Vitamin D supplementation to raise serum 25(OH)D concentrations can help reduce hospital-associated infections [ 131 ]. Concentrations of at least 40–50 ng/mL (100–125 nmol/L) are indicated on the basis of observational studies [ 132 133 ]. During the COVID-19 epidemic, all people in the hospital, including patients and staff, should take vitamin D supplements to raise 25(OH)D concentrations as an important step in preventing infection and spread. Trials on that hypothesis would be worth conducting.

Working in a hospital dealing with COVID-19 patients is associated with increased risk of COVID-19 infection. For example, 40 of 138 hospitalized COVID-19 patients in Wuhan in the Zhongnan Hospital from 1 to 28 January were medical staff, and 17 more were infected while in the hospital [ 58 ]. It was announced on February 14, 2020, that more than 1700 Chinese health workers were infected by COVID-19 and six had died ( https://www.huffpost.com/entry/chinese-health-workers-infected-by virus_n_5e46a0fec5b64d860fc97c1b).

Hospitals are a source of RTIs for both patients and medical personnel. For example, during the SARS-CoV epidemic, a woman returned to Toronto from Hong Kong with SARS-CoV in 2003 and went to a hospital. The disease was transmitted to other people, leading to an outbreak among 257 people in several Greater Toronto Area hospitals [ 129 ]. During the 2014–2015 influenza season, 36% of health care workers in a German hospital developed influenza infection [ 130 ].

4.2. Proposed Actions

3 supplementation should be started or increased several months before winter to raise 25(OH)D concentrations to the range necessary to prevent ARTIs. Studies reviewed here generally reported that 25(OH)D concentrations of 20–30 ng/mL reduced the risk of ARTIs [ 3 [ 3 over a four-month period showed no adverse effects, but did unmask two cases of primary hyperparathyroidism [ 3 and six who took 10,000 IU/d of vitamin D 3 for 8 weeks, reported that 25(OH)D concentrations increased from 20 ± 6 to 39 ± 9 for 4000 IU/d and from 19 ± 4 to 67 ± 3 for 10,000 IU/d and improved gut microbiota with no adverse effects [139, The data reviewed here supports the role of higher 25(OH)D concentrations in reducing risk of infection and death from ARTIs, including those from influenza, CoV, and pneumonia. The peak season for ARTIs is generally when 25(OH)D concentrations are lowest. Thus, vitamin Dsupplementation should be started or increased several months before winter to raise 25(OH)D concentrations to the range necessary to prevent ARTIs. Studies reviewed here generally reported that 25(OH)D concentrations of 20–30 ng/mL reduced the risk of ARTIs [ 134 ]. One reason for that result may be that the studies included few participants with higher 25(OH)D concentrations. However, one observational study reported that 38 ng/mL was the appropriate concentration to reduce the risk of CAP [ 57 ]. Although the degree of protection generally increases as 25(OH)D concentration increases, the optimal range appears to be in the range of 40–60 ng/mL (100–150 nmol/l). To achieve those levels, approximately half the population could take at least 2000–5000 IU/d of vitamin D 135 ]. Various loading doses have been studied for achieving a 25(OH)D concentration of 30 ng/mL. For example, one study used a weekly or fortnightly dose totaling 100,000–200,000 IU over 8 weeks (1800 or 3600 IU/d) [ 136 ]. However, to achieve 40–60 ng/mL would take higher loading doses. A trial involving Canadian breast cancer patients with bone metastases treated with bisphosphonates but without comorbid conditions reported that doses of 10,000 IU/d of vitamin Dover a four-month period showed no adverse effects, but did unmask two cases of primary hyperparathyroidism [ 137 ]. A study involving 33 participants, including seven taking 4000 IU/d of vitamin Dand six who took 10,000 IU/d of vitamin Dfor 8 weeks, reported that 25(OH)D concentrations increased from 20 ± 6 to 39 ± 9 for 4000 IU/d and from 19 ± 4 to 67 ± 3 for 10,000 IU/d and improved gut microbiota with no adverse effects [ 138 ]. Thus, from the literature, it is reasonable to suggest taking 10,000 IU/d for a month, which is effective in rapidly increasing circulating levels of 25(OH)D into the preferred range of 40–60 ng/mL. To maintain that level after that first month, the dose can be decreased to 5000 IU/d [ 135 140 ]. When high doses of vitamin D are taken, calcium supplementation should not be high to reduce risk of hypercalcemia.

A recent review suggested using vitamin D loading doses of 200,000–300,000 IU in 50,000-IU capsules to reduce the risk and severity of COVID-19 [ 43 ].

3 . For 36 patients who received 5000 IU/d for 12 months or longer, mean serum 25(OH)D concentration rose from 24 to 68 ng/mL, whereas for the 78 patients who received 10,000 IU/d, mean concentrations increased from 25 to 96 ng/mL. No cases of vitamin D–induced hypercalcemia were reported. This article includes a brief review of other high-dose vitamin D studies, including the fact that vitamin D doses of 60,000–600,000 IU/d were found to treat and control such diseases as asthma, rheumatoid arthritis, rickets, and tuberculosis in the 1930s and 1940s. Those doses are much higher than the 10,000–25,000 IU/d of vitamin D 3 that can be made from solar UVB exposure [ The efficacy and safety of high-dose vitamin D supplementation has been demonstrated in a psychiatric hospital in Cincinnati, Ohio [ 141 ]. The age range was from 18 to 90 years. Half of the patients were black, and nearly half were white. All patients entering since 2011 were offered supplementation of 5000 or 10,000 IU/d vitamin D. For 36 patients who received 5000 IU/d for 12 months or longer, mean serum 25(OH)D concentration rose from 24 to 68 ng/mL, whereas for the 78 patients who received 10,000 IU/d, mean concentrations increased from 25 to 96 ng/mL. No cases of vitamin D–induced hypercalcemia were reported. This article includes a brief review of other high-dose vitamin D studies, including the fact that vitamin D doses of 60,000–600,000 IU/d were found to treat and control such diseases as asthma, rheumatoid arthritis, rickets, and tuberculosis in the 1930s and 1940s. Those doses are much higher than the 10,000–25,000 IU/d of vitamin Dthat can be made from solar UVB exposure [ 142 ]. However, after reports of hypercalcemia associated with use of supra-physiological doses of vitamin D surfaced, e.g., [ 143 ], high-dose vitamin D supplementation fell out of favor.

3 did not affect the incidence rate of kidney stone events or hypercalcemia [ A recent article on a high-dose vitamin D supplementation trial in New Zealand involving 5110 participants reported that, over a median of 3.3 years, monthly supplementation with 100,000 IU of vitamin Ddid not affect the incidence rate of kidney stone events or hypercalcemia [ 144 ].

Unfortunately, most countries do not have guidelines supporting vitamin D supplementation doses and desirable serum 25(OH)D concentrations that would deal with wintertime RTIs. Guidelines for many countries consider 20 ng/mL (50 nmol/L) adequate. According to the statement from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases, “attainment of serum 25-hydroxyvitamin D levels well above the threshold desired for bone health cannot be recommended based on current evidence, since safety has yet to be confirmed” [ 145 ]. This statement, published in 2017, is no longer correct since a number of vitamin D supplementation studies have reported that long-term vitamin D supplementation has health benefits without adverse health effects, e.g., 2000 IU/d for cancer risk reduction [ 66 146 ] and 4000 IU/d for reduced progression from prediabetes to diabetes [ 67 ].

A recent review on the status of vitamin D deficiency worldwide stated that because of inadequate evidence from clinical trials, “a 25(OH)D level of >50 nmol/L or 20 ng/mL is, therefore, the primary treatment goal, although some data suggest a benefit for a higher threshold” [ 147 ]. A companion article in the same issue of the journal stated, “although 20 ng/mL seems adequate to reduce risk of skeletal problems and ARTIs, concentrations above 30 ng/mL have been associated with reduced risk of cancer, type 2 diabetes mellitus, and adverse pregnancy and birth outcomes” [ 148 ]. However, on the basis of the findings in several studies discussed here, as well as recommendations for breast and colorectal cancer prevention [ 149 ], the desirable concentration should be at least 40–60 ng/mL.

The U.S. Institute of Medicine issued vitamin D and calcium guidelines in 2011 [ 150 ]. The institute recommended vitamin D supplementation of 600 IU/d for people younger than 70 years, 800 IU/d for those older than 70 years, and a serum 25(OH)D concentration of 20 ng/mL (50 nmol/L) or higher. That recommendation was based on the effects of vitamin D for bone health. The institute recognized that no studies had reported adverse effects of supplementation with less than 10,000 IU/d of vitamin D, but set the upper intake level at 4000 IU/d, partly out of concerns stemming from observational studies that found U-shaped 25(OH)D concentration–health outcome relationships. However, later investigation determined that most reports of J- or U-shaped relationships were from observational studies that did not measure serum 25(OH)D concentrations and that the likely reason for those relationships was a result of enrolling some participants who had started taking vitamin D supplements shortly before enrolling [ 151 ].

Moreover, in 2011, the Endocrine Society recommended supplementation of 1000–4000 IU/d of vitamin D and a serum 25(OH)D concentration of 30 ng/mL or higher [ 152 ]. Those guidelines were for patients. It appears that anyone with chronic disease should be considered in that category. The U.S. Institute of Medicine noted that no adverse effects of vitamin D supplementation had been reported for daily doses <10,000 IU/d [ 150 ].

3 or 30,000–35,000 IU/wk would raise 25(OH)D concentration to 40 ng/mL. Taking 6235–7248 IU/d as proposed to ensure that 97.5% of the population has concentrations >20 ng/mL [ Measuring serum 25(OH)D concentration would be useful to determine baseline and achieved 25(OH)D concentrations. A recent article recommended testing for groups of people who were likely to have low concentrations and could benefit from higher concentrations, such as pregnant women, the obese, people with chronic diseases, and the elderly [ 148 ]. Part of the rationale for testing was to increase awareness of actual 25(OH)D concentrations and the benefits of higher concentrations. In addition, increases in 25(OH)D concentration with respect to vitamin D supplementation depend on various personal factors, including genetics, digestive system health, weight, and baseline 25(OH)D concentration. For about half the population, taking 5000 IU/d of vitamin Dor 30,000–35,000 IU/wk would raise 25(OH)D concentration to 40 ng/mL. Taking 6235–7248 IU/d as proposed to ensure that 97.5% of the population has concentrations >20 ng/mL [ 153 ] would not exceed the 10,000-IU/d threshold.

Vitamin D supplementation is required for many individuals to reach 25(OH)D concentrations above 30 ng/mL, especially in winter [ 154 ]. However, vitamin D fortification of basic foods such as dairy and flour products [ 83 155 ] can raise serum 25(OH)D concentrations of those members of various populations with the lowest concentrations by a few ng/mL. Doing so can result in reduced risk of ARTIs for individuals with extreme vitamin D deficiency [ 134 156 ]. However, for greater benefits, daily or weekly vitamin D supplementation is recommended [ 134 ], as is the annual determination of serum 25(OH)D concentration for those with health risks [ 148 ].

Magnesium supplementation is recommended when taking vitamin D supplements. Magnesium helps activate vitamin D, which in turn helps regulate calcium and phosphate homeostasis to influence the growth and maintenance of bones. All the enzymes that metabolize vitamin D seem to require magnesium, which acts as a cofactor in the enzymatic reactions in the liver and kidneys [ 157 ]. The dose of magnesium should be in the range of 250–500 mg/d, along with twice that dose of calcium.

The hypothesis that vitamin D supplementation can reduce the risk of influenza and COVID-19 incidence and death should be investigated in trials to determine the appropriate doses, serum 25(OH)D concentrations, and the presence of any safety issues. The RCT on vitamin D supplementation for ventilated ICU patients conducted in Atlanta, Georgia, is a good model [ 93 ].