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Seasonal variations in ultraviolet B (UVB) radiation cause seasonal variations in vitamin D status. This may influence immune responses and play a role in the seasonality of influenza. Pandemic and non-pandemic influenzas in Sweden, Norway, the USA, Singapore, and Japan were studied. Weekly/monthly influenza incidence and death rates were evaluated in view of monthly UVB fluences. Non-pandemic influenzas mostly occur in the winter season in temperate regions. UVB calculations show that at high latitudes very little, if any, vitamin D is produced in the skin during the winter. Even at 26°N (Okinawa) there is about four times more UVB during the summer than during the winter. In tropical regions there are two minor peaks in vitamin D photosynthesis, and practically no seasonality of influenza. Pandemics may start with a wave in an arbitrary season, while secondary waves often occur the following winter. Thus, it appears that a low vitamin D status may play a significant role in most influenzas. In temperate latitudes even pandemic influenzas often show a clear seasonality. The data support the hypothesis that high fluences of UVB radiation (vitamin D level), as occur in the summer, act in a protective manner with respect to influenza.
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The seasonality of pandemic and non-pandemic influenzas: the roles of solar
radiation and vitamin D
Asta Juzeniene
a,
*, Li-Wei Ma
a
, Mateusz Kwitniewski
a
, Georgy A. Polev
a
, Zoya Lagunova
a
,
Arne Dahlback
b
, Johan Moan
a,b
a
Department of Radiation Biology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310 Oslo, Norway
b
Institute of Physics, University of Oslo, Blindern, Oslo, Norway
1. Introduction
Nearly all human diseases related to respiratory pathogens
exhibit seasonal variations.
1,2
However, the reasons for this
seasonality are still not known. Among the tested hypotheses
are: seasonality of low temperatures, absolute humidity (aerosol
transmission), or of dry air, crowding together indoors during the
winter, travel patterns, vacations, seasonality of ultraviolet (UV)
radiation from the sun that might kill pathogens, circannual
rhythms of hormones, such as the ‘dark hormone’ melatonin,
etc.
1,3–8
Another founded hypothesis is that seasonal variations in
UVB radiation and consequently vitamin D photosynthesis,
causing seasonal variations in vitamin D status,
9,10
which plays
a role in the immune response to infections, may be responsible for
the influenza seasonality.
9–15
Additionally, the question of
whether it is the host or the virus/bacterium that exhibits
seasonality arises. However, there are exceptions from seasonality,
notably for pandemic influenzas, which often occur outside the
winter influenza seasons. Furthermore, in equatorial regions the
seasonal pattern is weak.
2,16
In the present work we have compared the seasonality of cases
and deaths caused by both pandemic and non-pandemic
influenzas with doses of UVB radiation (vitamin D photosynthesis).
Influenza may cause death either directly (due to a primary
complication caused by the influenza virus) or indirectly (due to
secondary non-influenza complications either pulmonary or non-
pulmonary in nature).
17,18
Recent studies have indicated that the
majority of deaths in previous influenza pandemics have been a
result of secondary bacterial pneumonias.
18–21
In this paper all
deaths related to influenza are referred to as ‘influenza deaths’
without further specification.
2. Materials and methods
2.1. Influenza cases and deaths
Data from various sources were used in the present study
(Figures 1–6). The numbers of weekly Russian influenza cases in
Sweden (Figure 1) are from the publication by Skog et al.
22
The
monthly death cases from influenza in Norway during 1980–1999
International Journal of Infectious Diseases 14 (2010) e1099–e1105
ARTICLE INFO
Article history:
Received 30 April 2010
Received in revised form 8 August 2010
Accepted 1 September 2010
Corresponding Editor: William Cameron,
Ottawa, Canada
Keywords:
Influenza
Solar radiation
Vitamin D
Seasonality
Immune effects
SUMMARY
Objectives:
Seasonal variations in ultraviolet B (UVB) radiation cause seasonal variations in vitamin D
status. This may influence immune responses and play a role in the seasonality of influenza.
Methods: Pandemic and non-pandemic influenzas in Sweden, Norway, the USA, Singapore, and Japan
were studied. Weekly/monthly influenza incidence and death rates were evaluated in view of monthly
UVB fluences.
Results: Non-pandemic influenzas mostly occur in the winter season in temperate regions. UVB
calculations show that at high latitudes very little, if any, vitamin D is produced in the skin during the
winter. Even at 268N (Okinawa) there is about four times more UVB during the summer than during the
winter. In tropical regions there are two minor peaks in vitamin D photosynthesis, and practically no
seasonality of influenza. Pandemics may start with a wave in an arbitrary season, while seconda rywa ves
often occur the following winter. Thus, it appears that a low vitamin D status may play a significant role
in most influenzas.
Conclusions: In temperate latitudes even pandemic influenzas often show a clear seasonality. The data
support the hypothesis that high fluences of UVB radiation (vitamin D level), as occur in the summer, act
in a protective manner with respect to influenza.
ß2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +47 22934260; fax: +47 22781207.
E-mail address: asta.juzeniene@rr-research.no (A. Juzeniene).
Contents lists available at ScienceDirect
International Journal of Infectious Diseases
journal homepage: www.elsevier.com/locate/ijid
1201-9712/$36.00 – see front matter ß2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ijid.2010.09.002
(Figure 2) are from the publication by Moan et al.
14
The weekly
death rates of the Spanish flu in some American cities (Figure 3)
were obtained from the work of Britten.
23
Monthly death rates
from 10 non-pandemic and two pandemic influenza seasons in the
USA during 1941–1976 (Figure 4) are from the publication by
Doshi.
24
The pattern of monthly influenza cases in Okinawa from
2001 to 2007 (Figure 6) are from Suzuki et al.,
25
while the data for
Singapore from 1990 to 1994 (Figure 5) are from the publication by
Chew et al.
26
2.2. Solar exposure and seasonal vitamin D synthesis in human skin
The main factors influencing UV irradiance at ground level are
solar zenith angle (variable with season, latitude, and time of day),
cloud and snow cover, aerosols, and the thickness of the ozone
layer.
27
In this study, global solar UV irradiances were calculated
using a radiative transfer model.
28,29
Daily total ozone amounts
used in this model were measured by the Total Ozone Mapping
Spectrometer (TOMS) onboard the Earth Probe satellite. The daily
cloud cover used in our model was derived from reflectivity
measurements by TOMS. The errors in ozone derived from TOMS
instruments onboard several satellites are generally less than
2%.
30,31
Not included in our calculations were atmospheric
aerosols, which may potentially have an impact on the solar
irradiance reaching the earth’s surface.
32–34
The calculated monthly UV exposures were based on the
satellite measurements in the period 1997–2004. A cylinder
geometry of the human body was used. The arguments for such a
choice have been presented previously.
35,36
Results are presented as vitamin D-forming UV doses. The
efficiency spectrum for vitamin D production gives the relative
effectiveness of solar radiation at different wavelengths in
converting 7-dehydrocholesterol (7-DHC) to previtamin D. An
efficiency spectrum is calculated by multiplying the intensity of
the solar radiation (wavelength by wavelength) with the action
spectrum for vitamin D production for the corresponding
[(Figure_1)TD$FIG]
Figure 1. Numbers of infected persons (&) per Thiessen area in Sweden for each
week from 1889 to 1890 during the Russian flu, obtained from Skog et al.
22
Weekly
photosynthesis of vitamin D (—*—) for a relevant latitude (Oslo, 608N) was
calculated by use of the vitamin D action spectrum, UV measurements, and
radiative transfer calculations (see Materials and methods).
[(Figure_2)TD$FIG]
Figure 2. The monthly influenza deaths (&) from 1980 to 1999 in Norway,
extracted from Moan et al.
14
Monthly photosynthesis of vitamin D (—*—) for Oslo
(608N) was calculated by use of the vitamin D action spectrum, UV measurements,
and radiative transfer calculations (see Materials and methods).
[(Figure_3)TD$FIG]
Figure 3. Weekly Spanish influenza death rates in Baltimore (398N), Augusta (338N),
and San Francisco (378N) from 1918 to 1919, taken from Britten.
23
[(Figure_4)TD$FIG]
Figure 4. The monthly death rates from two pandemic (A) and 10 non-pandemic (B
and C) influenza seasons in the USA during 1941–1976; data from Doshi.
24
Monthly
photosynthesis of vitamin D for San Francisco (378N) and Baltimore (398N) was
calculated by use of the vitamin D action spectrum, UV measurements, and
radiative transfer calculations (see Materials and methods).
A. Juzeniene et al. / International Journal of Infectious Diseases 14 (2010) e1099–e1105
e1100
wavelength. The vitamin D action spectrum was taken from the
publication of Galkin and Terentskaya,
37
and is similar to that
measured by MacLaughlin et al. in ex vivo skin specimens.
38
This
action spectrum is being used by a large number of investigators,
but is not ideal.
3. Results and discussion
3.1. Pandemic and non-pandemic influenzas
There are three types of influenza virus: influenza A virus,
influenza B virus, and influenza C virus.
39
Influenza A viruses are
the most important because they generally cause severe secondary
diseases and often cause seasonal epidemics and pandemics.
40,41
Influenza B is less common than influenza A, but can periodically
cause large epidemics, although not pandemics.
40
Influenza C virus
is less common than influenza A and B, and diseases caused by this
species are generally much milder; it is not thought to cause
epidemics.
40,42
Influenzas mainly attack weaker persons in a
population, such as children, the elderly, and the immune
incompetent.
39
The best known and documented influenza pandemics are the
Russian flu (1889–1890, about 1 million deaths), the Spanish flu
(1918–1919, about 50 million deaths worldwide), the Asian flu
(1957–1958, about 2 million deaths worldwide), and the Hong
Kong flu (1968–1969 about 0.7 million deaths worldwide).
43,44
In
April 2009, a novel H1N1 influenza A virus, the so-called pandemic
H1N1/09 virus (swine influenza, Mexican flu, North American flu)
was identified in Mexico.
45–47
The virus has since spread
throughout the world and has caused an influenza pandemic,
but it has not exhibited unusually high pathogenecity.
21
The full
impact of the current pandemic is not yet clear.
47,48
According to
the World Health Organization (WHO), more than 209 countries
have reported laboratory confirmed cases of pandemic influenza
H1N1 2009, and there have been at least 14 142 deaths.
49
The spread of Russian pandemic influenza, caused by the
influenza A virus subtype H2N2, was extremely rapid. The Russian
flu was first detected in Bokara (Central Asia) in May 1889, quickly
reached St Petersburg in October, and 6 weeks later was registered
in the UK.
22,44,50
In mid-December 1889 the flu was reported in
North America and in North and South Africa; in February 1890 it
was reported in Latin America and in Asia and in March in New
Zealand, Australia, and East Africa.
43,51
In Sweden, Russian flu
occurred in the winter, with maximal numbers of infected persons
between mid-December 1889 and late January 1890 (Figure 1),
22
almost coinciding in time with the seasonal (non-pandemic)
influenza deaths in Norway (Figure 2).
14
We can conclude that in
temperate latitudes even pandemic influenzas may appear with a
clear winter seasonality of incidence and mortality.
The Spanish flu, caused by influenza A virus subtype H1N1, is
sometimes referred to as ‘the mother of all pandemics’, because
since 1919 almost all influenza A pandemics have been caused by
descendants of this virus.
52
It is still uncertain whether the first
wave of the Spanish flu occurred in Europe or in America.
44,53–55
The first wave of the pandemic in European countries was in the
spring and summer of 1918. It was highly contagious, but caused
few deaths.
56
The second and largest peak was the most serious
and occurred in October 1918.
56
The third, most long-lasting
pandemic wave started in February 1919.
56
Influenza-related
mortality rates were high, ranging from 0.2 to 11 deaths per 1000
inhabitants in European countries.
56
In the USA, the first wave of the Spanish flu occurred in March
1918.
52,55,57
The second lethal wave peaked in the autumn of 1918,
and was responsible for most of the deaths, just as in Europe.
However, in Europe, only one autumn wave was seen in most
cities, whereas many of the USA cities had two peaks of mortality,
spaced by only a few weeks (Figure 3).
58
The second wave probably
spread from the east coast to the west coast, because the highest
death rates were registered on October 19 in Baltimore (398N,
768W), on October 26 in Augusta (338N, 818W), and on November 5
in San Francisco (378N, 1228W) (Figure 3).
23
The third wave came
in the classical influenza season (Figure 3).
23
In Baltimore the
winter wave was weak and came later, while in the other cities it
came in mid-January (Figure 3), i.e., when the vitamin D
photosynthesis rate is at its minimum (Figure 4A). One possible
mechanism explaining the differences in death rates between the
summer, autumn and winter waves of the Spanish flu could be
related to serum vitamin D levels and pre-existing heterosubtypic
immunity, probably induced by prior exposure to different
subtypes of influenza.
59
However, this pattern of three waves was not universal:
Australia, for example, due to the partial success of a maritime
quarantine that delayed the outbreak until early in 1919,
experienced a single, longer wave of influenza activity.
60–62
The
Spanish flu came in two waves in Singapore (18N), a tropical island
city-state: in June–July and in October–November 1918,
63,64
i.e.,
later than the first wave in Europe and in the USA.
Arguments for the role of UVB and vitamin D in Spanish flu in
the USA have been reviewed previously.
15
The lowest pneumonia
and influenza mortality rates were seen in the areas with the
highest solar UVB irradiance and lowest latitudes (these being
good indicators for high levels of vitamin D), while the highest
[(Figure_5)TD$FIG]
Figure 5. The pattern of mean monthly influenza A cases (&) from 1990 to 1994 in
Singapore; data from Chew et al.
26
Monthly photosynthesis of vitamin D (—*—) for
Singapore (18N) was calculated by use of the vitamin D action spectrum, UV
measurements, and radiative transfer calculations (see Materials and methods).
[(Figure_6)TD$FIG]
Figure 6. The mean number of monthly influenza cases (&) from 2001 to 2007 in
Okinawa, adapted from Suzuki et al.
25
Monthly photosynthesis of vitamin D (—*—)
for Okinawa (268N) was calculated by use of the vitamin D action spectrum, UV
measurements, and radiative transfer calculations (see Materials and methods).
A. Juzeniene et al. / International Journal of Infectious Diseases 14 (2010) e1099–e1105
e1101
rates were in the areas with the lowest UVB irradiance and highest
latitudes (indicators of low vitamin D levels).
15
The Asian pandemic influenza originated in the southwest of
China in February 1957 (i.e., in the influenza season).
2
It reached
Hong Kong in April, and then spread rapidly to Singapore, Taiwan,
and Japan. The causative agent, an influenza A H2N2 virus, was first
isolated in Japan in May 1957. This virus was found in June 1957 in
the UK and in July 1957 in the USA, but the peak of influenza
incidence and mortality occurred in October 1957.
2,54,65
This first
wave of disease in North America and in Europe was followed by a
second wave in January–February 1958, again in the influenza
season.
2,54,65
The Hong Kong influenza A virus subtype H3N2 was first
isolated in Hong Kong in July 1968, and in September it was
registered in Japan, the USA, England and Wales; it was registered
in France in January 1969.
66
Despite the rapid and extensive spread
of this virus, its impact was not the same in all geographical
regions: in North America, the majority of influenza-related deaths
occurred during the first pandemic season ((1968/1969), while in
Europe most deaths occurred during the second pandemic season
(1969/1970). The highest rates of influenza cases and mortality
were observed during the winter in all studied countries (the USA,
Canada, England and Wales, France, Japan, and Australia).
66,67
Thus, these two pandemics, the Asian flu and the Hong Kong flu,
followed an almost classical trend with high winter death rates,
similar to non-pandemic seasonal influenzas in the USA (Figure 4,B
and C).
24
Both of these pandemics occurred in Singapore, which has
almost no incidence variations in seasonal influenzas (see
below).
64,68
The Asian influenza pandemic in Singapore started
in May 1957 (earlier than in the USA, Figure 4A), and the Hong
Kong influenza pandemic first occurred in August–early Septem-
ber 1968 (also earlier than in the USA, Figure 4A).
64
All seasonal influenzas in the period from 1941 to 1976 in the
USA followed a similar winter trend, with the exceptions of the
1946–1947 and the 1975–1976 waves, which came late, peaking in
March–April (Figure 4, B and C).
24
However, these waves also came
before the vitamin D levels start to increase after the winter
(Figure 4A).
3.2. Seasonal variations in vitamin D photosynthesis and non-
pandemics
The monthly variations in vitamin D photosynthesis in human
skin in some selected countries were calculated using the action
spectrum of Galkin and Terentskaya
37
and assuming cylinder
geometry.
35,36
As shown in our earlier studies of the Nordic
countries,
69
the vitamin D level is maximal about a month after the
time of maximal rate of synthesis, which occurs close to
midsummer. This is due to the fact that the vitamin D level here
is determined as the concentration of 25-hydroxyvitamin D in
serum, and that the formation of this metabolite from previtamin
D, via vitamin D (mainly in the liver), takes around one week.
70
Above 378latitude, very low UVB fluences reach the ground during
the months of November through February.
71
Therefore, very little,
if any, vitamin D is produced in the skin during the winter. In fact,
the lowest vitamin D levels are found in February–March.
71
Seasonal variations in vitamin D photosynthesis decrease as the
equator is approached (Figure 5). In fact, as the curve for Singapore
(18N) shows (Figure 5), there are two minor maxima per year,
located almost symmetrically around the midsummer minimum.
The reasons why the symmetry is not complete are the slight ozone
asymmetry and changes in cloud cover, which were both taken
into account when we calculated the curves in Figure 5. November
and December are the months of the rainy season in Singapore. In
this city there is almost no seasonality of influenza,
26,64,72
as might
be expected from the small seasonal variation in vitamin D
photosynthesis (Figure 5). However, a small seasonal variation in
influenza has been observed, with small peaks in June and
December–January.
26,64,72
It appears that the influenza waves start
during periods of low vitamin D photosynthesis. These peaks may
be related to humidity, or possibly to contamination from seasonal
influenzas in the southern and northern hemisphere, and to the
seasonal variation in vitamin D photosynthesis (Figure 5).
For the subtropical region, influenza data are available for
Okinawa (268N) and Taiwan (238N).
25,73
In both of these places
there is a regular, major outbreak of influenza in the winter and a
minor outbreak in the summer. This pattern is also characteristic of
influenza circulation in other subtropical areas.
74
In these places
there is significant vitamin D photosynthesis throughout the year,
but it should be noted that the winter rate is only a fourth of the
summer rate (Figure 6).
In the USA, non-pandemics of influenza typically start during
the fall or winter months, but the peak of activity occurs in
January–March (Figure 4), just as we have found for Norway
(Figure 2). In both countries, very few cases are registered in the
summer time. Seasonal variations in immune system responses
have been reported in humans
75
and such variations may be
responsible for the increased incidence of infectious diseases
during winter and for the seasonality of non-pandemic influenza.
Vitamin D modulates the immune system, essentially strengthen-
ing it, in several ways, as reviewed elsewhere.
76–80
Norway is located between 60 and 708N, while the center of
population gravity of the USA is located between 35 and 458N. The
seasonal variations in vitamin D photosynthesis are larger for
Norway than for the USA (Figures 2 and 4). Thus, in the USA, as in
Norway, the numbers of deaths are small in the season when
vitamin D status is best.
3.3. Mechanisms behind seasonality
Being the main source of vitamin D, UVB radiation may affect
influenza via the immune system. It was demonstrated in two
independent studies
81,82
that children who were regularly exposed
to artificial UVB radiation had around two times lower incidence
rates of upper respiratory tract infections, influenza, and sore
throat than non-exposed children, and the phagocytic activity of
macrophages increased significantly in all exposed subjects in a
dose-dependent manner.
The impact of rurality on morbidity and mortality from the
1918 pandemic influenza in England, Wales, New Zealand, and
Japan was investigated.
83–85
The influenza morbidity in villages
was higher than or similar to that in towns and cities, while the
mortality appeared to be lowest in villages, revealing significant
differences compared to all cities and towns. The differences in
mortality rates between urban and rural regions may be related to
many factors, including differences in vitamin D status. People
living in rural areas have significantly higher vitamin D levels
compared to those living in urban areas.
86,87
3.4. Seasonal variations in host immunity or in pathogen virulence
An argument for the seasonal effect on the host are that
outbreaks of genetically similar strains occur simultaneously at
similar latitudes across different continents.
1
There seems to be, in
many cases, a continuous presence of pathogens throughout the
year.
88
Circadian variations of hormones, like melatonin, change
with the season.
88,89
This may lead to a seasonal variation in
immunity.
89
Thus, mice exhibit circadian variations of suscepti-
bility to pathogens, with the highest susceptibility in the
morning.
90
The same virus strain appears to be present in the hosts over
longer periods, two years or more, but leading to manifest disease
A. Juzeniene et al. / International Journal of Infectious Diseases 14 (2010) e1099–e1105
e1102
only under favorable conditions, mainly related to host immune
weakening.
88
One might expect variations in the immune system
to play a major role. The preventive effect of vitamin D
supplementation against influenza has also been demonstrated
in intervention studies.
11
Furthermore, Ginde et al.
91
found that
serum levels of vitamin D were inversely associated with upper
respiratory tract infections.
UV radiation interacts with the immune system in several ways,
as already mentioned. We believe that the main mechanism
involves vitamin D photosynthesis in the skin.
3.5. The influence of vitamin D on the immune response
Vitamin D plays an important immunomodulatory function in
primates. Deficiency has been linked with several autoimmune
diseases, the development of cancer, and an increased risk of
infection.
92–96
Better knowledge of the mechanisms through
which vitamin D regulates immune responses is essential for
understanding how it may prevent or reduce the impact of an
influenza pandemic in humans. Calcitriol, the metabolically active
form of vitamin D, influences host immunity in two different
important ways: generally it suppresses adaptive immunity,
particularly Th1 cellular immune responses, while it stimulates
innate non-specific immunity.
97
Vitamin D strengthens innate non-specific immunity in several
different ways. It up-regulates the expression of antimicrobial
proteins (AMPs) like cathelicidins or
b
-defensins.
98,99
The
synthesis of LL-37 antimicrobial peptide (the only human member
of the cathelicidin family, an important component of innate
defense) in human macrophages is one of the best known
mechanisms involving vitamin D.
98
In addition to its antimicrobial
properties, it is also effective against viruses, including influenza
virus.
100–102
Moreover, vitamin D induces the production of NF-
k
B
transcription factor inhibitor – I
k
B
a
.
103
The inhibition of NF-
k
B
signaling may impair influenza virus infection. Nimmerjahn
et al.
104
showed that human cells with low NF-
k
B activity were
resistant to influenza virus infection.
Other non-specific components of innate immunity regulated
by calcitriol are Toll-like receptors (TLRs) that recognize structur-
ally conserved molecules derived from microorganisms such as
bacteria, viruses, and fungi, and activate immune responses once
an antigen is recognized.
105
TLR signaling is strictly linked with
vitamin D. Influenza A is a single-stranded (ss)RNA virus. (ss)RNA
is a TLR7/8 ligand.
106,107
Furthermore, it can induce expression of
the gene coding for the LL-37 peptide.
102
While vitamin D may strengthen innate, non-specific immune
responses and possibly reduce the risk of influenza virus infection,
attenuation of adaptive immune responses might be linked with
decreased mortality.
9
Calcitriol down-regulates secretion of
proinflammatory cytokines and up-regulates the release of anti-
inflammatory cytokines, hence influences the Th1/Th2 bal-
ance.
108,109
Moreover, it suppresses antigen presentation by
antigen presenting cells (APC) like dendritic cells (DCs) and
macrophages.
110,111
The mortality caused by the highly pathogenic
influenza A virus strains appears to be related to the release of pro-
inflammatory mediators.
112
Thus, the attenuation of the Th1
immune response by vitamin D might be beneficial for infected
patients.
3.6. Use of vitamin D supplementation to prevent influenza
Solar radiation contributes significantly to vitamin D status. In
temperate regions vitamin D levels are higher in late summer than
in late winter, when the solar radiation contains too little UVB to
synthesize enough vitamin D in human skin. Cannell et al.
9,10
hypothesized that wintertime vitamin D insufficiency may explain
seasonal variation in influenza. Two preliminary studies support
this hypothesis.
11,113
A randomized controlled trial of bone loss in
postmenopausal, black women found that women given vitamin D
(800 IU/day) were three times less likely to report cold and flu
symptoms than controls given a placebo.
11
The intake of high doses
of vitamin D (2000 IU/day) for 1 year efficiently protected women
against the ‘typical’ winter colds and influenza, since only one
patient reported these symptoms.
11
Another randomized, double-
blind, placebo-controlled trial, comparing vitamin D supplements
with placebo in schoolchildren, found that intake of vitamin D
(1200 IU/day) during winter and early spring can reduce the
incidence of seasonal influenza A by a factor of around two, while
this is not true for influenza B.
113
4. Conclusions
Non-pandemic influenzas usually arrive in winter/early spring,
while the initial wave of pandemic influenzas may occur in any
season, but with secondary waves in midwinter. Seasonal waves of
all influenzas are small at low latitudes. It seems likely that
seasonal variations in the incidence and death rates of both
pandemic and non-pandemic influenza are related to seasonal
variations in vitamin D status. An argument against this hypothesis
might be that influenza death rates start to increase almost 2
months after the vitamin D levels have reached their minimum.
Similarly, the death rates start to decrease several months before
vitamin D levels start to increase significantly. This is likely to be
related to the generation of immunity.
Conflict of interest
We have no personal or financial conflict of interest to declare
and have not entered into any agreement that could interfere with
our access to the data on the research, or upon our ability to
analyze the data independently, to prepare this manuscript, and to
publish it.
Acknowledgements
Direct overpass TOMS data were provided by NASA/GSFC.
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... Although we still do not know whether the SARS-CoV-2 pandemic will follow a seasonal pattern, several lines of evidence seem to support this possibility [1]. The appearance of the initial cases in China during the wintertime and the extraordinary spread of the infection during this period of the year are noted rst [2]. ...
... Although these environmental factors are not modi able, some host defense mechanisms can interact or be directly related to them. In this regard, UVR has been used as a surrogate marker of vitamin D status in multiple studies [1,13], and low UVR during the wintertime has been associated with the seasonal pattern of several viral infections [13,14]. Vitamin D is a hormone related to multiple effects on the innate and acquired immune system and also involved in the proper production of antimicrobial peptides [13,15]. ...
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Background: Environmental factors play a central role in seasonal epidemics. SARS-CoV-2 infection in Spain has shown a heterogeneous geographical pattern This study aimed to assess the influence of several climatic factors on the infectivity of SARS-CoV-2 and the severity of COVID-19 among the Spanish Autonomous Communities (AA.CC.). Methods: Data on coronavirus infectivity and severity of COVID-19 disease, as well as the climatic variables were obtained from official sources (Ministry of Health and Spanish Meteorological Agency, respectively). To assess the possible influence of climate on the development of the disease, data on ultraviolet radiation (UVR) were collected during the months before the start of the pandemic. To analyze its influence on the infectivity of SARS-CoV-2, data on UVR, temperature, and humidity were obtained from the months of highest contagiousness to the peak of the pandemic. Results: From October 2019 to January 2020, mean UVR was significantly related not only to SARS-CoV-2 infection (cumulative incidence -previous 14 days- x10⁵ habitants, rho=-0.0,666; p=0.009), but also with COVID-19 severity, assessed as hospital admissions (rho=-0.626; p=0.017) and ICU admissions (rho=-0.565; p=0.035). Besides, temperature (February: rho=-0.832; p<0.001 and March: rho=-0.904; p<0.001), was the main climatic factor responsible for the infectivity of the coronavirus and directly contributed to a different spread of SARS-CoV-2 across the Spanish regions. Conclusions: Climatic factors may partially explain the differences in COVID-19 incidence and severity across the different Spanish regions. The knowledge of these factors could help to develop preventive and public health actions against upcoming outbreaks of the disease.
... It suppresses the adaptive immunity while stimulating the innate non-specific immunity. Accordingly, it acts on reducing mortality possibilities (Asta Juzeniene et al. 2010). Further studies proved that the appropriate exposure to solar radiation attains an immunomodulatory effect. ...
... High solar radiation cause skin burn and would lead to skin cancer.(Solargis,the world bank, 2017),(Sleijffers et al. 2002),(Asta Juzeniene et al. 2010),( Swaminathan and Harrison, 2019),(Junaid and Rehman 2019),(Sleijffers et al. 2002),(Bassil et al. 2013), (Deborah Weatherspoon 2020),( Flies et al. 2019).5-Natural ventilationair speed (Dilute infectious droplets • Enable droplets dispersion and avoid their accumulation. ...
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Although previous researches proved that frequent visits to urban spaces enhance the physical and mental health of people, most governments adopted lockdown policies after the outbreak of COVID-19. This decision has negatively impacted the wellbeing of communities and the livability of urban spaces. In this context the research questions how far the microclimatic conditions of urban space would influence its performance during respiratory pandemics? The study investigated this question through a dense literature survey including 47 scientific journal articles and governmental reports. The outputs were synthesized through a quantitative assessment framework. It detected the spatio-environmental parameters influencing the behaviour of respiratory pandemics in urban settings. To validate the framework's outputs, the research applied case study sampling for 3 urban spaces in historic Cairo. It generated digital simulations and computations addressing solar radiation, natural ventilation, air temperature, and humidity, besides space dimension and number of users. The results illustrated the areas of adequate and poor microclimatic performance during pandemics. They are demonstrated through numerical tables, digital simulations, and graphs. Eventually, a concluding assessment framework selected the optimum urban space performance to be engaged in the public life of historic Cairo during lockdown periods.
... Vitamin D must be in sufficient levels to keep an immune system to prevent any disease, and its deficiency leads to severe disease mortality and morbidity. There is a defined inverse proportionality with vitamin D levels and prolonged upper and lower respiratory tract infections [10]. Studies evaluating cervical-vaginal infections and vitamin D deficiency state that lower vitamin D levels are associated with bacterial vaginosis and chlamydia [11,12]. ...
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... The serum response to the given dose is largely varied between the individuals due to differences in demographic and biological variables, such as ethnicity, age, duration of exposure, seasonal variations, Body Mass Index (BMI), intake of certain medications, base-line concentration of vitamin D, genetics and type of vitamin D supplements [153,200,201]. It has been reported that in North America and Europe Influenza epidemics generally reach peaks in the months from December to March when UVB radiation exposure and serum levels of 1,25(OH) 2 D are lowest among the population [202,203]. ...
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As of now, there is no specific preventive and curative medicine available to treat coronavirus disease 2019 (COVID-19), the best weapon to fight against this highly contagious disease is to boost our immune system. There are two paths of the immune system in our body, the innate and adaptive immune axis working 24/7 with their specialized sentinels capable of orchestrating responses against invading agents. These components of the immune system cannot work optimally in a nutrients deficient consortium. Micronutrient deficiency, called the hidden hunger occurs unknowingly when the quality of food people used to consume daily is not meeting the optimum requirement of vitamins and trace elements. In terms of immunity, the importance of crosstalk between the gastrointestinal (GI) tract microbiome with other distant organs, especially the respiratory system is a recent area of understanding. This review highlighted the contribution of macronutrients as well as the potential role of few vitamins, trace elements, and probiotics on preventive and therapeutic applications to strengthen the immune system along with gut homeostasis.
... This finding, if correct, might be partly explained by the higher prevalence of vitamin D deficiency in these geographical regions (Rhodes et al., 2020). Furthermore, the seasonal fluctuation of serum vitamin D level might be responsible for the higher risk of respiratory infections in fall and winter (Juzeniene et al., 2010). ...
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Considering the high prevalence of vitamin D deficiency worldwide and its relationship with immune response to viral infections, this study attempted to identify the predictive power of serum vitamin D for poor outcomes among the COVID‐19 patients. This retrospective cohort study included all patients with confirmed COVID‐19 hospitalized between February 20, 2020, and April 20, 2020, at a designated COVID‐19 hospital, located in Tehran province, Iran. General characteristics, medical history and clinical symptoms were recorded by trained physicians. Blood parameters including complete blood count, creatinine, lactate dehydrogenase, creatine phosphokinase, erythrocyte sedimentation rate, C‐reactive protein and vitamin D were tested. This study included 290 hospitalized patients with COVID‐19 (the mean age [SD]: 61.6 [16.9], 56.6% males), of whom 142 had vitamin D concentrations less than 20 ng/ml, defined as vitamin D deficiency. COVID‐19 patients with vitamin D deficiency were more likely to die (Crude OR [95% CI]: 2.30 [1.25–4.26]), require ICU (2.06 [1.22–3.46]) and invasive mechanical ventilation (2.03 [1.04–3.93]) based on univariate logistic regression results. Although, after adjusting for potentials confounders such as gender and age, the association between vitamin D and need to invasive mechanical ventilation lost its significance, adjusted values for the risk of death and ICU requirement were still statistically significant. Vitamin D deficiency can be considered as a predictor of poor outcomes and mortality in COVID‐19 patients. Therefore, checking serum 25 (OH) D on admission and taking vitamin D supplements according to the prophylactic or treatment protocols is recommended for all COVID‐19 patients. According to our study, COVID‐19 patients with vitamin D deficiency were about twice as much at risk for ICU hospitalization and death, even after adjusting the statistical model for age and gender.
... Epidemiological reports indicated that vitamin D deficiency could raise the possible risk of virus infections like respiratory tract of infections and influenza (Juzeniene et al. 2010). The positive relationship of deficiency of vitamin D and viral infection is probably linked to its ability to modulation of the innate and adaptive immune system (Aranow 2011). ...
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There is limited information regarding the protective factors of SARS-CoV-2 infection. This research is focused on analyzing the role of vitamin D and albumin in the severity, progression, or possible prevention of COVID-19 infection. In this case–control study, 191 patients and 203 healthy individuals were enrolled. Blood samples were taken to test the albumin and vitamin D levels of both groups. Our results show a direct association of vitamin D deficiency with the infection of COVID-19 and severity. According to our findings, 84.4% of patients with COVID-19 in this study had vitamin D deficiency. Moreover, the average level of albumin was significantly decreased in those infected patients who had respiratory symptoms. In the present study, a considerable negative correlation was established between the levels of vitamin D and the severity of COVID-19 infection. This reflects on the immunomodulatory and inhibitory nature of vitamin D to the viral replication.
... In temperate latitudes even pandemic influenzas often show a clear seasonality. The data support the hypothesis that high levels of UVB radiation (vitamin D level), as occur in the summer, act in a protective manner with respect to influenza (Juzeniene et al 2010). Cannell et al (2008) suggest that the role of vitamin D in immune regulation explains the nine conundrums seen in influenza epidemiology. ...
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Public health agencies have promoted a single pathogen view of infection which simplifies the message about vaccination. However, research over the past 20 years shows a far more complex set of interactions between multiple pathogens, the nose/throat microbiota, the gut microbiota, immune function, and ageing. Influenza vaccination is effective at reducing General Practitioner (GP) visits for influenza like illness (ILI), for reducing health care staff sickness absence, and in reducing hospital admission due to influenza. The narrative regarding influenza mortality has been overly simplified and the levels of reported deaths are more correctly due to interactions between a mix of pathogens. There is no such thing as a single pathogen winter. There is mixed evidence that influenza vaccination protects against death from influenza - probably complicated by vaccination increasing life span and hence shifting death to a later point in time. Influenza vaccination does not seem to diminish excess winter mortality (EWM) – with EWM being the complex outcome of the mix of pathogens interacting with metrological variables. In those likely to die in the next year, while influenza vaccination may protect against death from influenza per se, this merely creates space for another pathogen to trigger final demise. The central problem is that there is no 100% accurate method to determine who is in the last year of life. For this reason, all elderly should be vaccinated. The ratio of male to female deaths and admissions appears to be an indicator of which mix of pathogens predominate each winter. Amid all the conflicting trends there is room for the action of a new type or kind of infectious disease. This new disease may be triggered by the novel action of a common pathogen or may be the outcome of the multiple interactions between pathogens throughout each year. While outbreaks of this new disease can occur throughout the year they seem to occur more commonly at the interface between winter and spring. These outbreaks cause deaths and medical admissions to suddenly shift to a higher level, stay at the higher level for most commonly 12 months but shorter and longer periods also occur, deaths then shift back to the usual levels while medical admissions seem to sustain a more lingering effect. The combined interaction of the mix of winter infections plus outbreaks of the new disease generate a complex set of cost and capacity challenges. This complex set of challenges is completely ignored in the funding formulas used to distribute resources between different populations. Issues of population density discussed in Parts 1 and 2 are highly relevant. Steady state thinking and silo mentality is a hindrance when seeking to fully understand issues of financial risk and capacity surges. Part 4 investigates why deaths are serving as a wider proxy for morbidity and how the number of deaths can be used as a tool to determine the optimum size for insurers, HMOs, healthcare commissioners to achieve minimum volatility in costs. A 14-minute interview covering the series is available, https://jjunland.egnyte.com/dl/CPdNnjCVle/?
... A nationwide ecological study found an inverse correlation between regional solar radiation as a proxy of vitamin D status and incidence of hospital admissions for bronchiolitis in Chile [8]. Seasonal variations in UV-B radiation cause seasonal variations in vitamin D status and this may account for increased susceptibility to infectious respiratory diseases [9]. Therefore, it could be speculated that winter vitamin D reduction may play a role in bronchiolitis. ...
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Seasonal variations in UV-B radiation may influence vitamin D status, and this, in turn, may influence the risk of bronchiolitis hospitalization. The aim of this study was using a causal inference approach to investigate, simultaneously, the interrelationships between personal and environmental risk factors at birth/hospital admission (RFBH), serum vitamin D levels and bronchiolitis hospitalization. A total of 63 children (<2 years old) hospitalized for bronchiolitis (34 RSV-positive) and 63 controls were consecutively enrolled (2014–2016). Vitamin D levels and some RFBH (birth season, birth weight, gestational age, gender, age, weight, hospitalization season) were recorded. The discovered RFBH effects on the risk ok bronchiolitis hospitalization were decomposed into direct and vitamin-D mediated ones through Mediation Analysis. Winter-spring season (vs. summer-autumn) was significantly associated with lower vitamin D levels (mean difference −11.14 nmol/L). Increasing serum vitamin D levels were significantly associated with a lower risk of bronchiolitis hospitalization (OR = 0.84 for a 10-nmol/L increase). Winter-spring season and gestational age (one-week increase) were significantly and directly associated with bronchiolitis hospitalization (OR = 6.37 and OR = 0.78 respectively), while vitamin D-mediated effects were negligible (1.21 and 1.02 respectively). Using a comprehensive causal approach may enhance the understanding of the complex interrelationships among RFBH, vitamin D and bronchiolitis hospitalization.
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"Dread risks" are threats that can have catastrophic consequences. To analyse this issue we use excess mortality and corresponding life years lost as simple measures of the severity of pandemic events. As such, they are more robust than figures from models and testing procedures that usually inform public responses. We analyse data from OECD countries that are already fully available for the whole of 2020. To assess the severity of the pandemic, we compare with historical demographic events since 1880. Results show that reports of high excess mortality during peak periods and local outbreaks should not be taken as representative. Six countries saw a somewhat more increased percentage of life years lost (over 7 percent), nine countries show mild figures (0 to 7 percent), while seven countries had life year gains of up to 7 percent. So, by historical standards, Covid-19 is worse than regular flu, but a far cry from the Spanish Flu, which has become the predominant frame of reference for the current pandemic. Even though the demographic impact is modest, psychological aspects of the pandemic can still lead to transformative futures, as the reactions of East Asian societies to SARS I in 2003 showed.
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Background: Numerous observational studies have found supplemental calcium and vitamin D to be associated with reduced risk of common cancers. However, interventional studies to test this effect are lacking. Objective: The purpose of this analysis was to determine the efficacy of calcium alone and calcium plus vitamin D in reducing incident cancer risk of all types. Design: This was a 4-y, population-based, double-blind, randomized placebo-controlled trial. The primary outcome was fracture incidence, and the principal secondary outcome was cancer incidence. The subjects were 1179 community-dwelling women randomly selected from the population of healthy postmenopausal women aged >55 y in a 9-county rural area of Nebraska centered at latitude 41.4°N. Subjects were randomly assigned to receive 1400–1500 mg supplemental calcium/d alone (Ca-only), supplemental calcium plus 1100 IU vitamin D3/d (Ca + D), or placebo. Results: When analyzed by intention to treat, cancer incidence was lower in the Ca + D women than in the placebo control subjects (P < 0.03). With the use of logistic regression, the unadjusted relative risks (RR) of incident cancer in the Ca + D and Ca-only groups were 0.402 (P = 0.01) and 0.532 (P = 0.06), respectively. When analysis was confined to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to 0.232 (CI: 0.09, 0.60; P < 0.005) but did not change significantly for the Ca-only group. In multiple logistic regression models, both treatment and serum 25-hydroxyvitamin D concentrations were significant, independent predictors of cancer risk. Conclusions: Improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00352170.
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Vitamin D has been an exciting field of research in recent years, with more than 1400 publications published on the subject in 2008. The lay press has published articles, the internet is full of information and pharmacies have prominent displays of vitamin D supplements. Historically, vitamin D has been thought only to have an effect on calcium metabolism and bone. Vitamin D deficiency was thought only to cause rickets or osteomalacia. Recent work has found that vitamin D affects many other cells and tissues. Basic science, epidemiological, case-control and cohort studies have been conducted that show an effect of vitamin D on infections and autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus and Type 1 diabetes. Further research is needed in each of these areas to elucidate the mechanism vitamin D uses to affect the immune system and to develop prevention and/or treatment guidelines.