Note: This is the seventy-first of a series of clinical briefs on the coronavirus outbreak. The information on this subject is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available.

Clinical Context

Vitamin D deficiency is common and associated with a number of negative health outcomes. Merzon and colleagues were interested in the interaction between vitamin D levels and the risk for COVID-19. They performed a case-control study using a large health maintenance organization database in Israel, and their results were published in the July 23 issue of The FEBS Journal.^[1]

Researchers compared patients with and without a positive reverse-transcriptase polymerase chain reaction (RT-PCR) test, with 25-hydroxyvitamin D (25[OH]D) levels investigated as the primary variable. Vitamin D deficiency was associated with an adjusted increase of 50% in the risk for a positive test. Mean 25(OH)D levels were low in both cohorts but were slightly lower in the group with a positive test for COVID-19.

The current study by Maghbooli and colleagues evaluated whether 25(OH)D may be a prognostic factor among patients symptomatic with COVID-19.

Study Synopsis and Perspective

The latest in a line of studies on vitamin D and COVID-19 supports a link between insufficiency and worse outcomes from the virus, but the jury remains out without robust, randomized controlled trials.

Patients hospitalized with COVID-19 who have sufficient levels of vitamin D show significant reductions in severe outcomes and a lower risk for death compared with patients who are insufficient, 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, Boston, Massachusetts, in a press statement from his institution.

The research examined hospitalized patients with severe COVID-19 in Iran, and Holick worked with lead researcher Zhila Maghbooli, MD, of Tehran University of Medical Sciences, and colleagues, on the study, which was published in PLoS One.^[2]

The findings come on the heels of another recently published study,^[3] 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 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes 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, New Mexico.

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

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

In the latest study published in PLoS One, involving 235 patients hospitalized with COVID-19 in Tehran, Iran, through May 1, most patients (67.2%) had insufficient vitamin D levels, defined as 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," noted Maghbooli and colleagues.

The mean age of persons included in the study was 58.7±15.2 years, and 37.4% were age 65 years or older.

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

Persons with sufficient vitamin D levels (≥ 30 ng/mL) had a significantly lower prevalence of severe disease (63.6%) vs persons with insufficient levels (77.2%; P = .02), and persons with sufficient levels had significantly lower levels of unconsciousness compared with persons with insufficient vitamin D levels (1.3% vs 8.2%, respectively; P = .03); the same was true for hypoxia (19.4% vs 39.2%, respectively; P = .004).

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

No patients younger than age 40 years died from COVID-19, yet among the 206 patients older age 40 years or older, the mortality rate was 16.3%.

Of those persons age 40 years or older with sufficient vitamin D levels, 9.7% died from COVID-19 compared with 20% of persons had insufficient vitamin D levels and 9.7% who died had a blood level of (25OH)D of at least 30 ng/mL(p = 0.04).

For persons with 25(OH)D levels ≥ 40 ng/mL, the mortality rate declined further to 6.3%.

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

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

Among the patients, 66% had a history of a chronic condition; 36.6% had a history of diabetes; 44.4%, hypertension; 1.3%, immunologic 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.

Still, 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 (CRP) (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 speculated.

"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 wrote.

Furthermore, vitamin D is known to modulate the renin-angiotensin pathway and downregulate angiotensin-converting enzyme 2, which has been implicated in COVID-19, the authors noted, but Maghbooli and colleagues did 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 concluded.

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 recommended "[v]itamin 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."

Clinical Implications

• A previous study by Merzon and colleagues found that vitamin D deficiency was associated with a higher risk for a positive COVID-19 test. Mean 25(OH)D levels were low among patients with and without a positive COVID-19 test, but average levels were slightly lower in patients with a positive test.
• In the current study by Maghbooli and colleagues, two-thirds of patients admitted with COVID-19 were found to have vitamin D deficiency. Vitamin D deficiency was associated with higher rates of severe illness, higher CRP levels, and lower-percentage lymphocyte counts, but it was not associated with a longer average duration of hospital stay or admission to the intensive care unit.
• Implications for the Healthcare Team: The current study suggested that vitamin D deficiency may be a risk factor for severe illness due to COVID-19, but further research is necessary.

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