yet, the other 3 found no statistically significant effect.9-11 The 6th meta-analysis, published in 2017 by Adrian Martineau et al, did report a statistically significant benefit, though smaller than Cannell and other proponents had predicted.12
Martineau’s group combined data from 25 randomized controlled trials (RCTs; N=11,321), and their analysis found that vitamin D supplementation reduced the risk of acute respiratory tract infection by about 12% (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, the protective effects were seen only in those receiving daily or weekly vitamin D without additional boluses (adjusted odds ratio 0.81, CI 0.72 to 0.91) but not in those receiving 1 or more bolus doses (adjusted odds ratio 0.97, CI 0.86 to 1.10; P for interaction=0.05). The protection was stronger in those with baseline vitamin D levels ≥25 nmol/L.12 (Note: 25 nmol/L=10 ng/mL.)
In recent weeks there have been several articles released that suggest vitamin D is associated with the severity of Covid-19.
(Note: Because of the urgency of the pandemic, we are suspending our normal citation standards and are mentioning studies that are still preprint.)
A short preprint report by Mark Alipio, released April 9, 2020, describes his retrospective multicenter study of 212 Covid-19 cases in the Philippines. Data on clinical features and vitamin D levels were obtained from patient medical records. The majority of cases had ordinary clinical outcomes. Mean 25(OH)D was 23.8 ng/mL. Vitamin D levels were lowest in the critical cases and highest in the mild cases. These associations were statistically significant. For each standard deviation increase in serum 25(OH)D, “…the odds of having a mild clinical outcome rather than a severe outcome were increased approximately 7.94 times (OR=0.126, P<0.001)…” The odds of a critical outcome were reduced nearly 20-fold (OR=0.051, P<0.001). “The results suggest that an increase in serum 25(OH)D level in the body could either improve clinical outcomes or mitigate worst (severe to critical) outcomes, while a decrease in serum 25(OH)D level in the body could worsen clinical outcomes of COVID-2019 patients.”13
Together these various studies begin to provide a compelling argument to supplement with vitamin D during this pandemic.
A group of Indonesian researchers, Raharusun et al, posted a second preprint article on vitamin D and Covid-19 to SSRN on April 30, 2020. Their study was also retrospective and included 780 Covid-19 cases. Data here too were extracted from medical records. The study’s goal was to determine mortality patterns and associated risk factors. The data analysis revealed that the majority of the fatalities were male, older, and preexisting conditions. Below normal vitamin D levels were associated with increasing chances of death. The outcome differences that the authors report were striking: “98.9% of Vitamin D deficient cases died … 87.8% of Vitamin D insufficient cases died … Only 4.1% of cases with normal Vitamin D levels died.”14
Taken together these 3 articles seem to provide a convincing argument for vitamin D supplementation. The problem is that finding an association does not prove causation. There has been a growing concern in recent years that there is something missing in our understanding of vitamin D. Studies that have supplemented vitamin D have not seen the dramatic decrease in morbidity and mortality that earlier studies reporting associations had predicted.
Low vitamin D status is associated with greater morbidity and mortality from a wide range of conditions. Patients assume that this proves taking vitamin D will help these conditions. Unfortunately, the studies that have attempted to prove the benefits of taking vitamin D have reported mostly weak results.
Low vitamin D status is strongly associated with increased cancer risk and heart disease, but supplementation has not been a reliable treatment. Manson et al reported in a 2019 issue of NEJM the results from their large (N= 25,871) nationwide clinical trial supplementing with vitamin D (2,000 IU/day). “Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo,” the authors wrote.15
In 2019 the British Medical Journal published results from Zhang et al from a meta-analysis that combined data from 52 clinical trials (N= 75,454) and looked at risk of all-cause, cardiovascular, and cancer mortality. Vitamin D supplementation was not associated with all-cause mortality, cardiovascular mortality, or noncardiovascular mortality, though it was significantly associated with a 16% reduction in risk of cancer death (with D3 having a significantly better impact than D2).16 While a 16% reduction is welcome, earlier predictions had suggested a greater benefit.17 Feskanich et al suggested vitamin D might cut colon cancer risk in older women by half.18 Cedric Garland predicted that 1,000 IU/day of vitamin D would decrease colorectal cancer risk by half.19
These weak results have led many researchers to wonder if there might be something more to ultraviolet exposure that confers health benefit; vitamin D levels might only be a way to assess long-term UV exposure.20
In this current paper under review, Petre Ilie et al provide a good rationale with which to argue that vitamin D supplements may work against Covid-19. He points out that vitamin D levels do not vary by latitude in Europe as we might expect. Mean vitamin D in Spain is 26 nmol/L (10.42 ng/mL), in Italy 28 nmol/L (11.22 ng/mL), and in the Nordic countries 45 nmol/L (18.03 ng/mL). In Italy, by the way, 76% of women over 70 years of age have been found to have circulating levels below 30 nmol/L (12.02 ng/mL).21
There are several explanations for this latitude reversal. Culturally Southern Europeans prefer shade to strong sun compared to Northern Europeans. Also, their darker skin pigmentation decreases vitamin D synthesis. But most importantly, people in Northern European countries consume vitamin D supplements, cod liver oil, and vitamin D–fortified foods, and this improves their status.22
This gives us reason to believe that D supplementation might be effective.
In recent weeks most of us have become familiar with the list of risk factors that increase severity of Covid-19 symptoms along with risk of death from the illness. Most of these same comorbidities are associated with low vitamin D status. African Americans, who are reported to have disproportionately high mortality rates from Covid-19, have lower-than-average vitamin D levels.23 In a 2018 study, average vitamin D (N=328) among black Americans living in St. Louis was less than 15 ng/mL.24 Obesity,25 hypertension,26 and diabetes,27 are all also associated with low vitamin D status.
Together these various studies begin to provide a compelling argument to supplement with vitamin D during this pandemic. Granted, some of the information we are relying on is still in preprint. This is balanced by a long history of vitamin D’s use for respiratory infections.
Returning to Martineau et al’s meta-analysis on vitamin D and respiratory infections, their findings provide information on dosing that we might want to generalize and apply to many of our patients, especially if considering Covid-19 prophylaxis. Their report suggests that large boluses of vitamin D decrease efficacy. In regard to prevention of respiratory infection, more protection was seen in study participants who took daily or weekly doses of vitamin D, a 19% reduction in risk of infection. In those who received 1 or more large bolus doses, even along with daily doses, no significant protection was observed. Although it was popular some years back to give very large vitamin D doses, extrapolating from these findings suggests we avoid bolus dosing if we seek to protect from respiratory infections.
- Gounelle H, Vallette A, Bachet M. Fortes surcharges en vitamine D2 chez les tuberculeux pulmonaires; hypercalcémie sérque. C R Seances Soc Biol Fil. 1945;139:930.
- Binet L, Bour H. Essais de traitement de la tuberculose pulmonaire par des nebulisations de vitamine D2. Prog Med (Paris). 1946;74(24):579-581.
- Phelan JJ. Calciferol in pulmonary tuberculosis. Lancet. 1947;1(6457):764.
- Hope-Simpson RE. The role of season in the epidemiology of influenza. J Hyg (Lond). 1981;86(1):35-47.
- Hope-Simpson RE. The Transmission of Epidemic Influenza. New York City, NY: Plenum Press; 1992.
- Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134(6):1129-1140.
- Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2013;356:e65835.
- Charan J, Goyal JP, Saxena D, Yadav P. Vitamin D for prevention of respiratory tract infections: a systematic review and meta-analysis. J Pharmacol Pharmacother. 2012;356:300-303.
- Mao S, Huang S. Vitamin D supplementation and risk of respiratory tract infections: a meta-analysis of randomized controlled trials. Scand J Infect Dis. 2013;356:696-702.
- Xiao L, Xing C, Yang Z, et al. Vitamin D supplementation for the prevention of childhood acute respiratory infections: a systematic review of randomised controlled trials. Br J Nutr. 2015;356:1026-1034.
- Vuichard Gysin D, Dao D, Gysin CM, Lytvyn L, Loeb M. Effect of vitamin D3 supplementation on respiratory tract infections in healthy individuals: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2016;356:e0162996.
- 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.
- Mark Alipio. Vitamin D supplementation could possibly improve clinical outcomes of patients infected with Coronavirus-2019 (COVID-19). SSRN. Written April 9, 2020. Last revised July 10, 2020.
- Raharusun P, Priambada S, Budiarti C, Agung E, Budi C. Patterns of COVID-19 mortality and vitamin D: an Indonesian study. SSRN.
- Manson JE, Cook NR, Lee IM, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380(1):33-44.
- Zhang Y, Fang F, Tang J, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ. 2019;366:14673.
- Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr. 2011;65(9):1016-1026.
- Feskanich D, Ma J, Fuchs CS, et al. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev. 2004;13(9):1502-1508.
- Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol. 2005;97(1-2):179-194.
- van der Rhee HJ, de Vries E, Coebergh JW. Regular sun exposure benefits health. Med Hypotheses. 2016;97:34-37.
- Lips P, Cashman K, Lamberg-Allardt C, 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
- 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. 2020:1-4. doi: 10.1007/s40520-020-01570-8 [Epub ahead of print].
- Ginde AA, Liu MC, Camargo Jr CA. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009;169(6):626–632.
- McKee A, Lima Ribeiro SM, Malmstrom TK, et al. Screening for vitamin D deficiency in black Americans: comparison of total, free, bioavailable 25 hydroxy vitamin D Levels with parathyroid hormone levels and bone mineral density. J Nutr Health Aging. 2018;22(9):1045-1050.
- Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013;10(2):e1001383.
- Joukar F, Naghipour M, Hassanipour S, et al Association of serum levels of vitamin D with blood pressure status in Northern Iranian population: the PERSIAN Guilan Cohort Study (PGCS). Int J Gen Med. 2020;13:99-104.
- Grammatiki M, Rapti E, Karras S, Ajjan RA, Kotsa K. Vitamin D and diabetes mellitus: causal or casual association? Rev Endocr Metab Disord. 2017;18(2):227-241.