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Reply
Reply: “Vitamin D Supplementation in Influenza and
COVID-19 Infections. Comment on: Evidence That
Vitamin D Supplementation Could Reduce Risk of
Influenza and COVID-19 Infections and Deaths
Nutrients 2020, 12(4), 988”
William B. Grant 1,* , Carole A. Baggerly 2and Henry Lahore 3
1Sunlight, Nutrition, and Health Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA
2GrassrootsHealth, Encinitas, CA 95101, USA; carole@grassrootshealth.org
32289 Highland Loop, Port Townsend, WA 98368, USA; hlahore@gmail.com
*Correspondence: wbgrant@infionline.net; Tel.: +1-415-409-1980
Received: 20 April 2020; Accepted: 8 May 2020; Published: 1 June 2020
Keywords:
African Americans; COVID-19; C-reactive protein; hemoglobin; influenza; randomized
controlled trials; respiratory tract infections; vitamin D; vitamin D2; vitamin D3
We thank Dr. Hasan for the comments [
1
] on our review [
2
] and for providing us the opportunity to
extend the discussion regarding the role of vitamin D in reducing the risk of respiratory tract infections.
Dr. Hasan’s first point: “However, we are rather concerned with authors’ recommendation that
people at risk of COVID-19 should consider ‘taking 10,000 IU/d of vitamin D
3
for a few weeks to
rapidly raise 25(OH)D concentrations, followed by 5000 IU/d to reduce the risk of infection’. We believe
that authors’ recommendation of using a high dose of vitamin D supplementation is inappropriate
as there is no robust clinical evidence to support such claims.” Our recommendation was based on
reaching a serum 25-hydroxyvitamin D [25(OH)D] concentration between 40 and 60 ng/mL in advance
of the winter viral respiratory tract infection (RTI) season. According to Figure 1 in an article by
Heaney [
3
], when starting at a level of around 20 ng/mL it takes about 35 days to reach 60 ng/mL
with 10,000 IU/d and 85 days with 4000 IU/d. A randomized controlled trial (RCT) published in 2015
showed that after a single dose of 250,000 IU of vitamin D
3
given to healthy volunteers between the
ages of 18 and 65 years with baseline serum levels of <17 ng/m, serum 25(OH)D concentrations at five
days increased to an average of 41 ng/mL [
4
]. There were no adverse effects. However, after 90 days,
25(OH)D concentrations were back to near baseline values. In the preprint of the first submitted
version of our review [
5
], we discussed the results of reported influenza-like illness (ILI) with respect to
serum 25(OH)D concentrations for GrassrootsHealth participants (this information was omitted from
the published review since it should go through the peer review process independent of its inclusion in
a review.) Table 1 reports that, compared to [25(OH)D] of <20 ng/mL, the adjusted odds ratio for ILI for
40–49 ng/mL, 50–59 ng/mL, and
≥
60 ng/mL were 0.04, 0.02, and 0.03, respectively. While this finding
was not related to COVID-19, there are indications that viral RTIs have similar etiologies. Those who
are concerned about exposure to the COVID-19 virus or who have symptoms of COVID-19 infection
might benefit from a much larger dose, although clinical trials need to be performed.
Very recently, a preprint reported severity of COVID-19 infections with respect to 25(OH)D
concentration in three Asian countries [
6
]. Out of 49 patients with mild symptoms, 47 had serum
25(OH)D concentrations of >30 ng/mL compared with only four of 59 with ordinary symptoms, two of
56 severe patients, and two of 48 critical patients. The mean serum 25(OH)D concentrations for mild,
ordinary, severe, and critical patients were 31, 27, 21, and 17 ng/mL, respectively.
Nutrients 2020,12, 1620; doi:10.3390/nu12061620 www.mdpi.com/journal/nutrients
Nutrients 2020,12, 1620 2 of 5
Results of a study of seroprevalence for COVID-19 in Santa Clara County, California were reported
in a preprint [
7
], with A total of 3330 people included; 50 people were found to have antibodies for
COVID-19. After adjusting the data to correspond to the demographic characteristics of the county,
the seroprevalence to COVID-19 was estimated at between 2.49% and 4.16%, with uncertainty bounds
ranging from 1.80% up to 5.70%. This estimate translates to 48,000 to 81,000 people in the county,
which is 50 to 80 times the 956 people that were identified by April 1, 2020. It should be noted that this
study has not been peer reviewed and may have some methodological issues to address. We think
it likely that many have contracted COVID-19 with minimal or no symptoms. Supporting this idea,
several coronaviruses exist that result in minor colds in the January–February timeframe, as found
from a study of children crossing the Southern China–Hong Kong border [8].
These two studies support our suggestion of 40 to 60 ng/mL, since one study presented COVID-19
infection with 25(OH)D concentrations of >30 ng/mL and the other found that many people were
infected without symptoms. Elderly people with chronic diseases are very likely to have low 25(OH)D
concentrations, as discussed in our review [
2
]. However, further studies are required to better determine
the threshold for protection against COVID-19 infection with symptoms.
As is well known, COVID-19 patients in critical condition often require a ventilator to help supply
oxygen to their blood. A meta-analysis of laboratory findings of clinical characteristics for COVID-19
patients found that the pooled frequency of anemia from two studies was 44% (95% CI, 30%–58%),
while the pooled frequency for high C-reactive protein (CRP) from eight studies was 72% (95% CI,
54%–85%) [
9
]. A study conducted in Egypt found that serum 25(OH)D concentration was inversely
correlated with the degree of severity of acute lower RTIs (r=0.80) in hospitalized infants with a
mean age of 11
±
3 months [
10
]. In addition, hemoglobin level was also highly correlated with serum
25(OH)D concentration (r=0.71), with the mean concentration ranging from 9 ng/dL for 6 ng/mL
25(OH)D to 14 ng/dL for 50 ng/mL 25(OH)D.
While low-dose vitamin D supplementation was not found to increase hemoglobin concentration
in short-term studies [
11
], high-dose vitamin D supplementation was. A clinical trial involving
30 mechanically ventilated, critically ill adults were assigned to three groups to receive a placebo,
250,000 IU vitamin D
3
, or 500,000 IU vitamin D
3
total during a five-day periods [
12
]. Mean baseline
hemoglobin concentration was between 8.5 and 10.5 g/dL for the three groups. Hemoglobin concentration
increased significantly only for the 500,000 IU vitamin D
3
group, who experienced a 2 g/dL increase in four
weeks. However, a phase 3 RCT involving 1078 critically ill vitamin D-deficient patients, with those in the
treatment arm given 540,000 IU vitamin D
3
supplementation within 12 h of admission to an intensive care
unit, found no significant benefit in terms of 90-day mortality rate (P=0.26) or with respect to secondary
clinical, physiological, or safety end-points [13].
A cross-sectional study using data from the USA’s National Health and Nutrition Examination
Surveys data found that CRP varied from 222 (95% CI, 205–241) mcg/dL for a 25(OH)D concentration
of <12 ng/mL to 199 (179–201) mcg/dL for >30 ng/mL 25(OH)D [14].
Thus, by analogy, vitamin D deficiency appears to be a very important risk factor for severe
COVID-19 infection.
Dr. Hasan’s second point: “The authors have conveniently ignored the results of some key clinical
studies evaluating the effectiveness of vitamin D supplementation in reducing the risk of developing
respiratory tract infections (RTIs).” The meta-analysis of 15 RCTs on the effectiveness of vitamin D
supplementation on risk of RTIs by Gysin et al. [
15
] had a serious flaw: the evaluations were made
based on vitamin D dose vs. placebo, not serum 25(OH)D concentration. Vitamin D does not have a
direct bearing on disease risk; it is 25(OH)D concentration that was found to be associated with disease
risk. Inspection of the RCTs used in their analysis in Figure 3 presented some with very low baselines
with significantly reduced risk of RTIs and very low vitamin D doses, while others with high baseline
25(OH)D concentrations and high vitamin D doses exhibited no effect. Heaney’s guidelines for RCTs
for nutrients such as vitamin D were discussed in our review [
16
], the most important factor being that
Nutrients 2020,12, 1620 3 of 5
they be based on 25(OH)D concentration, both baseline and achieved, and that sufficient vitamin D
3
be given.
Regarding the individual participant data meta-analysis of RTI in vitamin D RCTs [
17
], there were
few participants who achieved a 25(OH)D concentration of >40 ng/mL, so they could not adequately
assess the impact of high 25(OH)D concentration. We noted that a study in Connecticut found 38 ng/mL
as the threshold for a significantly lower risk of community-based pneumonia [18].
Dr. Hasan’s third point: “Although high dose vitamin D3 was not found to increase the risk
of kidney stone or hypercalcemia, it is not devoid of side effects as a randomized clinical trial only
observed significant lower radial bone and tibial bone mineral density with 3-year-treatment of
vitamin D at a dose of 10,000 IU/d”. Regarding the possible adverse effects of high-dose vitamin D
supplementation, we read the article by Burt et al. [
19
]. As mentioned in the comment, the only adverse
finding was a reduction (3.5%) in bone mass density. However, bone mass density does not equate to
bone strength, and the reductions in strength measured as failure load were not significant. That was a
three-year study, whereas we are suggesting a strategy for the winter RTI season. We also note that all
pharmaceutical drugs have adverse side effects. If high-dose vitamin D is considered a drug, it differs
from pharmaceutical drugs in that it has many side benefits [20].
Dr. Hasan’s fourth point: “Given the possible negative impact on bone mineral density with
high dose vitamin D3, it is probably wise to wait for the results of ongoing clinical trials that are
registered to explore the relationship between vitamin D and COVID-19.” We agree that RCTs should be
conducted to evaluate the role of vitamin D in preventing and treating COVID-19 infection. However,
we strongly disagree that vitamin D supplementation should be held in abeyance for prevention until
such RCTs are completed and reported. Those at highest risk of infection due to having chronic disease,
low 25(OH)D status, and/or being in frequent contact with others likely to be infected should be taking
vitamin D. As noted, there is mounting evidence that vitamin D can reduce the risk and severity
of RTIs, including that the mechanisms are known, that there are many health benefits of higher
25(OH)D concentrations, and that there are very few adverse effects of vitamin D
3
supplementation.
Vitamin D has demonstrated effectiveness in reducing the risk of overall cancer incidence and death,
as well as the risk of progressing from pre-diabetes to diabetes in secondary results of major vitamin
D RCTs [
21
]. Thus, there is much to gain and little to lose by taking vitamin D supplements now for
COVID-19 prevention. RCTs should be conducted for treatment to explore at which stages of infection
what baseline 25(OH)D concentrations, vitamin D doses, and achieved 25(OH)D concentrations are
associated with benefits and adverse effects, if any.
Dr. Hasan’s fifth point questioned our statement: “A clinical trial involving postmenopausal
women living on Long Island, NY with mean baseline 25(OH)D concentration 19
±
8 ng/mL found
that supplementation with 2000 IU/d resulted in significantly fewer upper respiratory tract infections,
including influenza, than a placebo or supplementation with 800 IU/d [
22
].” In this trial, 104 participants
took a placebo for three years and suffered from 29 RTIs in total, 104 took 800 IU/d vitamin D
3
for two
years and suffered 8 RTIs, and 104 took 2000 IU/d vitamin D
3
and one RTI was recorded. The odds
ratio for 800 IU/d vs. placebo was 0.39 (95% confidence interval, 0.17–0.87, P=0.02), while that for
2000 IU/d vs. placebo was 0.09 (0.01–0.50, P=0.02).
We use this opportunity to respond to two important comments by other readers of our review.
One questioned why we did not indicate that vitamin D
3
(cholecalciferol) be used rather than
vitamin D
2
(ergocalciferol), the answer being that, in some countries, the only high-dose vitamin D
is ergocalciferol. However, cholecalciferol is a better choice, in part since it is the type of vitamin D
produced in the skin through ultraviolet B irradiation of 7-dehydrocholesterol followed by a thermal
reaction. After publication of our review, an article was published reporting the effects of vitamin D on
gene expression of rat oligodendrocyte precursor cells. The study found that vitamin D
3
influenced
1272 genes in 24 h compared to only 574 for vitamin D [
23
]. Most of the effects of vitamin D are through
the hormonal metabolite 1,25-dihydroxyvitamin D, which activates vitamin D receptors bound to
chromosomes, thereby affecting the expression of many genes.
Nutrients 2020,12, 1620 4 of 5
The second question was why we did not point out that African Americans (AAs) have a much
higher risk of COVID-19 infection and death than white Americans. At the time we submitted our
manuscript, the data comparing AA COVID-19 infection and mortality rates were not available.
In addition, there are a number of other reasons why AAs have higher COVID-19 rates, including that
they have higher chronic disease rates than white Americans [24].
People with chronic diseases generally have low 25(OH)D concentrations (see Table 2 in [
2
]).
Now, however, it is well-known that AAs have much higher COVID-19 infection and mortality
rates [
25
]. Based on the National Health and Nutrition Examination Survey (NHANES) 2001–2010,
the prevalence of serum 25(OH)D concentrations <20 ng/mL was 72% for non-Hispanic blacks (NHBs),
43% for Hispanics, and 19% for non-Hispanic whites, with the prevalence of <10 ng/mL being 17%
in NHBs [
26
]. Of all the risk factors AAs have for becoming infected with COVID-19, raising serum
25(OH)D concentrations is the easiest one to counter.
Funding: No funding was received for this study.
Conflicts of Interest:
W.B.G. receives funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR). GrassrootsHealth
works with various supplement suppliers to test the efficacy of their products in various custom projects.
These suppliers may be listed as ’Sponsors’ of GrassrootsHealth. H.L. has no conflicts of interest to declare.
VitaminDWiki.com receives funding from Bio-Tech Pharmacal, Inc.
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