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Vitamin D and COVID-19: Is There a Lack of Risk/Reward Understanding Among Health Authorities?

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Vitamin D and COVID-19: Is There a Lack of Risk/Reward Understanding Among Health Authorities?

Abstract

The COVID-19 (SARS-CoV-2 infection) crisis is affecting the whole world; many people have died, even more have gotten very sick, and people in many regions have been directly affected in their daily lives due to lockdowns of society. A series of studies by various medical researchers strongly indicates that vitamin D supplements can offer preventive effects against COVID-19. Looking at the dichotomy of seasonal variations in COVID-19, patterns of infection seen in countries toward the southern and northern hemispheres seems to give additional compelling support to this hypothesis. The seasonal variations in the northern and southern hemispheres in relation to COVID-19 appear to be in line with previous studies in vitamin D serum levels in those populations. These findings, combined with the knowledge that vitamin D supplements in moderate dosages have minimal to no risk, mean that the risk/reward of taking vitamin D is very good. Yet, while health authorities in numerous countries must be well aware of the potential preventive benefits from taking vitamin D, they seem more focused on finding a definitive answer before taking action. This seems to be a grave mistake based on the information at this point in time. Potentially, hundreds of thousands of people could be saved if health authorities would recommend vitamin D to the population, even with the qualification that studies are still underway to ascertain their efficacy. If a stronger stand were taken on the positive use of vitamin D, authorities could also make sure that particular at-risk groups could obtain such supplements, the elderly in nursing homes and assisted living facilities, for example. At this point, the discussion should not be about whether it is helpful to take vitamin D during the COVID-19 pandemic or not, but rather about what dose to take and how to distribute vitamin D effectively among the population. Even if very promising vaccines are now entering production, it will likely take many months before they are available to all vulnerable groups. Further, one does not need to be an "anti-vaxxer" to understand that there can be considerable risk with a new vaccine. We recommend that health authorities act now and recommend vitamin D supplements based on risk/reward analysis.
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Vitamin D and COVID-19: Is There a Lack of Risk/Reward Understanding
Among Health Authorities?
Espen Gaarder Haug1 and Dominic de Lalouvière 2 and Laeeth Isharc2
1. Norwegian University of Life Sciences, Norway, corresponding author,
espen.haug@nmbu.no
2. Independent researcher, United Kingdom.
Abstract
The COVID-19 (SARS-CoV-2 infection) crisis is affecting the whole world; many people have
died, even more have gotten very sick, and people in many regions have been directly affected in
their daily lives due to lockdowns of society. A series of studies by various medical researchers
strongly indicates that vitamin D supplements can offer preventive effects against COVID-19.
Looking at the dichotomy of seasonal variations in COVID-19, patterns of infection seen in
countries toward the southern and northern hemispheres seems to give additional compelling
support to this hypothesis. The seasonal variations in the northern and southern hemispheres in
relation to COVID-19 appear to be in line with previous studies in vitamin D serum levels in
those populations. These findings, combined with the knowledge that vitamin D supplements in
moderate dosages have minimal to no risk, mean that the risk/reward of taking vitamin D is very
good. Yet, while health authorities in numerous countries must be well aware of the potential
preventive benefits from taking vitamin D, they seem more focused on finding a definitive
answer before taking action. This seems to be a grave mistake based on the information at this
point in time. Potentially, hundreds of thousands of people could be saved if health authorities
would recommend vitamin D to the population, even with the qualification that studies are still
underway to ascertain their efficacy. If a stronger stand were taken on the positive use of vitamin
D, authorities could also make sure that particular at-risk groups could obtain such supplements,
the elderly in nursing homes and assisted living facilities, for example.
At this point, the discussion should not be about whether it is helpful to take vitamin D during
the COVID-19 pandemic or not, but rather about what dose to take and how to distribute vitamin
D effectively among the population. Even if very promising vaccines are now entering
production, it will likely take many months before they are available to all vulnerable groups.
Further, one does not need to be ananti-vaxxer” to understand that there can be considerable
risk with a new vaccine. We recommend that health authorities act now and recommend vitamin
D supplements based on risk/reward analysis.
Keywords: COVID-19, Vitamin D, Seasonality, Risk/Reward, Decision under uncertainty.
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1. Vitamin D likely has positive effects against COVID-19 and minimal risk for side effects
in moderate doses
In May 2020, Zemb et al. [1] addressed new research on COVID-19, stating that “Randomized
controlled trials showed that vitamin D decreases acute respiratory infections (ARIs).” They also
concluded that “daily vitamin D supplementation with moderate doses is safe and cheap” and
therefore “even a small decrease in COVID-19 infections would easily justify this intervention.”
Meltzer et al. [2] found the relative risk of testing positive for COVID-19 was 1.77 times greater
for patients with likely deficient vitamin D status, compared with patients with likely sufficient
vitamin D status in a study of study of 489 patients. Kaufman et al. [3] have similar findings and
conclude that “SARS-CoV-2 NAAT positivity is strongly and inversely associated with
circulating 25(OH)D levels.”
Maghbooli et al. [4] carried out a study in which they show vitamin D sufficiency reduced risk
for adverse clinical outcomes in patients with COVID-19 infection. A pilot study done by
Castillo et al. [5] has shown that administration of a high dose of Calcifediol or 25-
hydroxyvitamin D significantly reduced the need for ICU treatment of patients requiring
hospitalization due to proven COVID-19.
Along these lines of thought, a series of other researchers have indicated that vitamin D likely
can be beneficial against COVID-19, see for example [6, 7, 8, 9].
The evidence of a correlation between low vitamin D and poor outcomes in COVID-19 disease
is extensive. The latest in a long line of such papers was published in Nature Scientific Reports
on 19 November 2020 [10] and concludes:
“Vitamin D level is markedly low in severe COVID-19 patients. Inflammatory response is
high in vitamin D deficient COVID-19 patients. This all translates into increased
mortality in vitamin D deficient COVID-19 patients. As per the flexible approach in the
current COVID-19 pandemic authors recommend mass administration of vitamin D
supplements to population at risk for COVID-19.”
A broader review of the literature yields 17 publications in September alone, including one RCT,
of which 15 are supportive of a role for vitamin D in COVID-19 and 2 found no association. We
conducted a Pubmed search which returned 73 publications, of which 70 were supportive of a
role for vitamin D in COVID-19. The National Institute for Health and Care Excellence (NICE,
UK) has already pointed out shortcomings [11] in the Spanish RCT, which found a reduction in
admission to ICU of 96% for those treated with vitamin D [5].
However, the discerning reader may note the emergence of a certain pattern in the numbers
above. These papers if looked at individually are, in general, not providing any solid evidence of
causality between vitamin D and resistance towards COVID-19, and could individually be
described as weak, but if one looks at the collected information from all of these studies
combined with others’ findings, then at least the risk/reward for recommending vitamin D to
prevent COVID-19 disease seems strong, as we will suggest in this paper.
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The paucity of the case against vitamin D
What are the arguments made against vitamin D supplementation? The primary argument is that
“the evidence” is not of sufficient quality to warrant any recommendations being made with
respect to ARTIs / flu or COVID-19. We address these objections in turn.
In June 2020, the Scientific Advisory Committee on Nutrition in the UK (SACN) published [11]
a rapid review of vitamin D and ARTIs, concluding that “overall, the evidence at this time does
not support recommending vitamin D supplementation to prevent ARTIs….” The report shows
no evidence of increased risk (excluding bolus doses), and a majority of the papers examined
therein showed a benefit, although not all of the papers concurred. This meant that the gold-
standard test was not met, leading to the conclusion of no “beneficial effect.” The absence of
downside was not considered.
In June 2020, The National Institute for Health and Care Excellence (NICE) in the UK published
a review [12] of the evidence regarding vitamin D and COVID-19. The most unfortunate aspect
of this paper is that within a few paragraphs it manages to contradict itself:
“There is no evidence to support taking vitamin D supplements to specifically prevent or
treat COVID-19.
Evidence was from 5 published studies in peer-reviewed journals… Four of the studies
found an association or correlation between a lower vitamin D status and subsequent
development of COVID-19.”
Perhaps, being charitable, the authors were under time pressure and didn’t realize that they had
become used to using “no evidence” to mean “insufficient evidence.” However, it might be
preferable in future to consider the proper use of language, particularly in matters of great
national and international importance.
The four studies that found an association are, quite rightly, deemed to be relatively low-quality
evidence on account of being observational studies or surveys (at least when considered
individually), and having numerous limitations. The fifth study [13] is noteworthy for being cited
multiple times as evidence against vitamin D supplementation.
This paper, by Hastie et al., reviewed biobank data and reported that there was no link between
catching COVID-19 in 2020 and the blood levels of vitamin D measured in 2006-2010. This
bears repeating: the evidence against supplementation includes the assertion that blood samples
from 10-14 years ago do not correlate with disease today. We count numerous other studies in
recent months that found the opposite in relation to blood samples taken recently [2, 14].
Also, we would like to point out that it would likely be a mistake to consider many of the smaller
sample studies in isolation; rather, they should be seen as pieces of a larger “puzzle” where we
think the overall sum of the pieces strongly indicates that vitamin D has preventive effects
against COVID-19. In a pandemic with deadly outcomes, we do not have the luxury of waiting
to see if we can reach a final conclusion. Risk/reward analysis should weigh heavily on decision
makers, as will be discussed further, but first we will look at the seasonality in serum levels, and
also good indications of seasonality in COVID-19 that are already emerging in the data.
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2. Seasonality
Direct exposure to sunlight (on the skin) plays an important role in the human body’s vitamin D
production. A series of studies shows population serum levels both in the northern and southern
hemispheres is seasonal with respect to spring, summer, fall and winter, see [15, 16, 17, 18,
19,20], for example.
As an example, the UK has one of the highest levels of vitamin D deficiency in Europe [21]; in
the winter months, at least 30-40% of the UK population is deficient in vitamin D, see [22]. Up
to 94% of some Black, Asian, and minority ethnic (BAME) communities have been found to be
deficient in winter [23]. Deficiency is likely to be higher this year given lockdowns and will
likely be considerably higher in populations that have to shield. Charts showing average seasonal
levels of serum concentrations of vitamin D can be found in [24], for example.
If there is a causal relationship between COVID-19 resistance and vitamin D serum levels, then
one should likely see seasonal patterns in number of infected people, as well as in mortality
statistics. The magnitude of these numbers should be in opposition for the northern and southern
hemispheres, since when it is winter in Australia, it is summer in Europe and the US, and vice
versa. In other words, we would expect to see an increase in both infections and death rates now
in Europe, the US, and Russia, due to falling vitamin D serum levels across these populations,
ceteris paribus. Naturally, several other factors also play an important role, including how much
the people within a population are in contact with each other and thereby spreading the virus, the
use of facemasks, rigorous hand washing hygiene measures, and so forth. So, one will not get a
complete picture from studying data alone, as the amount of contact can change dramatically on
short notice due to the official close down of a particular region, for example. However, if the
vitamin D serum levels play an important role, one should expect to see patterns in the data,
especially for large populations.
The COVID-19 pandemic has lasted for many months already, so it is an opportune time to look
for seasonal variations. If we evaluate recent data, even a simple visual representation clearly
seems to support this hypothesis. See Figures in Appendix A that represent countries far south in
the southern hemisphere. The pattern in Australia seems to fit this hypothesis very well, where
the COVID-19 infections peaked in their winter months (July, August, and September), and have
dropped dramatically moving into the Australian summer. Similarly, countries like Bolivia,
South Africa, Argentina, and Chile all have dramatic decreases in the numbers of infected people
and numbers of deaths now that they have entered the summertime. In some countries like
Madagascar, the seasonality is less clear, but overall, countries in the southern hemisphere seem
to follow a clear pattern. Longer days and more sun exposure are linked to increased vitamin D
serum levels. We cannot absolutely guarantee causality between falling rates of COVID-19
infection and increasing vitamin D serum levels in the southern hemisphere, but it is a plausible
connection if seen in combination with the extensive research that exists on vitamin D in relation
to the human immune system, flu seasons, and respiratory infections.
See Appendix B for seasonal variations in COVID-19 in select countries considerably far north
in the northern hemisphere. Again, in most countries we see low activity of COVID-19 in the
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summer, and increased infections now that there is less sun and falling vitamin D serum levels in
the population this fall.
We could complete a range of advanced statistical studies about seasonality, but it is unlikely to
bring us much closer to a final conclusion. At this stage we will not get clear-cut statistical
evidence of seasonality in COVID-19 infection; for that one would likely need to have more data
now and also wait for an ongoing COVID-19 pandemic, which would last for years. However,
the indications appear to be strong. Often a simple visual inspection of significant patterns can be
good enough and sometimes even better than long, complex analysis. Such patterns must not be
seen in isolation, but instead must be combined with knowledge we have about seasonality in D
vitamin serum level and other research on vitamin D in relation to COVID-19 and immune
response in general. Clearly, there is ample room for further research.
3. Risk/Reward consideration for decisions under uncertainty
When it comes to vitamin D in relation to COVID-19, one should make a strong distinction
between the perspective of researchers and that of decision makers, who are focused on saving
lives and trying to control the pandemic. A researcher’s aim is to get to the bottom of a question.
From a research standpoint, one should naturally complete thorough and rigorous research before
drawing final conclusions. Correlation and causality are not the same thing, so one can be tricked
by correlations. For example, the seasonal effects in relation to COVID-19, of which we have
good indications in many countries, could be linked to the fact that people are inside more often
and thus in closer contact with other in the fall and winter than they are during the summer. Still,
based on the extensive research available on vitamin D, we think it is a high probability that
vitamin D serum levels also play an important role; one factor does not exclude another factor.
As a counterpoint, our impression was that people actually socialized more in the summer in
several countries in Europe, as the rates of COVID-19 infection were seen to diminish. This took
place when there were fewer lockdowns in much of Europe during the summer than there were
in the spring and late fall.
Preferably, a researcher will have access to large scale Randomised Control Trials, where one
group is given placebo supplements, while the other group is given vitamin D, and one can
follow up closely on serum levels in both groups. Such studies will take time and could be
finalized long after the peak of the COVID pandemic has come and gone.
In contrast, from the decision-maker’s standpoint, several key elements emerge. First, we already
have good indications that vitamin D is beneficial in preventing COVID-19. Second, we have
been exposed to vitamin D for thousands of years, actually since the beginning of the human
existence, both from the Sun and from uptake from food. A series of studies show the safety of
vitamin D supplements, for moderate dosages and even for high dosages. Based on historical
studies, combined with the seasonal patterns in vitamin D serum levels and infection rates of
COVID-19 by hemisphere, from a risk/reward perspective it would seem highly beneficial to
recommend vitamin D supplements, with a low risk of adverse effects.
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In addition to protecting individuals, vitamin D supplements may also reduce the rapid spread of
the virus, as people will become less likely to infect others. Obviously, this is hard to quantify at
this time, but one would likely get good indications about a change in infection rates, even after a
couple of months of vitamin D supplementation for people within a given geographic area, or a
formal study. In other words, it makes sense to recommend vitamin D supplements, in addition
to other measures taken.
One could argue that recommending vitamin D before we are ``sure” about its benefits could be
counterproductive, at it could make people overconfident and reduce their focus on other
important preventive measures. However, this can be mitigated by effort to convey clear and
correct information, based on the knowledge we have at the moment.
Granted there are other risks to consider in recommending that a population should take vitamin
D supplements, although it is minimal if one gives proper information. As an example, some
vitamin D supplements are sold combined with vitamins A, which is known to be toxic in high
dosages. However, health authorities should not underestimate the populations’ ability to process
information. Naturally, a clear message, with valid information about vitamin D supplements
must be part of such a campaign. On a different level, even though vitamin D seems to be very
beneficial in the context of fighting the pandemic, it is important to emphasize that it is not a
proxy for immortality. The most vulnerable group for COVID-19 is seen in people who are
already seriously ill and facing potential death. All one can expect from vitamin D is increased
viral resistance in the population and reduced impact on our lives as the spread of COVID-19 is
reduced through such resistance. If managed carefully, better control of COVID-19 through
such means could also be beneficial for the economies and functionality of countries. A long-
term lockdown, or many repeated lockdowns, could lead to many severe side effects, including
peoples’ mental health, rates of long-term unemployment, educational impacts on young people,
and other individual, familial, and societal stresses.
To be clear, we are not trying to undermine other types of efforts to attack COVID-19. Large
pharmaceutical firms are working aggressively on developing vaccines and results are starting to
point to delivery by next year. The goal of this paper is not to promote vitamin D as opposed to
or at the expense of continuing the research on vaccines. Yet, we know that the risk of taking
vitamin D supplements is minimal, while administering a new vaccine may have unknown long-
term effects that are not apparent right now. At the logistical level, even once we have several
vaccines ready for production, they may not be available to a substantial percentage of the global
population for many months. It is best to act now, with simple and reliable measures and
strengthen ourselves for the road ahead.
Epistemic versus Phronetic
The claim to be “following the science” is a defining feature COVID-19 pandemic in most of at
least the western world. It betrays a failure to think clearly by prioritising the epistemic over the
phronetic when making decisions under uncertainty. This approach has shown the limits of
Evidence-Based Medicine (“EBM”) and a lack of phronesis on the part of political and public
health leaders. We argue that the advice regarding Vitamin D is a casualty of this approach given
the high probability of it being beneficial and the very low probability of associated health risks.
The policy inertia is a function of an inability to apply good judgement and to see beyond the
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bounds of EBM. In such circumstances of decision making under uncertainty the general (non-
naïve) Precautionary Principle applies and a decision not to act is also a decision with both
public health and moral consequences.
The limits of EBM
We do not dispute the value of EBM; rather we dispute the blanket application of EBM in
making policy and ethical decisions under uncertainty. Just because the answer in part relies on
scientific evidence does not mean the scientific evidence is the only component. This nothing
but-ism reflects a failure to understand that different types of question require different types of
knowledge and different ways of thinking. EBM reflects one way of thinking, but it may not be
appropriate in the early phase of a pandemic caused by a novel pathogen where, by definition,
evidence will be scarce. Writing for HBR Martin et al. [25] set out the problem:
“The experience of the 2020 pandemic offers a powerful lesson: A critical skill a leader
must bring to the table is the ability to figure out what kind of thinking is required to
address a given challenge. Bring the wrong kind of thinking to a problem and you’ll be
left fruitlessly analyzing scientific data when what’s desperately needed is a values-
informed judgment call.”
The distinctions drawn by the authors reflect problem solving capabilities outlined by Aristotle:
“Techne was craft knowledge: learning to use tools and methods to create something.
Episteme was scientific knowledge: uncovering the laws of nature and other inviolable
facts that, however poorly understood they might be at the moment, “cannot be other than
they are.” Phronesis was akin to ethical judgment: the perspective-taking and wisdom
required to make decisions when competing values are in play — when the answer is not
absolute, multiple options are possible, and things can be other than what they are”
We argue that phronesis is the appropriate way of thinking about decision making under
uncertainty and that waiting for certainty is itself a decision with potentially serious
consequences. The erroneous EBM-based approach claims that unless a certain standard of
evidence is met then no action can be taken. This is susceptible to a reductio ad absurdum as
Smith & Pell show in their 2003 paper [26] which points out that the lack of Randomised
Control Trials (“RCTs”) supporting the use of parachutes means from an EBM perspective that
their use cannot be recommended.
We also observe that, while claiming to be “following the science” which is another way of
describing the epistemic approach, many decisions during the pandemic have not relied on gold-
plated evidence: the decision to stop intubation was based on the observation that it was harmful
in many cases; the decision to place hypoxic patients in the prone position was equally based on
observation; and recommendations to wear masks in many countries relied on phronetic
judgements rather than on available evidence. This constitutes tacit acknowledgment of the
limitations of an approach which claims only to consider EBM.
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Vitamin D – the phronetic choice?
Ideal interventions are low cost, low risk, with a high probability of upside. Masks fall into this
category, as Greenhalgh et al. [27] have rightly argued since April. Vitamin D is another such
intervention: its safety is well-established, its effects on immune function are well-documented,
its correlation with worse outcomes in COVID-19 disease are very well established, and it is
cheap and widely available. Given that vaccines will be available initially only to a small
proportion of the global population, there remains an urgent need for cheap and safe
interventions such as vitamin D.
Dose Safety
From the perspective of someone who must make a decision amidst uncertainty, the first
question is: “What happens if I am wrong?” The National Institute for Health and Care
Excellence [28] and Public Health England in the UK already recommend supplementation of
vitamin D for musculoskeletal health. The UK recommendation is 400iu for adults and children
over 1 year, despite the fact that vitamin D is fat soluble. The safety of this dose has not been
questioned. Vitamin D toxicity leads to elevated levels of calcium in the blood, which can lead to
deposition in soft tissue and demineralisation of the bones [29]. The question then is: What
doses of supplementary vitamin D may result in toxicity?” The answer is given by research into
blood levels of those given long-term supplements of 1,000, 5,000, or 10,000iu per day for 5
months [30]. None of these led to levels anywhere near toxicity: the NHS reference range for
serum vitamin D is 50-200 nmol/L; the 10,000iu per day dose equated to average serum levels of
approx. 160 nmol/L. Research has suggested toxicity occurs > 375-750 nmol/L25. So, doses
even of 10,000iu per day lead to blood levels of vitamin D well below toxic levels. Publications
also indicate a role for Vitamin K / K2 in mediating calcium uptake, and thus in preventing
hypercalcaemia [31,32]. Thus, we can consider including vitamin K2 with higher doses of
vitamin D, but in adding another supplement to the mix, the risk/reward must also be considered,
a discussion that is outside the scope of this paper.
We note that Dr Fauci, Director of the National Institute of Allergy and Infectious Diseases
(NIAID, USA), has confirmed he is taking a vitamin D supplement of 6,000iu and that he
recommends others to take a supplement as well.
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4. Conclusion
A series of studies and medical experts have indicated that vitamin D supplements can help
prevent COVID-19 infection and also have been shown to make the symptoms in those already
infected less severe. We know from both from research and historical experience that vitamin D
supplements in moderate dosages have minimal risk. Combining this knowledge with studies
showing strong negative correlation in seasonal vitamin D serum levels in North-South
hemisphere populations and clear indications of seasonality in the spread of COVID-19 and
mortality rates means that health authorities should recommend that people take vitamin D
1
“If you are deficient in vitamin D, that does have an impact on your susceptibility to infection. So I would not mind
recommending, and I do it myself taking vitamin D supplements,” Dr Fauci said during an Instagram Live
session: https://www.instagram.com/p/CE7tWzinTI8/.
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supplements, in particular within vulnerable groups. This is based on a well-considered
risk/reward decision process, where there is substantial upside and very little downside;
communications would be clear around the recommendations and studies would continue, as we
advance our understanding of the pandemic and possible approaches to its mitigation.
Our background has entailed deep engagement with decision making under uncertainty and the
situation here is striking in that context. The pandemic is not a classical research situation where
there is a painless luxury of time in waiting for more research so we can come to a final
conclusion. In a pandemic, there is an unprecedented degree of urgency, where hundreds of
thousands if not millions of lives could be lost if we are not acting optimally, even given limited
information. Decision making based on a good understanding of risk-reward analysis should
therefore outweigh other considerations that would constitute norms in a more normal
environment.
In summary, the case for vitamin D is as follows: little downside, low cost, lives at stake, and a
high probability of a beneficial effect. *Not* to act is also a choice.
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Conflict of Interest and other information
The authors declare no conflict of interest. The authors are not involved in any business
involving vitamin D directly or indirectly. However, the authors have spent much of their careers
on understanding decision making under uncertainty, where risk/reward analysis is critically
important.
13
Appendix A: COVID-19 in the Southern Hemisphere
The data we have used are publicly available from https://ourworldindata.org/coronavirus-
source-data. We have removed one or two extreme spikes in a few countries, as these spikes
made it hard to see the trends in the remaining data. These spikes are likely due to corrections in
number of deaths. If this study was about tail events, then it would be wrong to remove such
spikes, but in this case removing them just makes it easier to see the seasonal trends. In the
southern hemisphere, we have included most countries that have decent data collection. In the
northern hemisphere, we have simply taken a number of the largest countries. It is possible to
check more countries through the website mentioned above, which updates every day, or
at worldometers.info, for example.
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15
Appendix B: COVID-19 in the Northern Hemisphere
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... Furthermore, two studies suggest that treatment with vitamin D may reduce adverse outcomes in hospitalised patients by the reduction of ICU admission and mortality [154,155]. However, the studies contributing to this evidence are heterogeneous, based on different dosing regimens and individually of weak quality, but cumulatively provide some evidence advocating for vitamin D supplementation [156]. ...
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