More Evidence That Vitamin D Sufficiency Equals Less Severe COVID-19

Patients hospitalized with COVID-19 who have sufficient levels of vitamin D show significant reductions in severe outcomes and a lower risk of death compared with insufficient levels, new research shows.

"This study provides direct evidence that vitamin D sufficiency can reduce the complications including the cytokine storm and ultimately death from COVID-19," said senior author Michael F. Holick, MD, PhD, of Boston University School of Medicine, Massachusetts, in a press statement from his institution.

The research examines hospitalized patients with severe COVID-19 in Iran, and Holick worked with lead researcher Zhila Maghbooli, MD, of the Tehran University of Medical Sciences, and colleagues, on the study, which was published in PLoS One.

The findings come on the heels of another recently published study, in which Holick and his team found that people with sufficient vitamin D levels in the United States had as much as a 54% reduced risk of getting infected with COVID-19.

Although this latest research adds to a plethora of data on the potential role of vitamin D in COVID-19, many questions and caveats remain, commented E. Michael Lewiecki, MD.

"This study adds to an accumulation of data showing an association between higher serum levels of vitamin D and better outcomes in patients infected with COVID-19," he told Medscape Medical News.

"There is biological plausibility for benefit of vitamin D, since it is known to regulate innate and adaptive immunity in ways that might reduce the viral load in patients exposed to SARS-CoV-2 and mitigate the severity and consequences of cytokine storm."

"However, it is important to recognize that associations reported in observational studies do not necessarily mean there is a causal relationship," cautioned Lewiecki, of the University of New Mexico School of Medicine in Albuquerque.

"It may be that higher vitamin D is a marker of better health and lower baseline risk of complications of COVID-19."

Although Iran Is Sunny, Prevalence of Vitamin D Deficiency Is High

In the latest study published in PLoS One, which involved 235 patients hospitalized with COVID-19 infection in Tehran, Iran, through May 1, 2020, most patients (67.2%) had insufficient vitamin D levels, defined as serum 25-hydroxyvitamin D [25(OH)D] levels < 30 ng/mL.

"Iran is a sunny country but the prevalence of vitamin D deficiency is high especially in elder people who present with more severe clinical manifestations after exposure to SARS-CoV-2," note Maghbooli and colleagues.

The mean age of those included was 58.7 years, and 37.4% were 65 years or older.

Overall, 74% of patients had severe COVID-19 infection, defined according to the Centers for Disease Control and Prevention criteria.

Those with sufficient vitamin D levels (≥ 30 ng/mL) had a significantly lower prevalence of severe disease (63.6%) versus those with insufficient levels (77.2%; P = .02).

And those with sufficient levels had significantly lower levels of unconsciousness compared to those with insufficient vitamin D levels (1.3% vs 8.2%; P = .03); the same was true for hypoxia (19.4% vs 39.2%; P = .004).

There were no significant differences in duration of hospital stay or ICU admissions between patients with and without vitamin D sufficiency, however.

No patients under the age of 40 died from COVID-19 infection, while among the 207 patients over 40, the mortality rate was 16.3%.

Of those over 40 with sufficient vitamin D levels, 9.7% died from COVID-19 infection, compared with 20% of those with insufficient vitamin D levels.

For those with serum 25(OH)D levels of 40 ng/mL or higher, the mortality rate declined further to 6.3%.

While the optimum serum level of 25(OH)D required for a healthy immune system remains debatable, the findings offer insights, Maghbooli and coauthors note.

"A blood level of at least 40 ng/mL may be optimal for vitamin D's immunomodulatory effect," they write.

Among the patients, 66% had a history of a chronic condition; 36.6% had a history of diabetes, 44.4% hypertension, 1.3% immunological disorders, 1.3% chronic obstructive pulmonary disease, 22.1% heart disorders, 0.9% malignancy, 5.5% lung disorders, 4.3% asthma, and 3% rheumatology disorders.

However, after adjusting for factors including age, sex, body mass index (BMI), smoking, and history of chronic medical conditions, vitamin D sufficiency was still significantly associated with decreased COVID-19 disease severity (P = .01), as was lower BMI (P = .02).

Is it Worth Supplementing Anyway?

Patients with vitamin D insufficiency also had significantly higher levels of the inflammatory marker C-reactive protein (P = .01) and lower lymphocyte levels (P = .03).

These data add to the evidence that vitamin D potentially mitigates the severity of the cytokine storm that can be detrimental in COVID-19, the authors speculate.

"Indeed, the anti-inflammatory role of 1,25(OH)2D could explain the protective role of vitamin D against immune hyper-reaction and cytokine storm in a subgroup of patients with severe COVID-19," they write.

Furthermore, vitamin D is known to modulated the renin-angiotensin pathway and down-regulate angiotensin converting enzyme 2, which has been implicated in COVID-19, the authors note.

But Maghbooli and colleagues do acknowledge their study has many limitations.

"It is recommended that further studies, including randomized controlled trials, need to be designed to evaluate the role of vitamin D status on risk of developing COVID-19 infection and mitigating complications and mortality in those infected with the virus," they conclude.

Opinions on this issue continue to be divided, as has been extensively reported by Medscape Medical News, starting back in April and May when the emerging association first became apparent.

Still, most experts repeatedly state that randomized controlled trials are needed to draw sound conclusions on the issue.

"I look forward to a higher level evidence from prospective randomized trials to determine whether there is indeed a causal relationship," Lewiecki told Medscape Medical News.

"Meanwhile, since vitamin D supplements are inexpensive and generally very safe, it is reasonable to follow current public health guidelines to assure vitamin D adequacy and consider supplementing COVID-19 patients with vitamin D 1000-2000 IU/day," he recommended.

Maghbooli and colleagues recommend "vitamin D supplementation, along the guidelines recommended by the Endocrine Society to achieve a blood level of 25(OH)D of at least 30 ng/mL, to children and adults to potentially reduce risk of acquiring the infection and for all COVID-19 patients especially those being admitted into the hospital."

Holick has reported being a consultant for Quest Diagnostics and being on a speakers bureau for Abbott and Hayat Pharmaceutical Industries. Lewiecki has reported no relevant financial relationships.

PLoS One. Published September 25, 2020. Full text

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