Jacob Schor, ND
A study by David Jolliffe et al has been nagging at me since it was published in September 2022 in the British Medical Journal, and it’s time to see if we might make sense of them. This was a comprehensive trial that asked whether measuring vitamin D levels and treating individuals found deficient would lower morbidity from upper respiratory infections (URIs), particularly from Covid-19. The results suggest that doing so is a waste of time.
In Joliffe’s phase-3 open-label controlled trial, some 2,958 people were tested for vitamin D levels. People considered low in vitamin D (r <30 ng/ml)), approximately 86% of those tested, were given six months of vitamin D, either 800 IU/day (n=1,328) or 3200 IU/day (n=1,346). A control group was neither tested nor supplemented (n=3,100). The researchers monitored the proportion of participants diagnosed with acute respiratory tract infections from any cause and the number of participants with confirmed Covid-19.
A total of 4.6% of those in the control group, who were neither tested nor supplemented with vitamin D, had at least one acute respiratory infection during six months of follow up (136/2949). In contrast, 5.7% of those given low dose (800 IU/day) (87/1515) and 5.0% in the higher dose group (76/1525) had an infection. The results were no more promising for Covid-19 in which 2.6% of the control group, 3.6% in the low dose, and 3.0% of the high dose group were infected during the trial.
These percentages did not differ statistically from each other so all we can accurately say is that no group had a better outcome, yet the trends seen in the numbers do suggest that doing nothing might have been better than intervening with vitamin D.1 If this is true, we have been wasting our time and our patients’ money when promoting the belief in vitamin D’s efficacy for preventing respiratory infections. Wow, did I really write that? No wonder this study is disturbing. Not only did vitamin D not help, it almost seemed to make things worse.
Our belief that vitamin D protects against pulmonary infection dates back nearly a century, to an article by A. R. Masten on heliotherapy used in Ancient Greece, published in a 1935.2 Recall that vitamin D was only isolated in 1931.3 In the 1940s, publications began suggesting that vitamin D generated by sun exposure might be the beneficial aspect of sunlight and could be used for treating tuberculosis.4-6 Yet it was relatively recently that this idea surfaced within modern naturopathic practice.
In 2016, John Cannell, MD, proposed that vitamin D was the “… ‘seasonal stimulus’ intimately associated with solar radiation [that] explained the remarkable seasonality of epidemic influenza…”, an idea that Hope-Simpson had pioneered back in 1981 in an article and his subsequent 1992 book.7,8
Hope-Simpson of course, was the famous self-taught epidemiologist, who first correlated development of shingles with earlier exposure to herpes zoster.9 Noting that influenza outbreaks display such a distinct seasonal variability, Hope-Simpson theorized that something in ultraviolet light (UV) exposure lowered incidence.
Cannell theorized that because UV exposure is so associated with vitamin D production that vitamin D was probably the agent providing protection. This conclusion seemed so obvious that it was surprising that no one had thought of it sooner. It made such good sense that we quickly accepted Cannell’s theory as fact. In doing so, we ignored a basic tenet of epidemiology: “Association does not prove causation.” Although 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 initially reported consistent associations between low vitamin D status and susceptibility to acute respiratory tract infections. This led to multiple randomized clinical trials to see whether vitamin D supplementation could change the course of acute respiratory infection. By 2017, five separate meta-analyses had been published aggregating data from up to 15 primary trials. Two of these studies reported significant protective effects,10,11 but the other three found no statistically significant benefit.12-14
A sixth meta-analysis published in 2017, by Adrian Martineau et al, reported a statistically significant benefit, though it was much smaller than Cannell and other proponents had predicted. Martineau’s group combined data from 25 RCTs (n=11,321) and their analysis found that vitamin D supplementation reduced the risk of acute respiratory tract infection by about 12%. The protective effects were seen only in those taking daily or weekly vitamin D doses. Those who took either large bolus doses alone or with daily doses saw no benefit.15
Over the past several years, since the Covid-19 pandemic’s onset, we have read numerous claims that vitamin D has efficacy in preventing or treating Covid-19 infection. A PubMed search while writing this piece in February 2023, found over 500 citations for “vitamin D and Covid19.” This list included 41 clinical trials and a series of meta-analyses. These later data groupings are of greatest interest.
Kümmel et al, writing in October 2022, described results from combining data from eight randomized controlled trials (n= 657 patients). Although their analysis showed a trend toward reduced mortality in those who used vitamin D compared to control groups, the differences did not reach statistical significance.16
An earlier meta-analysis by D’Ecclesiis et al., published in July 2022, which was more comprehensive, summarizing data from 38 studies (n= 205,565), did report significant benefit. Supplementation with vitamin D was associated with a significant lower risk of both Covid-19 severe disease (SRR 0.38, 95% CI 0.20-0.72, 6 studies) and mortality (SRR 0.35, 95% CI 0.170.70, 8 studies).17 These numbers were not just statistically significant but appear to be clinically significant: a 62% reduction in severe disease and a 75% reduction in mortality: effects this large could alter the behavior of the disease in a population.
A May 2022 analysis by Hosseini et al. was unable to calculate risk of hospitalization because of scant data but did report a significant reduction in ICU admission and mortality in those supplemented with vitamin D.18
A meta-analysis by Tentolouris et al, also published in May 2022, also reported positive findings. Data from 9 studies (n=2,078 of which 583 took vitamin D) suggest vitamin D significantly reduced ICU admission but not risk of mortality. In the D-treated groups 10.46% died, compared to 25.81% in the non-treated group (odds ratio [OR]: 0.597; 95% CI: 0.3181.121; p = 0.109). Although one might interpret such lowered number of deaths as important, the difference was not significant.
Differences in ICU admission rates however were: 12.19% of the treated group were admitted to ICU, compared to 26.27% in the non-treated group (OR: 0.326; 95% CI: 0.149-0.712; p = 0.005). One might be tempted to ignore statistics and believe these findings support the belief that D is helpful against Covid-19, yet the high p-value (looking at mortality) prevents us from talking about this as a finding. Still these numbers likely encouraged the use of vitamin D supplementation in recent years.
Dose size appeared to make a difference in this analysis. The very large doses (200,000 and 400,000 IU boluses) that had become common to use clinically to treat acute infection did not significantly reduce mortality while lower doses did reduce both mortality (OR: 0.437; 95% CI: 0.220–0.867, p = 0.018) and ICU admission (OR: 0.157; 95% CI: 0.033–0.743, p = 0.02). The tradition of giving patients large loading doses of vitamin D no longer seems appropriate.19
The variability of these findings should give one pause. Why do we see such dramatic effect in one pool of data and no effect in another? Vitamin D does seem to help in some studies and when it does, it makes a dramatic difference. Yet some of the time, vitamin D does nothing.
Am I just naïve in expecting scientific findings to be consistent and yield repeatable outcomes? Or are we missing some confounder to explain the instances when vitamin D fails? Why didn’t Joliffe et al. find any benefit in lowering respiratory infections when patients were tested for and then treated for D deficiency? Perhaps a second and careful reading of these meta-analyses may provide a hint?
A point worth noting in the D’Ecclesiis meta-analysis is that benefit of taking vitamin D was only significant if the analysis included studies that were conducted during March 2020. If those data were omitted the benefits were no longer statistically significant. In the northern hemisphere, vitamin D levels are generally at their lowest ebb in March. By March, people have also lost all of their tan left from the previous summer. People are at their palest in March.
A parallel but inverse situation was seen with studies conducted over the summer. If summer studies were included in the analysis, the results were also no longer significant even if the trends toward benefit persisted. This suggests to this reader that the benefits of supplementing with vitamin D are seasonal and sensitive to even slight seasonal fluctuations in sun exposure or paleness.
In simpler words, we might tell patients to take vitamin D in late winter and early spring and not to worry about taking it in the summer. Vitamin D may make a difference if taken during the dark months, but not so much the rest of the time. If this were true, one would think that testing D levels should be greatly helpful in predicting need and providing benefit but apparently not as much as we would think. I worry that we are missing something here.
This situation brings me back to Hope-Simpson’s initial findings that seasonal influenza fluctuated with sun exposure. Perhaps the hypothesis that sun exposure producing vitamin D is not entirely correct and that there are other factors triggered by sunshine aside from vitamin D? Vitamin D levels are a measure of sun exposure but perhaps D itself is not a full substitute for exposure to sunlight?
I confess that as a naturopathic doctor I bring certain prejudices to this discussion. Among these is a trust is nature and natural approaches to healing. Thus it is challenging for me to accept that the healing benefits of sunlight can be reduced to a synthesized chemical in pill form.
Sunlight triggers melanocytes, the specialized cells in the basal epidermis, to increase production of melanin, the chemical that gives skin its tan or brown color and helps protect the deeper layers of the skin from the harmful effects of the sun.20 That’s why skin changes color with sun exposure.
Melanin levels are directly associated with sun exposure and in turn are associated with vitamin D levels. The more melanin pigment in the skin, the less ultraviolet radiation penetrates and thus the less vitamin D is made. Their levels are closely related. This is why dark-skinned individuals are believed to be in greater need of vitamin D supplementation during the winter.21 Perhaps both vitamin D and melanin are both needed?
In the autumn of 2020, a paper theorized that there is a synergistic effect between vitamin D and melanin for preventing COVID-19 infection and suggested that “… by-products of melanin synthesis unequivocally tie to the dynamic site of human protease furin which is vital for the SARS-CoV-2- mediated disease progression.”22
A review by Sidiropoulou et al published in early 2021 appears to strongly suggest an interplay between melanin and vitamin D in preventing Covid, noting,
“Given that the vitamin D status is modulated by several intrinsic and extrinsic factors, including skin type (pigmentation), melanin polymers may also play a role in variable COVID- 19 outcomes among diverse population settings. Moreover, apart from the well-known limiting effects of melanin on the endogenous production of vitamin D, the potential crosstalk between the pigmentary and immune system may also require special attention concerning the current pandemic. ….. a range of mostly overlooked host factors, such as vitamin D status and melanin pigments, [that] may influence the course and outcome of COVID-19.”23
While theories support the benefit of vitamin D, a number also support a potential role for melanin in immunity: “… accumulating evidence from several systems suggests that melanins are potent immunomodulators with both pro- and anti-inflammatory properties, depending on the type of melanin and host response…. It should also be emphasized that melanin is considered to affect inflammatory responses directly and/or indirectly by influencing the host cytokine/chemokine production.”24
Both in vitro and ex vivo data have indicated that melanin can modulate cytokine-mediated signaling cascades, increasing the release of pro-inflammatory mediators, such as interleukin (IL)-1, IL-6, interferon γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Additional evidence supporting a potential role of melanin in the course of host immune responses during infection is provided by in vitro findings demonstrating a melanin-induced activation of the nuclear factor-κB (NF-κB) in monocytes through a Toll-like receptor (TLR)-dependent process.25,26
While we understand that vitamin D exerts many protective mechanisms against Covid-19 morbidity, melanin levels may also play a role in these benefits and their fluctuating levels may be what confounds the results of clinical trials that have sought to establish a clear causative benefit in supplementation.
The idea that melanin levels might have a synergistic effect with vitamin D opens an interesting line of diversion. Melanin is available as a food, what is commonly called sepia. The ink secreted by cuttlefish is about 10% melanin.27 There are strong hints in the literature that these animal inks have antifungal, antibacterial, and cytotoxic effects.28,29 Might the endogenous production of melanin triggered by sun exposure have similar impact? Should we be adding exogenous melanin from cuttlefish to our vitamin D pills? Or should we still encourage our patients to go outside and practice heliotherapy as the Ancient Greeks did? I admit I am prejudiced when it comes to nature.
Addendum
There is a problem with vitamin D research and how it’s been interpreted. Mica Hartley summed up this problem in 2015, writing:
“… although low 25(OH)D levels are associated with a range of chronic diseases, vitamin D supplementation trials and meta-analyses of trial data have not generally found a beneficial effect on the health outcomes tested….
“…results of observational studies may be incorrect because of reverse causation or failure to adequately control for confounding – or because the 25(OH)D level is simply a proxy for sun exposure, time outdoors or associated behaviours. Experimental studies show that sun exposure has positive effects on immune function and cardio-metabolic health, working through both vitamin D and non-vitamin D pathways.”30
Low vitamin D status is clearly associated with greater morbidity and mortality from a wide range of conditions. Many have concluded that this proves taking vitamin D will help these conditions. Unfortunately, the studies that have attempted to demonstrate benefit in taking vitamin D have reported mostly weak results.31
For example, low vitamin D status is strongly associated with increased risk of cancer and heart disease, but supplementation has not been a reliable treatment. JoAnn Manson et al reported in 2019 (n= 25,871), “Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo.”32
In 2019 the British Medical Journal published Zhang et al’s meta-analysis that combined data from 52 clinical trials (n= 75,454) and looked at risk of all-cause, cardiovascular, and cancer mortality. While vitamin D was associated with about a 15% reduction in death from cancer, with D-3 significantly superior to D-2, neither reduced all-cause mortality.33
While a 15% reduction in risk of dying of cancer is welcome, earlier predictions had suggested a greater benefit. Diana Feskanich et al suggested in 2004 vitamin D might cut colon cancer risk in older women by half.34 In 2006, Cedric Garland promised that 1,000 IU/day of vitamin D would decrease colorectal cancer risk to the same degree in men and women.35
These weak results have led many researchers to wonder if there might be something more to ultraviolet exposure that leads to health benefit; vitamin D levels might only be a way to assess long-term UV exposure. Vitamin D in the blood may drop when someone is unwell—that is, D is a reactive nutrient. Iron levels do this; they drop when infection, cancer, or chronic inflammation is present. This pseudo-iron deficiency can cause ‘anemia of chronic disease’ and ‘anemia of malignancy.’ These syndromes result from the original infection or chronic disease. Yet it is easy to think that iron deficiency is connected to these chronic conditions in a causal manner.
References
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Published May 6, 2023
About the Author
Jacob Schor, ND, now retired, had a general practice with a focus on naturopathic oncology in Denver, Colorado. He served as Abstract & Commentary Editor for the Natural Medicine Journal for several years (https://www.naturalmedicinejournal.com/) and posts blog articles on natural therapies, nutrition, and cancer (https://drjacobschor.wordpress.com/). He is a board member of CoAND and past president of OncANP, and someone who is happier outdoors than inside.