D is for Drama: Demystifying Vitamin D in COVID19

D is for Drama: Demystifying Vitamin D in COVID19

Vitamin D is the current subject of dramatic debates and a clutter of studies. So what’s the deal, Is vitamin D preventative and protective in COVID19? You’d better buckle up… it’s a bit of a mess.

TL;DR

• Current studies hint at correlation, not causation.
• Watch out for reviews funded by the supplement industry.
• Some studies show no impact of vitamin D supplementation on critical illness.
• Low levels of vitamin D may be a sign — not of inadequate intake — but of impaired production and metabolism due to illness.

Let’s start with an overview of Vitamin D — what it is, where we get it, and how it functions in the body.

Vitamin D is a fat-soluble vitamin produced by this skin in response to sun exposure. It’s also available in some foods, including fatty fish, like salmon, tuna, and mackerel, egg yolks and beef liver, fortified milk (dairy and non-dairy), and sun-dried mushrooms. This form of vitamin D, however, is biologically inert. For vitamin D to be used by the body it must be converted, first by the liver, then by the kidneys, to its active form — calcitriol.

Vitamin D serves several important roles in the body:

• Promotes calcium absorption in the gut; maintains serum calcium and phosphate concentrations for proper bone mineralization and to prevent hypocalcemic tetany (spasms caused by low calcium).
• Required for bone growth and bone remodeling by osteoblasts and osteoclasts. Insufficient vitamin D can lead to the condition of thin, brittle, misshapen bones known as rickets in children and osteomalacia in adults.
• Modulates cell growth, neuromuscular and immune function, and reduction of inflammation. Vitamin D partially modulates many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis (NIH, 2020).

Regardless of any impact in COVID19, we can all likely agree that having healthy levels of vitamin D is generally a good idea.

Correlation vs. Causation

Let’s take a look at some of the studies claiming that vitamin D is protective in COVID19. Many of these studies are based on the correlation between vitamin D deficiencies in the geographic regions (viz. Spain, Italy, and Switzerland) and demographics (the elderly) hit hardest by the disease. The literature is clear and consistent: vitamin D deficiency goes hand-in-hand with COVID19 (Ilie et al., 2020), (Biesalski, 2020), (Ebadi & Montano-Loza, 2020), (Davies et al., 2020)[pre-print; not peer-reviewed].

But does that mean vitamin D supplementation is a fix?

Despite the “crude associations” (Ilie et al., 2020) between vitamin D deficiency and COVID19, there are a few issues to consider before stress-buying supplements:

1. People with lower vitamin D levels are at higher risk for infection, but this seems to be explained by other risk factors, not vitamin D itself. In one study the association between COVID19 and vitamin D deficiency disappeared when the results were adjusted for factors like age, race, obesity, and socioeconomic status (Hastie et al., 2020).
2. Vitamin D production and metabolism is often altered in illness. Low vitamin D may be a signal of illness severity, not the cause of it (PulmCCM, 2020).
   3. These correlations do not confirm that supplementation with vitamin D will be preventative or protective in COVID19; only randomized clinical trials can establish the efficacy of supplementation (O’Connor, 2020).
3. It’s a great time to harken back to that favorite mantra from your high school statistics class: “Correlation does not imply causation.”

Keep an Eye on the Money

A paper published recently in Nutrients makes a case for using vitamin D supplementation to protect against COVID19. According to this review, vitamin D:

• Enhances cellular innate immunity by inducing antimicrobial peptides cathelicidins and defensins which destroy invading pathogens by destabilizing their cell membranes. Cathelicidins and defensins lower viral replication rates.
• Protects against a cytokine storm triggered by the innate immune system by reducing the production of proinflammatory cytokines TNFα and IFNγ and increasing the expression of anti-inflammatory cytokines by macrophages. Proinflammatory cytokines mediate inflammation that damages the lungs and leads to pneumonia.
• Modulates adaptive immunity, promotes resolution of inflammation via the induction of regulatory T cells.

Sounds reasonable, but a few red flags are going up. Many of the studies referenced by this paper, from which these mechanisms are extrapolated, are in vitro or animal studies, not human trials. One of the more compelling-looking citations is a documented predatory journal, the “European Journal of Biomedical and Pharmaceutical Sciences.” A glance at the journal Nutrients itself reveals that its publisher MPDI has a history of compromised standards.

All this aside, though, none of the cited studies investigate the effect of vitamin D supplementation on COVID19 patients. Keep in mind that theorizing about mechanisms of action is a great place to start, but speculation is not the same as science. The whole point of empiricism is that reality often doesn’t work the way we imagine it might. Hence the need for clinical trials.

The authors offer further observations to support the theory that vitamin D reduces the risk and severity of COVID19:

1. The outbreak occurred in winter, the season when 25-hydroxyvitamin D (a liver metabolite measured to assess vitamin D status) concentrations are lowest
2. The number of cases in the Southern Hemisphere near the end of summer are low
3. Vitamin D deficiency has been found to contribute to acute respiratory distress syndrome
4. Case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration

They conclude with the recommendation that people at risk of “influenza and/or COVID19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/mL (100–150 nmol/L)” (Grant et al., 2020).

Seems legit… maybe? But then again, look: not only are the conclusions drawn based on theoretical mechanisms and correlations, but several of the authors have a vested financial interest in vitamin D sales. One is a direct retailer of vitamin D, while another receives funding from vitamin D supplier Bio-Tech Pharmacal. It goes without saying that such conflicts of interest introduce bias.

*eyebrow raise* Are your skeptic senses tingling yet?

Some Studies Show No Effect

A trial conducted and funded through the National Heart, Lung, and Blood Institute (NHLBI) Prevention and Early Treatment of Acute Lung Injury (PETAL) Network found no effect of early high dose vitamin D3 on critically ill vitamin D deficient patients.

The subjects of this study were 1,078 critically ill patients admitted to the ICU in 44 hospitals around the US who had been screened for vitamin D deficiency. Most patients had pneumonia, sepsis, need for mechanical ventilation or vasopressors, and were at high risk for acute respiratory distress syndrome (ARDS). These patients were randomized to receive a single 540,000 IU enteral dose of vitamin D3 or placebo. This dose of vitamin D rapidly corrected vitamin D deficiency, but failed to provide an advantage over placebo with respect to mortality, length of stay, or days of mechanical ventilation.

There was no dose-response curve in those receiving supplementation, and those patients suffering from more severe deficiencies experienced no more positive outcomes than less-deficient patients (NEJM, 2019).

A review of this study published by Pulmonary Critical Care Medicine notes that vitamin D production and metabolism are significantly altered during illness, which often causes levels to fall below the threshold of what is considered normal. It is unclear if this low level is a direct cause of harm. Indeed, the classification of such ill patients as “deficient” in vitamin D is somewhat questionable (PulmCCM, 2020).

An earlier randomized trial found that supplementation exhibited better outcomes, but the mortality effect vanished within months (JAMA, 2014).

In sum: the role of vitamin D in preventing COVID19 infection and reducing disease severity is speculative at best. We have myriad correlations and plausible theoretical mechanisms, which indicate the possibility that vitamin D supplementation may be of use. What we still need, however, are clinical trials to establish a definitive causal relationship. Looks like a few of these are in the works, so keep an eye out for new findings.

COVID19 aside, Vitamin D deficiency is ubiquitous and causes well-established health problems. Even if vitamin D doesn’t resolve COVID19 the way you might hope and dream it does, it’s still worthwhile to seek nutrient repletion for all the credibly-recognized health benefits.

Be sensible, don’t take more than the recommended dose of vitamins without consulting a qualified healthcare provider, and save your money — massive doses of vitamins aren’t a magic bullet for COVID19. Instead, consider spending more socially distanced time outdoors, eat fatty fish like tuna, mackerel, and salmon, egg yolks, fortified milk, and sun-dried mushrooms.

You know, do the normal healthy things you should be doing anyways.